Vaccines, Children and a Better World

The International Vaccine Institute is founded on the belief that the health of children in developing countries can be

dramatically improved by the development, introduction, and use of new and improved vaccines, and that these vaccines

should be developed through a dynamic interaction among the scientific community, public health organizations, and

industry.

Created by the United Nations Development Programme (UNDP), the IVI began formal operations in October 1997

under an independent Board of Trustees. Its programs receive support from international organizations; from private

and public research institutions; and from national governments around the world. The Republic of Korea contributes

to the IVI’s operating budget and hosts the IVI at its state-of-the-art headquarters in Seoul. The IVI’s network of

partnerships and collaborations extends from the World Health Organization (WHO) to leading research laboratories

in the industrialized world and the foremost disease prevention research centers in the developing world. IVI

programs are operating in countries in Asia and Africa and range from field epidemiological and clinical studies to

vaccine development and technology transfer to qualified local vaccine producers.

International Vaccine Institute in Brief

Prof. Samuel Katz, Chairman of the Board of Trustees, with President Roh Moo-hyun

TABLE OF CONTENTS

Letter from the Director 1

Division of Translational ResearchIntroduction 5

Diseases of the Most Impoverished: Typhoid Program 7

Diseases of the Most Impoverished: Cholera Program 11

Diseases of the Most Impoverished: Shigellosis Program 15

Diseases of the Most Impoverished: Existing Data Collection Program 18

Pediatric Dengue Vaccine Initiative 20

Japanese Encephalitis Program 23

Respiratory Encapsulated Bacteria Program: Haemophilus influenzae type b (Hib) Disease 26

Respiratory Encapsulated Bacteria Program: Pneumococcal Disease 29

Rotavirus Diarrhea Program 31

Vaccine Safety Program 34

Division of Laboratory SciencesIntroduction 39

Vaccine Development and Process Research 41

Mucosal Immunology 43

Cellular Immunology 45

Humoral Immunology 47

Molecular Microbiology 50

Technology Transfer Program 52

Building SuccessTraining and Capacity Building 55

IVI Scientific Publications 57

Administration and Finance 61

Organizational Chart 63

Financial Statements 64

Donors to the IVI and the Korea Support Committee 76

International Collaborators 77

Board of Trustees 79

Dear Colleagues,I am pleased to share with you the International Vaccine

Institute’s annual report for 2003-2004, a period of both rapid

growth and change.

Professor Barry Bloom, the Chairman of the Founding Board

of Trustees for the Institute, completed his second term as Chair

in 2003, the maximum number of terms allowed by the IVI

Constitution. The Board elected as its new Chairman Professor

Samuel Katz, Chairman Emeritus of the Department of

Pediatrics at Duke University. Fortunately for the IVI, Professor

Bloom has agreed to stay on the Board as Chairman Emeritus.

In its July 2004 meeting, the Board voted to expand its

membership to include five new seats for representatives of

member countries, and also voted to name Doctor Nay Htun, the

United Nations Development Programme (UNDP) representative

on the Board, as the Chairman of the Institute Support Council

(ISC). Doctor Htun has exciting plans for the ISC, which has the

important mandate of increasing international awareness of the

IVI and its programs and accelerating institutional development.

For the past five years, the IVI has focused its research efforts

on translational research to provide an evidence base for the

rational introduction of new vaccines into programs for the poor

in developing countries. The main priorities of these research

programs, which have been implemented in 12 countries in Asia

and Africa, have been work on vaccines against enteric

infections; vaccines against encapsulated bacteria that cause

invasive infections, such as meningitis and pneumonia; and

vaccines against the mosquito borne Flavivirus infections,

Japanese encephalitis and dengue fever. The programs have

also addressed methods for creating population-based

computerized databases that link vaccination histories to severe

disease outcomes in developing countries, allowing detection

and evaluation of rare but potentially serious adverse vaccine-

related events.

In 2003 the IVI was awarded a US$ 55 million grant by the Bill

& Melinda Gates Foundation for the Pediatric Dengue Vaccine

Initiative (PDVI), a program of research, also funded by the

Rockefeller Foundation, to accelerate the rational introduction of

new vaccines against dengue fever for children in developing

countries. This is the second major grant to the IVI from the Bill &

Melinda Gates Foundation; the first, a grant of US$ 40 million,

was awarded in 2000 to support the Diseases of the Most

Impoverished (DOMI) Program, a program of research and

technical assistance to accelerate the rational introduction of new

vaccines against cholera, typhoid fever, and shigellosis into

public-health programs for the poor in developing countries.

During the past year the IVI has also received large grants from

the Korean International Cooperation Agency (KOICA) for

research that will accelerate the rational introduction of vaccines

against Japanese encephalitis and from the UBS Optimus

Foundation for research into vaccines against paratyphoid fever.

The IVI’s translational research agenda includes clinical trials of

experimental vaccine candidates in developing countries and of

Letter from the Director

1

IVI Director Dr. John Clemens visits a slum in Karachi prior to a trial of a vaccine against typhoid fever.

established vaccines that are not being used in developing

countries, providing the information policymakers need in order

to make rational decisions about vaccine introduction. This

information includes: assessments of the disease burden and its

financial costs; evaluations of the logistical and programmatic

feasibility of introducing new vaccines and of the impact on

disease to be expected of newly introduced vaccines; economic

studies of the cost-effectiveness of vaccine use; behavioral

studies of the public demand and willingness to pay for new

vaccines; and policy analyses of program options and channels

for vaccine introduction and of options for the financial

sustainability of vaccine programs. Recently, IVI scientists and

collaborators in the DOMI Program have begun an ambitious

project to synthesize the diverse epidemiological, clinical,

economic, and behavioral findings of these studies in order to

facilitate decision-making by policymakers at the national level

on the use of vaccines against the diseases targeted by DOMI.

A sample of the other activities of the IVI’stranslational research

programs during the past year, all conducted with local

collaborators, and many done in collaboration with international

groups, include the following:

A study in Mozambique found that recombinant B subunit,

killed whole-cell (rBS-WC) oral cholera vaccine was highly

protective in a population with a high seroprevalence of HIV

infection.

A study in Bangladesh demonstrated that the BS-WC oral

cholera vaccine conferred substantial herd immunity to non-

vaccinated neighbors living in neighborhoods with high levels

of vaccine coverage.

A study in Vietnam demonstrated that a locally developed and

produced, oral killed whole-cell vaccine against cholera

conferred protection for at least three years after immunization.

Coordinated, population-based studies of the shigellosis

disease burden in nearly 500,000 persons residing in

Bangladesh, China, Indonesia, Pakistan, Thailand, and

Vietnam revealed a much greater diversity of epidemiologically

prevalent Shigella species and serotypes than was previously

thought. This observation will have major implications for the

design of new-generation Shigella vaccines because vaccine-

induced protection is thought to be species- and serotype-

specific.

Work in China and Indonesia developed and validated a new

serological method for detecting culture-negative typhoid fever,

which can be used in evaluations of typhoid vaccines.

Large-scale demonstration projects of Vi polysaccharide

vaccine against typhoid fever were launched in approximately

150,000 subjects in China, Indonesia, Pakistan, and Vietnam.

A field site for the study of enteric vaccines was established in

a population of approximately 60,000 persons in the urban

slums of Kolkata, India. A large-scale effectiveness trial of Vi

vaccine against typhoid fever is due to begin in this site in

November 2004.

Studies of rotavirus diarrhea, completed in children in China

and Korea, demonstrated that although the G1-4 serotypes,

conventionally considered to be most prevalent, account for

most cases in China, the G9 serotype is responsible for an

important fraction of cases in Korea.

Population-based studies in China and Vietnam revealed an

unexpectedly high incidence of intussusception in infants, a

finding that indicates that detecting intussusception as a side-

effect of newer generation rotavirus vaccines may be more

difficult in these settings.

Population-based research in Bali, Indonesia, demonstrated an

incidence of Japanese encephalitis that is among the highest in

the world, contradicting the prevailing wisdom that Japanese

encephalitis is not a major problem in Indonesia and

suggesting that vaccination against Japanese encephalitis

needs to be considered for Indonesia.

An innovative, population-based computerized database,

linking vaccination histories to severe disease outcomes in Nha

Trang, Vietnam, was successfully established. It demonstrated

that a mass immunization of Vietnamese children and

adolescents against measles was not associated with

2

Letter from the Director

Dr. John D. Clemens, Director of the IVI

significant side-effects.

Technical assistance and training has continued to be a major

component of the IVI’sprograms. The Institute has continued to

participate in the Global Training Network of the WHO. The IVI’s

Annual International Course on Vaccinology, including basic

science, clinical, epidemiology, and policy topics, given in each of

the past four years with support from the Bill & Melinda Gates

Foundation, GlaxoSmithKline, the Rockefeller Foundation, and

Sartorius, expanded in 2004. In addition, during the past year, in

collaboration with GlaxoSmithKline, the IVI offered its first

courses on Good Clinical Practices for clinical trials to public-

health professionals in developing countries. With support from

the Bill & Melinda Gates Foundation and AusAID, the IVI

provided technical assistance to vaccine producers and national

regulatory authorities in China, India, Indonesia, Pakistan, and

Vietnam. Finally, in 2004, IVI scientific staff offered a Masters-

level course in vaccinology for students at the Seoul National

University School of Public Health. Several IVI scientists hold

adjunct professor appointments at Seoul National University, and

a Masters-level degree in vaccinology to be offered by Seoul

National University and supervised by the IVI is an important goal

for the future.

A watershed event in the IVI’s history was the completion in

mid-2003 of the new IVI headquarters building, located on the

campus of Seoul National University and generously provided by

the Republic of Korea. The building has 18,000 square meters of

floor space, including state-of-the-art laboratories, offices,

meeting areas, animal facilities, and a vaccine pilot production

plant. Under the leadership of Doctor Aldo Tagliabue, Deputy

Director for Laboratory Sciences, a Laboratory Science Division

is under development in the headquarters building. The Division

already consists of laboratories devoted to immunology,

molecular microbiology, and vaccine development. The Division

has been energized by the return to the IVI of talented young

Korean scientists sent by the IVI for two-year post-doctoral

fellowships at outstanding vaccinology laboratories at

Gothenburg University, Harvard University, Institut Pasteur, the

University of Alabama, and the University of Maryland. Although

the IVI laboratories are still in the process of being equipped, IVI

scientists have already embarked upon several important

research programs, including research on the basis of antigen

presentation in mucosal immunity; the evaluation of human

serological and cellular immune responses to infections and

vaccines; the genetic profiles of human bacterial pathogens;

improved manufacturing processes for killed, oral cholera

vaccine; and development of a subunit vaccine against Shigella.

With the completion of the IVI headquarters building and the

launch of the IVI’s Laboratory Sciences Division, the stage is

now set for the realization of the dream of the IVI’s founders: a

center devoted to vaccine science for developing countries, with

activities spanning the entire vaccine continuum, from vaccine

discovery, to vaccine production, to vaccine evaluation, to

vaccine introduction. We look forward to working with the global

public-health community in this important endeavor.

