Seasonal Influenza Vaccine Use in Low and Middle Income ...
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Seasonal Influenza Vaccine Use in Low and Middle Income Countries in the Tropics and Subtropics A systematic review HIRVE, Siddhivinayak Global Influenza Programme Department of Pandemic and Epidemic Diseases World Health OrganizationGeneva
January 2015
WHO Library Cataloguing-in-Publication Data
Seasonal Influenza Vaccine Use in Low and Middle Income Countries in the Tropics and
Subtropics. A systematic review.
I.World Health Organization.
ISBN 978 92 4 156509 7
Subject headings are available from WHO institutional repository
© World Health Organization 2015
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CONTENTS
Executive summary ................................................................................................................................................. 4
Abbreviations and acronyms .................................................................................................................................. 9
Introduction .......................................................................................................................................................... 10
Methods ............................................................................................................................................................... 13
Search of the literature ..................................................................................................................................... 13
Eligibility criteria and Information sources ....................................................................................................... 13
Study quality appraisal ..................................................................................................................................... 14
Data synthesis ................................................................................................................................................... 14
Results .................................................................................................................................................................. 15
Seasonal influenza immunization policy ........................................................................................................... 16
Influenza vaccine supply and availability .......................................................................................................... 20
When to vaccinate? .......................................................................................................................................... 21
Which vaccine formulation to use? .................................................................................................................. 25
Seasonal influenza vaccination coverage ......................................................................................................... 35
Effectiveness of Seasonal Influenza Vaccine in the tropics .............................................................................. 38
Vaccine effectiveness in elderly .................................................................................................................... 39
Vaccine effectiveness in healthy children..................................................................................................... 40
Vaccine effectiveness in healthy adults ........................................................................................................ 41
Vaccine effectiveness in pregnant women ................................................................................................... 42
Vaccine effectiveness in high risk individuals ............................................................................................... 43
Critical knowledge gaps ................................................................................................................................ 47
Discussion ............................................................................................................................................................. 48
Conclusion ............................................................................................................................................................ 51
Acknowledgements .............................................................................................................................................. 52
References ............................................................................................................................................................ 53
Appendix ............................................................................................................................................................... 69
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List of Figures
Figure 1: Seasonal influenza vaccine composition meeting (VCM) to vaccine availability ................................... 11
Figure 2: Flow diagram of selection and exclusion of articles .............................................................................. 15
Figure 3: Tropical and subtropical countries with national seasonal influenza vaccination policy ...................... 16
Figure 4: Seasonal influenza vaccine formulation used by countries in the tropics and subtropics .................... 17
Figure 5: Tropical and subtropical countries that vaccinate pregnant women against seasonal influenza ......... 18
Figure 6: Influenza circulation and vaccination timing in South and Southeast Asia ........................................... 22
Figure 7: Countries that shared influenza virus with WHO CCs for the NH 2014-15 vaccine formulation ........... 26
Figure 8: Countries that shared influenza virus with WHO CCs for the SH 2015 vaccine formulation ................. 26
Figure 9: Seasonal influenza virus isolates analyzed by WHO region ................................................................... 27
Figure 10: Seasonal influenza vaccine doses distributed in the tropics and subtropics (2011) ........................... 35
List of Tables
Table 1: National policy for seasonal influenza vaccination ................................................................................. 19
Table 2: Vaccination timing and influenza activity in Latin America and the Caribbean (2002 – 13)................... 25
Table 3: Antigenic and genetic relatedness of circulating influenza virus and contemporary vaccine strain ...... 30
Table 4: Seasonal influenza vaccine coverage in the tropics ................................................................................ 37
Table 5: Seasonal influenza vaccine effectiveness in the tropics ......................................................................... 45
List of Appendices
Appendix A: Strategies and keywords used for literature search ........................................................................ 69
Appendix B: List of countries and territories in the tropics and subtropics included in the review ..................... 70
Appendix C: National policies of tropical and subtropical countries on seasonal influenza vaccination ............. 71
Appendix D: Seasonal influenza vaccine doses distributed in the tropics and subtropics ................................... 77
Appendix E: Seasonal influenza vaccine effectiveness in the elderly in the tropics and subtropics .................... 84
Appendix F: Seasonal influenza vaccine effectiveness in children in the tropics and subtropics ........................ 88
Appendix G: Seasonal influenza effectiveness in healthy adults in the tropics and subtropics ........................... 92
Appendix H: Seasonal influenza vaccine effectiveness in pregnant women in the tropics and subtropics ......... 94
Appendix I: Seasonal influenza effectiveness in high risk individuals in the tropics and subtropics .................... 96
Executive summary
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EXECUTIVE SUMMARY
Background
Over the last decade an increasing number of Low and Middle Income Countries in the tropics have actively
considered initiating or expanding their national policy and guidelines for seasonal influenza vaccination. This
is critical following the WHO recommendation for giving the highest priority for maternal immunization against
seasonal influenza. The biannual WHO recommendations for influenza vaccine composition are suitable for
countries located in the temperate regions with distinct seasonality in influenza activity. Tropical and
subtropical countries with variable seasonality patterns need to make evidence-based decisions regarding
which population subgroups to vaccinate, which vaccine composition to use, when to vaccinate and what
public health benefits to expect.
Objectives
The overall aim of this review is to assess the scientific evidence on seasonal influenza vaccine use and
effectiveness in Low and Middle Income Countries in particular those situated in the tropical regions.
Specifically it aims to review the –
1. Status of national policies on seasonal influenza vaccination in Low and Middle Income Countries in
the tropics and subtropics
2. Seasonal influenza vaccine supply, availability and coverage in the tropics and subtropics
3. Seasonal influenza vaccine use in the tropic and subtropics with reference to timing of vaccination
and the vaccine composition recommended biannually by the WHO, and
4. Effectiveness of the seasonal influenza vaccine in the tropics and subtropics in the context of
seasonality and virological characteristics of the circulating influenza viruses
Methods
We searched multiple global and regional health databases using different combinations of pre-identified
search terms (with synonyms and closely related words) such as ‘seasonal influenza vaccine’, ‘tropics’,
‘effectiveness’, ‘timing’, ‘policy’, ‘campaign’, ‘Africa’, ‘Pacific’, ‘Latin America’ and ‘Africa’. Duplicates were
removed and the title and abstract was screened for eligibility by two reviewers independently. Articles were
included based on consensus discussions between the two reviewers. The full text of all included articles was
further assessed for eligibility. We included articles that were newly identified through cross-references from
articles that were already included. We contacted institutions and individuals involved in influenza research for
currently ongoing influenza vaccine related studies with a request to share preliminary summaries of
unpublished studies to assess their eligibility for inclusion in the review. An effort was made to identify
unpublished studies by searching conference proceedings and agency reports. We restricted our inclusions to
articles in the English language or any other language provided an abstract was available in English, articles
related to policies and guidelines for seasonal human influenza vaccine use in tropical and subtropical
countries, articles that referred to seasonal influenza vaccine composition, timing of vaccination, vaccination
supply, availability and coverage and vaccine effectiveness. We supplemented our literature search by
analysing four global databases. In addition, we administered an online survey to all the WHO Member States
situated in the tropics and subtropics to update information on influenza seasonality, vaccination policy, timing,
composition and coverage. We excluded studies that focused on the avian or pandemic influenza vaccine or
pandemic preparedness. Studies on safety and immunogenicity of influenza vaccines, determinants of
influenza vaccine uptake, licensing and regulatory aspects of influenza vaccine were also excluded. Studies that
focused solely on influenza seasonality, disease burden and genetic or antigenic characteristics of the influenza
virus without any linkage to seasonal influenza vaccine were beyond the scope of this review. We captured the
heterogeneity amongst studies based on study population, ascertainment of seasonal influenza vaccination
Executive summary
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and endpoint variables such as influenza-like illness, hospitalization, and laboratory confirmed influenza,
potential confounding and risk of bias. For all other articles, data extraction and synthesis was descriptive.
Wherever possible, we triangulated different data sources to validate the information extracted from
literature.
Results
Of the 3637 articles and 34 unpublished papers identified, 3247 were deemed ineligible based on the
screening of the title and abstract. A further 178 articles were excluded after a full-text appraisal. A total of
215 published and 31 unpublished articles and four global databases were included in the final review.
Most developed countries had national policies on immunization against seasonal influenza. In contrast, 64 of
the 138 (46%) Low and Middle Income Countries from the tropics and subtropics had a national vaccination
policy against seasonal influenza. Notably, populous countries such as Bangladesh, China, India, Pakistan and
Sri Lanka in Asia representing about 45% of the world’s population did not have a national vaccination policy
against influenza. Thirty-eight countries used the NH formulation, 21 used the SH formulation whereas four
countries (Brunei Darussalam, Marshall Islands, Peru and Singapore) used both formulations. Five countries
situated in the southern hemisphere tropics used the NH formulation whereas eight situated in the northern
hemisphere tropics used the SH formulation. Moreover, three countries (El Salvador, Guatemala and the
Philippines) situated in the northern hemisphere tropics switched from a NH to a SH formulation in recent
years.
National policies of most tropical countries recommended targeted seasonal influenza vaccination of the
elderly, children, and individuals with chronic illness and healthcare professionals. However the age groups
recommended for vaccination varied. Thirty-five (55%) of the 64 tropical countries recommend seasonal
influenza vaccination of pregnant women. A few countries in Asia required seasonal influenza vaccination for
Hajj pilgrims. Seasonal influenza vaccine was available through the private sector in most countries.
Vaccination campaigns in most tropical countries were timed prior to the onset of the typical influenza season.
Vaccination campaigns in Latin America and the Caribbean occurred in April – May prior to the influenza
season except in Cuba and Costa Rica which are reconsidering the timing of their vaccination campaign and
using the SH formulation. The vaccination campaign timing in Brazil was appropriate for its southern region but
may have been late for its northern region where the influenza season frequently occurs earlier. In most
countries in the Asia Pacific, vaccination was timed prior to the onset of their influenza season. However,
several countries reported vaccination timings that were inconsistent with their influenza peaks. Philippines
recently switched to the most recent SH vaccine formulation to time it prior to its influenza peak activity.
The vaccine and circulating virus antigen match has averaged 55 – 60% in both hemispheres since the
introduction of the biannual vaccine composition recommendation by the WHO in 1998. Since the
introduction of the first TIV in 1978 till the end of 2014, a total of 50 changes were recommended by the WHO
(A/H3N2 – 23; A/H1N1 – 9; influenza B – 18). The genetic / antigenic match between the vaccine and the
circulating virus varied in different seasons with a better match seen for influenza B viruses except in 2002
when the B/Victoria lineage re-emerged. Typically, there was a one-season delay before the circulating virus
was covered by the influenza vaccine. Sometimes virus strains persisted locally or seemed re-seeded by
international travellers and hence matched poorly with the vaccine strain that had subsequently changed in
line with antigenic shifts in the influenza viruses globally.
Though the global seasonal influenza vaccination coverage increased two-fold in recent years, it remained low
in all targeted groups in most Low and Middle Income Countries (<5 per 1000 pop.). Higher coverage was not
correlated with higher level of economic development. Furthermore, higher coverage was seen when the
vaccine was offered free through the public sector.
Executive summary
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Vaccine efficacy (VE) against seasonal influenza varied widely in different high risk groups in Low and Middle
Income Countries. VE against laboratory-confirmed influenza in the elderly was lower (0 – 42%) in Low and
Middle Income Countries than in High Income Countries. In children in Low and Middle Income Countries, VE
against laboratory-confirmed influenza ranged widely from 20 – 77% depending on antigenic match but was
largely comparable with High Income Countries. Similarly, VE against laboratory-confirmed influenza in healthy
adults in Low and Middle Income Countries ranged from 50 – 59% and was comparable with that in High
Income Countries. Vaccinating pregnant women against seasonal influenza prevented laboratory-confirmed
influenza in both mothers (VE: 50%) and their new born (VE: 49 – 63%). VE against laboratory-confirmed
influenza was 71% amongst COPD patients in Low and Middle Income Countries comparable to that in High
Income Countries.
Discussion
The tropics where an estimated 41% of the world’s population resides, is an important region that faces a
similar if not higher burden of influenza.
Latin America and the Caribbean have led the introduction of seasonal influenza vaccine into their
immunization campaigns since the 1990s. Large parts of sub Saharan Africa and the Indian subcontinent have
yet to formulate national policies against seasonal influenza though the vaccine is available through the private
sector in many countries in the region. Even as some High Income Countries expand their policies to vaccinate
all persons above 6mo age unless medically contraindicated, targeted vaccination of high risk population
subgroups remains the main strategy to reduce influenza disease burden. National policies recommended
vaccination of pregnant women against seasonal influenza in countries in Latin America and the Caribbean but
this has yet to happen in the South and Southeast Asia.
Historically countries in the tropics selected the WHO recommended NH or SH vaccine formulation largely
based on whether they were situated north or south of the equator. Countries also timed their vaccination
campaigns according to when the respective vaccine formulation became available irrespective of the
influenza seasonality pattern in the country. Recent evidence suggested that vaccination campaigns in tropical
countries (in both hemispheres), where peak influenza activity frequently coincides with the rainy season,
should be timed with the availability of the SH vaccine formulation. For countries such as Brazil, China and
India with a large latitudinal spread, a staggered approach that allows vaccination at different times in the year
to cover multiple influenza activity periods using the most recent vaccine formulation may be more
appropriate.
Antigenic and genetic studies from the tropics indicate a good antigenic match between the influenza virus
strains that circulated during peak activity and the appropriate vaccine strain that was recommended during
that period.
Overall seasonal influenza vaccination coverage was less than 1% in most parts of Africa and Asia. In contrast,
reported coverage in Latin America and the Caribbean countries was higher at times than that of High Income
Countries. Higher coverage was not correlated with the level of economic development but uptake improved
when the vaccine was offered free through the public sector.
Evidence on the cost-effectiveness of seasonal influenza vaccine in Low and Middle Income Countries
interested in improving coverage or expanding vaccination to pregnant women is scarce. Although the benefit
of influenza vaccines has been questioned recently by several studies, vaccine effectiveness in Low and Middle
Income Countries was comparable to that seen in High Income Countries. However comparison of VE
estimates between studies is subject to inherent challenges.
The Global Action Plan for influenza vaccines provides for expanding influenza vaccine production in Low and
Middle Income Countries in the tropics and subtropics to ensure greater equity, sustainability and public
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health benefits. The wide-scale manufacturing, supply and use of seasonal influenza vaccine globally is
inextricably linked with pandemic preparedness. To be able to respond quickly to a pandemic, there must exist
a high capacity to produce seasonal influenza vaccine. Only then can the production capacity be adapted and
up-scaled quickly to meet the urgent demand of a pandemic situation. However, global demand for seasonal
influenza vaccination is low and from an economic perspective, investment in further expanding production
capacity may be difficult to justify without a concomitant demand and market expansion to use the supply.
Understanding the temporal and geographic circulation of influenza is important to develop and apply
vaccination control strategies. As Low and Middle Income Countries consider introducing seasonal influenza
vaccination, surveillance systems need to be strengthened to better understand the epidemiology and
seasonality of influenza, to enable evidence-based decision on when to vaccinate, which groups to target,
what vaccine benefits to expect and so on.
Conclusion
The bulk of scientific evidence on vaccine use and effectiveness in the tropics comes from Latin America and
the Caribbean and Asia with large parts of Africa underrepresented. As more and more countries in the tropics
and subtropics consider vaccinating their populations at risk for influenza, their capacity to make critical
decisions on which vaccine to use, when to vaccinate, how much health benefit to expect etc., is greatly
restricted by the limited evidence that is available about the epidemiology and virology of the viruses that
circulate in their regions. Newly emerged evidence suggests that the timing of vaccination and the choice of
formulation should be solely guided by laboratory-confirmed influenza data facilitated by strengthening
capacity throughout the Global Influenza Surveillance and Response System. Countries in the tropics,
especially those nearer to the equator, countries with large latitudinal spread, countries with varying
seasonality, countries with influenza identifiable year-round, may need to consider a staggered approach that
allows vaccination at different times in the year to cover multiple or year-round influenza activity periods
based on their local seasonality pattern and the availability of the most recent WHO recommended
formulation. There is probably no ‘one size that fits all’ strategy to influenza vaccination. Influenza disease and
virological surveillance need to be strengthened to enable a better prediction and selection of the biannual
updates for the influenza vaccine composition. Research is needed to evaluate alternate strategies for
vaccination timing with the WHO recommended vaccine formulations that have the most recent vaccine virus
strains for countries in the tropics and subtropics.
Key Messages
1) The bulk of scientific evidence on vaccine use and effectiveness in the tropics comes from Latin
America and the Caribbean and Asia; Africa remains underrepresented.
2) Latin America and the Caribbean countries have led the seasonal influenza vaccination amongst Low
and Middle Income Countries in the tropics and subtropics. Most of Asia and Africa are yet to
introduce seasonal influenza vaccine into their national policy and program. Majority (61%) of the
countries for which information was available, prioritized pregnant women for vaccination against
seasonal influenza.
3) Vaccination campaigns in tropical countries (in both hemispheres) where increased influenza activity
frequently coincides with the rainy season, should be timed with the availability of the SH vaccine
formulation. The timing of vaccination and the choice of formulation in the tropics should be guided
by laboratory-confirmed influenza seasonality data facilitated by a strengthened surveillance capacity
throughout the Global Influenza Surveillance and Response System.
4) Countries with a large latitudinal spread, countries with varying seasonality patterns, countries with
more than one influenza peak or with identifiable activity year-round, should evaluate the impact of a
staggered approach that allows vaccination at different times in the year to cover multiple or year-
Executive summary
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round influenza activity periods using the most recent vaccine formulation. There may be no single
approach that fits the requirement of all tropical and subtropical countries.
5) Surveillance systems in tropical countries need to be strengthened to better understand seasonality,
epidemiology and virological aspects of influenza in the tropics so as to optimize the WHO
recommendation for the seasonal influenza vaccine composition for the tropics.
6) Future research is needed to evaluate the impact of alternate vaccination strategies including the
staggered approach, making the seasonal influenza vaccine available year-round, for countries in the
tropics and subtropics. More studies are needed to evaluate the impact of vaccinating pregnant
women at the time of their identification and / or during influenza season.
Abbreviations and acronyms
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ABBREVIATIONS AND ACRONYMS
AFRO African Regional Office
ARI Acute Respiratory Infections
CDC Centers for Disease Control and Prevention
CVD Cardio Vascular Disease
COPD Chronic Obstructive Pulmonary Disease
EMRO Eastern Mediterranean Regional Office
GISRS Global Influenza Surveillance and Response Systems
IFPMA International Federation of Pharmaceuticals and Manufacturers Association
ILI Influenza-like Illness
LCI Laboratory Confirmed Influenza
LAIV Live Attenuated Influenza Vaccine
NH Northern Hemisphere
PAHO Pan American Health Organization
P&I Pneumonia and Influenza
QIV Quadrivalent Influenza Vaccine
RCT Randomized Controlled Trial
SEARO South East Asia Regional Office
SH Southern Hemisphere
TIV Trivalent (Inactivated) Influenza Vaccine
UNICEF United Nations Children’s Fund
VE Vaccine Effectiveness / Efficacy
WHA World Health Assembly
WHO World Health Organization
WPRO Western Pacific Regional Office
Introduction
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INTRODUCTION
Background
Influenza disease impacts Low and Middle Income countries as much if not more than High Income Countries
[1, 2]. Vaccination remains the mainstay strategy to protect populations against influenza and its complications.
The WHO recommends a targeted annual vaccination against seasonal influenza for five priority high risk
population groups [3]. The World Health Assembly (WHA 56.19) resolved in 2003 to increase the use of
seasonal influenza vaccine to protect individuals at high risk for influenza and related complications [4]. The
WHO Global Action Plan for Influenza Vaccines launched in 2006 aims to promote demand for seasonal
influenza vaccine and increased use by Member States as a strategy towards pandemic preparedness [5]. The
continuing antigenic drift in the hemagglutinin gene necessitates a regular update of the vaccine strain
composition to confer protection against currently circulating influenza viruses. The WHO Global Influenza
Surveillance and Response System (GISRS) – previously the Global Influenza Surveillance Network – that
monitors the antigenic and genetic characteristics of the influenza virus globally and selects the candidate
vaccine virus strains for the seasonal influenza vaccine composition for the northern and southern
hemispheres biannually, is well established [6]. Seasonal influenza vaccination in Low and Middle Income
Countries in the tropics and subtropics provides not only public health benefits to its population but may also
deter the emergence and global spread of variant and novel influenza viruses [7].
A quick primer on seasonal influenza vaccination and timing
Vaccines are the mainstay for reducing the burden of seasonal influenza. They are safe and well tolerated.
