What’s new internationally in vaccinology a complex ... · What’s new internationally in...

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What’s new internationally in vaccinology

a complex challenging world

Nikki TurnerGP, Director Immunisation Advisory Centre University of Auckland

Member SAGE advisory group to the WHO, and Chair of Measles Rubella SAGE Working Group

Sep 2019

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Complex new vaccines - and strategies with old ones

Malaria Ebola Dengue Cholera

©The Immunisation Advisory Centre 2015

Malaria

• New episodes 214 million, 438,000 deaths 2015, – over 90% sub-Saharan Africa, most in children < 5 yrs– Rest South-East Asia , South America– Almost all deaths Plasmodium falciparum, – P. vivax – dominant in areas outside sub-Saharan Africa, others less prominent

• Malaria protozoan parasite– Vector-borne disease transmitted through bite of Anopheles mosquitoes (approx. 40 diff species),

most bite between dusk and dawn, breed in water– Can be endemic, seasonal or mixed– Intensity of transmission varies with density, biting and survival rates of the mosquito vector– Mosquito strongly influenced by temperature and humidity and vector control measures

©The Immunisation Advisory Centre 2015 4

The Jenner InstituteJenner.ac.uk


• Deaths have fallen by 60% globally since 2000– LLINs ( long-lasting insecticide nets)– IRS (indoor residual spraying of insecticides) in some settings– Prompt diagnosis using rapid diagnostic tests (RDTs)– Access to Rx with highly effective artemisinin-combination therapies (ACTs)

Also– Intermittent preventive treatment of malaria in pregnancy ( IPTp)

• At schedule antenatal visits after the first trimester (2014 17% update of 3 doses)

– Seasonal malaria chemoprevention (SMC)• Intermittent administration of full Rx course of antimalarial medicine to children during the

malaria seasons. Given monthly for 3-4 months = reduction severe malaria by 75% in kids <5 yrs

5REF: Malaria vaccine: WHO position paper – 29 January 2016 Weekly epidemiological record www.who.int/wer

http://www.who.int/wer

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Vaccines

• > 30 candidate vaccines– Recombinant protein antigens – Target different states of the parasite lifecycle

7Asian Journal of Pharmaceutics


RTS,S/AS01(Mosquirix)

Recombinant vaccine, engineered using genes from the outer protein of the Plasmodium falciparum malaria parasite and a portion of a hepatitis B virus (adjuvanted)

Action is to trigger immune system to produce Abs that prevent the invasion of hepatocytes and also elicit cellular responses enabling destruction of infected hepatocytes.

• R= central repeat region of Plasmodium falciparum circumsporozoite protein (CSP)• T – T-cell epitopes of the CSP • S = hepatitis B surface Ag • AS01 = liposome-based adjuvant

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Source: European Mecial Agency

RTS,S recombinant protein virus-like particle


October 2015 SAGE/MPAC meeting -RTS,S/AS01 malaria vaccine

• A pivotal Phase 3 clinical trial of RTS,S/AS01 complete– Approximately 15,000 infants and young children in 7 sub-Saharan African

countries, 11 sites with a range of low to high malaria transmission settings. – 2 age categories

• 6-12 weeks at first vaccination• 5-17 months at first vaccination

– RCT 3 doses a month apart and 4th dose 18 months later• 3 doses of vaccine and one of control vaccine• 4 doses of vaccine • 4 doses of control vaccine

– Control vaccine MenC or Rabies


Study period

6-12 weeks 5-17 months

VE against clinical malaria

VE against severe malaria

VE against clinical malaria

VE against severe malaria

2.5M-14M32.9%

(26.3, 38.9)38.5%

(7.8, 59.0)51.3%

(47.5, 54.9)44.5%

(23.8, 59.6)

2.5M-20M 26.6%(20.3, 32.4)

17.4%(-16.2, 41.3)

45.7%(41.7, 49.5)

37.7%(18.0, 52.6)

2.5M-SE*(3 doses)

18.2%(11.4, 24.5)

16.0%(-14.5, 38.4)

26.2%(20.8, 31.2)

-2.2%(-31.3, 20.4)

2.5M-SE*(4 doses)

26.7%(20.5, 32.4)

20.5%(-9.8, 42.5)

39.0%(34.3, 43.3)

31.5%(9.3, 48.3)

Vaccine efficacy (95%CI) against all episodes of clinical malaria and severe malaria


5-17 months

3-dose schedule

4-dose schedule

Study End

-2.2(-31.3, 20.4)

31.5(9.3, 48.3)