Sincerely,

John Clemens

3

Dr. John Clemens with President Roh and First Lady Ms. Kwon Yang-suk at IVI headquarters in Seoul

Introduction

Diseases of the Most Impoverished: Typhoid Program

Diseases of the Most Impoverished: Cholera Program

Diseases of the Most Impoverished: Shigellosis Program

Diseases of the Most Impoverished: Existing Data Collection Program

Pediatric Dengue Vaccine Initiative

Japanese Encephalitis Program

Respiratory Encapsulated Bacteria Program: Haemophilus influenzae type b (Hib) Disease

Respiratory Encapsulated Bacteria Program: Pneumococcal Disease

Rotavirus Diarrhea Program

Vaccine Safety Program

Division of Translational Research

Overcoming Hurdles to New Vaccine Introduction

Much has been written about the scientific challenges of

vaccine discovery and about strategies to improve the process of

discovering new vaccine candidates. There are many institutions

around the world, ranging from industrial corporations to

academic laboratories, attempting to overcome these challenges.

As well, the financial hurdles and administrative obstacles that

impede the movement of new vaccines into developing countries

are well known. Less well appreciated is the fact that, even for

exciting new vaccine candidates that have been discovered, there

are other, formidable scientific challenges that can impede their

introduction into public-health programs in developing countries.

These scientific challenges are of three types. Firstly, a

vaccine candidate may languish on the laboratory shelf without

an opportunity to be tested in humans. This developmental

impasse is most notorious for orphan vaccines, targeted to

diseases that are of little or no interest to populations in

industrialized countries and that have limited potential profitability

for vaccine producers. Examples of such vaccines include those

directed against leishmaniasis, hookwarm, and schistosomiasis.

Because such diseases primarily affect developing countries and

because affluent travelers to developing countries do not have a

particularly high risk of contracting these diseases, there is little

economic incentive for vaccine producers to undertake

expensive clinical development programs for these vaccines.

Secondly, even for vaccines that are of interest to populations

in both industrialized and less-developed countries alike, there

may be interest in and funding for human studies, but only in

industrialized countries, where the most profitable markets are

located. Indeed, conducting clinical development in developing

countries in parallel with clinical development in industrialized

countries risks delays in licensure in the latter, with major

potential losses of income. This creates a problem for developing

countries, because the results of studies done in populations in

industrialized countries do not always predict the performance of

5

IVI senior scientist Dr. Lorenz von Seidlein visits a DOMI field site in North Jakarta,Indonesia, in January 2003.

Vaccines for children in developing countries face significant obstacles.

Introduction

a vaccine in developing country populations. Such has been the

case for early generation vaccines against rotavirus, which were

highly protective in children in industrialized countries but poorly

protective in developing countries. Too often in the past, studies

of such vaccines have been done in developing countries many

years after licensure in industrialized countries, creating

unacceptable delays in the introduction of the vaccine into

developing countries.

Thirdly, even if a vaccine has been shown to be safe and

protective in developing countries in Phase III trials, in which the

vaccine is given to large groups of people, policymakers may still

have uncertainties about whether an adequate case can be

made for introducing the vaccine into public-health programs in

their countries. This is because the evidence provided by pre-

licensure evaluations, even those done in developing countries,

typically fails to address many of the practical questions about

implementing a new vaccine in real-life programs. The

insufficiency of this downstream evidence constitutes the third

scientific hurdle.

Overcoming these three hurdles requires three types of

translational research. The first scientific hurdle requires that initial

human studies (Phase I) of promising vaccine candidates be

conducted. The second scientific hurdle requires clinical trials in

settings in developing countries, ideally conducted in parallel with

evaluations in industrialized countries. And the third scientific

hurdle requires, for vaccines that have proven safe and effective in

Phase Ⅲtrials in the developing world, a constellation of

epidemiological, clinical, economic, behavioral, and policy

evidence sufficient to inform judgments about whether the

introduction of a new vaccine into public-health programs in a

developing country is rational, feasible, acceptable, and affordable.

The IVI has established a major downstream program of

translational research and technical assistance that addresses

these three challenges in order to accelerate the rational

introduction of new-generation vaccines against enteric and

invasive bacterial infections of children, as well as against

Japanese encephalitis and dengue fever, into programs for the

poor in countries affected by these diseases. These programs

are currently being conducted in Bangladesh, Cambodia, China,

Egypt, India, Indonesia, Mozambique, Pakistan, the Philippines,

the Republic of Korea, Thailand, and Vietnam. Details on the IVI’s

translational research activities for each of these diseases are

given in the sections that follow.

6

Introduction

BackgroundTyphoid fever is a major cause of morbidity with an estimated

global prevalence of between 16 million and 33 million cases and

500,000 to 700,000 deaths per year. Typhoid fever is both a

water-borne and food-borne gastrointestinal infection with an

annual incidence rate approaching one percent of the population

in some endemic areas. The disease typically lasts several weeks

and can lead to serious complications, including gastrointestinal

hemorrhage, perforation of the gut, and shock. Multidrug-resistant

Salmonella typhi has spread into many parts of the world, limiting

the ability to treat the disease with available antibiotics.

In the absence, in many less-developed countries, of near-

term programs to assure safe water and better sanitary

conditions, efforts have also been directed towards primary

prevention through vaccination. The widely available heat-

inactivated, phenol-preserved whole-cell typhoid vaccine, which

provides approximately 65% protection, has limited usefulness

because of the adverse reactions it evokes. However, two

licensed new-generation typhoid vaccines promise protection

without significant side effects: the live, attenuated oral vaccine

Ty21a and the injectable subunit Vi polysaccharide vaccine. Both

Vi and Ty21a vaccines have been shown to be safe.

There are several advantages of Vi over Ty21a for use in

developing countries. First, the protective efficacy of Vi has been

fairly consistent in all field trials, ranging from 64% to 77%, while

the efficacy of Ty21a has varied widely from one geographic

area to another, from as high as 95% to as low as 53%.

Secondly, Vi immunization consists of a single-dose regime,

while Ty21a requires at least three precisely timed doses.

Furthermore, Ty21a is heat-labile and requires storage in a strict

cold-chain, while Vi vaccine has much less strict cold-chain

requirements. Finally, Vi, unlike Ty21a, has not in the past been

protected by patent rights, making technology transfer to local

producers easier and the vaccine less costly to produce. In fact,

the technology for producing Vi has already been transferred to

local producers in Vietnam and China. For all these reasons, Vi

vaccine is considered by most public-health experts to be the

licensed new-generation typhoid vaccine that is best suited for

public-health programs in developing countries. The DOMI

Typhoid Program is consequently targeting Vi vaccine for

accelerated rational introduction into public-health programs.

Although Vi vaccine is particularly appropriate for vaccinating

specific target populations such as school-age children or

adolescents, it also has several limitations inherent to all

polysaccharide vaccines that would make improved vaccines

more attractive for use in routine infant immunization programs.

Firstly, the protective efficacy of Vi vaccine is not complete.

Secondly, like most polysaccharide vaccines, Vi vaccine does

not induce protective levels of antibodies in infants nor does a

booster response of Vi elicit memory responses. Finally, it is not

known whether the protective efficacy of Vi exceeds three years,

so that current recommendations for its use include periodic re-

vaccination.

7

Women get together to participate in a DOMI Typhoid project in Karachi, Pakistan.

Diseases of the Most Impoverished: Typhoid Program

An affordable vaccine that can provide long-term protection in

children and adults, that can induce immunological memory, and

that can be administered at the same time as other routine infant

vaccinations could be readily taken up by programs for the poor

in typhoid endemic countries and could dramatically reduce the

burden of this disease. Therefore, the DOMI program has, since

its inception, also sought to collaborate with public and private

institutions in the development and clinical evaluation of new

promising candidate vaccines.

Progress in 2003-2004Disease burden studies were launched at the inception of the

program alongside the implementation of Vi vaccine

demonstration projects, targeting more than 250,000 people.

Several disease burden evaluations were completed during

2003-2004 in: Hechi city (Guangxi, China); Sultanabad, Hijrat,

and Bilal colonies (Karachi, Pakistan); Hue city (Central

Vietnam); Kolkata (India); North Jakarta (Indonesia); and Dhaka

(Bangladesh). Annual typhoid fever incidence rates of blood-

culture-proven disease in these sites have varied from from 0.1

case per thousand per year in Hechi to 3 cases per thousand per

year in Karachi. The DOMI typhoid fever disease burden studies

have revealed various patterns of typhoid fever. The majority of

cases occur in school-aged children in Eastern Asia; in contrast,

a younger age spectrum in South Asia, particularly in urban

areas, is observed. This suggests that whereas school-based

immunization may be rational for Eastern Asian countries, in

South Asia both school-based and infant immunizations may be

warranted.

These DOMI typhoid fever disease burden studies have also

revealed two unexpected findings. Salmonella enterica serovar

Paratyphi A (S. paratyphi A) is emerging as a major pathogen in

some parts of Asia. In China, it is now much more common than

Salmonella enterica serovar Typhi (S. typhi) and its incidence is

approaching that of S. typhi in Pakistan. Since 1999, S.

paratyphi A has become 1.5 times more prevalent than S. typhi

in Hechi (China) and from 3 to 24 times more prevalent in the

entire Guangxi province. Additionally, in this province, most

enteric fever outbreaks have been caused by S. paratyphi A.

These results challenge the conventional view that more than

80% of enteric fever cases are caused by S. typhi. If this trend

continues, strong consideration will have to be given to

developing bivalent (S. typhi-paratyphi A) enteric fever vaccines

for Asia. In 2003, the UBS Optimus Foundation awarded the IVI

a US$ 714,000 three-year grant to generate the multidisciplinary

evidence needed to inform policymakers in the Chinese province

of Guangxi (population of approximately 50 million) on whether

introducing new vaccines against S. paratyphi A is necessary

and can be accomplished in a sustainable fashion.

Another noteworthy finding is that DOMI serology-based

typhoid fever studies indicate that blood-culture based typhoid

fever may greatly underestimate the real incidence. A new

analytical use of traditional (Widal) and newer generation

serology-based detection methods (Tubex and Typhidot-M) in

culture-negative febrile patients, which diagnoses culture-

negative typhoid cases with 100% specificity, has demonstrated

that the disease burden of culture-negative typhoid fever in these

Asian countries is high. The real burden of typhoid may therefore

be two or three times that revealed by blood-culture methods.

8

Diseases of the Most Impoverished: Typhoid Program

The objectives of the DOMI Typhoid Program are:

To generate and disseminate the evidence needed by policymakers to rationally introduce existing, licensed, new-

generation Vi vaccine. This evidence derives from measuring the disease burden; assessing vaccine efficacy and

effectiveness; evaluating vaccine demand, cost-effectiveness, and acceptability; and analyzing policy strategies for vaccine

introduction.

To assure an adequate and cost-competitive supply of Vi vaccines by assisting the transfer of production technologies to

qualified producers in Asia and by providing training in vaccine production and regulation.

To ensure that the pipeline of newer generation experimental vaccines against typhoid is exploited by accelerating the

development of new candidates and evaluating these vaccines in endemic settings.

To help develop consensus at the national, regional, and international levels on the use of vaccines against typhoid fever.

This important finding has major implications for accurately

estimating the true disease burden and provides a stronger

reason for introducing typhoid fever vaccines.

Data on re-injection safety, effectiveness, and duration of

protection are pivotal to tailoring future Vi vaccination programs.