Inactivated influenza vaccines available since the 1940s, have been recommended for anyone at risk for
influenza or its complications. For countries considering initiation or expansion of seasonal influenza
vaccination programs, the WHO recommends pregnant women to have the highest priority. Additional risk
groups include children aged 6 – 59 months, the elderly, individuals with specific chronic medical conditions
and healthcare workers. It advises countries to make informed decisions on seasonal influenza vaccination
strategies based on their disease burden and vaccine cost-effectiveness [3]. Nasally administered cold-adapted
live attenuated influenza vaccines (LAIV) first developed in the 1960s were licensed in the United States only
after 2003 [8]. They are recommended only for non-pregnant healthy individuals of 2 – 49y of age. LAIV is not
recommended in pregnancy, in children <2y or children <4y with a recurrent wheezing or reactive airway
disease and in the elderly with a chronic medical condition. Inactivated influenza vaccines are more effective in
healthy adults than in younger children or the elderly [9]. Influenza vaccines with adjuvants are promising as
they provide improved immune response at lower antigen dose [10, 11]. LAIVs are more effective than
inactivated vaccines in children [12]. Two doses of the vaccine are recommended for children <9y of age who
have not received influenza vaccines in earlier seasons. Influenza vaccination induces antibodies against
hemagglutinin and neuraminidase surface glycoproteins [13]. However, the correlates for protection continue
to rely on serum antibody titres even when LAIV induce immunity through other immune pathways [14]. The
immune response peaks at 2 – 4wks and has been sometime seen to decline within the same season [15-17].
The efficacy of influenza vaccines ranges between 70 – 90% in controlled trials but is lower in immunization
program settings and depends on the age and immune competence of the vaccine recipient and the antigenic
similarity of the vaccine strain to the circulating influenza virus strain amongst other factors.
Seasonal influenza activity peaks during the winter months (November – February for the NH and May –
October for the SH) in countries with temperate climate [18] whereas it is more variable and complex in
tropical and subtropical climates with identifiable year-round activity that frequently coincides with the rainy
season [19, 20]. The vaccine production cycle from vaccine strain selection to vaccine delivery takes about 6 –
8mo (a finely balanced reconciliation between scientific requirement for detailed antigenic characterization of
viruses, manufacturing practicalities and regulatory requirement) and is timed such that the vaccine is
Introduction
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available before the next influenza season [21, 22]. A short cycle time may maximize the chances of a correct
match between the vaccine strains in the vaccine composition and the putative circulating strains [23]. The
production cycle may take longer if a new strain is recommended for inclusion in the vaccine as this then may
require revalidation of the manufacturing process for the new strain and an evaluation of the immunogenicity
and safety of the new vaccine formulation [21]. Two such cycles are undertaken each year. The WHO formally
selects the candidate strains for the NH vaccine in February based on the most recent circulating virus strains
in the current season for it to become available in October prior to the next season (November – April) in the
northern hemisphere [24].
Figure 1: Seasonal influenza vaccine composition meeting (VCM) to vaccine availability
Similarly, for the SH vaccine cycle, the candidate strain selection for the SH vaccine takes place in September
based on the most recent strains of the circulating influenza viruses for it to become available in April prior to
the start of the next influenza season (May - October) in the southern hemisphere (see Figure 1).
Gaps and opportunities
Over the last decade an increasing number of Low and Middle Income Countries, more so following the 2009
A/H1N1 pandemic, have actively considered initiating or expanding their national policy and guidelines for
seasonal influenza vaccination [25, 26]. This is critical given the WHO Strategic Advisory Committee of Experts
on Immunization recommendation in 2012 to prioritize the vaccination of pregnant women against seasonal
influenza at any stage of their pregnancy. The biannual WHO recommendations for influenza vaccine
composition are suitable for countries situated in the temperate regions with distinct seasonality in influenza
activity. However countries situated in the tropics and subtropics have variable seasonality patterns often with
influenza identifiable year round. The evidence-base needed for decision making regarding influenza
vaccination for many Low and Middle Income Countries is lacking [27]. Countries in the tropical and
subtropical regions need to make evidence-based decisions about which subgroups to target, which vaccine
composition to use, when to vaccinate and the anticipated disease and economic burden impact of vaccination.
Following the WHO Strategic Advisory Committee of Experts on Immunization recommendation in 2012, there
have been increased international collaborative efforts to implement the Global Action Plan for Influenza
Vaccines. One such effort is a Bill & Melinda Gates Foundation grant to the WHO to optimize the process of
seasonal influenza vaccine composition recommendation for tropical regions. The scope of this grant is to
further the WHO efforts through its global network (GISRS) to (1) review scientific evidence for influenza
Introduction
12
seasonality, virus characteristics and seasonal influenza vaccine use in tropical and subtropical countries, (2)
assess and optimize the current process of WHO biannual influenza vaccine composition recommendations to
take into consideration the needs for tropical areas, and (3) pilot and evaluate the optimized guidance for
tropical and subtropical countries. This manuscript systematically reviews the experiences, use and
effectiveness of seasonal influenza vaccine in Low and Middle Income Countries in the tropics and subtropics.
It complements another concurrent systematic review of seasonality and virology of seasonal influenza in the
tropics. Together, they would serve to optimize the current vaccine composition recommendations and
provide guidance regarding the use of seasonal influenza vaccination specific to Low and Middle Income
Countries in the tropics and subtropics.
Objectives
The overall aim of this review is to assess the scientific evidence on seasonal influenza vaccine use and
effectiveness in Low and Middle Income Countries in particular those situated in the tropical regions.
Specifically it aims to review the –
1. Current status of national policies on seasonal influenza vaccination in Low and Middle Income
Countries in the tropics and subtropics
2. Seasonal influenza vaccine supply, availability and coverage in the tropics and subtropics
3. Experiences of tropical and subtropical countries in the use of seasonal influenza vaccine with
reference to timing of vaccination and the vaccine composition recommended biannually by the WHO,
and
4. Effectiveness of the seasonal influenza vaccine in the tropics and subtropics in the context of
seasonality and virological characteristics of the circulating influenza viruses
Methods
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METHODS
SEARCH OF THE LITERATURE
We aimed to systematically review experiences of Low and Middle Income Countries in the use of Seasonal
Influenza Vaccine following the biannual recommendation of vaccine composition by the WHO and the
subsequent outcome on vaccine effectiveness in the tropical and sub-tropical regions. We searched the United
States National Library of Medicine (PubMed), the Cochrane Library, the World Health Organization Library
Information System (WHO LIS), the Latin American and Caribbean Health Sciences Literature (LILACS), the
National Databases of Indian Medical Journals (IndMed) using different combinations of pre-identified search
terms (with synonyms and closely related words) such as ‘seasonal influenza vaccine’, ‘tropics’, ‘effectiveness’,
‘timing’, ‘policy’, ‘campaign’, ‘Africa’, ‘Pacific’, ‘Latin America’ and ‘Africa’ (see Appendix A). After removing
duplicates from the results of the search of different databases, the title and abstract of all articles were
screened by two reviewers (SSH, HM) to independently determine eligibility. Consensus was reached through
discussions between the two reviewers in case of discordance on whether to include or exclude. Articles that
did not meet the eligibility criteria based on the title and abstract were excluded. The full text of all included
articles was further assessed for eligibility by the first reviewer (SSH). In addition, we included articles that
were newly identified through cross-references from articles that were already included.
In addition to the published literature, we contacted institutions and individuals known to be involved in
influenza research for currently ongoing influenza vaccine related studies. An effort was made to identify
unpublished studies by searching conference proceedings and agency reports. Researchers were requested to
share preliminary summaries of unpublished studies to assess their eligibility for inclusion in the review. We
also took the support of the Immunization, Vaccines and Biologicals (IVB) cluster in the WHO to contact the
vaccine industry to access summaries of information on country wise sales of seasonal influenza vaccine in the
tropics. We also searched and identified global databases and surveys on seasonal influenza vaccine use
maintained by the WHO, UNICEF and the vaccine industry. Finally we developed and administered a short
online survey on Seasonal Influenza Vaccine Use in Member States of the WHO that are situated in the tropical
zone.
ELIGIBILITY CRITERIA AND INFORMATION SOURCES
Inclusion criteria
We restricted our inclusions to articles in the English language or any other language provided an abstract was
available in English. Published and unpublished studies that were related to policies and guidelines for
seasonal human influenza vaccine use in tropical countries were included in the review. We limited the
countries to be included in the review as those that were situated partly or wholly between the Tropic of
Cancer (23° 26’ 16” N) latitude in the northern hemisphere and the Tropic of Capricorn (23° 26’ 16” S) latitude
in the southern hemisphere. We additionally included countries in the subtropics situated between the tropic
circle of latitude and the 38th
parallel in both hemispheres. We included the WHO position papers on
vaccination against seasonal influenza, studies that documented which of the seasonal influenza vaccine
composition (Northern or Southern Hemisphere formulation) was used, vaccination timing and strategies,
vaccine coverage, vaccine effectiveness in the general population and in priority or vulnerable groups including
pregnant women. We also included studies that documented issues of production, supply and distribution of
the seasonal influenza vaccine. Published and unpublished literature was included if available or accessed on
or before 30th
September 2014. We also supplemented our literature search by examining two databases that
carried country specific information on seasonal influenza vaccination policy, vaccine procurement, supply and
Methods
14
coverage viz. the UNICEF – WHO Joint Reporting Form (2013) and the WHO Global Influenza Vaccine Survey
(2010). We requested the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)
Influenza Vaccine Supply task force to provide seasonal influenza vaccine sales and coverage (2008 – 2011) for
the tropical regions. In addition, we administered an online survey to all countries situated in the tropics and
subtropics to update information on influenza seasonality, vaccination policy, timing, composition and
coverage.
Exclusion criteria
Studies that focused on pandemic influenza vaccine were excluded from the review. So also were studies that
dealt primarily with avian influenza vaccines or pandemic influenza preparedness. Randomized control trials
that focused on safety and immunogenicity of specific seasonal or pandemic influenza vaccines were also
excluded. Studies that examined the cross protective effect of seasonal and pandemic influenza vaccine on
pandemic influenza were excluded. We also excluded compliance studies that focused on seasonal influenza
vaccine uptake – their determinants or predictors, or KAP studies of either providers or recipients of seasonal
influenza vaccine. Position papers on guidelines for seasonal influenza vaccination for international travellers
were outside the scope of this review. Similarly, studies that addressed the regulatory aspects of seasonal
influenza vaccine viz. licensing, lot release etc. were beyond the scope of this review. Studies that referred
solely to influenza disease burden without seasonality or studies on the antigenic or genetic characteristics of
the influenza virus without any linkages to seasonal influenza vaccine use were excluded. Finally studies
related to different aspects of seasonal influenza vaccine use were excluded if they were based on populations
from countries in the temperate zone.
STUDY QUALITY APPRAISAL
The methodological quality of all seasonal influenza vaccine effectiveness studies that were included was
assessed by one reviewer (SH). We included studies that had already been graded for quality in other
systematic reviews and meta-analysis. We qualitatively assessed each study based on clarity of information
about study population, representativeness and comparability, ascertainment of seasonal influenza
vaccination and endpoint variables such as influenza-like illness, hospitalization, and laboratory confirmed
influenza, potential confounding and risk of bias. Wherever possible, we triangulated different data sources
(influenza vaccine survey data, WHO-UNICEF Joint Reporting Form data) to validate the information extracted
from literature.
DATA SYNTHESIS
We extracted information on the main characteristics of each study. Heterogeneity was captured through
characteristics of the study like study design, study population, target groups, case definitions used to
ascertain exposure and outcome, type of vaccine etc. Vaccine effectiveness was calculated as 100% - odds or
risk ratio separately for each target group as defined by the studies. For all other studies data extraction and
synthesis was descriptive.
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RESULTS
A search of the major healthcare libraries identified 3637 and 34 articles in the published and grey literature
respectively. After screening the title and abstract for eligibility, 3247 articles were excluded as they dealt
primarily with pandemic or avian influenza vaccine, or studies that focused on safety and immunogenicity
amongst other reasons. After assessing the full text of the remaining 424 articles, a total of 178 articles were
excluded (153 articles were based on populations situated outside the tropical and subtropical regions, 20
articles dealt with determinants of influenza vaccination uptake and five articles focused on influenza
vaccination for international travellers from High Income Countries (see Figure 2).
Figure 2: Flow diagram of selection and exclusion of articles
A total of 215 published articles and 31 unpublished articles / conference presentations were included in the
final review. In addition, four global databases (UNICEF – WHO Joint Reporting Form (2013), the Global
Influenza Vaccine Survey (2010), the Survey of the National Influenza Centres in the GISRS (2014) and the
Seasonal Influenza Vaccine use in the Tropics survey (2014) were analysed. The review covers 138 countries
and territories representing about 79% of the world’s population situated in the tropical and subtropical
regions (see Appendix B).
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SEASONAL INFLUENZA IMMUNIZATION POLICY
A consolidated analysis of the UNICEF – WHO Joint Reporting Form data (2013), the Global Influenza Vaccine
Survey (2010), the 2014 Survey of the National Influenza Centres in the GISRS and the Seasonal Influenza
Vaccine use in the Tropics survey (2014) data showed that 64 of the 138 (46%) countries and territories from
the tropics and subtropics had a national vaccination policy against seasonal influenza (Figure 3) [28, 29].
Figure 3: Tropical and subtropical countries with national seasonal influenza vaccination policy
Most (90%) of countries in Latin America and the Caribbean had seasonal influenza vaccination policies except
Guyana, Haiti and the territories of Saint Kitts & Nevis and Saint Vincent & the Grenadines [30]. Only six
countries (Côte d’Ivoire, Egypt, Libya, Mauritius, Tunisia and South Africa) in Africa had national immunization
policies or guidelines against seasonal influenza (see Table 1). A total of 18 countries comprising 93% of the
population in the WHO Western Pacific region had established policies for seasonal influenza vaccination. An
additional seven countries in this region recommended influenza vaccination for high risk individuals whereas
eleven countries had no policies or recommendations [31]. Eleven countries in this region, largely island
nations but also Cambodia, Democratic People’s Republic of Korea, Lao People’s Democratic Republic and
Papua New Guinea did not have a policy for seasonal influenza vaccination. Most countries in the Indian
subcontinent (Bangladesh, India, Pakistan and Sri Lanka) and neighbouring China did not yet have a national
vaccination policy against influenza. In contrast, the majority of the High Income Countries situated in the
temperate regions in the northern and southern hemisphere had national policies on immunization against
seasonal influenza [28, 32].
Policy guidelines for influenza vaccine formulation
National policy guidance on the seasonal influenza vaccine formulation was available for 63 countries (see
Table 1). Refer to Appendix C for country-specific details. Thirty-eight countries used the NH formulation, 21
used the SH formulation whereas three countries (Brunei Darussalam, Marshall Islands and Singapore) used
both formulations (see Figure 4). Additionally, Peru experimented with both formulations in 2012 but reverted
to a single formulation subsequently. Interestingly, five countries / territories (Democratic Republic of the
Congo, Ecuador, American Samoa, French Polynesia and New Caledonia) situated in the southern hemisphere
tropics close to the equator used the NH formulation in their vaccination program. On the other hand, the SH
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formulation was used by eight countries (Cameroon, Kenya, Uganda in Africa and Colombia, Nicaragua and
Panama in Latin America and the Caribbean and Thailand and Malaysia in Southeast Asia) situated in the
northern hemisphere tropics. Additionally, El Salvador, Guatemala and the Philippines situated in the northern
hemisphere tropics switched from a NH to a SH formulation in recent years.
Figure 4: Seasonal influenza vaccine formulation used by countries in the tropics and subtropics
Policy guidelines for targeted influenza vaccination
In the US, the Advisory Committee on Immunization Practices recommends annual influenza vaccination for
everyone 6mo or older if there are no medical contra-indications such as vaccine allergy [33]. The WHO
recommends targeted vaccination against seasonal influenza for five priority groups viz. children aged 6mo to
5y, elderly persons aged 65y and above, persons with specific chronic illness, pregnant women, and healthcare
professionals [3]. It recommends that all countries have a policy to vaccinate at least one priority group by
2016. Refer to Appendix C for country-specific details. Latin America and the Caribbean countries have been
quick in adopting influenza vaccination recommendations [34]. Thailand’s influenza vaccination policy has
evolved rapidly from a seasonal vaccination focus on healthcare professionals and poultry cullers following the
A/H5N1 outbreak in 2005 to providing free vaccination to the elderly and persons with chronic conditions in
2008 and to children aged 6mo – 2y and pregnant women in 2010 [35].
The United States advocates vaccination against seasonal influenza in all trimesters of pregnancy in the
influenza season since 2004 [36]. For countries considering initiating or expanding seasonal influenza
vaccination, the WHO recommends since 2011 that pregnant women become the highest priority for influenza
vaccination [3]. All six countries in Africa, 15 (48%) of 31 countries in Latin America and the Caribbean, 11 (69%)
of 16 countries in Asia and 3 (75%) of 4 countries in the Middle East for whom information was available,
recommended seasonal influenza vaccination for pregnant women (see Table 1, Figure 5). Most of these
countries included pregnant women as a priority group for influenza vaccination after the 2009 pandemic [34].
In contrast, less than half of the countries in Europe prioritized pregnant women for seasonal influenza
vaccination.
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Figure 5: Tropical and subtropical countries that vaccinate pregnant women against seasonal influenza
Most countries with national influenza vaccination policies targeted children (see Table 1). However, the age
groups recommended for vaccination varied between countries. Globally, about half the countries targeted
children 6mo – 2y, whereas about a third of the countries included children aged 2 – 5y as a priority group [28].
The United States recommends universal immunization for all children aged 6mo – 18y. Few countries in
Europe recommend universal immunization for all children aged 6mo – 2y or 3y. Countries such as the United
Kingdom are now considering expanding influenza immunization to school-age children. Influenza vaccination
is recommended for children only if they are at risk for influenza complications due to severe underlying
disease in Asia, South Africa and Australia [37].
Similarly, almost all countries with a national influenza vaccination policy targeted the elderly though the age
at which influenza vaccination is targeted varied between countries [38]. Similarly, the majority of countries in
Europe and Latin America and the Caribbean with a national influenza vaccination policy prioritized individuals
with underlying chronic illnesses compared to countries in other regions (see Table 1).
Many countries recommend and reimburse vaccination of healthcare professionals against influenza [34].
Interestingly there was no correlation between the development status of the country and free influenza
vaccination to healthcare professionals [39]. Nine out of 13 tropical and subtropical countries surveyed in 2005
recommended influenza vaccination to healthcare professionals [25]. A more recent survey in 2009 showed
that 32 of the 35 Latin America and the Caribbean countries administered influenza vaccines to their
healthcare professionals through the public systems [40]. Healthcare professionals were more commonly
targeted for vaccination after the 2009 pandemic [34].
Many High Income Countries recommend seasonal influenza vaccination for international travellers intending
to travel during the influenza season [41-43]. Saudi Ministry of Health recommends influenza vaccination to all
Hajj pilgrims especially those with underlying chronic illnesses. The vaccine is mandatory for all health
professionals working in the Hajj pilgrimage centres of Mecca and Medina [44]. Countries like Brunei
Darussalam, India, Indonesia and Malaysia (the latter three countries despite not having a national influenza
vaccination policy) mandate or recommend seasonal influenza vaccination as a prerequisite for people
intending to travel to Saudi Arabia for the Hajj pilgrimage (see Table 1). However it was unclear whether the
influenza vaccination cost was borne by the traveller or by the public health system.
Table 1: National policy for seasonal influenza vaccination
Countries (%) with
Europe, N America
[32] (n=27)
Asia Pacific [31]
(n=38)
Central, South Americas [40]
(n=39)
Africa
(n=48)
Middle East
(n=13)
National seasonal influenza vaccination policy 76%1 26% 90% 8% 62%
Vaccine formulation recommended - NH 18% 56% 2% 23% - SH 11% 31% 2% 0% - Both 8% 0% 0% 0% - None 63% 13% 96% 77%
Target groups in policy - Elderly 100%
2 26% 87% 8% 31%
- Children 22% 16% 79% 4% 23% - Persons with chronic illnesses 100% 16% 79% 4% 23% - Pregnant women 37% 16% 41% 0% 23% - Healthcare professionals 85% 26% 74% 4% 23% - Hajj travellers 8%
3
Availability of influenza vaccine4
- public sector only 0% 10% 0% 0% - private sector only 37% 13% 25% 0% - both sectors 21% 59% 4% 23%
Vaccination free in public sector 13% 56% 2% 15%
Countries able to meet WHA 56.19 resolution (coverage>75% in elderly)
5
4% 13% 33% 0% 15%
1 This percentage is based on a denominator of 53 countries in the WHO EURO region [45].
2 This percentage and others below it in the Europe column are based on a denominator of 27 countries of Europe [32].
3 Brunei Darussalam, India, Malaysia
4 Includes countries with or without national influenza vaccination policy
5 Data source – as reported by the Global Influenza Vaccine Survey 2010
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INFLUENZA VACCINE SUPPLY AND AVAILABILITY
The 58th
World Health Assembly (WHA58.5) in 2005 mandated the WHO to work with international and
national partners to increase access to influenza vaccines [46]. Since its launch in 2006, the WHO Global Action
Plan for Influenza Vaccines aims to boost evidence-based demand for seasonal influenza vaccine, increase its
production, licensing and use by countries and promote influenza vaccine research and development that
would in turn serve to stimulate an increased pandemic preparedness [5, 47]. The immediate goal is to
increase by 2016, the global vaccine production capacity to produce enough vaccine to equitably immunize 70%
of the world population with a pandemic vaccine that gives an adequate protection within 6mo of vaccine
seed transfer to manufacturers in the event of a pandemic [48].
Seasonal influenza vaccine production increased from 350 million doses in 2006 to around 900 million in 2009.