6-12 weeks

3-dose schedule

4-dose schedule

Study End 16.0

(-14.5, 38.4)20.5

(-9.8, 42.5)

Vaccine efficacy against severe malaria by time interval

October 2015 SAGE/MPAC meeting -RTS,S/AS01 malaria vaccine

• Based on efficacy data from the Phase 3 trial:– SAGE/MPAC does not recommend the use of the malaria vaccine in the younger

(6-12 weeks) age group. The vaccine efficacy is lower than in the older one.• To address how best to ensure that 4 doses of malaria vaccine can be

given between 5 to 27 months of age:– recommend evaluation of RTS,S in staged pilot implementations,

• Other questions that should be addressed as part of the pilot implementation include:– The extent to which RTS,S vaccination impacts mortality. – Whether the excess cases of meningitis and cerebral malaria, identified during

the Phase 3 trial are causally related to RTS,S vaccination.


Malaria vaccine RTS,S (Mosquirix)

A planned implementation programme in 3 countries– Starting late 2018– Ghana - 8 million cases malaria/yr and 12,880 deaths– Kenya – 3.5 million cases malaria/yr and 10,780 deaths– Malawi – 4.5 million cases malatia/yr and 7000 deaths


Malaria Vaccine Implementation ProgrammeProposed step-wise approach to policy recommendation

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Challenges.....• Vaccine likely to be effective but

moderate– High burden of disease, so valid to

use• Low income settings

– Complex implementation– ?Effect on other malaria prevention

strategies, will it take away focus– ?Could vaccine introduction help or

hinder needed improvements for healthcare services and access


• First appears in 1976 – south Sudan and DRC ( near the Ebola River)• Transmitted from wild animals to people

– Main natural hosts = fruit bats– Close contact with infected animals – Human-to human: bloods or body fluids, contaminated objects

• Outbreak control– Case management– Infection prevention and control practices– Surveillance and contact tracing– Good laboratory service– Safe and dignified burials– Social mobilisation

• Average case fatality rate 50% ( 25% - 90%)

19www.who.int/news-room/fact-sheets/detail/ebola-virus-disease

World Bank, Vincent Tremeau/Frickr cc

https://www.who.int/news-room/fact-sheets/detail/ebola-virus-disease

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Ebola Vaccines• 13 candidate vaccines

– 8 phase one trials– Two phase 2– One completed phase 3– Single dose OR prime-boost– No serious side effects to date, limited data on children and special

populations– All show detectable humoral and cellular immune responses– Surrogates of protection not defined yet– Only efficacy/ effectiveness data to date for rVSV-ZEBOV

21REF: https://viropourtous.ch/un-virus-ca-peut-servir-le-vaccin-vsv-eboz/

rVSV-ZEBOV

https://viropourtous.ch/un-virus-ca-peut-servir-le-vaccin-vsv-eboz/

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rVSV-ZEBOV

• Live attenuated recombinant vesicular stomatitis virus-based vector expressing the envelope GP gene of Zaire Ebola virus

• RCT Guinea 2015– 11841

• 5837 received vaccine, no cases• 6004 no vaccine, 23 cases 10 or more days after vaccination

• Application for licensure to US FDA and EMA – ongoing discussions to shorten regulatory approval time ? 2020

• No WHO prequalification yet

Ebola in DRC

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rVSV-ZEBOV• Being used in 2018-2019 DRC outbreak since Aug 2018

– Ring Vaccination using the Expanded Access/Compassionate Use protocol in a clinical trial protocol with informed consent

• Aug 1 2018 – March 25 2019: 951 cases Ebola– Defined 679 rings and contacts and contacts of contacts around 776 cases

» Security reasons and lack of community consent not possible to define rings around 175 (18%) of cases

» 71 cases in 93,965 vaccinated but only 15 onset symptoms 10 days or more post vaccination

» Estimated vaccine efficacy of 97.5% (95.8 – 98.5%)– Also vaccinated 28,888 HCW/front line workers– No pregnant/lactating women or children < 1 year (were excluded in clinical trials)!