DOMI has generated policy-relevant data on the safety of Vi re-

injections. In collaboration with the Jiangsu Center for Disease

Control (CDC) in China, a randomized placebo-controlled

double-blinded trial of 998 school children was conducted in

Suzhou city, Jiangsu province, China. Though a statistically

significantly higher incidence of local pain was reported in the Vi

re-injection group, compared to the placebo group and primary Vi

injection group, all of the reported symptoms were restricted to

mild grade reactions. No difference in the frequency of systemic

adverse events was detected. Also a locally produced and

routinely administered Vi vaccine in China was 70% protective

when evaluated in the course of a typhoid fever outbreak in a

middle school (Guangxi). The program has generated evidence

on the duration of Vi polysaccharide protection. A six-year follow-

up of a population that participated in two placebo-controlled,

randomized trials of locally produced Vi vaccine in Guangxi and

Jiangsu, China, indicated that Vi protects for at least three years

after inoculation.

Preliminary cost-of-illness data for typhoid fever indicate a high

economic burden, costing approximately US$ 100 per episode to

a family earning on average US$ 50 per month in a Delhi slum.

More than half of these costs correspond to out-of-pocket

expenses and the rest is borne by the public-health system.

Furthermore the annual expected costs of typhoid fever illness

are approximately US$ 8 for each child 2-5 years old in the

community; these total costs in pre-school children were higher

than for any other age group, especially the institutional costs.

The high disease burden and several-fold higher non-patient

costs of typhoid fever in preschool children compared to older

children and adults imply that attention should also be given to

developing preventive interventions that are efficacious in young

children. These are the first estimates of the costs of illness for

typhoid in a specific community in India, and among the most

detailed estimates available for any developing country, and

should facilitate cost-benefit analyses of various preventive

strategies, including mass and selective immunization.

Other important parallel activities of the program are capacity-

building and facilitating technology transfer for the production of

vaccines by qualified local producers in Asia. Regarding the

former, local scientific staff have received periodic training in

several areas: Good Clinical Practice (GCP) guidelines,

laboratory detection methods, and database management.

Fellowship programs have been launched and project monitoring

teams have been formed among local scientific staff coordinated

by IVI. Technology transfer of Vi polysaccharide production to

BioFarma (Indonesia), Shantha Biotechnics (India), and Amson

(Pakistan) is currently being facilitated by the DOMI program.

Furthermore, the IVI together with local investigators has

launched large Vi effectiveness trials in: Hechi city, China (April

2003); three slums in Karachi, Pakistan (August 2003 and

August 2004); Hue, Vietnam (December 2003); and North

Jakarta, Indonesia (February 2004). These trials have been

performed in accordance with the principles of Good Clinical

Practice. Over 200,000 individuals have been immunized;

typhoid fever surveillance is underway and final results will be

available after two years of follow-up. Each trial administered the

vaccine via the routine public-health system, albeit with different

target age groups and venues, and each trial found that large-

scale administration of Vi vaccine is feasible and acceptable.

Finally, during 2003 the IVI successfully reached an

agreement with Microscience (U.K.) to clinically evaluate its

single-dose, genetically attenuated, live oral typhoid vaccine.This

candidate is the most advanced of any live oral vaccine and is

already in a Phase II outpatient trial in the U.S. Furthermore, the

IVI, together with the National Institute of Child Health & Human

Development (NICHD/NIH), has launched a program of research

and development for Vi conjugate vaccine that includes

laboratory-scale development at IVI laboratories, technology

transfer to qualified manufacturers, large-scale production,

clinical evaluation, and licensure in the countries of manufacture.

Future ActivitiesA mass vaccination campaign with Vi vaccine will be launched

in Kolkata (Nov 2004) targeting 60,000 people. Furthermore,

analysis will be completed of a case-control study conducted in

Jiangsu province in collaboration with the Jiangsu CDC in order

to generate data on the effectiveness of Vi vaccine in another

province in China (besides that reported in Guangxi).

During the year 2004 and beyond, the DOMI Typhoid Program

will conduct a safety and immunogenicity study of a bivalent

vaccine (Meningococcal A and Vi polysaccharide) in Guangxi,

China. It is also anticipated that the DOMI Typhoid Program will

conduct Phase II studies of the Microscience live oral attenuated

typhoid vaccine in Vietnam, while simultaneously setting up a

field site for a Phase III study in that country.

9

10

Diseases of the Most Impoverished: Typhoid Program

In the next few years, the DOMI Typhoid Program and the

Division of Laboratory Sciences will work jointly to ensure the

following:

development of a serum bank at the IVI from the samples

originating in the DOMI typhoid fever study sites;

standardization and optimization of typhoid fever serologic

rapid diagnostic assays;

standardization and validation of an ELISA (enzyme-linked

immunosorbent assay) to measure anti-Vi antibodies; and

research on other molecular markers in relation to vaccine

protection in large efficacy trials.

Finally, the DOMI Typhoid Program increasingly will focus on

synthesizing the results of its multidisciplinary studies into

coherent investment cases that comprehensively analyze the

impact, cost, and cost-effectiveness of different Vi vaccination

programs, and communicating these to local policy makers.

Three countries, Indonesia, Vietnam, and Pakistan, will be the

focus of the first three investment cases for Vi immunization.

These investment cases will be based on a rigorous analysis of

the data emerging from the country-level epidemiological studies

on disease burden, antibiotic resistance, and risk factors;

economic studies on the costs of illness of typhoid fever, on Vi

vaccine delivery costs, and on the public’s willingness to pay for

vaccine; sociobehavioral analyses on public perceptions of the

importance of typhoid fever and the need for vaccinating against

it; demonstration studies on the practical feasibility, acceptability,

and impact of Vi vaccination programs; and policy analyses of

channels for vaccine introduction and financing mechanisms.

IVI Associate Director Dr. Luis Jodar discusses investment cases for the accelerated introduction at the country level of Vi vaccines.

BackgroundCholera remains a serious public-health problem worldwide. In

2002, a total of 142,311 cases and 4,564 deaths were reported

to the WHO from 52 countries, primarily in Africa, Asia, and Latin

America. The true figures are likely much higher due to under-

reporting. Besides the high mortality and morbidity figures,

cholera outbreaks cause economic and social disruption as well.

Providing safe water and food, establishing adequate sanitation,

and implementing personal and community hygiene constitute

the main public-health interventions against cholera. These

measures cannot be implemented fully in the near future in most

cholera-endemic areas. A safe, effective, and affordable vaccine

would be a useful tool for cholera prevention and control.

Considerable progress has been made during the last decade

in the development of new-generation oral vaccines against

cholera. A monovalent (anti-O1) killed, oral cholera vaccine

consisting of inactivated whole cells of V. cholerae supplemented

with a purified recombinant-DNA derived B-subunit of the cholera

toxin (rBS-WC) was developed by Professor Jan Holmgren at

the University of Gothenburg in Sweden. The vaccine was

licensed by the Swedish Bacteriologic Laboratories (SBL) in

several industrialized countries and is used mainly by Western

travelers. Unfortunately, the vaccine is still expensive for public-

health use in developing countries. Starting in the mid-1980s,

following technology transfer from Sweden, Vietnamese

scientists at the National Institute of Hygiene and Epidemiology

(NIHE) in Hanoi developed and produced a killed, oral cholera

vaccine that contains killed whole cells but lacks the toxin B

subunit. The vaccine has undergone field trials in Vietnam and is

locally licensed and used in the country’s public-health

programs. The DOMI Cholera Program demonstrated in head-

to-head immunogenicity trials in Vietnam that the Vietnamese-

produced vaccine, which is considerably less expensive to

produce, was as safe and protective as the SBL vaccine.

The Vietnamese killed, oral cholera vaccine, although safe and

affordable, is only moderately effective (60-70%) after two doses.

For these reasons, investigators have been developing several

new-generation, live-attenuated oral cholera vaccines that could

be administered in single-dose regimens. The first such vaccine

candidate to be tested extensively, CVD 103-HgR, was

developed at the Center for Vaccine Development (CVD) of the

University of Maryland. When a single-dose regimen of this

vaccine was tested in a large-scale, randomized, placebo-

controlled field trial that enrolled more than 67,000 children and

adults in Jakarta, Indonesia, no statistically significant protective

efficacy was shown against the cholera cases identified during 4

years of follow-up. Other live-oral vaccines requiring only single-

dose regimens were also developed at Harvard University.

Especially promising results were obtained with the O1

serogroup candidate, Peru-15. This candidate, which is now

produced by AVANT Immunotherapeutics, has been found to be

safe and highly immunogenic when administered as a single

dose (108 cfu) to North American volunteers.

11

IVI researcher Mr. Mahesh Puri visits an IVI cholera study site in Beira, Mozambique, during the rainy season, when diarrheal diseases reach a peak.

Diseases of the Most Impoverished: Cholera Program

The DOMI Cholera Program has generated data to inform the

introduction of both the internationally and locally-produced killed,

oral cholera vaccines; developed collaborations with producers,

providing technical assistance and facilitating technology transfer

in order to create an ample and cost-competitive vaccine supply;

sponsored clinical trials of Peru-15 in Bangladesh; and

conducted advocacy activities.

Progress in 2003-2004By mid-2003, a prospective, population-based cholera

surveillance study in an urban slum site in North Jakarta,

Indonesia, was completed. The surveillance in North Jakarta is

part of a combined study of the disease burden of cholera,

typhoid fever, and shigellosis, conducted in collaboration with the

National Institute of Health Research and Development and the

Naval Medical Research Unit 2 (NAMRU-2) in Indonesia. The

incidence of detected cholera was highest at 4 cases per

thousand per year in children less than one year of age (Figure

1). The overall incidence of detected diarrhea due to V. cholerae

O1 was 0.5 per thousand per year. V. cholerae O139 was not

detected during the surveillance period.

By early 2004, the first year of a prospective population-based

cholera surveillance study was completed in an urban slum site

in Kolkata, India. Cholera surveillance in Kolkata is part of a

combined study of the cholera and typhoid disease burdens,

which is being conducted in preparation for vaccine trials of

killed, oral cholera vaccine and Vi typhoid vaccine at the same

study site. Similar to the Jakarta data, the disease burden of

cholera was highest among those less than one year of age at

15 cases per thousand person-years and gradually decreased

among the older age groups (Figure 2). The overall incidence

12

Diseases of the Most Impoverished: Cholera Program

The goals of the DOMI Cholera Program are:

To provide the data and analyses necessary for the rational targeting and implementation of vaccines against cholera in

endemic areas.

To facilitate the introduction, in a rational fashion, of killed, oral cholera vaccine into the public-health programs in cholera-

endemic countries in Asia.

To provide pre-licensure clinical evidence of the safety and immunogenicity of at least one experimental cholera vaccine in

a cholera-endemic setting in Asia.

To enhance the global production capacity of killed, oral cholera vaccine by working with international producers, facilitating

technology transfer for local production of the vaccine to qualified producers in Asia, and providing training to improve local

production and regulation of the vaccine.

Figure 1. Annual incidence of V. cholerae by age group in North Jakarta, August2001 to July 2003.

The Cholera Treatment Centre is crowded with patients during the cholera seasonin Beira, Mozambique.

rate of detected diarrhea due to V. cholerae O1 was 2 cases per

thousand person-years. V. cholerae O139 was not detected

during the surveillance period. In May 2003, a cholera outbreak

occurred in Hue city, Vietnam, and its surrounding districts. An

outbreak investigation was conducted that revealed 115

clinically-suspected and laboratory-confirmed cholera cases in

Hue (Figure 3). Interestingly, Hue city was also the site of

cholera vaccination demonstration projects in 1998 and 2000.