An industry sponsored survey of seasonal influenza vaccine distribution in 157 countries showed an increase of
87% between 2004 and 2011 but only 3% per annum in the last three years [49]. Fourteen manufacturers from
Low and Middle Income Countries (Brazil, India, Indonesia, Democratic People’s Republic of Korea, Thailand
etc.) received technology transfer support that has resulted in a current pandemic capacity of 330 million
doses which is predicted to reach 795 million doses by 2016 [50-53]. Of the 25 countries with seasonal
influenza vaccine manufacturing facilities in 2010, twelve were Low and Middle Income Countries situated in
the tropics and subtropics, most of them had yet to start production. Despite the emergence of new
manufacturers in Low and Middle Income Countries, more than 80% of the global seasonal influenza vaccine
was produced by the seven large manufacturers located in High Income Countries (United States, Canada,
Australia, Western Europe, Russia, China and Japan) [54]. There was, as yet, no production capacity in the
Eastern Mediterranean region, Central Asia and sub-Saharan Africa except one facility in South Africa capable
of filling imported bulk vaccine and packaging [55]. India, Indonesia and Thailand have since registered and
started production of seasonal influenza vaccine. Brazil, Mexico, South Africa, Egypt, the Islamic Republic of
Iran, Thailand and Viet Nam are expected to have production capacity within 5 – 10y [56]. China’s five
multinational and eleven domestic manufacturers with a maximum production capacity of 126 million doses,
supplied 32.5 million doses (2% of the total population) of seasonal influenza vaccine in 2008-09 season
against an estimated domestic need based on national recommendations, of 570 million doses per year (43%
of the total population) [57]. Though the vaccine supply in China has increased by 18% annually since 2005, the
gap to meet domestic needs remains large.
Less than half of all countries include seasonal influenza vaccination in their national programs with large
regional variation [28]. Some countries introduced influenza vaccine only through the public sector. Whereas
most Latin America and the Caribbean countries additionally ensured some degree of vaccination coverage
through the private sector at times to cover more than 50% of the vaccination needs [30]. Other countries that
did not have a national influenza vaccination policy (e.g. China, India, etc.), the vaccine was available at cost
through the private sector. Countries that targeted health professionals for influenza vaccination, the vaccine
was made available free through the public health system (e.g. most Latin America and the Caribbean
countries and the Pacific region) [34]. Only 14 of the 31 countries surveyed in Africa reported availability of the
seasonal influenza vaccine – six in the private sector (Democratic Republic of the Congo, Senegal, Togo,
Uganda, Zambia and Zimbabwe) and the remaining eight in both public and private sectors (Cameroon, Côte
d’Ivoire, Egypt, Kenya, Madagascar, Mauritius, Morocco and South Africa) [58].
Latin America and the Caribbean
The developing countries of Latin America and the Caribbean have often led the introduction of new or
underused vaccines. The Latin America and the Caribbean region have a strong tradition of manufacturing
vaccines through the public sector. Technology transfer of the entire process of influenza vaccine production
was initiated between a major vaccine manufacturer in France with Brazil in 1999 [30, 59, 60]. Another
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agreement established a capacity to formulate, fill and package seasonal influenza vaccine with a State-owned
manufacturer in Mexico in 2009 [61]. Brazil, Cuba and Mexico in Latin America and the Caribbean region
showed the greatest self-sufficiency in national vaccine production. These countries have created markets for
new and underused vaccines by improved and equitable access to health services, accelerated disease control
and improved public health infrastructure [62]. The PAHO’s ProVac Initiative to develop country expertise to
make the best technical decisions, take ownership and reduce dependence on external sources to pay for and
distribute vaccines supported by strong international partnerships has worked well to achieve higher and
equitable vaccine coverage in Latin America and the Caribbean. Tax exemptions for importation of vaccines,
creation of national vaccine funds, legislation that requires obligatory use of the PAHO’s Revolving Fund to
purchase influenza and other vaccines intended for public use has ensured cost-effective and sustainable
management of immunization programs in Latin America and the Caribbean [63]. As part of the Global Action
Plan for Influenza Vaccines, the WHO has strengthened capacity of national regulatory authorities in Brazil and
Cuba in licensing vaccines within the WHO prequalification framework.
Challenges for the tropics
The capacity of Ministries of Health to make evidence-based policy decisions on introduction or expansion of
influenza vaccination programs is an important challenge in settings where information on disease burden,
vaccine cost-effectiveness is lacking [64]. First, the demand for seasonal influenza vaccine is variable and often
unpredictable influenced by the timing and severity of influenza activity, public perception and awareness of
vaccination and availability of vaccine [65]. Second, there is gross regional disparities in vaccine supply and
availability in the tropics. It is estimated that Africa, Eastern Mediterranean and Southeast Asia receive only 1 –
4% of the global supply of the seasonal influenza vaccine [66]. Third, vaccine cost and low vaccine production
capacity in developing countries further contribute to low availability and usage of the seasonal influenza
vaccine. Fourth, when vaccines are introduced or their supply expanded in Low and Middle Income Countries,
vaccine supply chains are overburdened, bottlenecks created with reduced availability of both influenza and
other EPI vaccines. The choice of target populations for influenza vaccination and the limited time-frame of 2 –
3mo available to deliver the vaccine prior to the influenza season can adversely affect the flow of all vaccines
in the supply chain. A simulation of Thailand’s vaccine supply chain showed that trying to cover 25% of the
population recommended for influenza vaccination, would hinder overall vaccine availability so that only 62%
of potential vaccines who arrive at clinics would receive vaccine [67]. Fifth, national regulatory systems in
many Low and Middle Income Countries in the tropics lack capacities to perform core functions of vaccine
licensing, laboratory testing, lot release systems, Good Manufacturing Practices inspections, monitoring and
evaluation of clinical trials and post-marketing surveillance. This in turn undermines confidence and credibility
of manufacturers to produce within weak regulatory environments [30].
WHEN TO VACCINATE?
Challenges for the tropics
Though the timing of the annual production cycle has worked well for NH and SH temperate regions, its
applicability to the tropical region face several challenges. First, the biggest challenge for the tropics is the
diversity of seasonal patterns that occasionally lacks synchronicity with influenza activity in the temperate
regions [68, 69]. In tropical regions, influenza can be identified throughout the year and frequently
demonstrates one or two epidemic periods. Countries in the subtropics can also occasionally have two
epidemic periods. The occurrence of two peaks in some tropical countries in some years was sporadic as seen
in Nicaragua [70]. Viet Nam and Cameroon show high influenza activity identifiable year-round [71, 72]. Some
show within-country diversity in seasonality patterns [73]. For reasons not yet fully understood, influenza
activity in the tropics frequently coincides with the rainy season [74-77]. Example, there is a wide variation in
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the timing of the rainy season in Bangkok and Kuala Lumpur, only 1100 km apart but with influenza peaks at
opposite times of the year. Second, the timing of the vaccine selection – production cycle may not be optimal
for the tropical region with less distinctive seasonality patterns though WHO recommendations reflect
progressive antigenic changes in the circulating viruses and therefore relevant to all regions of the world. Third,
the dearth of evidence from some tropical regions about the influenza disease burden and seasonality makes it
difficult for countries to make rational decisions about when to vaccinate their populations against influenza.
Fourth, a lack of a national policy on immunization against influenza, weak surveillance systems and poor
capacities of national regulatory authorities makes informed decisions related to vaccine virus manufacture,
licensing and release difficult in many tropical Low and Middle Income Countries.
Asia Pacific
A few recent efforts have addressed the question of vaccination timing for tropical regions. A cumulative
analysis of influenza activity from 2006 to 2011 in ten tropical countries of South and Southeast Asia found two
major patterns of influenza activity – a distinct summer / monsoon peak between June and October
(corresponding to the winter peaks in the SH) in Bangladesh (June to September), Cambodia (July to
December), India (June to August), Lao People’s Democratic Republic (August to December), Philippines (June
to October), Thailand (June to November) and Viet Nam (July to August) [78]. Furthermore, countries such as
India (northern region) and Thailand showed an additional secondary peak between December and March
(corresponding to the winter peaks of the NH) (see Figure 6). This suggested that the tropical countries in
South and Southeast Asia even though situated in the NH may not follow the typical winter peaks of
temperate countries of the NH. However, some of these tropical countries with large latitudinal spread and
situated further away from the equator may additionally have a secondary minor peak that follows the typical
NH winter peak [79].
Figure 6: Influenza circulation and vaccination timing in South and Southeast Asia
Countries such as Indonesia and Malaysia closer to the equator showed identifiable influenza activity year-
round with variable peaks in some years. Despite some possible carry-over protection from previous years
vaccination, a NH influenza vaccine delivered in October would be too late to cover the current influenza
season and too early to offer optimal protection for the next influenza season due to declining vaccine induced
antibody titres [80]. Instead the authors proposed the most recent formulation of the SH influenza vaccine
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that becomes available in April for these tropical countries prior to the influenza season (June to October) [78].
Furthermore, countries such as Thailand and China, Hong Kong SAR with a secondary peak, may benefit from a
second vaccination schedule – the NH vaccine (available in October) prior to the secondary winter peak
(November to February) [79, 81-83]. The additional health benefit needs to be weighed against the cost and
effort of providing a second vaccination campaign against the second and smaller epidemic. Singapore with
biannual peaks provides formulations and schedules recommended for both the northern and southern
hemispheres [19].
This proposed vaccination timing relates well with the timings of vaccination campaigns conducted by some of
these countries as seen from questionnaire based surveys on seasonal influenza vaccine policy,
recommendation and practice administered to EPI managers in 36 countries in the Western Pacific region [28,
31]. Most countries in the Western Pacific region (American Samoa, China, French Polynesia, Guam, China,
Hong Kong SAR, Marshall Islands, the Federated States of Micronesia, China Macao SAR, New Caledonia, Palau,
Democratic People’s Republic of Korea, Viet Nam and Wallis and Futuna) reported influenza peaks typical of
the NH winters (December to April). However some countries (Niue, Philippines, Pitcairn Islands and Tokelau)
reported peak activity from June to November while a few countries (Brunei Darussalam, Cambodia, Cook
Islands, Malaysia and Singapore) reported identifiable activity year-round. Most of these countries conducted
their seasonal influenza vaccination campaigns in the months before or during peak influenza activity though
several countries (French Polynesia, Guam, the Federated States of Micronesia, China Macao SAR and Niue)
reported vaccination timings that were not aligned with their influenza epidemics [31]. A realization in the
Philippines that the NH formulation was being administered after the June / July peak in seasonal influenza
activity brought about a policy shift to use the SH formulation in 2002 [35].
Latin America and the Caribbean
An ongoing CDC study used laboratory confirmed ILI and SARI surveillance data from 2002 – 2013 from 16
countries from Latin America and the Caribbean to explore timing of influenza epidemics during a hypothetical
calendar year to ascertain the optimal month for vaccination [84]. After excluding the pandemic years (2009 –
10) and the years with less than 25 specimens, preliminary analysis of a total of 95y of surveillance data
indicated that influenza activity in tropical Latin America and the Caribbean countries (with the exception of
Guatemala and Mexico that followed a NH seasonality pattern, and Jamaica that had epidemics as early as
February) typically started in May (± two months) and lasted for about 4mo. In 56% of study years in most
countries of Latin America and the Caribbean (with the exception of the Dominican Republic and tropical
Mexico that followed a SH and NH seasonality pattern respectively), a second smaller influenza epidemic
typically started in November (± two months) and lasted for about 4mo (see Table 2). Furthermore, the
predominant strain of the circulating virus had a good antigenic match with the SH formulation in 77% of years
compared to 60% match with the NH formulation [84]. Countries of Latin America and the Caribbean, with the
exception of Guatemala, Jamaica and Tropical Mexico, should consider vaccination in April prior to the primary
influenza season from May to September.
Vaccination campaigns in most countries in this region, use the SH formulation which becomes available just
before the influenza season. Ecuador and the Bolivarian Republic of Venezuela are the only two countries in
South America that use the NH vaccine formulation. Both NH and SH formulations are available in Nicaragua –
the SH formulation through the public sector and the NH formulation in the private sector [40]. El Salvador and
Guatemala in Central America which used the NH formulation in the past, switched over to the SH formulation
in recent years. Interestingly, it was seen that Cuba and Honduras vaccinated its population in November using
the NH formulation (that became available in October) after the end of the influenza season and several
months ahead of the next season. On the other hand, Costa Rica used the NH formulation in February – March
(several months later after its availability) to target the influenza season (July – November). Costa Rica and
Honduras are now considering timing their vaccination campaign in April – May using the most recent SH
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formulation while Cuba has already changed to this new schedule. Similarly the Bolivarian Republic of
Venezuela, Costa Rica, and Ecuador should explore the potential impact of switching their vaccination policy
from the NH to the SH formulation as they accrue more years of laboratory-confirmed influenza data.
Brazil
The timing of influenza vaccination poses a paradox for Brazil which has a large latitudinal spread. Influenza
activity peaks in the northern region of Brazil (near the equator) in March and April. It peaks later (May to June)
in the south of Brazil (near the tropic of Capricorn). The vaccination campaign in all of Brazil begins in April
when the SH vaccine becomes available. By the time the vaccine rolls out, it is too late for the vaccine to have
an optimal protective effect as the influenza activity in north Brazil is almost at an end whereas in south Brazil
the influenza activity has already started [85]. Historically, the success rate of vaccination campaigns in both
north and south Brazil (as judged by the proportion of influenza seasons from 1999 – 2007 where strains were
correctly matched in terms of composition and timing of vaccine delivery) is 30%. A study simulating the effect
of different vaccination formulations and timings showed that a SH vaccine if delivered 3mo earlier (by January)
would increase the vaccination campaign success rate to 70% in both north and south Brazil whereas a NH
formulation delivered in October would increase the campaign success rate to 65%. Paradoxically, the SH
vaccine delivered in April may not be the optimal choice for Brazil [23]. A more practical approach with existing
vaccine delivery schedules would continue to use the SH formulation in south Brazil where most of its
population lives with an optional second schedule during October using the NH formulation for the northern
regions of Brazil. The Brazil vaccination timing dilemma may also be relevant to other large tropical countries
such as China and India. As in Brazil, influenza activity starts earlier in the north and moves towards the central
and southern regions [86].
China
Similar to the latitudinal gradient in the timing of influenza activity in Brazil, a spatiotemporal modelling using
surveillance data from 2005-11 identified three provincial regions in China with distinct seasonality patterns
that broadly aligned with climatic zones. Northern provinces of China (latitudes >33° N) experienced winter
peaks (January); southernmost provinces (latitudes <33° N) experienced spring peaks (April – June); whereas
provinces at intermediate latitudes experienced semi-annual peaks (March and October). Vaccination timing is
further complicated by differences in the seasonality of influenza A and B especially in south China. It may not
be possible for a single annual influenza vaccination campaign to be effective against both virus types and in all
provinces of China. A NH vaccination schedule (October) would be optimal for Northern China. In contrast, to
have an effect on the spring peak (April – June), a SH vaccination schedule (albeit a month earlier in March)
would be optimal for Southernmost China. The situation was more complex in the intermediate provinces of
China due to the semi-annual peaks and longer periods of influenza activity to suggest an effective vaccination
strategy [87].
India
Similar to other countries with a large latitudinal spread, the seasonality pattern varies in different regions of
India. Limited influenza activity is seen year-round with a distinct peaking of activity from June to August
during the rainy season throughout the country. In addition Tamil Nadu State in the southern India has a
second spell of rains (the North East Monsoon) from October to December. Moreover, a second albeit smaller,
peak in influenza activity occurs in the winter months from December – February in the northern regions of
India that follows a NH temperate pattern [77, 88]. Though India is yet to formulate a vaccination policy
against seasonal influenza, it may consider a staggered schedule – SH formulation in April – May in the whole
country prior to the main influenza season and a second schedule with the NH formulation in October prior to
the secondary winter peak (November to February) in northern India as also for the northeast monsoon peak
during the same period in Tamil Nadu in South India [89-91].
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Table 2: Vaccination timing and influenza activity in Latin America and the Caribbean (2002 – 13)
Years (2009 – 10 excluded)
Influenza epidemic period
Vaccination campaign timing
Vaccine formulation used
Good match between circulating and NH formulation
Good match between circulating and SH formulation
Central America
Costa Rica 2006 – 12 Jun – Jul Nov – Jan
February – March
NH 5 / 7y 5 / 7y
Cuba 2011 – 13 Apr – Sep November NH
Dominican Republic
2011 – 13 Apr – Aug NH
El Salvador 2005 – 12 May – Jul Sep – Oct
SH 2 / 4y 3 / 4y
Guatemala 2007 – 12 Jan - Jun April SH NH (<2012)
5 / 7y 5 / 7y
Honduras 2008 – 13 Jul – Dec December NH 3 / 5y 4 / 5y
Jamaica 2011 – 13 Feb – Apr Sep – Nov
NH
Mexico (Tropical)
2011 – 13 Oct – Mar NH
Nicaragua 2008 – 12 Jun – Nov April - May SH 3 / 5y 4 / 5y
Panama 2008 – 12 May – Sep April – May SH 1 / 3y 2 / 3y
Bolivia (Plurinational State of)
2011 – 13 May – Oct May – June SH
Brazil 2003 – 13 Mar – Jul April SH 5 / 7y 5 / 7y
Colombia 2002 – 07, 2011 – 13
Apr – Jul Dec – Jan
March SH
Ecuador 2011 – 13 Jul – Sep Jan – Mar
NH
Paraguay 2003 – 05, 2011 – 13
Jun – Jul Oct – Jan
April SH 2 / 5y 5 / 5y
Peru 2003 – 08, 2011 – 13
Apr – Aug Dec – Mar (N&E); May – Sep (rest)
SH
WHICH VACCINE FORMULATION TO USE?
The WHO GISRS comprises of year-round testing of clinical specimens for influenza virus by more than 103
NICs in 99 countries and timely sharing of representative virus isolates with WHO CCs for further antigenic and
genetic analysis [29, 69, 92]. The majority of countries that shared viruses for the NH 2014-15 and SH 2015
vaccine formulation were High Income Countries situated in the temperate regions (see Figure 7 and Figure 8).
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Figure 7: Countries that shared influenza virus with WHO CCs for the NH 2014-15 vaccine formulation
(Data source: WHO CCs reports for the WHO influenza composition consultation in February 2014, Map
production: WHO GISRS Team, WHO)
Figure 8: Countries that shared influenza virus with WHO CCs for the SH 2015 vaccine formulation
(Data source: WHO CCs reports for the WHO influenza composition consultation in September 2014, Map
production: WHO GISRS Team, WHO)
South and Southeast Asia contributed viruses for composition selection of both hemisphere vaccines whereas
countries in Latin America and the Caribbean contributed viruses primarily for the SH 2015 vaccine formulation.
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Figure 9: Seasonal influenza virus isolates analyzed by WHO region
(Source: Global Influenza Surveillance and Response System, WHO)
Figure 9 shows the distribution of the number of seasonal influenza viruses analysed by the WHO CCs for the
NH 2013-14 and SH 2014 vaccine formulation. The majority of the viruses analysed were from the Western
Pacific region, mostly from mainland China, China, Province of Taiwan and China, Hong Kong SAR. Fewer
viruses were analysed from Europe relative to the countries from Latin America and the Caribbean. The
number of influenza viruses from countries in the tropics and subtropics that were analysed by the WHO CCs
for the biannual vaccine formulations were far fewer compared to China and the Americas.
Based on antigenic and genetic analysis by the WHO CCs coupled with human serology data and epidemiology
data, the WHO recommends the influenza vaccine composition for the next season for the NH and SH. It is
presumed that a vaccine strain that has a match with the circulating virus as determined by antigenic
characterization is more likely to confer protection against clinical influenza. The addition of a separate
recommendation for the SH in 1998 by the WHO improved the antigenic match for the A/H3N2 viruses from
31% to 59% in the southern hemisphere and made it comparable with that in the NH [93]. Since then, vaccine
antigenic match has averaged 55 – 60% in both hemispheres. However, the antigenic match for the influenza B
virus decreased from ~100% to 33 – 54% in both hemispheres following the unexpected resurgence of the
B/Victoria lineage in 1997.
Challenges for the tropics
Though this process has worked well for countries with temperate climates, its application to countries with
tropical and subtropical climates faces a few challenges. First, the NH and SH vaccine formulations were largely
based on evidence from temperate countries of the respective hemispheres where an estimated 57% and 2%
of the world’s population reside. The relative dearth of evidence from the tropical regions (where 41% of the
world’s population reside) on the antigenic and genetic characteristics of the viruses, prevalence, geographic
distribution and rate of spread – evidence that forms the basis for vaccine strain recommendation – made it
difficult to determine whether a NH and / or SH vaccine strain was more appropriate for a country in the
tropics. Second, it was unclear how much representation and weightage the viruses from tropical regions had,
in the final consideration for the vaccine recommendation. Third, the antigenic drift of the influenza virus was
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more likely to occur with year-round transmission often seen in the tropics. Fourth, the co-circulation of
rapidly evolving strains of the A/H3N2 virus in the same season made it difficult to assess the match between
the different circulating viruses and the recommended vaccine strain. Only a few studies from the tropics
indicated which strains were dominant or otherwise. Moreover the co-circulation of both the B/Victoria and
B/Yamagata lineage of the influenza B viruses especially in the tropics, made prediction of which lineage would
circulate in the next season, difficult. The dominant circulating influenza B lineage matched in only 5 out the
last 10 seasons with the recommended vaccine strain [94]. Fifth, most genetic studies reported on the virus
strains aggregated for the year of circulation. As the month of circulation of the virus was not reported it was
difficult to determine which vaccine formulation the virus strain clustered with.