REF: https://www.who.int/csr/resources/publications/ebola/ebola-ring-vaccination-results-12-april-2019.pdf?ua=1

https://www.who.int/csr/resources/publications/ebola/ebola-ring-vaccination-results-12-april-2019.pdf?ua=1

Ebola

• Ring vaccination strategies currently the most effective strategies• Geographic targeting a fall-back strategy • Mass vaccination and ring plus – less favourable impact overall• High attack rates and high fatality rates, and accumulating data on

vaccine safety and efficacy for other groups – justify inclusion of children >6 months and lactating women in the ongoing ring

vaccination efforts in North Kivu, DRC

• SAGE strongly recommends urgent implementation of studies to evaluate additional Ebola candidate vaccines to include where at all possible pregnant, lactating women and infants

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Confirmed and probable Ebola virus disease cases by week of illness onset by health zone. Data as of 20 August 2019*

https://www.who.int/csr/don/22-august-2019-ebola-drc/en/

https://www.who.int/csr/don/22-august-2019-ebola-drc/en/

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Equity issues....!

• A disease that should be managed by resourcing healthcare services

• New effective vaccine/s– Impetus arose when Ebola spreads

outside of LICs!– Does it distract from improving

health services – First vaccine candidate excluded

important groups

29Internationaglobalhealth.com


Dengvaxia® (CYD-TDV) • Recombinant, live-attenuated tetravalent vaccine • (CYD-TDV) – a chimera

– Attenuated Yellow fever 17D strain as the replication backbone

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Dengvaxia® (CYD-TDV) Original clinical trials

– Lower efficacy for children 2-5 yrs– Safety signal for this age group, not seen in older age groups

• But based on small immunogenicity data set (baseline samples in 10% of trial popn)

SAGE conclusion April 2016• Vaccine efficacy ( over a 25 month period) 65.6% among 9-16 year olds

– severe disease reduced by 93% and hospitalisation by 82%• Efficacy varies by age, dengue serotype, disease severity, and previous contact with infection• An increase in risk for hospitalised dengue is seen in 2-5 year age group, not seen in 9 years up

– Vaccine acts like a silent primary infection, priming individuals not previously exposed to the more serious infections

– Countries should consider introduction only in high endemicity settings (seroprevalence >70%)

– Further studies are needed to address concerns re the possibility that the vaccine may increase the risk of severe dengue

Licensure for 9 years and above– Licensed Dec 2015, approved in 20 countries: Asia, Latin America and Australia


Nob 2018 Further analysis(Sanofi-Pasteur):New assay to infer pre-vaccination status

Over 5 years plus post-vaccinationSeropositive prior to vaccination:

•severe dengue 1.0/1000Seronegative:

•severe dengue 4/1000 in vaccinated •Severe dengue 1.7/1000 in not vaccinated

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Modelling the use of DengvaxiaAreas of 70% dengue seroprevalence over 5 years:

• One excess case of hospitalised dengue in vaccinated seronegativesversus 13 hospitalised cases prevented in vaccinated seropositives

• One excess severe dengue in vaccinated seronegatives versus 4 severe cases prevented in vaccinated seropositives

Areas of 85% dengue seroprevalence - benefit is ever higher• 1 excess case of hospitalised in vaccinated seronegatives versus 18

cases prevented in seropositives• 1 excess case of severe dengue in seronegatives versus 10 severe

cases prevented in serpoisitives vaccinated REF: Dengue VaccineWHO position paper, Sept 2018


SAGE recommendations April 2018

• Two possible vaccination strategies in high prevalence settings– Strategy one: Use only in high prevalence setting– Strategy two: Screening individuals for seropositivity prior to

vaccination

“ For countries considering CYD-TDV vaccination as part of their dengue control program, a ‘pre-vaccination screening strategy” in which only dengue-seropositive persons are vaccinated, is the

preferred option”

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Ethics....

• A good vaccine for highly endemic populations– Potential to prevent many severe

cases in the majority – Vs in non-immune higher risk of

severe disease

• Now not likely to be used until effective point of care testing available– Not likely in low income settings– ?Individual versus community good...

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Old vaccines in new world– disease outbreaks

Cholera • Is predictable and preventable

– clean water, sanitation and hygiene• Endemic in many setting across Africa, Asia and Haiti• 1.3- 1.4 million case annually

– 21,000 – 143,000 deaths– Case management : WaSH interventions vital (water, sanitation, hygiene)

Vaccines• 3 killed oral cholera vaccines (OCV) WHO pre-qualified• Good safety profiles, sustained protection > 60% for at least 3 years after 2 doses• Not for routine travellers, only if very high risk• Should be used in

– Endemic areas– Humanitarian crises– During outbreaks

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“The map of cholera is essentially the same as a map of extreme poverty”

45www.who.int/cholera/en

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... outcomes from systems failures

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47REF: https://unicef.shinyapps.io/wuenic_analytics/

https://unicef.shinyapps.io/wuenic_analytics/

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