Two doses of the Vietnamese killed, oral whole-cell cholera

vaccine were administered during a mass immunization in 13

communities in Hue city from March to April 1998. The second

mass immunization of the remaining 12 communities was

conducted in August 2000. These immunization campaigns

targeted residents one year and older and excluded pregnant

women. A case-control study linking previous vaccination with

cholera was conducted in 2003. It was found that vaccination in

1998 or 2000 was associated with a protection of about 50%.

No protective effectiveness was observed against non-cholera

diarrhea. A feasibility study of the use of an oral cholera vaccine

in Beira, Mozambique, was undertaken in collaboration with the

Mozambique Ministry of Health, the WHO, and Medicins Sans

Frontieres/Epicentre. Mass vaccination with the internationally

13

Stagnant, unclean water and unhygienic conditions are common causes of the DOMI diseases.

Figure 2. Annual incidence rate of cholera by age group in Kolkata, India, May2003 to April 2004.

Figure 3. Outbreak curve of the 115 clinically-diagnosed and culture-confirmedcholera cases by week, Hue city, Vietnam, May to September 2003.

′

licensed rBS-WC, killed, oral cholera vaccine took place from

December 2003 to January 2004. A major outbreak of cholera

occurred in Beira from January 12 to May 26, 2004. A case-

control study found that receipt of one or more doses of the rBS-

WC vaccine was associated with a 76% protection against

cholera severe enough for the patient to have sought care. No

protective effectiveness was observed against non-cholera

diarrhea.

In collaboration with the International Centre for Diarrhoeal

Disease Research, Bangladesh (ICDDR,B), DOMI is conducting

Phase II trials in Bangladeshi adults and children of the Peru-15

live oral vaccine, developed at Harvard Medical School and

produced by AVANT Immunotherapeutics in the U.S. The trials

of safety, immunogenicity, fecal excretion, and genetic stability

of Peru-15 have been completed in adults and toddlers, and

studies in infants are ongoing.

Transfer of the technology for producing the killed, oral WC

cholera vaccine from the National Institute of Hygiene and

Epidemiology (NIHE) in Hanoi, Vietnam, to BioFarma of

Indonesia has been completed and is ongoing for Shantha

Biotechnics in India. For details see the Technology Transfer

section.

Future ActivitiesDOMI has shown that the oral, killed whole-cell cholera

vaccines are safe, effective, feasible to administer, and

affordable (at least for locally-produced vaccine).

An inexpensive, locally produced oral, killed whole-cell cholera

vaccine will achieve widespread international use only after

licensure by a WHO pre-qualified producer. DOMI is working

towards this goal through a technology transfer to Shantha

Biotechnics in India and a large Phase III efficacy trial in Kolkata.

Accelerated, rational introduction of both the internationally and

locally-produced killed oral vaccines will require continued

advocacy at international, regional, and national levels. Policies

for cholera vaccination in endemic areas and for the control of

outbreaks need to be developed.

Aware of the shortcomings of the killed, oral cholera vaccine,

the DOMI Cholera Program is also providing Phase II evidence

of the Peru-15 live oral cholera vaccine in Bangladesh. This new-

generation vaccine is envisioned to be given in a single dose,

with potentially better and longer-lasting protection. The results

so far have shown the vaccine to be safe and immunogenic.

Ultimate deployment of this single dose vaccine in developing

countries will require a large Phase III trial.

14

Diseases of the Most Impoverished: Cholera Program

BackgroundShigellosis causes considerable morbidity and mortality

worldwide. Before the establishment of the DOMI program, there

was very limited information available regarding the country-

specific disease burden of Shigella and the regional distribution

of Shigella species and serotypes that cause shigellosis. As no

vaccine against shigellosis is licensed outside China, these data

are crucial to informing decisions on Shigella research and in

budgeting for the development of future Shigella vaccines.

Results from DOMI policymaker surveys in six Asian countries

done in 2000 showed a high demand for a safe, affordable, and

effective Shigella vaccine, enthusiasm for including such a

vaccine in routine infant immunization programs, and a

corresponding willingness to pay for such a vaccine with public-

and private-sector resources.

While the ultimate goal of shigellosis research is the

development of a safe and protective vaccine candidate, the

DOMI program decided to undertake, even at a relatively early

stage of vaccine development, a translational research agenda

to answer key policy questions about the ultimate deployment of

potential new Shigella vaccines in public-health practice. As it did

for cholera and typhoid, this translational research agenda

included not only epidemiological studies but also: analyses of

the economic consequences of vaccine introduction;

assessments of the perceived importance of the target disease,

the usefulness of current, non-vaccine control measures, and the

need for vaccination against shigellosis; and policy research to

assess potential channels for vaccine introduction, as well as

feasible, transparent, and sustainable mechanisms for financing

the purchase and delivery of the new vaccine.

To assess the magnitude of the Shigella problem, in 2001 the

DOMI Shigellosis Program launched prospective, population-

based disease burden studies in six Asian countries using

standardized epidemiological and laboratory methods. To

increase the sensitivity of the surveillance studies, heath-care

utilization surveys were conducted in each study site to estimate

the number of people likely to be missed by surveillance.

Furthermore, highly sensitive, experimental diagnostic methods

were used to estimate the proportion of infections missed

through the use of traditional microbiological methods.

Embedded in the surveillance studies were social science

studies that allowed the measurement of social perceptions of

the disease and the economic impact of laboratory-confirmed

Shigella cases.

Although at the time of the program’s inception there were

several promising approaches to vaccine development, except

for the Lanzhou FS vaccine, which is not licensed outside of

China, there was no licensed vaccine available to protect

individuals against shigellosis. The major technological platforms

for modern Shigella vaccines included oral live attenuated and

parenteral subunit vaccines. An early DOMI study of a live oral

attenuated SC602 S. flexneri 2a vaccine in Bangladesh showed

poor colonization and immunogenicity in young children (in

15

A child receives rehydration therapy at the International Centre for Diarrhoeal Disease Research, Bangladesh, a collaborating institution in the DOMI program.

Diseases of the Most Impoverished: Shigellosis Program

contrast to very promising results in North American adults).

These findings indicate that live oral Shigella vaccines face

substantial challenges for inducing good immune responses in

Shigella-endemic populations where there may be subgroups

that have high levels of preexisting natural immunity. Additionally,

conjugate vaccines against Shigella looked promising in one

proof-of-principle human efficiency study, but DOMI found no

major manufacturers interested in producing these vaccines, in

part because of the complexity and expense of detoxifying the

lipopolysaccharide (LPS) prior to conjugation and, in part,

because of the limited market in industrialized countries. Thus,

DOMI included in its agenda the development and, if warranted,

the ultimate technology transfer to local producers of a promising

subunit vaccine technology (ribosomal) that is potentially

inexpensive to produce and capable of eliciting T-cell dependent

immune responses in animals, analogous to those elicited by

conjugate vaccines. Details on the development of this vaccine

by the IVI are described in the Laboratory Sciences section.

Progress in 2003-2004By the end of 2003 and the first half of 2004, prospective

population-based two-year disease burden studies of shigellosis

were completed for the six selected study sites, namely:

Zhengding, China; North Jakarta, Indonesia; Kaengkhoi District,

Thailand; Dhaka, Bangladesh; Karachi, Pakistan; and Hue,

Vietnam. In total, 568,000 individuals were under surveillance. In

these study sites 62,867 episodes of diarrhea were detected,

2,944 (5%) of which were shigellosis. Preliminary estimates

indicate very high incidence rates of treated shigellosis in

children under five years of age in China (52 cases per thousand

children per year) and Bangladesh (48 cases per thousand

children per year) (Figure 1).

The incidence of treated shigellosis was observed to be high

not only in children under five years old, but also in the elderly,

resulting in a bimodal disease distribution. Furthermore, to get a

better understanding of the disease burden caused by Shigella in

Nha Trang, Vietnam, real-time TaqMan polymerase chain

reaction (PCR) tests were used to detect Shigella-associated

DNA in fecal specimens. The data from real-time TaqMan PCR

amplification indicated that the culture-proven prevalence of

Shigella among diarrheal patients (3%) may severely

underestimate the true prevalence of shigellosis among treated

episodes of diarrhea, which could be as high as 35%. Following

the example of the study in Vietnam, stool specimens from

Saraburi, Thailand, were evaluated in a similar fashion with

similar observed results. Further studies making use of real-time

TaqMan PCR are planned in the remaining study sites.

Considerable heterogeneity of Shigella species and serotypes

was observed between sites. In five sites S. flexneri was the most

16

Diseases of the Most Impoverished: Shigellosis Program

The objectives of the DOMI Shigellosis Program are:

To measure the disease burden for shigellosis in six Asian sentinel sites, supplementing prospective data with a systematic

collection of existing data.

To explore the perceptions of at-risk communities and health care providers towards shigellosis and a potential shigellosis

vaccine.

To estimate the economic implications of introducing a vaccine against shigellosis.

To accelerate the development of a shigellosis vaccine.

A child with shigellosis receives care in Bangladesh.

frequently isolated Shigella species. In Thailand the large majority

(80%) of shigellosis cases was caused by S. sonnei and

interestingly, in Bangladesh, more than 30% of isolated Shigella

belonged to S. boydii species, which is not commonly observed

either in developed or developing countries (Figure 2). In addition,

DOMI studies detected significant differences in distributions of S.

flexneri serotypes and subtypes between sites (Figure 3).

Since immunity against Shigella is thought to be species- and

serotype-specific, a vaccine against Shigella will need to

comprise a broad “cocktail” of antigens from different Shigella

organisms to have an important epidemiological impact. It is

conceivable that tailor-made vaccines against prevalent Shigella

strains could be developed for certain endemic regions.

Finally, complementing the epidemiological data to enable

rational decisions about introducing new Shigella vaccines, cost-

of-illness studies were completed for Zhengding, China; North

17

Figure 1. Incidence rates of culture-proven shigellosis in six Asiancountries.

Figure 2. Relative distribution ofShigella species in the six DOMIsites in Asia.

Figure 3. Distribution of S. flexneriserotypes in five DOMI sites.

Jakarta, Indonesia; Kaengkhoi district, Thailand; and are in

progress for Dhaka, Bangladesh; Karachi, Pakistan; and Hue,

Vietnam. Surveys collecting socio-behavioral data to ascertain

perceptions both in the community and among health-care

providers about the importance of Shigella and the need for

vaccinating have been completed in Dhaka, Zhengding, North

Jakarta, Karachi, Kaengkhoi district, and Nha Trang.

Future ActivitiesThe collection of epidemiologic disease burden data has been

completed. Analysis of the data is in progress. In-house

development of a ribosomal candidate vaccine against S. flexneri

2a is ongoing (for details see the Vaccine Development and

Process Research section). Clinical evaluation of other vaccine

candidates is under discussion.

BackgroundRecent interviews with policymakers conducted in the DOMI

program highlighted the need for accurate disease burden data

on cholera, shigellosis, and typhoid fever. The DOMI program

has developed a new activity to systematically collect

epidemiological data on diarrhea, cholera, shigellosis, typhoid

fever, and enteric fever between 1991 and 2000 from three

sources: government statistics, representative hospital and

laboratory data, and published and unpublished literature, both

local and international.

The data has been collected for six DOMI participating

countries: Pakistan, India, Thailand, Vietnam, China, and

Indonesia. As a part of this study, the DOMI team has also

developed the Existing Data Collection (EDC) web site

(http://220.93.120.132:10002/main/main.asp). This web site

allows investigators to review materials related to the EDC study,

such as background, methods, data, and preliminary results.