The influenza virus subtype A/H3N2 is known for its rapid evolution and dominance in most seasonal
epidemics since 1968 when it first appeared in humans. Since the introduction of the first TIV in 1978 till the
end of 2014, a total of 50 changes were recommended by the WHO – A/H3N2 (23); A/H1N1 (9); and influenza
B (18) including recommendation for both lineages of influenza B since 2013. In the 1987 – 1997 decade, the
circulating strains differed in antigenicity from the vaccine strains in 5 of the 10 seasons [95]. Modelling the
antigenic change has shown that the current vaccine virus selection has historically matched well with the
subsequently circulating influenza virus except in 1997/98 due to the late emergence of the A/Sydney/5/97-
like virus in mid-1997 and again in 2003/04 due to non-availability of a suitable vaccine candidate for the
emergent A/Fujian/411/2000-like virus [92].
Latin America and the Caribbean
There was a partial to poor match between the vaccine and the circulating virus (especially A/H3N2 virus
subtype) in most influenza seasons in Latin America and the Caribbean countries (see Table 3). Typically, there
was a one to two season delay before the influenza vaccine covered a circulating A/H3N2 virus strain [96, 97].
The genetic / antigenic match between the vaccine and the circulating virus varied in different seasons with a
better match seen for influenza B viruses [98-100] except in 2002 when the B/Victoria lineage reappeared
[101]. Similarly a poor antigenic match was seen for influenza B virus and the vaccine strain from 2001-13 in
Brazil [102]. Genetic studies of influenza A/H3N2 viruses circulating in South America from 1999 to 2007
indicated that multiple clades co-circulated during most influenza seasons. Different genetic lineages co-
circulated in large countries like Brazil, Argentina and Chile and even in smaller countries like Uruguay. Only
vaccine strains recommended for the 2007 influenza season shared the same cluster with the circulating
influenza viruses in that season [103]. A genetic survey of influenza A/H3N2 viruses circulating from 1999 –
2012 in Brazil showed that the strains circulating in 1999 and 2003 were significantly different from the
vaccine strains for those seasons. Moreover both A/Perth/2009-like and A/Victoria/2009-like strains co-existed
in different regions of Brazil during 2010 to 2012. The circulating virus strain matched with the SH vaccine
formulation in only 5 out of 13 seasons [104]. In contrast to an earlier study in Brazil [23], this study found that
the vaccine formulation (NH or SH) was irrelevant in the northeast regions, whereas the SH formulation was
superior in the south and southeast regions of Brazil.
Africa
A study in Kenya showed that 78% and 89% of the influenza virus strains circulating between May – October
and November – April respectively between 2007 – 2012 had antigenic relatedness with the corresponding SH
and NH vaccine formulation for that season [105]. The circulating virus matched with the SH formulation in
2007 but was delayed by one season in 2008 [106]. As influenza activity in Kenya showed seasonality patterns
seen in both northern and southern hemispheres, it remains to be seen if a vaccination strategy using both NH
and SH vaccine formulations would be cost-beneficial in Kenya. Influenza dynamics in Africa is complex and
differences in influenza activity cannot be explained by the simple dichotomy between northern and southern
hemisphere [107]. Here again, the genetic / antigenic match between the vaccine and the circulating virus
varied in different seasons with often a one-season delay before the influenza vaccine covered a circulating
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A/H3N2 virus strain [108, 109]. A poor match often resulted when both lineages of influenza B co-circulated or
when the B/Victoria lineage re-emerged in 2002 [109, 110].
Asia Pacific
Southeast and East Asia has been hypothesized to be the source reservoir for new strains to seed and spread
globally [69, 111]. Here again, the genetic / antigenic match between the vaccine and the circulating virus
varied in different seasons with often a one-season delay before the influenza vaccine covered a circulating
virus strain [112-122]. Strains sometimes persisted locally or were re-seeded by international travellers and
hence matched poorly with the newer vaccine strain [91, 123]. Here again, a poor match resulted when both
lineages of influenza B co-circulated or when the B/Victoria lineage re-emerged in 2002 [116, 124].
The decision about which vaccine formulation to use depends on the antigenic match between the vaccine
virus strain and the circulating influenza viruses within the country. In the absence of such evidence,
irrespective of whether the country lies north or south of the equator, practical considerations of which
vaccine formulation is or would be available prior to or at the time of peak influenza activity in the country
determines the choice of the vaccine formulation. Example, countries like American Samoa, China, French
Polynesia, Guam, China, Hong Kong SAR, Marshall Islands, the Federated States of Micronesia, New Caledonia,
Palau, Democratic People’s Republic of Korea, Wallis and Futuna used the NH vaccine formulation that
becomes available in October, as they had influenza peaks from December to April. Whereas countries that
used the SH vaccine formulation that becomes available in April (Niue, Philippines, Pitcairn Islands and Tokelau)
reported influenza peaks from June to November (except China Macao SAR that reported influenza activity in
February and March). Countries (Brunei Darussalam, Cook Islands, Malaysia and Singapore) that used both NH
and SH vaccine formulations reported influenza activity throughout the year [31]. Another interesting example
is of Cambodia and Viet Nam. Though situated in the northern hemisphere, seasonal influenza activity in
Cambodia and Viet Nam often peaks between May and November. Furthermore, the virus shows close
antigenic relatedness to the SH vaccine strains [118, 120].
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Table 3: Antigenic and genetic relatedness of circulating influenza virus and contemporary vaccine strain
(Note: A match between the vaccine strain and the circulating virus is inferred based on antigenic characteristics testing. However, some studies infer a match based on the
location of the vaccine strain within the same clade as the circulating viruses in a phylogenetic tree. Seasons in which circulating virus matches with corresponding vaccine
strain are highlighted in red)
Reference Country (Vaccine)
Season A/H1N1 A/H3N2 B
Latin America and the Caribbean
Uez (1998) [96]
Argentina (SH)
1990, 1993
1990, 1993 virus closer to vaccine strain for subsequent rather than corresponding season
Savy (1999) [97]
Argentina (SH)
1994-1997
1994-97 virus partial match with vaccine strain; Two seasons delay for circulating virus to be matched with the SH formulation
Pontoriero (2003) [99]
Argentina (SH)
1995-1999
1995-97, 1999 virus poor match; 1998 virus good match
1995-98 virus poor match; 1999 virus good match
1995-97, 1999 virus good match; 1998 poor match
Motta (2006) [101]
Brazil (SH)
1999-2002
2002 virus poor match with NH 2001-02, SH 2002 due to reappearance of Victoria lineage
Laguna-Torres (2009) [98]
Peru (NH / SH)
2006-2008
2006 virus SH 2006, NH 2006-07; 2006 virus (jungle region) NH 2007-08, SH 2008; 2007 virus NH 2007-08, SH 2008; 2008 virus NH 2008-09, SH 2009
2006 virus SH 2007; 2007-08 virus SH 2008
2006-07 virus SH 2006, NH 2006-07, SH 2007, NH 2007-08; 2008 virus SH 2008, NH 2008-09
Douce (2011) [100]
Ecuador (NH)
2006-2010
2006-07 virus poor match; 2008-09 virus good match
2006-07 virus good match; 2008 virus poor match; 2010 virus good match
2006 virus SH 2006, NH 2006-07; 2007-08 virus SH 2008; 2009 virus SH 2009
Africa
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Reference Country (Vaccine)
Season A/H1N1 A/H3N2 B
Niang (2012) [109]
Senegal (NH) 1996-2009
1999 virus NH 1998-99, SH 1999; 2000 virus SH 2000, NH 2000-01; 2003 virus SH 2003, NH 2003-04; 2008 virus NH 2008-09, SH 2009
1997 virus NH 1997; 2003 virus SH 2004; 2009 virus SH 2010
1997, 1999 virus SH 2001; 2001 virus SH 2001, NH 2001-02; 2002 virus poor match as Victoria lineage re-emerges; 2007 virus NH 2006-07, SH 2007; 2008 virus SH 2008, NH 2008-09
Bulimo (2012) [106]
Kenya (SH)
2007-2008
2007 virus SH 2007; 2008 virus SH 2009
Byarugaba (2011) [108]
Uganda (SH)
2008-2009
2008-09 virus SH 2010, NH 2010-11
Heraud (2012) [107]
Cameroon (SH) Côte d’Ivoire (NH) Madagascar (SH) Niger (--) Senegal (NH)
2008-2009
2008 virus NH 2008-09, SH 2009 2009 virus SH 2010, NH 2010-11
El Moussi (2013) [110]
Tunisia (NH)
2008-2011
2009 virus good match; 2010-11 virus Poor match (Yamagata lineage not included in NH 2010-11)
Asia Pacific
Chadha (2012) [91]
India (--) 2004-2008
2005-07 virus good match; Late 2005 early seeding of A/Brisbane/59/2007-like virus; 2008 virus NH 2008-09, SH 2009
2004 virus good match; A/Panama/2007/99 persisted in Delhi till Sept 2005 poor match; 2004-05 virus NH 2005-06, SH 2006; 2006 virus SH 2005 (virus re-seeded due to international travel)
2004-08 virus good match with predominant lineage; both lineages circulated
Agrawal (2010) [112]
India (--) 2005-2009
2006-07 virus NH 2007-08 2009 virus SH 2009 Virus strain precedes vaccine strain by 1 – 2y
2005-2007 virus SH 2008, NH 2008-09; 2008-2009 virus SH 2010, NH 2010-11; Virus strain precedes vaccine strain by 1 – 2y
Roy (2014) [113]
India (--) 2007-2009
2007-09 NH 2009-10
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Reference Country (Vaccine)
Season A/H1N1 A/H3N2 B
Barr (2003) [125]
Thailand (SH) Malaysia (SH) China-Taiwan(NH) New Caledonia (NH)
2000-2002
A/H1N2 virus – H1 gene matched with vaccine strain
A/H1N2 virus – N2 gene matched with vaccine strain
2002 virus NH 2002-03, SH 2003;
Thawatsupha (2003) [126]
Thailand (SH) 2001 2001 virus good match 2001 virus good match 2001 virus good match
Chutinimitkul (2008) [114]
Thailand (SH) 2006-2007
2006-07 virus NH 2007-08 2006-07 virus NH 2007-08
Chittaganpitch (2011) [83]; Waicharoen (2008) [127]; Suwannakarn (2010) [128]
Thailand (SH) 2004-2010
2004-08, 2010 virus good match; 2009 virus partial match (due to emergence of pandemic virus)
2004, 2007, 2009 virus partial match; 2005-06, 2008, 2010 virus good match
2004, 2009-10 virus good match; 2005-08 virus partial match
Dapat (2009) [115]
Myanmar (--) 2005-2007
2005 virus NH 2007-08;
2005 virus NH 2006-07; 2007 virus SH 2008, NH 2008-09;
2005 virus partial match; 2007 virus good match
Hsieh (2005) [129]
China-Taiwan (NH)
1997-2004
1997-2004 virus good match (82%)
1997-2004 virus good match (53%) 1997 – 2004 virus good match (47%)
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Reference Country (Vaccine)
Season A/H1N1 A/H3N2 B
Shih (2005) [116]
China-Taiwan (NH)
2000-2004
1999-2000 virus NH 2000-01; 2000-02 virus good match; 2003-04 virus good match;
1999-2000 virus partial match; 2000-03 virus good match; 2003-04 virus NH 2004-05;
1999-2001 virus good match; 2001-02 virus partial match as both lineages co-circulated; 2002-04 good match;
Tsai (2006) [124]
China-Taiwan (NH)
1998-2005
1999-2000, 2002-03 virus good match; 2001, 2004-05 virus partial match as both lineages co-circulated;
Lee (2009) [130]
China-Taiwan (NH)
2006-2007
2006-07 virus good match; HA gene of Victoria lineage, NA gene of Yamagata lineage
Shu (2005) [119]
China (NH) 2004 2004 virus mutations from NH 2004-05, SH 2005
Nguyen (2007) [131]
Viet Nam (NH) 2001-2003
2001-03 virus good match 2001-03 virus good match 2001 virus good match; 2003 virus good match
Li (2008) [117]
Viet Nam (NH) 2001-2006
2001-06 virus good match; One 2006 virus (A/Hanoi/BM344/06) clustered with A/Solomon Islands/3/06 later included in NH 2007-08
2002 virus clustered between NH 2001-02 and NH 2004-05; 2003-04 virus SH 2005; 2005 virus NH 2005-06;
Vuong (2013) [120]
Viet Nam (NH) 2001-2009
2001-05 virus good match; 2006-07 virus poor match
2001-04 poor match; 2003-04 SH 2005; 2004 virus SH 2004; 2005 virus SH 2005; 2008 virus SH 2008; 2009 virus SH 2010
Mardy (2009) [118]
Cambodia (--) 2006-2008
2007 virus good match; 2008 virus NH 2008-09
2006-08 virus good match 2007-08 virus good match
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Reference Country (Vaccine)
Season A/H1N1 A/H3N2 B
Kosasih (2013) [121]
Indonesia (--) 2003-2007
2003-06 virus good match; A/Solomon Islands/3/06 virus first detected in 2006 – included in NH 2007-08
2003 virus SH 2004, NH 2004-05; 2004 virus NH 2005-06; 2005 virus NH 2005-06, SH 2006; 2006-07 virus good match; A/California/7/04 virus first detected in 2004 – included in NH 2005-06; A/Wisconsin/67/05 virus first detected in 2005 – included in NH 2006-07
2003 virus good match; 2004-05 virus poor match; 2006-07 virus good match
Saat (2010) [122]
Malaysia (SH) 2005-2009
2005 virus SH 2005, NH 2005-06; 2006 virus SH 2006, NH 2006-07; 2007 virus NH 2007-08, SH 2008; 2008 virus NH 2008-09, SH 2009;
2005 virus NH 2005-06; 2006 virus NH 2006-07, SH 2007; 2007 virus SH 2008; 2008 virus SH 2008; 2009 virus SH 2010
2005 virus SH 2004; 2006 virus SH 2006; 2007 virus SH 2008; 2008 virus SH 2008; 2009 virus NH 2009-10, SH 2010
Middle East
Moattari (2010) [132]
Iran (Islamic Republic of) (NH)
2005-2007
2005-07 virus good match 2005-07 virus poor match
Soltani (2009) [123]
Iran (Islamic Republic of) (NH)
2005-2007
2005-07 virus good match 2005-07 virus NH 2003-04 (previous vaccine strain)
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SEASONAL INFLUENZA VACCINATION COVERAGE
Challenges for the tropics
Initiatives to document vaccine use are recent [25, 28, 31, 66]. There are several challenges for estimating
influenza coverage in Low and Middle Income Countries. First, national data on seasonal influenza vaccine
coverage remains scarce and not routinely available. Second, most countries (up to 88% in the WHO regions of
the eastern Mediterranean and Africa) were unable to estimate coverage by target groups in the absence of
reliable group-specific population denominators. Vaccine coverage was available only for four out of 14
countries in Africa that reported availability of seasonal influenza vaccine [58]. Third, though there have been
efforts to create global databases on seasonal influenza vaccine coverage (annual WHO UNICEF Joint Reporting
Form, Global Survey on Seasonal Influenza Policy Development and Implementation 2010, seasonal influenza
vaccine sales consolidated from the vaccine manufacturers), the coverage was estimated as a proportion of
procured doses that were administered or as a proportion of doses distributed to an estimated population.
Fourth, few countries had information on vaccines doses that were returned, unused or wasted. Fifth, the
WHO-UNICEF Joint Reporting Form and other databases do not capture vaccine coverage amongst pregnant
women separately. Sixth, it was often unclear whether the estimated coverage for children less than 9y age
was based on a one-dose or two-dose schedule.
Overall vaccination coverage
The global use of seasonal influenza vaccine increased two-fold between 1994 – 2003 with highest coverage in
High Income Countries – 344, 311, 286 per 1000 population in Canada, Democratic People’s Republic of Korea
and the United States respectively [25]. Coverage, estimated as the proportion of seasonal influenza vaccine
doses distributed in the general population, was less than 1% in 2011 in all of Africa (except Algeria, Mauritius,
Morocco, Namibia, Tunisia and South Africa) and most countries in Asia (Bangladesh, India, Indonesia,
Myanmar, Nepal and Sri Lanka) (see Appendix D). Though the greatest rate of growth (2008 – 11) was seen in
Asia, the total number of seasonal influenza vaccine doses distributed remained relatively small at 8.2 million
in 2011. In contrast, Europe showed a decline of 29% in influenza vaccine use during this period. Most
countries of Latin America and the Caribbean (except Guatemala, Guyana, Haiti and Jamaica), Mauritius and
China, Hong Kong SAR, had vaccine coverage >100 doses per 100,000 population (see Figure 10) [49].
Figure 10: Seasonal influenza vaccine doses distributed in the tropics and subtropics (2011)
(Source: adapted from data provided by IFPMA Influenza Vaccine Supply International Task Force)
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Higher vaccination coverage was not correlated with higher level of economic development. Higher coverage,
however, was seen when the vaccine was offered free through the public sector [25]. Seasonal influenza
vaccination coverage remains low in Low and Middle Income Countries [11]. In Africa seasonal influenza
vaccine coverage varied from <0.5 – 2% of the population and was not associated with World Bank indicators
of income level [58]. Seasonal influenza vaccine sales in ten Southeast Asian countries increased from <5 to
about 10 per 1000 population post-pandemic. Vaccine sales were low in Indonesia (<2 per 1000) and higher in
Thailand (about 6 – 7 per 1000). The coverage was higher (7 – 12 per 1000) in Singapore despite influenza
vaccines being offered at a cost in public hospitals [133]. The coverage in China was less than 5% of that in
High Income Countries like the United States and Canada and similar to Low and Middle Income Countries [25,
26, 57, 134, 135].
Children
Routine influenza immunization in children was first recommended in the United States in 2004 for those aged
6 – 23 months. This was further expanded to include children aged 2 – 4y in 2006 and 5 – 18y in 2008 [136].
Coverage in children in High Income Countries has varied with seasons but have overall remained low (4 – 19%
in Europe) [137] (see Table 4). In the United States, influenza vaccine coverage was 35% for children aged 6 –
23mo and about 15% for children aged 13 – 18y. Coverage in children has generally been lower than in the
elderly, but higher than for adults. Seasonal influenza vaccine coverage varied markedly in a ten-country
survey in Africa, Asia Pacific, Central America and the Middle East during the influenza seasons of 2005 and
2006 [138]. Coverage was higher amongst children (range: 23 – 62% when public funded, 8 – 10% when not)
and reflected the generally high coverage with other childhood vaccines seen in children in Low and Middle
Income Countries. Most countries in Latin America and the Caribbean had coverage in children of more than
80%. Lower coverage was reported by Peru (23%), Uruguay (26%), Paraguay (35%), Bolivia (Plurinational State
of) (36%), and Honduras (45%) [139]. Coverage varied from 32% amongst pre-school children aged above 6mo
to 72% amongst children in elementary school in China, Province of Taiwan [140]. On the other hand, coverage
amongst young children in Thailand was less than 2% [141].
Elderly
The 56th
World Health Assembly (WHA56.19) resolved to immunize at least 75% of its elderly population
against seasonal influenza [4]. Most countries lagged far behind this target (see Table 4). The Latin America
and the Caribbean countries performed better in being able to meet the WHA target compared to other
regions including Europe where only the Netherlands was able to attain this goal followed closely by the
United Kingdom [28]. Influenza vaccination coverage amongst the elderly varied from 14 – 70% in Europe [137].
Within Europe, there have been large disparities (40-fold difference) in coverage amongst the elderly [32, 142].
Few countries (around half of all countries in the WHO WPR, less than a third in the PAHO region, two of nine
countries in the WHO EMR, one country in the WHO European region and none in Africa or South and
Southeast Asia, are set to achieve this target [45]. On the other hand, Latin America and the Caribbean
countries (Chile, Costa Rica, Dominican Republic, El Salvador, Honduras, Mexico, and Nicaragua) have
consistently achieved coverage of more than 75% amongst the elderly since 2005 though others like Argentina,
Belize, Bolivia (Plurinational State of), Colombia, Ecuador, Panama, Paraguay, Peru and Uruguay have shown
declining coverage in recent years [40, 139].
The influenza vaccine coverage in Argentina was 36% in the overall population and 30% amongst the elderly
[143]. Brazil has sustained an influenza vaccine coverage between 70 – 90% since 1999 [144]. Population
surveys to estimate influenza vaccination coverage are rare amongst Low and Middle Income Countries. A
review of VE in Brazil [144] identified ten studies that also presented seasonal influenza vaccine coverage
amongst elderly population [145-151] and elderly patients attending outpatients clinics [152-154]. Vaccine
coverage generally ranged from 66 – 88%. In three surveys, differences of 20 – 25% points were seen between
the survey coverage and those reported by the Ministry of Health [145, 151, 152]. Coverage was generally
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higher when the influenza vaccination was public funded [138]. It ranged from 14 – 41% in Low and Middle
Income Countries with public funded immunization programs whereas it was less than 10% where influenza
vaccination was not publicly funded. On the other hand, a government funded influenza vaccination program
in Thailand and China, Province of Taiwan reported coverage of 12% and 40% respectively amongst the elderly
[140, 141]. Coverage was high in Republic of Korea (41%) and Chile (25%) and lowest in Turkey (5%). Coverage
was lower amongst healthy adults aged 18 – 65y (16% when public funded and 5% when not). A strong
recommendation together with public funding of immunization campaigns may increase influenza vaccination
coverage [138].
Chronically ill
Influenza vaccine coverage amongst chronically ill patients in High Income Countries varied from 11 – 72% [32,
136, 137] (see Table 4). No influenza vaccination coverage data was available for chronically ill patients from
Low and Middle Income Countries.
Pregnant women
Despite the WHO recommendation that pregnant women should have the highest priority for seasonal
influenza vaccination [3], influenza vaccination in pregnancy remains low (2 – 49%) [136]. In the US, coverage
ranges from 32 – 49% [155, 156] (see Table 4). National data on influenza vaccine coverage amongst pregnant
women in Low and Middle Income Countries is scarce. None of the 1000 pregnant women attending an
antenatal clinic in a hospital in India received influenza vaccination during pregnancy in the 2012 – 13 influenza
seasons [157]. Studies from China, Hong Kong SAR and Thailand reported coverage from 1 – 4% amongst
pregnant women [141, 158, 159].
Healthcare professionals
Influenza vaccination coverage amongst healthcare professionals varies widely based on their category. Most
often the vaccine coverage amongst healthcare professionals are low (17 – 26%) even in High Income
Countries but can reach up to 89% for those working with high risk patients [136, 137, 142, 160-163].
Vaccination coverage for healthcare professionals averaged 30 – 34% in Europe [32]. Coverage amongst
healthcare professionals are higher (44 – 62%) in the United States [164]. Coverage amongst healthcare
professionals in Low and Middle Income Countries have been estimated between 20 – 56% in the post-
pandemic years [165-167] (see Table 4).
Table 4: Seasonal influenza vaccine coverage in the tropics
Seasonal influenza vaccine coverage
High income countries Low and Middle Income Countries
Children 4 – 19% [137]; 1 – 83% [32]; 55% (6mo – 23mo), 38% (2 – 4y), 27% (5 – 12y), 15% (13 – 18y) [136]
Argentina, Belize, Chile, Colombia, Ecuador, El Salvador, Mexico, Nicaragua, Panama: >80%; Bolivia (Plurinational State of), Honduras, Paraguay, Peru, Uruguay: 23 – 45% [139]; Public funded: 23 – 62%, User paid: 8 – 10% [138]; China, Province of Taiwan: 32 – 72% [140]; Thailand: <2% [141]
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Seasonal influenza vaccine coverage
High income countries Low and Middle Income Countries
Elderly 14 – 70% [137]; 2 – 82% [142]
Chile, Costa Rica, Dominican Republic, El Salvador, Honduras, Mexico, and Nicaragua: >75%; Argentina, Belize, Bolivia (Plurinational State of), Colombia, Ecuador, Panama, Paraguay, Peru and Uruguay: 20 – 69% [40, 139, 143]; Brazil: 66 – 90% [144-154]; Public funded: 14 – 41% (Republic of Korea (41%)); User paid: <10% (Turkey (5%)) [138]
Chronically ill 11 – 56% [137]; 33 – 72% [32]; 19 – 40% [136]
Pregnant women 32 – 49% [155, 156] 0 – 4% (India, China, China, Hong Kong SAR, Thailand) [141, 157-159]
Healthcare professionals 17 – 89% [32, 136, 137, 142, 160-163]
20 – 56% [165-167]
EFFECTIVENESS OF SEASONAL INFLUENZA VACCINE IN THE TROPICS
Challenges for the tropics
Evidence for vaccine efficacy and effectiveness has been almost exclusively derived from studies in High
Income Countries [168, 169]. There are several inherent challenges in applying efficacy trial results to
population effectiveness [170]. First, the continuing antigenic evolution of the influenza virus, the different
types and subtypes of the virus with varying virulence, transmissibility and seasonality, and the relative
prevalence of each type or subtype of virus means that the vaccine effect varies between seasons and
locations. Second, the lack of a standardized outcome to measure effectiveness makes it difficult to interpret
and compare VE across seasons, locations and populations. Immune correlates of vaccine protection are not
reliable end-points especially in groups that respond less well to vaccination viz. children, elderly and the
immunocompromised. Case ascertainment by laboratory confirmation varies due to variations in virology
testing both within and between laboratories. Clinical case ascertainment is subject to even more variability
due to the generally low specificity of clinical case definitions. Vaccine impact on more severe outcomes like
hospitalization or mortality though easier to ascertain differs from the vaccine impact on less severe disease;
ascertaining mortality impact also requires large samples. Third, the estimate of vaccine efficacy depends upon
the comparator used against the test vaccine. Relative vaccine efficacy measured against a comparator vaccine
(e.g. pneumococcal vaccine) is likely to be lower than the absolute vaccine efficacy measured against a placebo.
Fourth, VE at the population level is typically greater than the vaccine efficacy at the individual level due to the
herd protective effect of vaccination. Information on factors that influence herd immunity such as infectivity of
the virus strain, the individual’s susceptibility, population mixing, vaccine coverage are difficult to measure in
most trials. Fifth, the earlier inactivated influenza vaccines were considered identical and comparable.
However, with the advances in the purity and potency of newer vaccines, it is a challenge to compare vaccine
efficacy and effectiveness between these specialized vaccine products [171]. Sixth, VE varies with how well the
antigenicity of the vaccine virus strain matches with that of the circulating influenza virus. Notwithstanding
these challenges, VE data is critical for policy decisions by countries to introduce and evaluate influenza
vaccination programs.
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VACCINE EFFECTIVENESS IN ELDERLY
Vaccine effectiveness has been extensively studied in two higher priority groups – elderly (60y or 65y and older)
in the general population and residents of nursing homes or long-term care facilities. It is believed that
vaccines in general are less effective in the elderly as the immune response diminishes at later ages. A
literature search for seasonal influenza vaccine effectiveness in the elderly identified ten systematic reviews
[27, 172-179] with 10 to 75 studies. A total of 26 studies including three unpublished, nine cohorts, four RCTs,
four case control, seven ecological and two non-RCTs, from the tropics and subtropics were identified [143,
153, 180-203]. One review [27] that focused on VE in Low and Middle Income Countries included ten studies
on the elderly of which nine were from the tropics and subtropics. For details, refer to Appendix E. Table 5
summarizes the VE against influenza outcomes in the elderly.
Influenza-like illness
The pooled efficacy from different reviews against ILI or ARI varied from 36% [172] to 56% [177]. The studies
from Low and Middle Income Countries yielded a pooled efficacy of 4% (not significant) for LAIV and 59% (95%
CI: 44 – 70) for TIV [27]. The VE against ILI ranged widely from no effect [153] to 76% [194, 195] in the tropical
studies. A study from South Africa was inconclusive about the relative efficacy of LAIV and TIV [190].
Laboratory confirmed influenza
Both Inactivated Influenza Vaccine and LAIV were found to be efficacious against laboratory-confirmed
influenza in the elderly. The pooled efficacy in Low and Middle Income Countries for LAIV and TIV was 43% (25
– 56) and 58% (23 – 78) respectively [27]. This compared well with the pooled efficacy estimates from High
Income Countries [172, 173] as well as with individual studies from the tropics [187, 198] .
Pneumonia
The pooled efficacy of the vaccine in preventing influenza related complication of pneumonia in the elderly
ranged between 30% and 53% [173, 174, 177, 193]. The efficacy was at least 10% points higher with a good
antigenic match between the vaccine and circulating virus strain [177].
Hospitalization
The pooled VE estimate for preventing all-cause hospitalization in the elderly was 50% [174, 177]. The pooled
efficacy estimate for preventing hospitalization due to P&I or cardiovascular or respiratory cause was lower
(range 25% – 33%) [172, 176, 178]. In contrast, neither LAIV nor TIV had a significant effect in preventing
hospitalization in the elderly in Low and Middle Income Countries [27]. Two studies from the tropics showed
no effect of LAIV or TIV in preventing any or P&I related hospitalization in the elderly [187, 188]. Four other
studies from Brazil showed a modest reduction in hospitalization in the elderly [182, 184, 189, 191]. However
more recent studies from the tropics showed a significant reduction in hospitalization related to P&I (range 31%
– 77%) and cardiovascular disease (range 15% – 41%) in the elderly similar to that seen in High Income
Countries [143, 180, 185, 193, 196, 199-201].
Mortality
The majority of the studies that were included for meta-analysis in the systematic reviews after quality
appraisal were from High Income Countries. VE was higher when laboratory-confirmed influenza rather than
ILI or ARI were used as outcomes for evaluation. The effectiveness of the vaccine against ILI, laboratory-
confirmed influenza and pneumonia ranged widely and was unclear in the tropical settings. However barring
two studies (one RCT and one cohort), more recent studies showed significant protection against influenza
related and all-cause mortality in the elderly in the tropics that was comparable with that seen in High Income
Results
40
Countries. The pooled efficacy estimate for preventing influenza related mortality in the elderly varied from 8%
to 30% [173, 174]. The VE was higher for preventing all-cause mortality (range 36% – 68%) [172, 174, 176-178].
Two individual studies from the tropics showed no vaccine effect on preventing mortality [187, 188]. In
contrast more recent trials from the tropics showed a significant reduction in influenza related mortality
(range 20% – 53%) [181, 183, 200] and all-cause mortality (range 24% – 44%) [183, 193, 199, 200]. Excepting
the two studies that showed no effect, VE against influenza related mortality in tropical studies appeared to be
higher than that in High Income Countries whereas the VE against all-cause mortality was seen to be lower in
the tropical studies compared to that from High Income Countries. The benefit of influenza vaccines in the
elderly has been questioned recently with at best a 4% reduction in mortality in the elderly [204]. Excess
mortality studies were unable to confirm a decline in elderly mortality since 1980 despite an increase in
vaccination coverage from 15 – 65%. Frailty bias and use of non-specific endpoints like all-cause mortality have
possibly led cohort studies to overestimate vaccine effectiveness [205].
VACCINE EFFECTIVENESS IN HEALTHY CHILDREN
LAIV and TIV have been extensively evaluated for safety and efficacy in children aged > 6mo for whom the
vaccine is currently licensed for use. A literature search for seasonal influenza vaccine effectiveness in children
identified 14 systematic reviews [13, 27, 169, 206-216] that meta-analysed up to 47 studies most of which
were from High Income Countries. Most studies included in the reviews evaluated laboratory-confirmed
influenza as the primary outcome separately for LAIV and TIV further stratified by antigenic match. A total of
13 studies including three unpublished – 8 RCTs, one cohort and 4 case controls, were identified from the
tropics [180, 195, 217-227]. One review [27] that focused on VE in Low and Middle Income Countries included
12 studies on healthy children of which six were from the tropics and subtropics. For details refer to Appendix
F. Table 5 summarizes the VE against influenza related adverse outcomes in healthy children.
Influenza-like illness
The pooled efficacy for both LAIV and TIV from different reviews against ILI or ARI varied from 31% – 45% in
High Income Countries. This compared well with the 36% and 27% efficacy for LAIV and TIV respectively in Low
and Middle Income Countries [27]. The pooled efficacy against ILI with a poor antigenic match between the
vaccine strain and the circulating virus was 32% (95% CI: 27 – 36). It increased to 41% (95% CI: 31 – 49) in the
presence of a good antigenic match [212]. The vaccine efficacy against ILI ranged widely from 8% to 85% in
two tropical studies from China [195, 218].
Laboratory confirmed influenza
In High Income Countries the overall vaccine efficacy in preventing laboratory-confirmed influenza in healthy
children ranged between 67% – 74% [209, 212, 213]. In contrast, vaccine efficacy varied widely from 20% – 77%
in Low and Middle Income Countries from the tropics [180, 223, 224, 226, 227].
In High Income Countries, the pooled efficacy varied from 62% – 83% [169, 206, 207, 211-213] and 48% – 67%
[206, 207, 211-213] for LAIV and TIV respectively. The pooled efficacy for LAIV (72%, 95% CI: 65 – 77) and for
TIV (81%, 95% CI: 58 – 92) seen in Low and Middle Income Countries was comparable with that seen in High
Income Countries [27]. In contrast, vaccine efficacy for LAIV (range: 64% – 72%) [219-221] and for TIV (range:
33% – 62%) was lower in individual studies from Low and Middle Income Countries from the tropics. In both
high and low income settings, the LAIV was more efficacious than TIV in preventing laboratory-confirmed
influenza in healthy children. However, new observational data from the Flu Vaccine Effectiveness Network
unexpectedly showed no effect of the LAIV against the A(H1N1)pdm influenza virus when compared with the
inactivated influenza vaccine in children aged 2 – 8y [228].
Results
41
In High Income Countries, the pooled efficacy in the presence of a good antigenic match between the vaccine
strain and the circulating virus (range 61% – 88% and 48% – 81% for LAIV and TIV respectively) was higher than
for a poor antigenic match (range 60% – 87% and 49% – 56% for LAIV and TIV respectively) [207, 215] except in
two reviews [208, 212]. In Low and Middle Income Countries from the tropics, the vaccine efficacy in the
presence of a good antigenic match was comparable (range for LAIV: 70% – 78%) [219-221] with that for High
Income Countries.
In High Income Countries, the pooled efficacy increased from 58% with one dose to 75% with two doses of
LAIV [210]. A similar increase was also seen for LAIV and TIV in the Low and Middle Income Countries from the
tropics [219, 225] though one study from China showed a significant protective effect only after two doses of
TIV [223]. The protection persisted into the second year without re-vaccination [219] whereas there was no
protective effect of the vaccine at the end of one year [224].
In High Income Countries, the pooled efficacy against influenza A virus ranged widely between 31% – 91%
whereas the efficacy was 45% against influenza B infection [214]. In contrast the efficacy against influenza A
(range: 25% – 57%) and influenza B (range: no effect – 50%) was lower in Low and Middle Income Countries
from the tropics [217, 218].
Herd effect following vaccination of children
In High Income Countries, vaccinating children with seasonal influenza vaccine provided up to 30% protection
against ARI amongst family members [216, 229, 230]. One RCT showed a significant protection of 61% against
laboratory-confirmed influenza amongst contacts [231]. This was similar to the efficacy of 61% (6 – 85) seen in
a RCT from Sao Paulo, Brazil against laboratory-confirmed influenza amongst household contacts [232].
The majority of the studies that were included for meta-analysis in the systematic reviews, after quality
appraisal, were from High Income Countries. Though the vaccine efficacy studies of LAIV and TIV with and
without good antigenic match from high and Low and Middle Income Countries were comparable, the vaccine
effectiveness varied widely in Low and Middle Income Countries from the tropics.
VACCINE EFFECTIVENESS IN HEALTHY ADULTS
Healthy adults excepting healthcare professionals and pregnant women are not considered high priority for
immunization against seasonal influenza. A literature search for efficacy and effectiveness studies of the
seasonal influenza vaccine in healthy adults identified seven systematic reviews that meta-analysed between
10 to 46 studies predominantly from High Income Countries [13, 27, 169, 207, 215, 233, 234]. Most studies
included in the reviews evaluated laboratory-confirmed influenza as the primary outcome separately for LAIV
and TIV and further stratified by antigenic match. A total of eight studies including one unpublished, one RCT,
three cohorts and three case controls, were identified from Low and Middle Income Countries in the tropics
[195, 235-240]. All these six studies evaluated efficacy of TIV. One review [27] that focused on VE in Low and
Middle Income Countries included 10 studies on healthy adults of which five were from the tropics and
subtropics. For details refer to Appendix G. Table 5 summarizes the VE against influenza related adverse
outcomes in healthy adults.
Influenza-like illness
In High Income Countries, the pooled vaccine efficacy against ILI was 10% for LAIV [233] and ranged from 20%
– 69% for TIV [169, 233, 234]. The pooled vaccine efficacy of 62% (45 – 73) for TIV in Low and Middle Income
Countries [27] was comparable to that in High Income Countries. The vaccine efficacy for TIV ranged from 39%
– 73% in individual studies from the Low and Middle Income Countries in the tropics [235-238].
Results
42
Laboratory confirmed influenza
In High Income Countries, the pooled vaccine efficacy for TIV was higher (range: 57% – 80%) when there was a
good antigenic match compared to a poor match (range: 44% – 52%) [207, 215, 233, 234]. The pooled efficacy
against laboratory-confirmed influenza for TIV irrespective of antigenic match ranged from 59% – 61% [169,
207, 233]. In contrast, the pooled vaccine efficacy against laboratory-confirmed influenza for TIV was high at
82% (61 – 92) in Low and Middle Income Countries [27]. Only three studies from the tropics evaluated
laboratory-confirmed influenza as the outcome. The vaccine effectiveness (all ages) varied between no effect
to 67% in different influenza seasons in South Africa [239, 240]. The study from Singapore showed a high
efficacy of 84%, 33% and 84% against the pandemic influenza virus, influenza A(H3N2) virus and influenza B
virus infection respectively [238]. In contrast, the pooled efficacy from a review that analysed 34 RCTs (five
from the tropics) was lower for TIV at 64% and 52% against influenza A and B infection respectively [215].
The majority of the studies that were included for meta-analysis in the systematic reviews, after quality
appraisal, were from High Income Countries. There were no studies from Low and Middle Income Countries in
the tropics that evaluated the efficacy of LAIV. The vaccine efficacy for TIV in Low and Middle Income
Countries from the tropics appeared to be at the lower end of the range of vaccine efficacy seen in High
Income Countries.
VACCINE EFFECTIVENESS IN PREGNANT WOMEN
Maternal immunization with TIV is a safe and cost-effective strategy to reduce the risk of influenza related
complications in mothers and also offers indirect protection to the new born till they are 6mo old, an age
which has a significant influenza disease burden, yet for whom the vaccine is not licensed for use [241]. There
have been no RCTs to assess the safety of LAIV or adjuvant TIV or efficacy in preventing maternal or neonatal
disease. TIV is recommended for pregnant women during the influenza season in several High Income
Countries including Australia, Canada, United Kingdom and the United States [242]. TIV in pregnancy reduces
the influenza disease burden amongst pregnant women as well as in the new born through breast milk and
trans-placental transfer of maternal antibodies [243, 244].
The WHO recommends that pregnant women should have the highest priority for seasonal influenza
vaccination [3]. Though TIV has been administered to millions of pregnant women in developed countries
without safety concerns, few studies have looked at its efficacy and effectiveness in preventing adverse
outcomes in the mother, foetus and infant. A literature search for seasonal influenza vaccine effectiveness in
pregnant women and their new born identified eleven systematic reviews [13, 241, 242, 245-252] that
reviewed a total of 13 studies (RCTs – 2, cohorts – 10 and case control – 1) of which the sole study from the
tropics (a RCT) was from Bangladesh [253]. Two recent reviews [245, 248] identified three additional ongoing
RCTs on efficacy of TIV in the tropics (Bangladesh, Nepal and Mali) [254-256] and one RCT amongst HIV-
infected pregnant and non-HIV pregnant women in South Africa which was published recently [257]. For
details refer to Appendix H.
Table 5 summarizes the VE against influenza related adverse outcomes in mothers and infants following
maternal immunization with TIV. Adverse outcomes in mothers and their new born assessed by VE studies
following maternal immunization with TIV varied. Most studies from High Income Countries from temperate
climates used cohorts or case control design to assess VE against clinical end-points such as ILI or ARI [258-261].
None of these studies from High Income Countries assessed VE against laboratory-confirmed influenza in
either mothers or their infants – instead some studies assessed VE using serological correlates for protection
against influenza [262-267].
Results
43
VE against laboratory-confirmed influenza and clinical ILI in mothers:
Laboratory-confirmed influenza was significantly reduced in both healthy mothers (VE: 50%, 95%CI: 15 – 71)
and HIV infected mothers (VE: 58%, 95%CI: 0.2 – 81) following maternal immunization with TIV in South Africa
[257]. The vaccine significantly reduced the risk of clinical ILI in healthy mothers (VE: 36%, 95%CI: 4 – 57) in
Bangladesh [253] but had no effect in reducing clinical ILI in both healthy and HIV-infected mothers in South
Africa. Similarly, the vaccine had no significant effect in reducing clinical ILI or ARI in mothers in the United
States [258, 261] except in one study (VE: 44%, 95%CI: 9 – 65) [264].
VE against laboratory-confirmed influenza and clinical ILI in new born infants of women vaccinated in
pregnancy:
Seasonal influenza vaccination of healthy pregnant women significantly reduced the risk of laboratory-
confirmed influenza in the infant – VE varied from 49% (95%CI: 12 – 70) in South Africa to 63% (95%CI: 5 – 85)
in Bangladesh. However, this effect (VE – 27%) was not significant for infants born to HIV-infected mothers.
The vaccine given to healthy pregnant women significantly reduced the risk of clinical ILI in their infant (VE:
29%, 95%CI: 7 – 46) in Bangladesh but had no effect in reducing clinical ILI in the infant of both healthy and
HIV-infected women in South Africa. Similarly, the vaccine had no significant effect in reducing clinical ILI or
ARI in infants of mothers who received the vaccine in pregnancy in the United States [258, 260].
VE against adverse new born outcomes of women vaccinated in pregnancy:
VE against both prematurity and intra-uterine growth retardation in the United States varied from no effect
[268, 269] to 72% (95%CI: 26 – 89) when pregnant women were vaccinated during peak influenza season [270].
Maternal immunization showed no significant effect against prematurity or intra-uterine growth retardation in
Bangladesh [253].
A study based on seasonal influenza data from the US, models the timing of seasonal influenza vaccination on
effectiveness. Infants and mothers benefited the most when pregnant women were vaccinated within four
weeks of vaccine availability. Once all women who were pregnant at time of vaccine availability were
vaccinated, vaccination of newly pregnant women benefited the mothers but not their infants. The study
predicted reduction in VE when vaccination was delayed beyond November [271]. Such modelling studies
need to be tested in tropical settings that lack distinct influenza seasons.