This newly developed tool will be essential in enabling

collaborating economists to appreciate the economic impact of

the target diseases.

Examples of past findings from the Existing Data Collection

Program include recently completed work in China, where

considerable differences were revealed in the distribution of

dysentery between seven regions. High rates were reported from

the North-West (Xingjiang) and South (Guangxi) but not from the

eastern regions (Hebei, Jiangsu). A systematic review of

government data on diarrhea, dysentery, typhoid fever, and

cholera in Indonesia during the decade from 1991 to 2000

revealed a striking increase in the annual incidence of enteric

infections following the onset of the Asian economic crisis in 1997.

This finding may be due to the close correlation between water-

and food-borne gastrointestinal diseases, on the one hand, and

water supply and environmental sanitation, on the other, which is

in turn closely related to national economic well-being.

Progress in 2003-2004In the years 2003 and 2004 special attention has been placed

on the meta-analysis of the data compiled for typhoid fever in

18

The IVI's Existing Data Collection Program is designed to create a database of governmental data, research literature, and hospital records for the DOMI diseases.

Diseases of the Most Impoverished: Existing Data Collection Program

IVI staff in Mozambique conduct a household survey.

Vietnam, Indonesia, and Pakistan as part of the development of

investment cases for the accelerated introduction of Vi typhoid

vaccines in these countries (for details see the DOMI Typhoid

Program). For example, the data used to calculate average

incidence rates in Vietnam originates from routine government

data¹on enteric fever (1991-2003) and the population-based

surveillance study on typhoid fever in Hue city conducted in 2001

by the DOMI program, after accounting for a test sensitivity

multiplier.²

The results of the triangulation of the data suggest that there is

under-reporting of the annual incidences for all provinces in

Vietnam.

Future ActivitiesThe Existing Data Collection Program is an ongoing activity.

New data are continually collected and added to the database

from which a variety of investigators extract relevant information.

19

The goals of the DOMI Existing Data Collection Program are:

To determine the incidence of treated episodes of cholera, shigellosis, and typhoid fever.

To determine the mortality due to shigellosis, cholera, and typhoid fever.

To determine the age-specific incidence and mortality of treated episodes of cholera, shigellosis, and typhoid fever.

To determine the number or fraction of cases requiring hospital admission and the number or fraction of cases treated as

outpatients.

To determine the antibiotic-resistance profiles of the causative organisms.

To determine the distribution of V. cholerae by serogroup, biotype, and serotype, and of Shigella by species and serotype.

¹Statistics on Infectious Diseases 1991-2003. National Institute of Hygiene and Epidemiology, Ministry of Health, Hanoi, Vietnam.

²Crump, J.A. et al. (2003). Estimating the Incidence of Typhoid Fever and Other Febrile Illnesses in Developing Countries. Emerging Infectious Diseases 9(5): 539-544.

BackgroundVaccines against dengue are urgently needed; they offer a

realistic and near-term solution for controling the twentieth- and

twenty-first-century dengue pandemic. Since World War II, the

four dengue viruses, of the genus Flavivirus, have spread

geographically to virtually all tropical countries as a result of

trends in life-style and demographics, such as the population

explosion, growing urbanization, and global mass transportation.

Dengue can be acquired two or more times, and the disease

may be more severe in individuals who, prior to infection, already

have dengue antibodies acquired either passively or actively

from a previous dengue infection. Late in the course of this

enhanced illness, there is the sudden onset of increased capillary

permeability, varying amounts of bleeding, and hypovolemic

shock. Fortunately, modern intensive-care treatment can be life-

saving but, untreated, fatality rates in both adults and children

can be as high as 33%. Each year there are tens of millions of

cases of dengue fever, and several hundred thousand persons

are hospitalized for dengue hemorrhagic fever or dengue shock

syndrome (DHF/DSS). Dengue infections can result in life-long

immunity. Related viruses, yellow fever and Japanese

encephalitis, are successfully prevented by live attenuated

vaccines.

Existing technologies have resulted in a number of robust, live

attenuated dengue vaccine candidates, and several with

commercial pharmaceutical sponsors are in Phase I or II human

testing. One or more of these candidates may be eligible for

Phase III trials in the near future. In December 2001, a meeting

of international medical scientists held in Ho Chi Minh City,

Vietnam, and sponsored by the Rockefeller Foundation and the

IVI, recommended a ten-year plan of action. To accelerate the

introduction of safe and effective dengue vaccines, a new

alliance was formed in mid-2002, the Pediatric Dengue Vaccine

Initiative (PDVI). Governance is provided by the PDVI Board of

Councillors and the IVI Board of Trustees. The PDVI has

received support from the Rockefeller Foundation, and in June

2003, the IVI was awarded a US$ 55 million five-year grant by

the Bill & Melinda Gates Foundation.

Progress in 2003-2004

Establishment of the PDVI

The PDVI Board of Councillors (chaired by Professor Duane

Gubler of the University of Hawaii) met in Geneva, Switzerland,

in April 2003, by conference call in June, and in Washington,

D.C., in November. Doctor Scott Halstead served as Interim

Director until June 2004, when Doctor Harold Margolis was

appointed Director of the PDVI. The Board of Councillors

approved the submission of a grant renewal proposal to the

Rockefeller Foundation, as well as a new grant proposal to the

Bill & Melinda Gates Foundation, and a portfolio of activities with

a budget for 2003.

20

A child with dengue hemorrhagic fever in Ca Mau Provincial Hospital, Ca Mau, Vietnam in 2002

Pediatric Dengue Vaccine Initiative

The PDVI sponsored two scientific meetings in 2003. In April,

the Antibody Protection Against Viral Infection meeting at the

World Health Organization, Geneva, Switzerland, attracted 50

participants. In June, at the University of Vienna, Vienna, Austria,

70 participants attended Dengue Virus: Molecular Basis of Cell

Entry and Pathogenesis.

Disease Burden Studies

To prepare budgets for the purchase of newly introduced

vaccines, governments of dengue-endemic countries need to

estimate the cost burden imposed by nationwide mosquito

control programs and by the deaths, hospitalized and non-

hospitalized illnesses, and loss of work by patients or family

members as a result of the illness. A request for proposal (RFP)

was placed in international journals in August 2003 to find an

institution to manage this program component. Proposals were

received in September and a grant made in October to the

Schneider Institute for Health Policy at the Heller School for

Social Policy and Welfare, Brandeis University, Waltham,

Massachusetts. To date, disease burden studies in El Salvador,

Nicaragua, Panama, Venezuela, Brazil, Cambodia, and Laos

have been received. A consultant visited four Asian countries,

finding a high level of concern regarding the impact of dengue

illness and interest in the purchase and distribution of dengue

vaccines. This report was published.¹

Field Sites

PDVI studies of prospective population cohorts in hyperendemic

countries have dual goals. Initially, they will supply data and

research materials relevant to the outcome of dengue infections:

severe, mild, or inapparent. The clinical, epidemiological, and

laboratory management of these population cohorts will also train

and prepare teams to design and manage Phase III vaccine

efficacy trials. In August 2003, a Scientific Advisory Group was

appointed (chaired by Doctor David Vaughn, Walter Reed Army

Institute of Research), and an RFP was written and advertised in

21

The goal of the Pediatric Dengue Vaccine Initiative is to accelerate the development and introduction ofaffordable dengue vaccines for children in endemic countries. The initiative has four components:

To measure the disease burden of dengue illness in affected countries.

To create two or more new dengue field sites in preparation for Phase III vaccine clinical trials.

To carry out targeted research to achieve safe and effective long term vaccine-induced protection against severe dengue

disease.

To negotiate and form vaccine development partnerships to achieve products designed for and affordable to dengue-

endemic countries.

A child suffering from dengue fever in Kamphong Cham Hospital, Kamphong Cham, Cambodia.

international journals. PDVI seeks to establish or maintain a

study cohort to measure Flavivirus infection and dengue disease

rates in a population at risk for primary and secondary (which will

include tertiary or quaternary) dengue virus infections. It is

planned that these sites will be made available for Phase III trials

of candidate dengue vaccines. As a secondary objective,

organized and funded by the PDVI under a separate initiative,

the cohort study will produce pedigreed clinical samples to

support laboratory-based research on dengue. In response to

the RFP, 22 letters of intent were received by November 15,

2003. These were reviewed and four applicants invited to provide

a full proposal, with a submission date of May 2004.

Vaccine Safety Studies

The goal of this component is to lessen vaccine-related risks

by developing an in vitro test for vaccine recipients that

correlates with protective immunity. It is intended that such a test

will facilitate the design of schedules for administering vaccines

and booster doses that will achieve the desired protective

response. The PDVI is seeking proposals in the following areas:

dengue virus structure; viral and cell receptors and entry

mechanisms; identification of dengue neutralizing, protective,

and enhancing antibodies; and animal models to study natural

and vaccine protection. The RFP was published in international

journals resulting in 78 letters of intent received by November

2003. Twenty-nine candidate investigators were invited to submit

full proposals, and 13 were approved and funded.

Future ActivitiesIn 2004 and 2005 it is expected that new proposals will be

solicited for disease burden studies. Grants will be awarded for

the management of a total of at least three prospective cohort

studies in dengue-endemic areas and, following the

recommendations of a peer-review committee, for ten or more

targeted research proposals. Field site managers and targeted

research investigators will share information at annual meetings

and through an interactive website. At the first meeting, held in

June 2004, efforts were made to standardize reagents, viral

strains, and laboratory methods among PDVI investigators.

22

Pediatric Dengue Vaccine Initiative

¹DeRoeck, D. et al. (2003). Vaccine 22: 121-9.

BackgroundJapanese encephalitis (JE) is a greatly neglected disease of

Asia, affecting virtually all countries of the continent. JE is a viral

infection, transmitted by mosquitoes in mostly rural areas

inhabited by Asia’s poorest populations. Approximately 35,000

cases are reported to the WHO annually. Well over 99% of all

cases of JE reported globally occur in Asia. Because of this

geographical localization to Asia and because JE tends to target

Asia’s poorest people, JE has not attracted the interest or

support of the global vaccine research and development

community. Nor have vaccines against JE been of great interest

to commercial producers.

Korea, Japan, and Taiwan have effectively controlled JE with

vaccines, which are the most effective public-health tools to

protect populations at risk. Despite the success in these three

countries, other countries afflicted with JE have been slow to

pursue the use of vaccines, in part due to an inadequate

appreciation of the actual JE disease burden, as well as of the

cost-effectiveness of vaccinating. In addition, commercially

available vaccines against JE, although protective, are not ideal

due to their side-effects and expense. Similarly, the SA 14-14-2

vaccine developed and used in China, although protective and

apparently safe, has so far failed to gain international acceptance

due to its production in primary cell cultures that are not known to

be free of contaminating infectious agents that might themselves

pose health risks to vaccine recipients. Moreover, local

production of JE vaccines, in both China and Vietnam, occurs

under manufacturing conditions still in need of international

recognition.

Newer generation, potentially safer, but as yet unlicensed

vaccines have been developed against JE. A particularly

attractive vaccine candidate is the so-called “chimeric vaccine”,

in which genes from the JE virus are inserted into the genome of

the existing licensed vaccine strain 17D against yellow fever.

Unfortunately, however, because JE is an “orphan disease”with

little commercial interest, funds have not been available in the

past to conduct the necessary trials of these newer generation

vaccines in humans to determine whether or not they should be

introduced into public-health practice.

The Japanese Encephalitis Program at the IVI was

established in 2001 with the support of the Children’s Vaccine

Program at the Program for Appropriate Technology in Health

(PATH) and the Korean International Cooperation Agency

(KOICA) to conduct a comprehensive set of activities to develop

investment cases for JE vaccine introduction into selected

countries of Asia. The aim is to generate and disseminate the

evidence needed by policymakers for rationally introducing JE

vaccines. This evidence derives from measuring the disease

burden; assessing vaccine effectiveness in public-health

programs; estimating vaccine demand and the cost-effectiveness

of vaccination; and analyzing determinants of and obstacles to

the implementation of JE immunization in public-health

programs.

23

Dr. Liu Wei, an IVI scientist, works with an Indonesian collaborator.

Japanese Encephalitis Program

Progress in 2003-2004

A prospective field assessment of the JE disease burden has

been finalized in Bali, Indonesia. A high annual incidence of

approximately 10 cases per 100,000 children under 12 years of

age was found during surveillance from July 2001 to December

2003. To put this figure into perspective, it is of the same order of

magnitude as the incidence in endemic areas of Thailand,

Japan, Korea, and China before vaccine programs were

launched in these countries. Historically, Asian countries near the

Equator Indonesia, Malaysia, and the Philippines have been

considered to be at low risk for JE. The IVI’s findings challenge

this conventional wisdom and call for more studies of the disease

burden in these countries.

An innovative, controlled and blinded cohort study of the long-

term neurobehavioral sequelae of JE among children

hospitalized for JE in Shanghai, China, has also been completed.

This study revealed a high rate of major neurologic deficits in

survivors 6 to 26 years after acute meningoencephalitic illnesses.

Of the post-JE patients, 22% had objective neurologic deficits

compared with 3% in non-JE encephalitis patients. Moreover,

28% of post-JE patients had subnormal IQs compared to 2% in

non-JE encephalitis patients.

A computerized decision analysis model was developed by IVI

scientists to assess the cost-effectiveness of JE vaccine

introduction for China. This analysis, which used empiric data on

JE incidence and costs from Shanghai, showed clearly that the

two JE vaccines currently in use in China (P3 and SA 14-14-2)

are saving costs for the health-care system in that city.

Compared to the outcome of no JE immunization program, a

program using the P3 vaccine would prevent 420 JE cases and

105 deaths and would save 6,456 Disability Adjusted Life Years

(DALYs) per 100,000 persons. The use of the SA 14-14-2

vaccine would prevent 427 cases and 107 deaths and would

save 6,556 DALYs per 100,000 persons. In Vietnam, the same

methodology was used to estimate the cost-effectiveness of a JE

immunization program that used a locally produced, mouse-brain

derived, inactivated JE vaccine and was delivered either through

the Expanded Program on Immunization (EPI) or by charging a

user’s fee. Compared to a strategy of no vaccinations, the EPI

delivery of the inactivated vaccine to 100,000 persons would

prevent 117 JE cases, 12 deaths, and 1,076 DALYs lost; the

costs of treating acute JE cases would be reduced from US$

29,971 to US$ 4,945. In comparison, modeling a vaccination

strategy with a user’s fee attached shows that 84 JE cases and

771 DALYs would be averted. The net cost of each JE case

avoided was US$ 1,332, and US$ 144 for each DALY averted.

Cost-effectiveness analyses, in cooperation with the Thai

Ministry of Health, are in progress in Thailand.

Finally, the JE program has finished surveys of policymakers

about their perceptions of the importance of JE in their countries,

the need for introducing JE immunization, and determinants of

obstacles to implementing JE immunization in public-health

programs in China and Vietnam. Similar analyses are ongoing in

Thailand, where JE vaccines are being used in the EPI.

24

Japanese Encephalitis Program

The goals of the Japanese Encephalitis Program are:

To generate and disseminate the evidence needed by policymakers to rationally introduce existing, licensed, new-

generation JE vaccine in developing countries of Asia through measurements of disease burden; assessment of vaccine

effectiveness; evaluation of vaccine demand, cost-effectiveness, and acceptability; and analysis of policy strategies for

vaccine introduction.

To assure an adequate and cost-competitive vaccine supply of JE vaccines by the provision of training in vaccine

production and regulation to qualified local producers in Asia.

To ensure that the pipeline of newer generation experimental vaccines against JE is exploited by evaluating these vaccines

in endemic settings.

To help develop consensus at the national, regional, and international levels on the use of JE vaccines.

Future ActivitiesIn the next few years, the IVI expects to complete the

development of investment cases for the rational, accelerated

introduction of JE vaccines in several countries in Asia.

In Indonesia, after the successful completion of the

population-based surveillance study in Bali, local and central

health authorities have requested further studies to address the

feasibility, acceptability, and effectiveness of vaccine

introduction; analysis of the economic consequences of JE

illness; and the cost-effectiveness and policy determinants of

introducing the vaccine. Furthermore, in order to determine the

disease burden of JE in non-Hindu areas (the Bali study

described above was conducted in Hindu populations), the JE

vaccine program will be launching a series of hospital-based

studies in Muslim regions.

In Vietnam, a prospective hospital-based surveillance study

in a northern Vietnamese province linked with economic and

socio-behavioral analyses will be launched. As epidemiological

data becomes available, a large demonstration project will be

conducted using the mouse-brain derived, inactivated JE vaccine

produced by the local Vietnamese manufacturer VaBiotech. It is

hoped that these multidisciplinary studies will provide

Vietnamese policymakers with the analytic framework and data

needed to evaluate its current JE immunization program as well

as to expand it in the most efficient way.

Finally, the Japanese Encephalitis Program will be launching a

multidisciplinary research program in Cambodia. The program

will start with hospital-based surveillance studies and will follow-

up with economic and vaccine demonstration studies if the

epidemiological data justify such interventions.

25

BackgroundGlobally, invasive bacterial disease due to Haemophilus

influenzae type b (Hib) accounts for three to four hundred

thousand deaths and 2.2 million cases annually. While

hospitalizations and deaths are often the most frequently

considered Hib-associated outcomes, neurologic sequelae

following Hib meningitis may occur in 20% to 30% of children

with Hib meningitis. The majority of this disease burden may

occur in populations in developing countries. Hib conjugate

vaccines have been shown to be safe and effective and have

dramatically reduced the incidence of Hib disease when

introduced into routine infant immunization programs. However,

Hib conjugate vaccines have not yet been introduced in many

developing countries in Asia and around the world. A number of

factors may account for this relatively slow integration of safe and

highly effective Hib vaccines, including limitations in

immunization program infrastructure, the cost of vaccines, and a

dearth of Hib disease burden data. In 1997, a number of

countries gathered at an international conference in Bali,

Indonesia, to review and discuss the existing data on Hib

disease. Many countries documented the presence of Hib as a

cause of meningitis, pneumonia, and bloodstream infections,

including life-threatening sepsis. Hib was also identified as the

most common bacterial etiology of these invasive disease

manifestations. At this meeting, it was concluded that while

important data, largely from hospital-based studies, was

available in Asian countries, there was little data that allowed

population-based disease burden estimates. At that time, it was

felt that studies providing population-based data would allow

national agencies to directly and accurately estimate the true

incidence of Hib disease and Hib-associated mortality. In 1997,

few countries in Asia had credible laboratory-based data on Hib

incidence or mortality from which they could begin to estimate

their national disease burdens.

To determine the incidence of invasive Hib disease in selected

countries in Asia, the IVI, together with a group of collaborating

scientists, launched population-based surveillance studies for Hib

meningitis in field sites in Jeonbuk province, South Korea; Hanoi

city, Vietnam; and Nanning city and Wuming and Yongning

counties, China. These field sites were well-known to local

investigators and were chosen because of the high level of

cooperation that could be achieved with local doctors and the

demographic stability of their populations. In Jeonbuk province,

South Korea, from September 1999 to December 2001, 2,176

children were evaluated for possible meningitis, 605 had

26

Prof. Jung Soo Kim (right) of Chonbuk National University Hospital, Korea, reviews digital images of childhood pneumonia for a joint study by the Korean Society forPediatric Infectious Diseases and the IVI in 2003.

Haemophilus influenzae type b (Hib) Disease

Respiratory Encapsulated Bacteria Program

cerebrospinal fluid (CSF) abnormalities indicating suspected

bacterial meningitis but no pathogen identified; six patients had

probable Hib meningitis and eight had confirmed Hib meningitis.

Annual incidence of suspected bacterial meningitis in children

under five years old was 258.4 cases per 100,000 children, and for

probable or confirmed Hib meningitis the incidence was 6.0 cases

per 100,000. Suspected bacterial meningitis incidence was high,

but proven invasive Hib meningitis incidence was low.

Nonetheless, Hib was the leading cause of bacterial meningitis,

although bacterial pathogens were identified in only 4% of

abnormal CSF samples. This may have reflected a truly low

incidence, presumptive antibiotic treatment, or partial Hib

immunization of the population. In Hanoi, Vietnam, from March

2000 through March 2002, among 580 children enrolled in active

surveillance, 254 (44%) had suspected bacterial meningitis, 167

(29%) had probable bacterial meningitis, and 23 (4%) had

culture-confirmed or probable Hib meningitis. Hib meningitis

annual incidence was 12.2 cases per 100,000 in children less

than 60 months in age and 25.7 cases per 100,000 among

children less than 24 months of age. Passive surveillance in

children referred from outside Hanoi identified additional Hib (95),

pneumococcal (23) and meningococcal (5) meningitis cases and

two cases of pneumococcal sepsis. These data suggest that

invasive bacterial meningitis due to Hib and other pathogens is a

major source of morbidity and mortality in Vietnamese children.

In Nanning city, China, and adjacent counties the population-

based study started in 2001 and finished at the end of 2003.

Progress in 2003-2004In Nanning city and Wuming and Yongning counties, China, from

January 2001 through December 2003, 1,192 patients were

evaluated and 287 (24.1%) had suspected bacterial meningitis, 144

(12.1%) had probable bacterial meningitis, and 5 (0.4%) had CSF

27

The objectives of the Hib Disease Program are:

To generate and disseminate the evidence needed by policymakers for the rational introduction of licensed, new-

generation Hib conjugate vaccines. This evidence derives from measuring the disease burden; assessing vaccine

effectiveness; evaluating vaccine demand, cost-effectiveness, and acceptability; and analyzing policy strategies for vaccine

introduction.

To develop consensus at the national level on the use of Hib conjugate vaccines.

A bedside examination of a child with severe diarrheal illness at the Beijing Friendship Hospital, Beijing, China (Credit: Dr. Fang Zhao Yin).

28

Respiratory Encapsulated Bacteria Program

laboratory-confirmed Hib meningitis. Among children aged less

than five years, the annual incidence of suspected bacterial

meningitis was 101.3 cases per 100,000 and the annual incidence

of probable bacterial meningitis was 50.9 cases per 100,000. The

annual Hib meningitis incidence rate was 1.8 cases per 100,000 in

children less than five years old, 3.4 among children aged less than

two years, and 6.9 cases per 100,000 among young infants aged 7

to 11 months. The low rates of laboratory-confirmed Hib meningitis

found in this study suggest the possibility that Hib infections are

unusual in Chinese children compared with other countries or that

one or more factors currently limit laboratory-based detection of Hib

infections. The high rate of probable bacterial meningitis and the

apparent injudicious use of antimicrobials in the field-site population

suggest that additional studies to evaluate Hib vaccine

effectiveness and the attributable fraction of meningitis or

pneumonia due to Hib may be necessary to establish appropriate

Hib immunization policies for infants in China.