Earlier studies were suggestive though not definitive of the benefits of maternal immunization with TIV to
reduce influenza related morbidity in pregnancy and in the new born. These observational studies that were
based on retrospective cohorts and case control designs used clinical ILI or ARI as end-points and were sub-
optimal to assess VE. However, recent evidence from RCTs from Bangladesh and South Africa [253, 257]
provide clear evidence that maternal immunization can be an effective strategy in low-resource settings to
combat the significant influenza related morbidity during pregnancy and in the new born. In the tropics and
sub-tropics, various influenza virus types and subtypes may circulate for most part of the year thereby
potentially exposing every pregnancy and the new born to the risk of influenza infection all year round.
Introducing the most recent TIV in the antenatal immunization program year-round may be the most effective
strategy to reduce influenza related morbidity in pregnancy and in infants in tropical settings.
VACCINE EFFECTIVENESS IN HIGH RISK INDIVIDUALS
High risk individuals comprised those with underlying conditions such as COPD, coronary heart disease,
diabetes, cancer and immunocompromised conditions that put them at greater risk for developing
complications if infected by the influenza virus or those individuals (e.g. healthcare professionals) who had a
Results
44
greater exposure to and / or had greater possibility to transmit the infection to other high risk individuals such
as patients, elderly etc. For details refer to Appendix I. Table 5 summarizes the VE in high risk individuals.
COPD patients
A literature search for seasonal influenza vaccine efficacy in COPD patients identified a Cochrane review [272]
that included eleven RCTs (ten of which were from High Income Countries). A total of three studies were
identified from Low and Middle Income Countries (India, Thailand) in the tropics [273-275].
In High Income Countries, the pooled efficacy estimate (VE – 11%) against ARI was not significant. In contrast,
vaccine efficacy against ARI ranged from 60% – 85% amongst COPD patients from Low and Middle Income
Countries in the tropics [274, 275].
Only one study from the tropics evaluated laboratory-confirmed influenza as the outcome [273]. The VE
against laboratory-confirmed influenza amongst COPD patients in Thailand was 71% that was comparable to
the pooled vaccine efficacy estimate of 81% (95% CI: 52 – 93) from High Income Countries.
The vaccine was 72% effective in preventing ARI related hospitalization amongst COPD patients in India
comparable to the pooled efficacy estimate seen in High Income Countries [274]. Seasonal influenza
vaccination had no effect on mortality amongst COPD patients [272].
Coronary heart disease patients
A literature search for seasonal influenza vaccine efficacy in coronary heart disease patients identified a
Cochrane review [276] that included three studies (one from the tropics). A total of two studies (Argentina and
Thailand) were identified from Low and Middle Income Countries in the tropics [277-279].
The 66% (95% CI: 29 – 83) efficacy of the vaccine in preventing coronary heart disease related mortality
amongst coronary heart disease patients in Argentina was similar to the pooled efficacy estimate of 61% (95%
CI: 23 – 80) for High Income Countries [276, 278]. However, the Thai study did not show any significant
protective effect against coronary heart disease related mortality [277].
HIV infected and other immunocompromised patients
A literature search for seasonal influenza vaccine efficacy in HIV infected patients identified two systematic
reviews that included up to four studies, all from High Income Countries [280, 281]. One study amongst HIV
infected adults from South Africa was additionally identified [282].
The vaccine efficacy for TIV of 76% (95% CI: 9 – 96%) amongst South African HIV infected adults against
laboratory-confirmed influenza was higher than the efficacy of 27% – 78% seen in High Income Countries. The
South African study did not show any significant protective effect against clinical ARI [282]. In another study
from Brazil amongst recipients of bone marrow transplants, seasonal influenza vaccination showed a
protective effect of 80% against laboratory-confirmed influenza infection [283].
Healthcare professionals
A literature search for efficacy of seasonal influenza vaccination of healthcare professionals who care for the
elderly who live in long-term care institutions identified one Cochrane review that included three RCTs, all of
which were from High Income Countries [284]. In addition one study from Singapore evaluated the VE in
healthcare professionals providing care to hospital patients for protecting themselves from influenza related
adverse outcomes [285].
Results
45
Vaccination of healthcare professionals who took care of elderly residents living in long-term care institutions
in High Income Countries did not show any protective effect against laboratory-confirmed influenza and
influenza related hospitalization or mortality in the elderly who received care from the healthcare
professionals [284]. On the other hand, the Singapore study showed a vaccine efficacy (in the event of a good
antigenic match) of 51% (95% CI: 34 – 63) against ILI amongst healthcare professionals involved in providing
care to patients in hospitals. This protective effect was not significant if the antigenic match was poor [285].
Pilgrims
The annual congregation of thousands of pilgrims (mostly from Low and Middle Income Countries in the
tropics) in Saudi Arabia for Hajj during the last month of the Islamic calendar is thought to possibly facilitate
spread of influenza globally. Some countries in the tropics prioritize Hajj pilgrims to target seasonal influenza
vaccination. A literature search for efficacy of seasonal influenza vaccination of pilgrims traveling to Saudi
Arabia for Hajj identified two studies from Pakistan and Malaysia [286, 287]. The vaccine efficacy against ILI
ranged between 38% – 77% with a pooled efficacy of 72% (95% CI: 59 – 80) [27].
Table 5: Seasonal influenza vaccine effectiveness in the tropics
Outcome Pooled efficacy from reviews in High Income Countries
Pooled efficacy from reviews in Low and Middle Income Countries
Vaccine efficacy from individual studies in Low and Middle Income Countries in tropics
Elderly ILI 36 – 56% 4 – 59% 0 – 76% Laboratory-confirmed influenza 50 – 77% 43 – 58% 0 – 42% Pneumonia 30 – 53% 0 – 43% Hospitalization - influenza related - all-cause
25 – 33% 50%
No effect No effect
31 – 77%
1
--- Mortality - influenza related - all cause
8 – 30% 36 – 68%
20 – 53%
1
24 – 44%1
Children ILI 31 – 45% LAIV: 36%
TIV: 27% 8 – 85%
Laboratory-confirmed influenza - overall - LAIV - TIV - LAIV good match - TIV good match - LAIV poor match - TIV poor match - 1 dose 2 doses - influenza A - influenza B
67 – 74% 62 – 83% 48 – 67% 61 – 88% 48 – 81% 60 – 87% 49 – 56% 58% 75% 31 – 91% 45%
72% 81%
20 – 77% 64 – 72% 33 – 62% 70 – 78% 58% 74%
2
25 – 57% 0 – 50%
Healthy adults ILI - LAIV - TIV
10% 20 – 69%
62%
39 – 73%
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46
Outcome Pooled efficacy from reviews in High Income Countries
Pooled efficacy from reviews in Low and Middle Income Countries
Vaccine efficacy from individual studies in Low and Middle Income Countries in tropics
Laboratory-confirmed influenza - TIV good match - TIV poor match - TIV any match - TIV influenza A - TIV influenza B
57 – 80% 44 – 52% 59 – 61% 64% 52%
82%
50 – 59% H1N1pdm – 84% H3N2 – 33% 84%
Pregnant women ILI (mother) - healthy mothers - HIV infected mothers
0 – 44%
0 – 36% No effect
Laboratory-confirmed influenza (mother) - healthy mothers - HIV infected mothers
50% 58%
ILI (infant) - healthy mothers - HIV infected mothers
No effect
0 – 29% No effect
Laboratory-confirmed influenza (infant) - healthy mothers - HIV infected mothers
49 – 63% 27%
3
Preterm / IUGR (infant) 0 – 72% No effect
High risk individuals COPD patients - ARI - Laboratory-confirmed influenza - Hospitalization (ARI)
11%
3
81% 67%
3
60 – 85% 71% 72%
Coronary heart disease patients - Coronary heart disease mortality
61%
0 – 66%
HIV infected patients - ARI - Laboratory-confirmed influenza
27 – 78%
No effect 76%
Healthcare professionals No effect on laboratory-confirmed influenza, hospitalization or mortality in elderly who received care from healthcare professionals
51% against ILI if good antigenic match; no effect if poor antigenic match
Pilgrims - ILI
38 – 77% Pooled efficacy – 72%
1 No effect in 2 studies
2 One study showed protective effect only after two doses
3 Not significant at 5% significance level
Results
47
CRITICAL KNOWLEDGE GAPS
Vaccine effectiveness studies can provide additional information in hindsight to the vaccine composition
selection process. Even as an increasing number of Low and Middle Income Countries from the tropics and
sub-tropics introduce influenza into their immunization program, the evidence base for vaccine efficacy and
effectiveness face critical knowledge gaps in these settings. First, though recent efforts review data from Low
and Middle Income Countries [27, 85, 288] or for certain risk groups like pregnant women in Low and Middle
Income Countries [241], most studies included in these reviews provide data on safety, immunogenicity and
disease burden and lack information on vaccine effectiveness and efficacy. Second, the majority of VE studies
were performed in urban settings in middle income countries. Third, the high prevalence of underlying
infections, malnutrition, tuberculosis, limited access to antibiotics for treatment of secondary bacterial
infections in Low and Middle Income Countries may increase the risk of influenza related complications or may
influence vaccine effectiveness. However, no studies assessed vaccine effectiveness in patients with
tuberculosis or malnourished individuals. Fourth, though children and the elderly are at high risk of severe
influenza outcomes, few studies from Low and Middle Income Countries in the tropics assessed severe
outcomes such as influenza-related hospitalization or mortality. Fifth, almost a third of the studies from Low
and Middle Income Countries were observational and prone to bias due to self-assessment of the influenza
outcomes. Sixth, only a few studies from Low and Middle Income Countries evaluated vaccine effectiveness
stratified by antigenic match or reported data on vaccine coverage, influenza incidence and seasonality. Lastly,
waning immunity in the months following vaccination may decrease vaccine benefits in tropical and sub-
tropical settings where influenza activity prevails all year round.
Discussion
48
DISCUSSION
The tropics where an estimated 41% of the world’s population resides, is an important region that faces a
similar if not higher burden of influenza [289-291]. This systematic review is the first to present a
comprehensive global overview of experiences of tropical and subtropical countries in the use of seasonal
influenza vaccine in the context of the WHO recommendations for vaccine composition for the northern and
southern hemispheres.
Main findings
Latin America and the Caribbean have led the introduction of seasonal influenza vaccine into their
immunization campaigns since the 1990s. Large parts of sub Saharan Africa and the Indian subcontinent are
yet to formulate national policies against seasonal influenza though the vaccine is available through the private
sector in many countries in the region. Targeted vaccination remains the main strategy to minimize the impact
of influenza in high risk individuals for more than four decades even as High Income Countries expand their
policies to vaccinate all persons aged > 6mo unless medically contraindicated [26]. National policies
recommended vaccination of pregnant women against seasonal influenza in countries in Latin America and the
Caribbean but not yet in the South and Southeast Asia.
Historically countries in the tropics selected the WHO recommended NH or SH vaccine formulation largely
based on whether they were situated north or south of the equator and timed their vaccination campaigns
according to when the respective vaccine formulation became available irrespective of the timing of influenza
epidemics in their country. Recent evidence indicated that in many such instances, the vaccination campaign
occurred too late to cover the influenza season or too early to offer optimal protection for the upcoming
influenza season. Recent evidence suggested that vaccination campaigns in many tropical countries (in both
hemispheres), where peak influenza activity frequently coincides with the rainy season, should be timed with
the availability of the SH vaccine formulation. Several countries (e.g. Cuba, El Salvador, Guatemala and the
Philippines) situated in the northern hemisphere that switched from a NH to a SH vaccine formulation in
recent years need to be evaluated for vaccination impact. Recent studies from Brazil, China and India indicated
that a staggered approach that allows vaccination at different times in the year to cover multiple influenza
activity periods using the most recent vaccine formulation may be more appropriate for countries with a large
latitudinal spread.
The addition of a separate recommendation for the SH in 1998 by the WHO improved the antigenic match for
the influenza viruses from 31% to 59% in the southern hemisphere and made it comparable with that in the
NH [93]. Despite the inherent limitations in the vaccine composition selection process, the vaccine – virus
match has averaged 55 – 60% in both hemispheres. Simulation modelling of antigenic change suggested that
the vaccine selection had historically matched well with the circulating virus strains in the subsequent season
for which the vaccine was targeted. The genetic / antigenic match between the vaccine and the circulating
virus varied in different seasons with a better match seen for influenza B viruses except in 2002 when the
B/Victoria lineage re-emerged. In the years of mismatch, there was typically a one-season delay before the
circulating virus was covered by the influenza vaccine. Virus strains persisted locally or were re-seeded by
international travellers and consequently matched poorly with the vaccine strain.
Overall vaccination coverage was low in most parts of Africa and Asia. In contrast, coverage in Latin America
and the Caribbean countries was higher than even among High Income Countries. Higher coverage was not
correlated with the level of economic development but uptake improved when the vaccine was offered free
through the public sector [25]. Increasing seasonal influenza coverage in the Low and Middle Income Countries
in the tropics faces several challenges. First, competing health agendas, lack of information on influenza
disease burden, vaccine effectiveness and impact, a poor definition of individuals at risk of influenza-related
complications, and a low perceived severity of influenza disease, places seasonal influenza vaccination low on
Discussion
49
the list of a country’s public health priorities [292]. Second, a lack of a cogent immunization policy, high vaccine
costs coupled with limited resources for supply and delivery along with public adverse opinions against
vaccination impede wider usage of the vaccine in the Low and Middle Income Countries from the tropics. Third,
the low vaccine demand and poor coverage further contributes to the already poor or absent vaccine
production capacity to make sustainability a major challenge for the influenza vaccine industry in Low and
Middle Income Countries.
The benefit of influenza vaccines has been questioned recently by several studies – the vaccine was about 59%
effective in adults – far lower than the 70 – 90% previously believed – with at best a 53% reduction in mortality
in the elderly in the tropics. Vaccine effectiveness against laboratory confirmed influenza varied widely in Low
and Middle Income Countries in the tropics and subtropics amongst the elderly (no effect – 42%) and children
(20 – 77%) based on antigenic match. While the VE appears modest in comparison to other vaccines, the direct
effect of influenza vaccination in averting hospitalizations and deaths may be substantial as was seen in the
United States [293].
The Global Action Plan for influenza vaccines provides for expanding influenza vaccine production in Low and
Middle Income Countries in the tropics and subtropics to ensure greater equity, sustainability and public
health benefits [64, 294]. Furthermore, the wide-scale manufacturing, supply and use of seasonal influenza
vaccine globally is inextricably linked with pandemic preparedness [56]. Pandemic and seasonal influenza
vaccines share inherently similar infrastructure, manufacturing and regulatory processes. To be able to
respond quickly to a pandemic, there must be a high capacity to produce seasonal influenza vaccine. Only then
can the production capacity be adapted and scaled up quickly to meet the urgent demand of a pandemic
situation. However, global demand for seasonal influenza vaccination is low and from an economic perspective,
investment in further expanding production capacity is difficult to justify without a concomitant demand and
market expansion to use all the supply [22]. Sustainable demand also serves as a stimulus to invest in research
and adopting newer vaccine technologies to enhance vaccine production, immunogenicity and efficacy.
Critical gaps in evidence
Understanding the temporal and geographic circulation of the influenza is important to develop and apply
vaccination control strategies. As Low and Middle Income Countries consider introducing seasonal influenza
vaccine into their national policy and program, their surveillance systems need to be strengthened to better
understand the epidemiology and seasonality of influenza to enable evidence-based decision on when to
vaccinate, which groups to target and so on. Countries need to regularly monitor the antigenic characteristics
of the influenza viruses that circulate every season to ensure that an optimal selection of the vaccine
formulation occurs. This needs to be supplemented by routine monitoring of vaccine effectiveness each
influenza season in the tropics and subtropics. Additionally, gaps in knowledge remain about vaccination
delivery and regulatory systems, marketing and vaccine uptake at the country-level [64].
Limitations
Our review though systematic was subject to several methodological and substantive limitations. First, we
excluded articles in languages other than English. However we took efforts to search regional databases such
as LILACS especially for articles in Spanish language as countries from Latin America and Caribbean have
contributed substantially to influenza research in the recent past. Another review of influenza (seasonal and
pandemic) vaccine effectiveness in Low and Middle Income Countries identified 132 articles of a total of 361,
in languages other than English [27]. More than 75% of these non-English language articles were from Russia,
another 15 articles were from Romania, countries that were outside the scope of our review. Nevertheless,
our review may be limited to some extent by the exclusion of potential studies from China.
Discussion
50
Second, there was wide disparity in the geographic distribution of studies. For example, of the 26 studies from
the tropics and subtropics of VE amongst the elderly, eleven (including Brazil (9)) were from countries in Latin
America and the Caribbean, twelve from Asia Pacific (including China, Hong Kong SAR (4), China – Province of
Taiwan (2), Thailand (3)) and three from Africa (all from South Africa). Most of sub-Saharan Africa and the
Middle East were not represented in the review. Large populous countries like Bangladesh, India, Indonesia,
Pakistan and Sri Lanka were relatively under-represented in the review.
Third, most of the evidence from the tropics and subtropics came from urban settings and may not adequately
represent rural populations.
Fourth, the seasonal influenza vaccination scenario in the tropics and subtropics is dynamically evolving.
Several seasonal influenza studies initiated in Low and Middle Income Countries in the recent past are at
various stages of implementation and their results are not yet available for dissemination.
Fifth, there was a wide heterogeneity in terms of study design, study population groups, case definitions used
for influenza and related complications, the limited years of surveillance data, and the ecologic diversity of the
study settings. This may affect the extent but not the overall trend of comparability.
Sixth, the seasonal influenza vaccination coverage estimated by various studies was potentially biased. Studies
based on the seasonal influenza vaccination databases used the proportion of seasonal influenza vaccine doses
distributed per 1000 population as a crude estimate for vaccination coverage. This may overestimate coverage
to the extent of unaccounted wastage, non-usage or return of unused vaccines. Moreover it was at times
unclear if the denominator used to estimate the coverage referred to the general population or to the high risk
population groups targeted for vaccination in a country. Furthermore, the coverage estimated from the IFPMA
database did not account for the seasonal influenza vaccine distributed by non-IFPMA vaccine manufacturers
that accounts for about 21% of the total seasonal influenza vaccines distributed predominantly to Low and
Middle Income Countries in the tropics and subtropics [49, 56]. Nevertheless, we feel that the coverage
though crude and possibly biased, is still indicative of global trends. Except in a few instances, the coverage as
estimated from different data sources such as the UNICEF – WHO Joint Reporting Form, the global influenza
vaccine surveys and the data from IFPMA were reasonably correlated.
Conclusion
51
CONCLUSION
The bulk of scientific evidence on vaccine use and effectiveness in the tropics comes from Latin America and
the Caribbean and Asia with large parts of Africa underrepresented. As more and more countries in the tropics
and subtropics consider vaccinating their populations at risk for influenza, their capacity to make critical
decisions on which vaccine to use, when to vaccinate, how much health benefit to expect inter alia, is greatly
restricted by the limited evidence that is available on the epidemiology and virology of the viruses that
circulate in their regions. Newly emerged evidence suggests that the vaccine formulation recommended by the
WHO for the northern and southern hemispheres and the time at which it becomes available may not be
appropriate for some tropical countries when this decision is based solely on the country’s geographical
location. Countries that are situated in the tropics especially those nearer to the equator, countries with large
latitudinal spread, countries with varying seasonality, countries with influenza identifiable throughout the year,
may need to consider alternate approaches in their vaccination timing based on their local seasonality pattern
and the availability of the most recent WHO recommended formulation. There probably is no ‘one size that fits
all’ strategy for influenza vaccination. Influenza disease and virological surveillance need to be strengthened to
enable a better prediction and selection of the biannual updates for the influenza vaccine composition. Future
research is needed to evaluate the impact of alternate strategies for vaccination timing with the WHO
recommended vaccine formulations that have the most recent vaccine virus strains, for countries in the tropics
and subtropics.
Acknowledgements
52
ACKNOWLEDGEMENTS
This review was funded through a grant no. OPP1084574 from the Bill & Melinda Gates Foundation. The author
would like to acknowledge the support of Eduardo Azziz-Baumgartner, Joshua Mott, Fatimah Dawood, Katie
Lafond, Kimberly Lindblade, Gina Samaan and Marc-Alain Widdowson of the Centers for Disease Control and
Prevention, US for sharing data from their ongoing work on influenza seasonality. Thanks are also due to Jorge
Jara, Guatemala and Mark Katz for sharing some of their preliminary findings of ongoing work. Thanks are due
to Alba Maria Ropero Alvarez and Nathalie El Omeiri of PAHO, Kimberly Fox and Jinho Shin of WPRO, Pushpa
Wijesinghe of SEARO, Bartholomew Dicky Akanmore of AFRO and Nadia Abd El-Aziz Teleb of EMRO, and to all
the Member States for participating in the Survey of Vaccine Use in the Tropics. Thanks are due to my
colleagues Oona Bilbao and Giovanna Gutierrez of WHO HIP department for the Spanish translation of the
Survey. I also acknowledge the sharing of information and support given by Laure Dumolard, Erin Sparrow
and Joachim Hombach of the WHO. I value the summary data on seasonal influenza vaccine distribution
shared by Margarita Xydia-Charmanta of IFPMA.
I gratefully acknowledge the critical feedback on the review manuscript provided by John Paget of NIVEL,
Netherlands, Justin Ortiz and Philipp Lambach from WHO IVB, Jan Hendriks from WHO PHI, and Theodore
Ziegler, Julia Fitzner, Katelijn Vandemaele, Terry Besselaar and Wenqing Zhang of the WHO Global Influenza
Program for their critical feedback on the review. Lastly, I would like to thank Maja Lievre for creating the
maps and Hannah Moak of George Washington University, DC for screening for eligibility all the literature that
was retrieved during the literature search.
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291. Li, C.K., B.C. Choi, and T.W. Wong, Influenza-related deaths and hospitalizations in Hong Kong: a subtropical area. Public Health, 2006. 120(6): p. 517-24.
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Appendix
69
APPENDIX
Appendix A: Strategies and keywords used for literature search
Set Query Results
#1 “influenza vaccines”[mesh] AND (“seasonal” [tiab] OR "seasons"[mesh] OR “seasonal influenza vaccination”[tiab])
1982
#2 “Tropics”[tiab] OR “Asia”[mesh] OR “Africa”[mesh] OR “Pacific”[tiab] OR “Latin America”[mesh] OR “Tropical”[tiab] OR “subtropical”[tiab] OR “Africa South of the Sahara”[mesh] OR “sub-Sahara”[tiab] OR “AFRO”[tw] OR “Algeria”[tw] OR “Angola”[tw] OR “Benin”[tw] OR “Botswana”[tw] OR “Burkina Faso”[tw] OR “Burundi”[tw] OR “Cameroon”[tw] OR “Cabo Verde”[tw] OR “Central African Republic”[tw] OR “Chad”[tw] OR “Côte d'Ivoire”[tw] OR “Congo”[tw] OR “Equatorial Guinea”[tw] OR “Eritrea”[tw] OR “Ethiopia”[tw] OR “Gabon”[tw] OR “Gambia”[tw] OR “Ghana”[tw] OR “Guinea”[tw] OR “Guinea-Bissau”[tw] OR “Kenya”[tw] OR “Liberia”[tw] OR “Madagascar”[tw] OR “Malawi”[tw] OR “Mali”[tw] OR “Mauritania”[tw] OR “Mauritius”[tw] OR “Mozambique”[tw] OR “Namibia”[tw] OR “Niger”[tw] OR “Nigeria”[tw] OR “Rwanda”[tw] OR “Senegal”[tw] OR “Sierra Leone”[tw] OR “South Africa”[tw] OR “Togo”[tw] OR “Uganda”[tw] OR “Tanzania”[tw] OR “Zambia”[tw] OR “Zimbabwe”[tw] OR “EMRO”[tw] OR “Afghanistan”[tw] OR “Israel” [tw] OR “Bahrain”[tw] OR “Djibouti”[tw] OR “Egypt”[tw] OR “Iran”[tw] OR “Iraq”[tw] OR “Jordan”[tw] OR “Kuwait”[tw] OR “Libya”[tw] OR “Morocco”[tw] OR “Oman”[tw] OR “Pakistan”[tw] OR “Qatar”[tw] OR “Saudi Arabia”[tw] OR “Somalia”[tw] OR “Sudan”[tw] OR “Tunisia”[tw] OR “United Arab Emirates”[tw] OR “Yemen”[tw] OR “PAHO”[tw] OR “Anguilla”[tw] OR “Antigua”[tw] OR “Barbuda”[tw] OR “Argentina”[tw] OR “Bahamas”[tw] OR “Barbados”[tw] OR “Belize”[tw] OR “Venezuela”[tw] OR “Bolivia”[tw] OR “Brazil”[tw] OR “Cayman Islands”[tw] OR “Chile”[tw] OR “Colombia”[tw] OR “Costa Rica”[tw] OR “Cuba”[tw] OR “Dominica”[tw] OR “Dominican Republic”[tw] OR “Ecuador”[tw] OR “El Salvador”[tw] OR “Grenada”[tw] OR “Guatemala”[tw] OR “Guyana”[tw] OR “Haiti”[tw] OR “Honduras”[tw] OR “Jamaica”[tw] OR “Mexico”[tw] OR “Montserrat”[tw] OR “Netherland Antilles”[tw] OR “Nicaragua”[tw] OR “Panama”[tw] OR “Paraguay”[tw] OR “Peru”[tw] OR “Saint Kitts and Nevis”[tw] OR “Saint Lucia”[tw] OR “Saint Vincent ”[tw] OR “Grenadines”[tw] OR “Suriname”[tw] OR “Trinidad”[tw] OR “Tobago”[tw] OR “Turks”[tw] OR “Caicos”[tw] OR “Uruguay”[tw] OR “SEARO”[tw] OR “Bangladesh”[tw] OR “Bhutan”[tw] OR “India”[tw] OR “Indonesia”[tw] OR “Maldives”[tw] OR “Myanmar”[tw] OR “Nepal”[tw] OR “Sri Lanka”[tw] OR “Thailand”[tw] OR “Timor-Leste”[tw] OR “WPRO”[tw] OR “Brunei Darussalam”[tw] OR “Cambodia”[tw] OR “China”[tw] OR “Cook Islands”[tw] OR “Fiji”[tw] OR “French Polynesia”[tw] OR “Guam”[tw] OR “Hong Kong”[tw] OR “Kiribati”[tw] OR “Lao”[tw] OR “Malaysia”[tw] OR “Marshall islands”[tw] OR “Nauru”[tw] OR “New Caledonia”[tw] OR “Papua New Guinea”[tw] OR “Philippines”[tw] OR “Samoa”[tw] OR “Singapore”[tw] OR “Solomon islands”[tw] OR “Taiwan”[tw] OR “Tonga”[tw] OR “Vanuatu”[tw] OR “Viet Nam”[tw]
1248012
3 #1 AND #2 AND (“effectiveness”[tiab] OR “efficacy”[tiab]) 76
4 #1 AND #2 AND (“timing” [tiab] OR “composition” [tiab]) 17
5 #1 AND #2 AND “policy”[tiab] 12
6 #1 AND #2 AND (“campaign”[tiab] OR “coverage”[tiab] OR “uptake”[tiab]) 50
7 #1 AND #2 AND (“production” [tiab] OR “availability” [tiab] OR "manufacturing"[tiab] OR "manufacturer"[tiab])
25
Note: [tiab] – title abstract; [tw] – text word; [mesh] – medical subject heading;
Appendix
70
Appendix B: List of countries and territories in the tropics and subtropics included in the review
AFRO Algeria, Angola, Benin, Botswana, Burkina Faso, Burundi, Cabo Verde, Cameroon, Central African Republic, Chad, Congo (the), Côte d'Ivoire, Democratic Republic of the Congo, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius, Mozambique, Namibia, Niger, Nigeria, Rwanda, Senegal, Sierra Leone, South Africa, Togo, Uganda, United Republic of Tanzania, Zambia, Zimbabwe
EMRO Afghanistan, Bahrain, Djibouti, Egypt, Iran (Islamic Republic of), Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Pakistan, Qatar, Saudi Arabia, Somalia, Sudan, Syrian Arab Republic, Tunisia, United Arab Emirates, Yemen
PAHO Anguilla, Antigua and Barbuda, Argentina, Bahamas, Barbados, Belize, Bolivia (Plurinational State of), Brazil, Cayman Islands, Chile, Colombia, Costa Rica, Cuba, Dominica, Dominican Republic, Ecuador, El Salvador, Grenada, Guatemala, Guyana, Haiti, Honduras, Jamaica, Mexico, Montserrat, Netherland Antilles, Nicaragua, Panama, Paraguay, Peru, Saint Kitts and Nevis, Saint Lucia, Saint Vincent and the Grenadines, Suriname, Trinidad and Tobago, Turks and Caicos Islands, Uruguay, Venezuela (Bolivarian Republic of)
SEARO Bangladesh, Bhutan, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand, Timor-Leste
WPRO American Samoa, Brunei Darussalam, Cambodia, China, China, Hong Kong SAR, China – Province of Taiwan, Cook islands, Democratic People’s Republic of Korea, Fiji, French Polynesia, Guam, Kiribati, Lao People's Democratic Republic, Malaysia, Marshall islands, Nauru, New Caledonia, Niue, Palau, Papua New Guinea, Philippines, Samoa, Singapore, Solomon islands, Tonga, Vanuatu, Viet Nam
EURO Israel
Appendix
71
Appendix C: National policies of tropical and subtropical countries on seasonal influenza vaccination
Country National
Policy
Year introdu
ced Sector Free Children Elderly
Chronic illness
Healthcare
Professional
Pregnancy
Vaccine timing
Formulation
Climate region
1
Africa
Algeria no
private
yes
NH subtropics
Angola no
SH tropics
Benin no
private
NH tropics
Botswana no
private
SH tropics
Burkina Faso no
NH tropics
Burundi no
SH tropics
Cabo Verde no
NH tropics
Cameroon no
both
SH NH tropics
Central African Republic no
NH tropics
Chad no
NH tropics
Congo (the) no
private
yes
SH tropics
Côte d'Ivoire yes
both
yes yes yes yes yes NH NH tropics
Democratic Republic of the Congo
no
private
NH SH tropics
Djibouti no
both
NH tropics
Egypt yes 1999 both yes no no yes yes yes NH NH subtropics
Equatorial Guinea no
NH tropics
Eritrea no
NH tropics
Ethiopia no
NH tropics
Gabon no
SH tropics
Gambia no
NH tropics
Ghana no
NH tropics
Guinea no
NH tropics
Guinea-Bissau no
NH tropics
Appendix
72
Country National
Policy
Year introdu
ced Sector Free Children Elderly
Chronic illness
Healthcare
Professional
Pregnancy
Vaccine timing
Formulation
Climate region
1
Kenya no
both
SH NH tropics
Liberia no
NH tropics
Libya yes 2007
no no yes
NH subtropics
Madagascar no
both
SH SH tropics
Malawi no
SH tropics
Mali no
NH tropics
Mauritania no
NH tropics
Mauritius yes
both
yes yes yes yes yes SH SH tropics
Morocco no
both
yes yes yes yes yes NH NH subtropics
Mozambique no
SH tropics
Namibia no
SH tropics
Niger no
NH tropics
Nigeria no
NH tropics
Rwanda no
SH tropics
Senegal no
private no
NH NH tropics
Sierra Leone no
NH tropics
Somalia no
NH tropics
South Africa yes
both no yes yes yes yes yes SH SH subtropics
Sudan no
NH tropics
Tanzania, United Republic of no
SH tropics
Togo no
private
NH tropics
Tunisia no
NH subtropics
Uganda no
private
SH NH tropics
Zambia no
private
SH tropics
Zimbabwe no
private
SH tropics
Asia
Appendix
73
Country National
Policy
Year introdu
ced Sector Free Children Elderly
Chronic illness
Healthcare
Professional
Pregnancy
Vaccine timing
Formulation
Climate region
1
Afghanistan no
NH subtropics
American Samoa no 2003 both
yes yes yes yes yes NH SH tropics
Bangladesh no
private
NH subtropics
Bhutan no
NH subtropics
Brunei Darussalam yes 2010 both yes yes yes yes yes yes Both NH tropics
Cambodia no
private no
NH tropics
China no 1998 both no yes yes yes yes yes NH NH subtropics
China, Hong Kong SAR yes
yes yes yes yes yes yes
NH tropics
China, Province of Taiwan yes
both yes yes yes yes yes yes
NH subtropics
Cook Islands no
private no
SH SH tropics
Fiji no
private
SH tropics
French Polynesia yes 2002 both
no yes yes yes yes NH SH tropics
Guam yes 1996 both yes yes yes yes yes yes NH NH tropics
India no
private no
NH tropics
Indonesia yes 2009 both no no no no no no Hajj
SH tropics
Kiribati no
SH tropics
Korea, Democratic People's Republic
no
private
NH subtropics
Lao People's Democratic Republic
no
private no
yes yes yes NH NH tropics
Malaysia yes 1988 both no no yes no yes no All year SH NH tropics
Maldives yes
no no yes
NH tropics
Marshall islands yes 2002 both yes yes yes yes yes no Both NH tropics
Myanmar no
private
Jun-Aug
NH tropics
Nauru no
SH tropics
Nepal no
private
NH subtropics
New Caledonia yes 1994 both
no yes yes yes no NH SH tropics
Appendix
74
Country National
Policy
Year introdu
ced Sector Free Children Elderly
Chronic illness
Healthcare
Professional
Pregnancy
Vaccine timing
Formulation
Climate region
1
Niue yes 2013
no yes no
SH tropics
Pakistan no
NH subtropics
Palau yes 1996
no yes yes
NH tropics
Papua New Guinea no
SH tropics
Philippines no 2011 private no yes yes yes yes yes May-Dec NH-->SH NH tropics
Samoa no
no
SH tropics
Singapore yes
private no yes yes yes yes yes Dec-Feb Both NH tropics
Solomon islands no
SH tropics
Sri Lanka no
private no
NH tropics
Thailand yes 2004 both yes yes yes yes yes yes Jun-Aug SH NH tropics
Timor-Leste no
SH tropics
Tonga no
SH tropics
Vanuatu no
SH tropics
Viet Nam yes
private no yes yes yes yes no NH NH tropics
Latin America and the Caribbean
Anguilla yes 2005
yes
yes
NH NH tropics
Antigua and Barbuda yes 2007 both
yes yes
NH NH tropics
Argentina yes 1993 both yes yes yes yes yes yes Feb-Nov SH SH subtropics
Bahamas yes 2005 private
yes yes yes yes yes NH NH subtropics
Barbados yes 2006 both yes no yes yes yes no NH NH tropics
Belize yes 2008 both yes yes yes yes yes no Oct-Nov NH NH tropics
Bolivia (Plurinational State of) yes 2011 private no yes yes yes yes no May-Jun SH SH tropics
Brazil yes 1999 both yes no yes yes yes yes SH SH tropics
Cayman Islands yes 1990
yes yes yes yes yes NH NH tropics
Chile yes 1975 both yes yes yes yes yes yes Mar-Apr SH SH subtropics
Colombia yes 2005 both yes yes yes yes yes yes Apr SH NH tropics
Appendix
75
Country National
Policy
Year introdu
ced Sector Free Children Elderly
Chronic illness
Healthcare
Professional
Pregnancy
Vaccine timing
Formulation
Climate region
1
Costa Rica yes 2004 both yes yes yes yes yes no Feb NH NH tropics
Cuba yes 1998 both
yes yes yes yes yes NH NH tropics
Dominica yes 2011 private no yes yes yes
NH tropics
Dominican Republic yes 2006 both
yes yes yes yes no Sep-Nov NH NH tropics
Ecuador yes 2006 public yes yes yes no no no Oct-Dec NH SH tropics
El Salvador yes 2004 both yes yes yes no yes yes May-Sep NH-->SH NH tropics
Grenada yes 2007 public yes yes yes no no no NH NH tropics
Guatemala yes 2007 both yes yes yes yes yes no NH-->SH NH tropics
Guyana no
private
NH tropics
Haiti no
private
NH tropics
Honduras yes 2003 both yes yes yes yes yes no Dec NH NH tropics
Jamaica yes 2006 both yes yes yes yes yes no NH NH tropics
Mexico yes 2004 both yes yes yes yes yes yes Oct-Feb NH NH subtropics
Montserrat yes 2009
yes no no no no NH NH tropics
Netherlands Antilles yes 2007
yes yes yes no no NH NH tropics
Nicaragua yes 2007 both yes yes yes yes yes yes Apr-May SH NH tropics
Panama yes 2005 both yes yes yes yes yes yes SH NH tropics
Paraguay yes 2005 both yes yes yes yes yes no Apr-May SH SH tropics
Peru yes 2008 both yes yes yes yes yes yes Dec-Mar; May-Sep
NH SH
SH tropics
Saint Kitts and Nevis no
NH tropics
Saint Lucia yes 2006 public
yes yes yes no NH NH tropics
Saint Vincent and the Grenadines
no
public
NH tropics
Suriname yes 2009 both yes yes yes yes yes yes NH NH tropics
Trinidad and Tobago yes 2007 both yes yes yes yes yes no NH NH tropics
Turks and Caicos Islands yes 2006
yes yes yes yes no NH NH tropics
Appendix
76
Country National
Policy
Year introdu
ced Sector Free Children Elderly
Chronic illness
Healthcare
Professional
Pregnancy
Vaccine timing
Formulation
Climate region
1
Uruguay yes 1996 both yes yes yes yes yes yes Apr SH SH subtropics
Venezuela (Bolivarian Republic of)
yes 2006 both yes yes yes yes yes yes NH NH tropics
Middle East
Bahrain yes
both yes yes yes yes yes yes NH NH subtropics
Iran (Islamic Republic of) yes 2005
no yes yes
yes
NH subtropics
Iraq yes 2009
yes
NH subtropics
Israel yes
yes yes yes
NH subtropics
Jordan no
yes
NH subtropics
Kuwait yes
no no yes
NH subtropics
Lebanon no
NH subtropics
Oman yes 2004
no no yes
NH tropics
Qatar no
NH subtropics
Saudi Arabia yes 2000 both yes yes yes yes yes yes NH NH subtropics
Syrian Arab Republic no
NH subtropics
United Arab Emirates yes 2006 both
no no yes yes no NH NH subtropics
Yemen no
NH tropics
1 Climate region for a country is defined by its geographical location in relation to the Tropic of Cancer, Equator and Tropic of Capricorn
Appendix
77
Appendix D: Seasonal influenza vaccine doses distributed in the tropics and subtropics
Appendix
78
Appendix
79
Appendix
80
Appendix
81
Appendix
82
Appendix
83
Appendix
84
Appendix E: Seasonal influenza vaccine effectiveness in the elderly in the tropics and subtropics
Reference Study type, year, place
ILI Laboratory-confirmed influenza
Pneumonia Hospitalization Mortality Remarks
Breteler (2013)[27]
Meta-analysis
LAIV: 4% (ns); TIV: 59% (44 – 70)
LAIV: 43% (25 – 56); TIV: 58% (23 – 78)
All-cause (LAIV): 8% (ns); P&I (LAIV): no effect; P&I (TIV): 26% (ns)
RCTs (7), cohort (2), case control (1) 9/10 studies from tropics Low middle income countries
Darvishian (2014)[172]
Meta-analysis
36% (ns) 77% (ns) P&I: 25% (6 – 40) All-cause: 36% (8 – 56) 1/14 studies from tropics (China, Province of Taiwan)
Beyer (2013)[173]
Meta-analysis
~40% ~50% ~30% P&I: ~30% Jefferson 2010 review reanalysed
Jefferson (2010)[174]
Meta-analysis
Healthy elderly: 41%;
Healthy elderly: 50%; At risk elderly: 26%
P&I: 8%; All-cause: 61%
1/75 studies from tropics (China, Hong Kong SAR)
Moreno (2009)[175]
Meta-analysis
20% – 26% 1/28 studies from tropics (China, Province of Taiwan)
Rivetti (2006)[176]
Meta-analysis
P&I: 27% (21 – 33) Respiratory: 22% (15 – 28) CVD: 24% (18 – 30)
All-cause: 47% (39 – 54) Review updated by Jefferson in 2010; 0/64 studies from tropics
Vu (2002)[178]
Meta-analysis
P&I: 33% (27 – 38) Respiratory: 30% (25 –35)
All-cause: 50% (45 – 56)
Gross (1995)[177]
Meta-analysis
ARI: 56% (39 – 68)
53% (35 – 66)
50% (28 – 65) All-cause: 68% (56 – 76) 0/20 studies from tropics
Studies from the tropics
Forrest (2011)[190]
RCT (2002) South Africa
inconclusive
LAIV v/s TIV
Gutierrez (2001)[153]
Cohort (2000) Sao Paulo, Brazil
6% (ns) TIV
Isahak (2007)[194]
Non-RCT (2003-04) Malaysia
55% to 76%
TIV v/s placebo
Appendix
85
Reference Study type, year, place
ILI Laboratory-confirmed influenza
Pneumonia Hospitalization Mortality Remarks
Plasai (2006)[197]
Non-RCT (2004-05) Thailand
48% TIV v/s no vaccine
Jianping (1999)[195]
RCT (1996-97) China
74% TIV Control group unclear
Praditsuwan (2005)[198]
RCT Thailand
56% (14 – 77)
Significant reduction
TIV v/s placebo No effect on reduction of serious complications
Façanha (2005)[188]
Cohort (1995-2003) Brazil
No effect No effect
Brondi (2000)[182] Daufenbach (2009)[184] Ferrer (2008)[189] Francisco (2004)[191]
Ecological (1998-2002) Brazil
Modest reduction Articles in Portuguese – not retrieved; Identified through cross-references
De Villiers (2009)[187]
RCT (2001) South Africa
Good match: 42% (23 – 57); Any match: 42% (22 – 57);
P&I: Inconclusive Inconclusive LAIV v/s placebo
Hung (2010)[193]
Cohort (2008-09) China, Hong Kong SAR
43% (36 – 49)
CVD: 41% (21 – 56); ICU: 55% (6 – 78); Stroke: 33%
All-cause: 35% (23 – 45) TIV v/s PPV1 v/s TIV+PPV v/s
placebo; VE against myocardial infarction (48%)
Lin (2014)[196]
Case control (2006-09) China, Province of Taiwan
Stroke: 24% (3 – 40) TIV VE increases as no. of vaccinations in previous seasons increases
Appendix
86
Reference Study type, year, place
ILI Laboratory-confirmed influenza
Pneumonia Hospitalization Mortality Remarks
Van Vuuren (2009)[199]
Case control (2003-04) South Africa