These three epidemiological studies done in South Korea,

Vietnam, and China were also unique because they were some of

the first epidemiologic studies on invasive bacterial diseases that

included methods for testing spinal fluid by polymerase chain

reaction (PCR). This testing was incorporated because there was

some information from Asia suggesting that antibiotic administration

to children before coming to the hospital was very common. This

meant that cultures done on spinal fluid or blood might be negative

due to the use of antibiotics. Latex agglutination testing (LAT) was

also used to evaluate spinal fluid specimens that were abnormal (by

biochemical or cytologic tests) but were culture-negative.

Future ActivitiesThe IVI is planning a research agenda that could substantially

contribute to the accelerated introduction of Hib conjugate

vaccines in the region, if funds become available. This research

agenda includes implementing studies of vaccine effectiveness,

cost of illness, cost-effectiveness, and long-term sequelae in

several Asian countries.

The Study Investigative Team for Rotavirus Diarrhea at Ma-An-Shan Hospital, Ma-An-Shan, China (Credit: Dr. Wang Bei).

BackgroundStreptococcus pneumoniae causes high morbidity and

mortality, even in regions where antibiotics are readily available.

It is the single most common cause of community-acquired

bacterial pneumonia, and has become the most common cause

of meningitis in many regions. Pneumococcal disease is

estimated to kill one to two million children under the age of five

each year in developing countries, accounting for up to 20% to

25% of all deaths in this age group. The problem of

pneumococcal disease is being further exacerbated by the rate

at which this organism is acquiring resistance to multiple classes

of antibiotics and the rapid global spread of highly resistant

clones. In developed countries this is necessitating the use of

newer, more expensive alternative antimicrobials, but this option

is not available in the developing world.

A 7-valent pneumococcal conjugate vaccine has recently been

licensed for use in children, is effective against invasive disease,

and provides some protection against nasal carriage and otitis

media. Unfortunately, however, it protects against only 50% to

70% of invasive pneumococcal infections in many developing

countries. Alarmingly, trials of the conjugate vaccine have shown

that although carriage of serotypes targeted by the vaccine was

reduced, the vacated niche was promptly occupied by non-

vaccine serotypes. Thus, the introduction of such vaccines may

simply alter the serotype distribution of pneumococcal disease

rather than reducing its overall impact. In addition, the high cost

of the vaccine is prohibitive for use in developing countries. Other

conjugate vaccines covering 11 serotypes are currently under

development. In collaboration with the Pneumococcal Vaccine

Accelerated Development and Introduction Program (Pneumo

ADIP) at Johns Hopkins University and other partners, and in

order to help answer key policy questions about the ultimate

deployment of pneumococcal vaccines in public-health practice,

the IVI aims to conduct epidemiologic studies in Asia that

measure the actual disease burden of pneumococcus.

Progress in 2003-2004A network consisting of 13 hospitals and departments of

pediatrics in South Korea has been organized to describe

disease patterns in children who are hospitalized with

pneumonia. This study is designed to identify hospitals in which

future prospective disease burden studies can be done in South

Korea. Geographically, the study covers all of South Korea and

includes hospitals where members of the Korean Society of

Pediatric Infectious Diseases (KSPID) are working. IVI scientists

29

Respiratory Encapsulated Bacteria Program

A laboratory scientist working on pneumococcal disease research in Vietnam

Pneumococcal Disease

have visited each hospital to review preliminary results of the

data collected at each individual hospital. Results are now being

prepared for review by members of KSPID and will be published

at the end of 2004 or early 2005.

Future ActivitiesIn collaboration with Pneumo ADIP and vaccine

manufacturers, the IVI will develop and conduct hospital-based

studies to estimate patterns of pneumococcal pneumonia in

children aged less than five years in Vietnam. These studies

will build on existing infrastructure, collaborations, and expertise

among clinicians, laboratorians, and epidemiologists with

experience in conducting population-based surveillance for Hib

disease. In Vietnam, a provisional field site in Nha Trang

province has been identified for a pilot study to ensure that

appropriate screening procedures are in place to identify children

with invasive pneumococcal disease. The first phase of the study

in Vietnam will be conducted over an 8- to 12-month period.

30

The objectives of the Pneumococcal Disease Program are:

To generate and disseminate the evidence needed by policymakers for the rational introduction of new-generation

pneumococcal vaccines through the evaluation of disease burden, vaccine effectiveness, cost of illness, public demand,

and the cost-effectiveness, feasibility, and acceptability of vaccination.

To ensure that the pipeline of newer generation experimental vaccines against pneumococcal disease is exploited and to

evaluate these vaccines in endemic settings in developing countries.

Respiratory Encapsulated Bacteria Program

A health worker prepares to immunize students against typhoid fever in Hue,Vietnam, in November 2003.

BackgroundRotavirus is the most common cause of severe diarrhea in

infants and children less than five years old. Rotavirus also kills

an estimated 440,000 children each year, and in Asia, many of

these deaths occur among the poorest children where access to

health care is limited. A new rotavirus vaccine has been licensed

in Mexico and the Dominican Republic and is likely to be

licensed within the next year in several other countries. As

licensure moves forward, a number of countries have initiated

studies to estimate the local disease burden. These studies are

focused on identifying children with severe diarrhea who require

rehydration therapy.

Rotavirus diarrhea has been identified in every country where

children have been tested. However, few systematic studies

have been conducted in Asia, and in particular, studies in China

have been limited either by the testing methods used or are

applicable only to areas where surveillance was conducted.

Previous studies in South Korea were also limited as they were

based at selected hospitals and conducted surveillance over a

limited period, typically either one rotavirus season (i.e., four to

five months), or were conducted only in hospitals in Seoul. In

both China and South Korea, policymakers now need credible

estimates of the disease burden of rotavirus in order to decide

whether to introduce current and future vaccines. In China and

South Korea, the IVI has launched prospective hospital-based

surveillance for rotavirus diarrhea among children aged less than

five years, as well as studies to characterize G and P types of

rotavirus isolates using genotyping methods (reverse

transcription-PCR).

Intussusception is an acute obstructive process that occurs

rarely in segments of the small intestine in infants and young

children. During the past five years, intussusception gained

increased recognition when, after an oral, live, attenuated rhesus

reassortant tetravalent rotavirus vaccine was introduced in the

United States, intussusception cases were observed in infants

after receiving doses of the vaccine. The IVI has launched

retrospective intussusception studies among children aged less

than five years to determine intussusception patterns in Vietnam

and South Korea. From January 2000 through December 2002,

282 children (168 in Korea; 114 in Vietnam) were diagnosed with

intussusception. In both Korea and Vietnam, 80% of diagnosed

children were aged less than 24 months. In Korea, one

intussusception-associated death was found but none were

found in Vietnam. The mean annual incidence of intussusception

in Korea (43.5 cases per 100,000 for children aged less than five

years) was similar to that in Vietnam (39.3 cases per 100,000).

While clinical patterns of intussusception and diagnostic

approaches varied between Korea and Vietnam, incidence rates

were similar.

31

IVI scientists Dr. Paul Kilgore (third from left) and Dr. Nyambat Batmunkh (second from left) visit Jeongeup Health Center, South Korea, with Prof. Jung-soo Kim (third fromright) of Chunbuk National University Hospital prior to the launch of a rotavirus disease burden study in August 2002.

Rotavirus Diarrhea Program

Progress in 2003-2004In China, from August 2001 through July 2003, prospective

hospital-based surveillance for rotavirus diarrhea among children

aged less than five years was conducted in six sentinel hospitals

using standardized methods for clinical screening, data

collection, and laboratory testing. Rotavirus strains collected from

these children were characterized to describe G and P types

circulating during the study. Among 3,260 children screened for

rotavirus, 1,590 (49%) were positive by antigen detection assay,

and 95% of all the rotavirus episodes reported occurred in the

first two years of life. Among 454 strains typed, the most

common strain (20%) was G3[P8] while 4% contained the G9

serotype. Ongoing efforts are now underway to define more

precisely the burden of rotavirus in urban and rural populations,

as well as the proportion that may be due to unusual or emerging

human rotavirus strains.

In Jeongeub province, South Korea, from July 2002 through

June 2003, a total of 1,920 patients were evaluated for rotavirus

diarrhea, representing one out of every four children in the study

population aged less than five years. Among the 1,080 children

with diarrhea, 200 (18.5%) fecal specimens were rotavirus

positive 175 children visited outpatient clinics and 25 children

were hospitalized. By extrapolating the proportion of rotavirus-

positive patients to all children with diarrhea in the surveillance

system, it was calculated that 356 children suffered from

rotavirus diarrhea in Jeongeub province (311 and 45 clinic visits

and hospitalizations, respectively). Genotyping of rotavirus

strains showed 41% were G9P[8] and 25% were G1P[8]. The

incidence rate for all rotavirus-diarrhea outcomes was 45.9 cases

per thousand in children under five years old. The annual

incidence rate for rotavirus hospitalizations was 5.8 cases per

thousand.

To determine the distribution of rotavirus genotypes in children

throughout South Korea, rotavirus-positive specimens were

collected from July 2002 through June 2003 in eight hospitals of

the Korean Rotavirus Strain Surveillance Network and

genotyped by reverse transcription-PCR. The globally

32

The goals of the Rotavirus Diarrhea Program are:

To generate and disseminate the evidence needed by policymakers to rationally introduce new-generation rotavirus

vaccines. This evidence derives from measuring the disease burden; assessing vaccine effectiveness; evaluating the cost

of illness; assessing the public demand for and the cost-effectiveness, feasibility, and acceptability of vaccination; and

analyzing policy strategies for vaccine introduction.

To ensure that the pipeline of newer generation rotavirus vaccines is exploited by clinically evaluating these vaccines in

developing countries.

Rotavirus Diarrhea Program

IVI senior scientist Dr. Zhi-yi Xu and Dr. Zhao-ying Fang inspect evaluations ofdiarrheal specimens at the National Center for Disease Control in Beijing, China.

Dr. Zhi-yi Xu and Dr. Zhao-ying Fang visit a diarrheal disease clinic in the BeijingFriendship Hospital in Beijing, China.

uncommon G4P[6] type was most prevalent (27%), the newly

emerging strain G9P[8] accounted for 11% of strains, and

globally common genotypes constituted only 55% of the strains

characterized. Ninety percent of G4P[6] strains were detected in

specimens from neonates. Common genotypes were responsible

for a rotavirus epidemic that began in January and ended in May

2003, but G4P[6] strains showed an early peak from August

through October 2002 and were detected throughout the

remaining study period. G4P[6] strains were most commonly

identified in large urban centers, but they were absent from two

rural centers. The newly emerging G9P[8] strain represented a

relatively greater proportion of strains from a central region

hospital and two hospitals in southern South Korea. The

identification of novel rotavirus genotypes in this laboratory-

based surveillance underscores the public-health importance of

continued strain surveillance among children for whom

vaccination against rotavirus might be considered.