CVD: 15% (ns); Respiratory: 15% (ns)
All-cause: 24% (1 – 41) TIV
Anonymous (unpub)[180]
Case control (2013) Central, South America
Influenza: Chile: 45% (7 – 65); Brazil: 77% (62 – 86); Argentina, Colombia, Costa Rica, El Salvador, Honduras, Panama, Paraguay: 57% (43 – 68)
TIV
Dawood (2014)[185]
Case control (2010-11) Thailand
Influenza: 47% (5 – 71) TIV Vaccination coverage low; Vaccine and virus strain match good
Stamboulian (1999)[143]
Cohort (1993) Argentina
P&I: 38% (21 – 51); P&I (elderly high risk): 45% (29 – 58);
TIV Vaccination coverage: 6 – 30%
Wang (2004)[201] Wang (2007)[200]
Cohort (2001) China, Province of Taiwan
Overall: 11% (8 – 14) high risk elderly: All-cause: 20% (16 – 23) Stroke: 4% (ns) CVD: 9% (ns) P&I: 31% (17 – 42) Low risk elderly: All-cause: 33% (19 – 26) Stroke: 36% (24 – 46) CVD: 16% (2 – 29) P&I: 33% (18 – 47)
All-cause: 44% (40 – 48); Pneumonia: 53% (35 – 66); Stroke: 65% (55 – 73); CVD: 22% (4 – 36);
TIV VE against mortality from renal disease (60%), diabetes (55%), COPD (45%)
Yung (unpub)[202, 203]
Cohort (2010-12) Singapore
All-cause emergency: 11% (7 – 15)
75% (70 – 80) TIV All ages, all cause emergency hospitalizations
Appendix
87
Reference Study type, year, place
ILI Laboratory-confirmed influenza
Pneumonia Hospitalization Mortality Remarks
Antunes (2007)[181]
Ecological (1998-2002) Sao Paulo, Brazil
P&I: 26% TIV P&I mortality reduced by 26% after vaccination campaign (1998-2002) compared to before vaccination (1993-97)
Francisco (2005)[192]
Ecological (1980-2000) Sao Paulo, Brazil
All-cause (men): 7%; All-cause (women): 6%
TIV VE (1998-2000) after vaccination compared to before vaccination (1993-97)
De Padua Mansur (2009)[186]
Ecological (1980-2006) Sao Paulo, Brazil
IHD: 46% (1 – 71) Articles in Portuguese – not retrieved; Identified through cross-references
Chan (2013)[183]
Cohort (2010-11) China, Hong Kong SAR
All-cause: 28% (5 – 46); P&I: 20% (2 – 38)
TIV
1 PPV – Pneumococcal Polysaccharide Vaccine
(ns) – Not statistically significant at the 5% significance level
Appendix
88
Appendix F: Seasonal influenza vaccine effectiveness in children in the tropics and subtropics
Reference Study type, year, place
ILI Laboratory confirmed Influenza Remarks
Breteler (2013)[27]
Meta-analysis Low middle income countries
LAIV: 36% (28 - 54); TIV: 27% (21 - 33)
LAIV (good match): 72% (65 - 77); TIV (good match): 81% (58 - 92)
RCTs (10), cohorts (2) 6/12 studies from tropics; LAIV (P&I hospitalization): no effect
Luksic (2013)[206]
Meta-analysis LAIV: 31% (25 – 40); TIV: 32% (20 – 53)
LAIV: Good match: 82% (77 - 89); Any match: 77% (69 – 86); TIV: Any match: 67% (58 - 78)
LAIV: RCTs (12), cohorts (4) 2/16 studies from tropics TIV: RCTs (11), cohorts (5), case control (2) 1/18 studies from tropics
Tricco (2013)[215]
Meta-analysis (1970-2009)
LAIV: Good match: 77% (67 - 86); Poor match: 60% (44 – 71); TIV: Good match: 65% (57 – 72); Poor match: 56% (43 – 66);
RCTs (34) 5/34 studies from tropics VE against mismatched influenza A (LAIV-75%, TIV-62%) significantly higher than mismatched influenza B (LAIV-42%, TIV-52%) respectively
Osterholm (2012)[169]
Meta-analysis (1967-2011)
LAIV: 83% (69 – 91) RCTs (6); 3/6 studies from tropics
DiazGranados (2012)[207]
Meta-analysis LAIV: Any match: 80% (70 – 87) Good match: 88% (83 – 92); Poor match: 80% (50 – 92); TIV: Any match: 48% (31 – 61) Good match: 48% (15 – 68); Poor match: 49% (3 – 73);
RCTs or CCTs (30) 2/30 studies from tropics (Cuba, multi-site, Asia); LAIV efficacy better than TIV in children
Michiels (2011)[209]
Meta-analysis 36% (24 – 46) 69% (55 – 78); RCTs (3), CCT (1); 0/4 studies from tropics;
Appendix
89
Reference Study type, year, place
ILI Laboratory confirmed Influenza Remarks
Carter (2011)[208]
Meta-analysis LAIV v/s placebo: Good match:69%(53-80); Poor match:87%(77-93); Otitis-85%(78-90) LAIV v/s TIV: Good match:53%(27-69); Poor match:54%(42-65); Otitis-54%(27-72)
RCTs (8); 5/8 studies from tropics; LAIV more effective than TIV in children with recurrent ARI and adolescents with asthma LAIV v/s placebo: Otitis-85%(78-90) LAIV v/s TIV: Otitis-54%(27-72)
Rhorer (2009)[210]
Meta-analysis (LAIV)
Good match (2 doses): 75% (71 - 79); Good match (1 dose): 58% (49 - 66);
RCTs (9); 4/6 LAIV-placebo studies from tropics; 1/3 LAIV-TIV studies from tropics; Good match (H1N1): 85% (78 - 90); Good match (H3N2): 76% (70 - 81); Good match (B): 73% (63 - 80); LAIV more effective than TIV in children
Jefferson (2008)[211]
Meta-analysis LAIV: 33% (28 – 38); TIV: 36% (24 – 46)
LAIV: 82% (71 – 89); TIV: 59% (41 – 71)
RCTs (17), cohorts (19), case control (11); 2/47 studies from tropics;
Manzoli (2007)[212]
Meta-analysis Overall: 36% (31 – 40); LAIV: 35% (30 – 40); TIV: 45% (33 – 55); Good match: 41% (31 – 49); Poor match: 32% (27 – 36);
Overall: 67% (51 – 78); LAIV: 72% (38 – 87); TIV: 62% (45 – 75); Good match: 61% (40 – 75); Poor match: 78% (63 – 87);
RCTs (19); 1/19 studies from tropics; Otitis Media: Overall: 51% (21 – 70); LAIV: 78% (25 – 90); TIV: 32% (ns);
Negri (2005)[213]
Meta-analysis (1985-2001)
Overall: 33% (29 – 36); LAIV: 34% (3 – 38); TIV: 33% (22 – 42);
Overall: 74% (57 – 84); LAIV: 80% (53 – 91); TIV: 65% (45 – 77);
RCTs (13); 1/13 studies from tropics
Ruben (2004)[214]
Review Influenza A: 31% - 91%; Influenza B: 45%;
RCTs (7); 0/7 studies from tropics; Otitis Media: 32% - 36%
Studies from the tropics
Jianping (1999)[195]
RCT (1996-97) China
85% TIV Control group unclear
Appendix
90
Reference Study type, year, place
ILI Laboratory confirmed Influenza Remarks
Cowling (2010)[218]
RCT (2009) China, Hong Kong SAR
8% (ns) A(H1N1): 25% (ns); A(H3N2): 50% (ns); B: no effect
TIV v/s placebo
Jain (2013)[217]
RCT (2010-11) Bangladesh, Dominican Republic, Honduras, Lebanon, Panama, Philippines, Thailand
Good match: 48% (16% - 67%); Any match: 59% (41% - 72%); Influenza A: 57% (36 – 71); Influenza B: 50% (17 – 70); Any severity: 55% (39 - 67); Mod to severe: 73% (47 - 86); 3 – 4 y: 35% (ns); 5 – 8 y: 68% (50 - 79)
QIV v/s hepatitis A vaccine
Bracco Neto (2009)[219]
RCT (2001-02) Argentina, Brazil, South Africa
LAIV (1 dose) any match: 56% (43 – 67); LAIV (1 dose) good match: 58% (45 – 68); LAIV (2 doses) any match: 72% (62 – 80); LAIV (2 doses) good match: 74% (64 – 81);
LAIV Two doses provided additional protection; protection persisted into 2
nd year without
revaccination
Tam (2007)[220]
RCT (2000-03) China, China, Hong Kong SAR, India, Malaysia, Philippines, Singapore, China, Province of Taiwan, Thailand
LAIV good match: 70% (61 – 77); LAIV any match: 68% (59 – 75)
LAIV v/s placebo
Lum (2010)[221]
RCT (2002-03) Bangladesh, China, Hong Kong SAR, Malaysia, Mexico, Philippines, Singapore, Thailand
Good match (LAIV): 78% (51 – 91); Any match (LAIV): 64% (36 – 80)
LAIV v/s placebo
Belshe (2007)[222]
RCT (2004-05) Asia (3), Middle East
Good match: 45% (22% - 61%); Poor match: 58% (47% - 67%); Any match: 55% (45% - 63%);
LAIV v/s TIV Subjects from 3 countries in Asia (6%), United States (49%), Europe, Middle East (45%)
Appendix
91
Reference Study type, year, place
ILI Laboratory confirmed Influenza Remarks
He (2013)[224] Fu (2013)[223]
Case control (2010-12) Guangzhou, China
2010-12: 34% (5 – 54); 6mo-3y (2 doses): 47% (9 – 70); 6mo-3y (1 dose): 5% (ns)
TIV Partial vaccination had no protective effect; Till 6mo: 35% (5% - 55%); After 6mo till 1y: no protection
Yang (2012)[225]
Case control (2009-10) Guangzhou, China
2010 (2 doses): 58% (44 – 68); 2010 (1 dose): 33% (16 – 46); 2009 (2 doses): 52% (41 – 60); 2009 (1 dose): 32% (19 – 43)
TIV
Anonymous (Unpub)[180]
Case control (2013) Central, South America
Brazil: 20%; Chile: 75% (32 – 98); Colombia: 77%; Costa Rica, El Salvador, Honduras, Panama: 48% (22 – 66)
TIV
Victor (unpublished) (2013)[226]
RCT (2009-10) Senegal
33% (6 – 52); Contacts: 19% (ns)
TIV v/s inactivated polio vaccine
Kittikraisak (unpublished)[227]
Cohort (2011-13) Thailand
2011-12: 62% (0 – 91); 2012-13: 37% (0 – 76)
TIV
Herd effectiveness amongst family contacts
Kim (2014)[230]
Review ARI: 24 – 30% 61% RCTs (3), non-RCT (1); 0/4 studies from tropics
Jordan (2006)[216]
Review ARI: No effect – 30% No effect RCTs (8), non-RCTs(3); 0/11 studies from tropics
Glezen (2006)[229]
Review ARI: 8 – 18% RCTs (2); 0/2 studies from tropics
Studies from the tropics
Gattas (unpublished)[232]
RCT (2009) Brazil, Sao Paulo
Family contacts: 61% (6 – 85) TIV v/s meningococcal and varicella vaccine Effectiveness of vaccination of children against influenza in household contacts
(ns) – Not statistically significant at the 5% significance level
Appendix
92
Appendix G: Seasonal influenza effectiveness in healthy adults in the tropics and subtropics
Reference Study type, year, place
ILI Laboratory confirmed Influenza Remarks
Breteler (2013)[27]
Meta-analysis Low middle income countries
62% (45 – 73); ARI: 75% (ns)
TIV: 82% (61 – 92)
RCTs (5), cohorts (5) 5/10 studies from tropics
Tricco (2013)[215]
Meta-analysis (1970-2009)
TIV: Good match: 65% (54 – 73); Poor match: 52% (37 – 63); Poor match (influenza A): 64% (23 – 82); Poor match (influenza B): 52% (19 – 72)
RCTs (34) 5/34 studies from tropics
DiazGranados (2012)[207]
Meta-analysis LAIV: Any match: 39% (16 – 55) Good match: 8% (ns); Poor match: 53% (15 – 74); TIV: Any match: 59% (50 – 66) Good match: 57% (43 – 68); Poor match: 50% (22 – 68);
RCTs or CCTs (14) 2/14 studies from tropics; LAIV efficacy better than TIV in children
Osterholm (2012)[169]
Meta-analysis (1967-2011)
TIV: 69% (60 – 93) TIV: 59% (51 – 67) RCTs (11); 1/11 studies from tropics
Jefferson (2010)[233]
Meta-analysis LAIV: Any match: 10% (4 – 16) Good match: 8% (ns); Poor match: 11% (3 – 18); TIV: Any match: 20% (11 – 29) Good match: 30% (17 – 41); Poor match: 7% (ns);
LAIV: Any match: 62% (45 – 73) Good match: 56% (19 – 76); Poor match: 64% (18 – 84); TIV: Any match: 61% (48 – 70) Good match: 73% (54 – 84); Poor match: 44% (23 – 59);
RCTs (35) 2/35 studies from tropics; LAIV: Pneumonia: 75% (ns) TIV: Pneumonia: 20% (ns) Hospitalization: 11% (ns)
Demicheli (2014)[234]
Meta-analysis TIV: 30% (17 – 41) TIV: Good match: 80% (56 – 91); Poor match: 50% (27 – 65)
RCTs (38), CCTs (8); 2/46 studies from tropics;
Studies from the tropics
Jianping (1999)[195]
RCT 39% TIV Control unclear
Appendix
93
Reference Study type, year, place
ILI Laboratory confirmed Influenza Remarks
Hui (2008)[235]
Cohort (2008) Malaysia
53% TIV Dental students and faculty
Samad (2006)[236]
Cohort (2001) Malaysia
73% TIV Factory workers
Morales (2004)[237]
Cohort (2000-01) Colombia
63% TIV Bank employees
Ho (2014)[238]
Case control (2010-13) Singapore
A(H1N1)pdm: 84% (78 – 88); A(H3N2): 33% (4 – 57); B: 84% (79 – 86)
TIV
Ntshoe (2014)[240]
Case control (2005-09) South Africa
2005: 49% (5 – 73); 2006: no effect; 2007: 12% (ns); 2008: 67% (12 – 90); 2009: no effect
TIV All ages
McAnerny (unpublished)[239]
Case control (2010-12) South Africa
2010: 58% (7 – 81); 2011: 59% (22 – 78); 2012: 50% (40 – 85)
TIV All ages
(ns) – Not statistically significant at the 5% significance level
Appendix
94
Appendix H: Seasonal influenza vaccine effectiveness in pregnant women in the tropics and subtropics
Reference Study type, year, place
Maternal outcome Infant outcome Remarks
Moriarty (2014)[248] Adegbola (2012)[245]
Review 1. Effect of vitamin A on Inactivated Influenza Vaccine response in mothers and infants [254]; 2. Field trial of Maternal Influenza Immunization in Asia [255]; 3. Maternal Flu Vaccine Trial in Bamako, Mali [256]; 4. Vaccination of HIV-uninfected Pregnant Women With Trivalent Influenza Vaccine in the Prevention
of Influenza Illness During Early Infancy and in Mothers: Randomized Controlled Phase III Trial Evaluating Safety, Immunogenicity and Efficacy [257]
RCTs (20) presently ongoing in safety, immunogenicity and efficacy of TIV in pregnant women; 4/20 are efficacy studies from tropics;
ILI or laboratory-confirmed influenza
ILI or laboratory-confirmed influenza
Hospitalization Other infant outcomes
Steinhoff (2014)[250]
Review Preterm: 16% (ns)[268], 25%[269], 73%[270]; SGA: 7% (ns)[269], 25%[268], 71%[270]; LBW: 27% (5 -44)[269]
RCTs (8); 4/8 studies on pandemic vaccine; 1/4 studies on TIV from tropics;
Galvao (2013)[247]
Review ILI: Significant reduction Significant reduction; ARI: no effect
Preterm, SGA, Still birth, neonatal mortality: no effect
RCT (1), cohorts (7); 1/8 studies from tropics
Omer (2012)[249] Blanchard-Rohner (2011)[246] Ortiz (2011)[241] Skowronski (2009)[251] Naleway (2006)[163]
Review ILI: no effect[258, 261], 44% (9 – 65)[264], 36%[253]; Ab titres: high titres [253, 263, 265], similar[262, 264]
ARI: no effect[258, 260], 41%[259] – 63%[253]; Ab titres: higher[263, 265-267]
No effect[258, 261], 39%[259], 45% – 48%[156], 92%[295]; Ab titres: increased[266, 267]
Preterm: 40% (6 – 62); During peak: 72% (26 – 89); SGA: 69% (25 – 87) [270];
RCTs (2), cohorts (10), Case control (1); 1/13 studies from tropics; Most studies did not use laboratory-confirmed influenza as outcomes
Appendix
95
Reference Study type, year, place
Maternal outcome Infant outcome Remarks
Mak (2008)[242]
Review ARI: no effect (United States studies)
61% (9 – 84)[253]; ILI: 65%; ARI: no effect (United States studies)
1/8 studies from tropics;
Myers (2011)[271]
Modelling (2006-07) USA
Once all pregnant women are vaccinated at time of vaccine availability, vaccination of newly pregnant women benefits mothers but not infants; VE reduces as starting date of vaccine availability is delayed; All reduction in infant morbidity is seen within the first 4 weeks of vaccine availability;
Studies from the tropics
Madhi (2014)[257]
RCT (2011-12) South Africa
HIV infected mothers: LCI: 58% (0.2 – 81); ILI: no effect HIV non-infected mothers: LCI: 50% (15 – 71); ILI: no effect
HIV infected mothers: LCI: 27% (ns); ILI: no effect HIV non-infected mothers: LCI: 49% (12 – 70); ILI: no effect
TIV
Zaman (2008)[253]
RCT 2004-05 Bangladesh
ILI: 36% (4 – 57);
ILI: 29% (7 – 46); LCI: 63% (5 – 85);
Preterm: 28% (ns); SGA: 37% (ns)
TIV v/s PPV
Note: PPV: Pneumococcal Polysaccharide Vaccine; LCI: Laboratory confirmed influenza
(ns) – Not statistically significant at the 5% significance level
Appendix
96
Appendix I: Seasonal influenza effectiveness in high risk individuals in the tropics and subtropics
Reference Study type, year, place
ILI laboratory-confirmed influenza
Hospitalization Mortality Remarks
COPD patients
Poole (2006)[272]
Meta-analysis ARI: 11% (ns) 81% (52 – 93) 67% (ns) No effect RCTs (11); 1/11 studies from tropics
Studies from the tropics
Kositanont (2004)[273]
RCT (1997-98) Thailand
71% TIV v/s placebo COPD patients
Menon (2008)[274]
Cohort (2004-06) India
ARI: 67% (p=.005); Mild COPD: 60% (ns); Mod. COPD: 60% (ns); Severe COPD: 75% (p=.02)
ARI: 72% (p=.02) TIV COPD patients
Wongsurakait (2004)[275]
RCT (1997-98) Thailand
Mild COPD: 84%; Mod. COPD: 45%; Severe COPD: 85%
TIV v/s placebo COPD patients
Coronary heart disease patients
Keller (2008)[276]
Meta-analysis Coronary Heart Disease: 61% (23 – 80)
RCTs (3); 1/3 studies from tropics; Acute MI: 15% (ns)
Studies from the tropics
Phrommintikul (2011)[277]
RCT (2007-08) Thailand
Acute coronary: 32% (2 – 53); Heart failure: 38% (ns)
38% (ns) TIV v/s no vaccine CVD patients
Gurfinkel (2002)[279]; Gurfinkel (2004)[296]
Cohort (2001) Argentina
Coronary Heart Disease: 66% (29 – 83);
TIV MI patients; Ischemic events: 41% (14 – 96)
HIV patients
Anema (2008)[280]
Meta-analysis 34% (18 – 64) RCTs (3), Case control (1); 0/4 studies from tropics
Appendix
97
Reference Study type, year, place
ILI laboratory-confirmed influenza
Hospitalization Mortality Remarks
Atashili (2006)[281]
Meta-analysis 27% - 78% RCT (1), non-RCT (2), outbreak investigation (1); 0/4 studies from tropics
Studies from the tropics
Madhi (2011)[282]
RCT (2011) South Africa
8% (ns); ARI: 16% (ns)
76% (9 – 96) TIV v/s placebo
Immunocompromised patients
Machado (2005)[283]
Cohort Sao Paulo, Brazil
80% TIV Bone marrow transplant recipients
Healthcare professionals
Thomas (2013)[284]
Meta-analysis No effect on those who receive care from HWs
Respiratory: no effect Respiratory: no effect RCTs (3); 0/3 studies from tropics
Studies from the tropics
Kheok (2008)[285]
Cohort (2004-05) Singapore
Good match: 51% (34 – 63); Poor match: no effect
TIV
Pilgrims
Breteler (2013)[27]
Meta-analysis Low middle income countries
72% (59 – 80); ARI: 55% (ns)
Cohorts (2); 2/2 from tropics
Studies from the tropics
Qureshi (2000)[287]
Cohort (1999) Pakistan
38% (29 – 45) TIV Haj pilgrims
Mustafa (2003)[286]
Case control (2000) Malaysia
77% (69 – 83) TIV Haj pilgrims
(ns) – Not statistically significant at the 5% significance level