Future ActivitiesIn collaboration with national leaders, pediatricians, and

national public-health leaders in four Asian countries (Cambodia,

Laos, Mongolia, and Sri Lanka) and supported by the rotavirus

ADIP at PATH, the IVI will conduct a multi-country hospital-

based rotavirus surveillance study that will estimate the

proportion of diarrheal hospitalizations among children under five

years of age who have laboratory-confirmed rotavirus diarrhea

over a 24-month period. Clinical and epidemiologic data will be

combined with characterization data for the strains of rotavirus to

provide a current picture of rotavirus epidemiology in each

country. The WHO Collaborating Centre for Research in Human

Rotavirus will assist countries in characterizing rotavirus strains

by G and P types.

33

BackgroundThe success of vaccines in preventing diseases has created a

sense of complacency about these diseases among the public,

leading to an underestimation of the value of ongoing vaccination

for disease control, and an overemphasis on potential vaccine

side-effects. Allegations about putative severe vaccine side-

effects emerge almost daily in the lay press, reducing public

confidence in vaccines. Recent examples include allegations that

measles vaccine causes autism and inflammatory bowel disease

and that hepatitis B vaccine causes multiple sclerosis. At times

these allegations have led to a reduced public acceptance of

vaccination, with the result that old diseases have re-emerged in

major epidemics, as has been illustrated with pertussis in both

Sweden and the United Kingdom, and more recently with

measles in the United Kingdom. While many of these allegations

about vaccine safety have come from the industrialized world,

progressively, they are emerging in the developing world as well.

To maintain credibility, it has been essential for the public-

health community to evaluate in a timely fashion and with

scientific studies concerns about potential vaccine side-effects.

Because it is usually necessary to address the concerns with

controlled studies in human populations, most of these scientific

studies employ epidemiological methods. However, it can take

years to organize and conduct such epidemiological studies.

Because of the need for much more rapid epidemiological

analyses, several countries in the industrialized world, including

the United States and the United Kingdom, have created large,

computerized, population databases that contain linked

information on all vaccines received and all illnesses occurring in

defined populations of children. With such a database, one can

immediately address a concern as to whether “vaccine X causes

disease Y”by comparing the rates of disease Y in children who

received vaccine X versus those who did not. Because the data

is computerized in a continuously updated database, the analysis

can be done very rapidly and cheaply. Moreover, because the

databases are continuously updated and are large, the analyses

can address safety concerns in current populations of children

and can evaluate very rare, but serious potential side-effects.

With the exception of one pilot project in Vietnam, large, linked

computerized databases for evaluating concerns about vaccine

safety do not exist in the developing world. Yet concerns about

potentially serious vaccine side-effects are beginning to emerge

in developing countries and could threaten vaccination programs

for vulnerable children in these settings. A recent example was a

publication in the British Medical Journal that reported that DTP

(diptheria, tetanus, pertussis) vaccine elevates the overall risk of

death in infants and children in Guinea Bissau. If this association,

which was not substantiated in replication studies, had resulted

in the withdrawal of DTP vaccine, the rebound in deadly cases of

whooping cough could have been disastrous. Clearly, large-

linked databases, similar to those in the industrialized world,

34

Vaccine Safety Program

IVI scientist Dr. Mohammad Ali and IVI fellow Dr. Vu Dinh Thiem train community workers on vaccine safety at the Khanh Hoa Health Service office in Nha Trang, Vietnam,in August 2002.

need to be developed in the developing world.

To date, there has been relatively little experience in

establishing large, linked databases for evaluating vaccine safety

concerns in developing countries. Creating such systems in

developing countries will entail several challenges not

encountered in industrialized settings: poor recording of

vaccination histories, limited clinical facilities for making accurate

diagnoses in patients who present themselves for care, lack of

standardized systems for coding such diagnoses, and limited

capabilities in creating computerized databases.

The IVI has created a large, linked database for a semi-rural

province in central Vietnam to allow the systematic collection and

analysis of adverse events potentially related to vaccinations.

The design overcomes several problems inherent in databases

of medical events and vaccinations in developing countries.

Medical identification cards with permanent, unique identification

(ID) numbers were distributed. Assigning a permanent ID

number to each resident avoided the ambiguities of ID numbers

based on addresses. Medical records of all admissions were

coded according to the International Classification of Diseases

(ICD-10) and transcribed into a computer system. Project staff

checked records on vaccinations and hospital admissions

35

The objectives of the Vaccine Safety Program are:

To develop model, large, linked databases for use in scientific evaluations of vaccine safety concerns in selected

developing countries in the Asia-Pacific region.

To validate the accuracy of these databases.

To demonstrate the use of these databases in evaluating the safety of routine childhood vaccines in each of the settings for

the model databases.

A child getting vaccinated in Karachi, Pakistan

through regular household visits. Data describing vaccinations

and medical events were linked to the data collected by the

project staff in a computer system.

Progress in 2003-2004During the study period, September 2002 to July 2003, a total

of 107,022 immunizations of children in a catchment area in Nha

Trang, Vietnam, an area with a population of about 350,000,

were recorded. Five vaccines, BCG, DTP, oral polio (OPV),

hepatitis B, and measles were provided free of charge by the

national immunization program. Target population sizes and

vaccine coverage are shown in Table 1.

The number of medical events recorded in the target

population was 32,527. The majority of the medical events,

22,005 (68%), were recorded in the Nha Trang provincial

hospital; 7,918 (24%) were recorded in Ninh Hoa hospital; and

the remaining 2,604 events were recorded in six polyclinics.

Overall, the study detected nine cases of intussusception

resulting in an intussusception rate among children five years old

or younger of 3.2 per 10,000 per year. Seven (77%) of the

intussusception cases were male and all but two of the patients

were below one year of age (the mean age was eight months).

The study recorded 20 episodes of convulsions, six of which

were in children under two years of age. None of the convulsions

were detected within 30 days of vaccination. A patient’s distance

from the hospital had some effect on health-care utilization.

Individuals living near the two hospitals had higher rates of

reported medical events compared to individuals living further

away from the hospitals.

A mass measles vaccination campaign was conducted in the

study area in March and April of 2003. The aim of the campaign

was to provide a measles vaccination to children between nine

months and ten years of age, regardless of their previous history

of measles vaccination. Children already vaccinated against

measles received a booster dose. Parents and guardians of

eligible children residing within the catchment area were invited

to participate in the campaign. There were 61,856 children

between nine months and ten years of age registered in the

vaccine safety datalink and eligible for a measles vaccination.

The study documented vaccinations of 53,267 children resulting

in an estimated 86% coverage. The mean age of the children

participating in the campaign was six years. There were 337

medical events reported during the 60 days before the

vaccination, and 355 medical events were registered following

the vaccination. Incidence rate ratios for the ten most frequent

presentations are shown in Table 2. No cases of syncope, local

reactions, allergic reactions, or encephalopathy were detected.

There was no statistically significant difference in the incidence

rates of medical events detected by the datalink before and after

the mass measles vaccination.

Between September 2002 and September 2003 the study

36

Immunization Target population % Coverage

BCG

DTP1

DTP2

DTP3

OPV1

OPV2

OPV3

HepB1

HepB2

HepB3

Measles 1

Measles vaccination campaign

4,568

4,485

4,240

3,926

4,505

4,276

4,021

4,568

4,469

4,013

2,095

61,856

94.2

93.7

92.8

87.7

94.1

93.7

89.1

78.3

75.6

67.5

91.2

86.1

Vaccine Safety Program

Table 1. Target population and coverage with BCG vaccine; diphtheria, tetanus,pertussis vaccine (DTP); oral polio vaccine (OPV); hepatitis B vaccine; andmeasles vaccine in Nha Trang, Vietnam, in 2002-2003.

Presentation

Acute respiratory infection

Gastroenteritis

Pneumonia

Tonsillitis

Pharyngitis

Asthma

Skin infection

Dengue

Lymphadenitis

Convulsions

During 60 days

before vaccination

n=53,267

63

59

22

14

10

9

5

3

4

1

During 60 days

after vaccination

n=53,267

69

45

34

16

10

8

8

4

3

3

Rate ratio

adjusted

for age

1.18

0.86

1.66

1.12

1.00

0.87

1.63

1.31

0.80

3.21

95% confidence

interval

0.84 to 1.65

0.58 to 1.26

0.97 to 2.84

0.55 to 2.30

0.41 to 2.40

0.34 to 2.27

0.53 to 5.00

0.29 to 5.85

0.18 to 3.57

0.33 to 30.90

Table 2. The ten most frequently observed medical events following the measles vaccination campaign in in Khanh Hoa province, Vietnam.

detected 33 deaths in children under 15 years of age. The mean

age of the 33 children was 6.2 years. None of the children had a

vaccination within 30 days of their death. The presumptive cause

of death was reported for seven children, three of whom died of

pneumonia and one child each died of gastroenteritis, congenital

heart disease, hydrocephalus, and leukemia.

The detection of operational problems was an essential part of

the study. Medical ID (MID) cards were distributed to all 67,129

households in the study area to facilitate the retrieval of the ID

number of any patient presenting him of herself to health-care

providers. However, in 99% of visits to participating health-care

providers, the parents or guardians failed to bring the MID card.

Repeated attempts by political leaders and representatives of the

public health-care system to encourage the population to bring

the MID card when requesting medical services did not improve

compliance. In the absence of an MID card, a computer-based

ID search program was used to identify patients. This computer-

based system was able to identify 4,548 children (73%) out of

6,272 children presenting for care in the target age group. A

second problem detected was the large discrepancy between

the number of visits to health-care providers reported by the

health-care system and the number of visits reported during

quarterly household visits. Health-care providers recorded 5,707

visits, but during the quarterly validation visits to households, only

2,062 visits to health-care providers were reported. Household

visits therefore proved to be expensive but insensitive in

identifying these visits.

Future ActivitiesThe successful creation of this database in Vietnam, and the

lessons learned from this pilot project, provide a platform for

exporting the system to other developing countries. In the

future, the IVI expects to create and validate model large,

linked, computerized databases in several developing countries

in the Asia-Pacific region.

37

Introduction

Vaccine Development and Process Research

Mucosal Immunology

Cellular Immunology

Humoral Immunology

Molecular Microbiology

Technology Transfer Program

Division of Laboratory Sciences

Vaccines at a Turning PointVaccines and vaccination are at a turning point. The

development of new vaccines and the accelerated introduction of

existing vaccines face several challenges.

First, the rapid development and introduction of new vaccines

for populations in developing countries needs a cost-competitive

and sustainable supply of these vaccines. Although vaccination

has been demonstrated to be the most effective way to prevent

infectious diseases, its major public-health impact has been

restricted essentially to the control of a limited number of human

diseases, including smallpox, poliomyelitis, tetanus, diphtheria,

pertussis, and measles. An inequity in access to existing and

newly licensed vaccines has increased over the past two

decades as new vaccines have become available at prices that

most low-income countries cannot afford. Until recently, many of

the poorest countries lacked the capacity to deliver existing

vaccines, let alone add newer, more expensive ones such as the

hepatitis B vaccines and Haemophilus influenzae type b (Hib) or

pneumococcal conjugate vaccines. From the first introduction of

these vaccines in Europe or the U.S., it can take a decade or

more for their adoption in a limited number of developing

countries. For diseases primarily affecting developing-country

populations, prospects that vaccines could be introduced into

public-health programs are limited. The high cost to vaccine

companies of vaccine development or of building additional

production facilities to increase capacity, as well as the high

“opportunity”costs of failing to pursue more profitable projects,

all act as powerful deterrents for these companies. Additional

vaccine development and the establishment of a sustainable

cost-competitive supply of vaccines for the “orphan diseases”of

the poor may therefore also require a number of highly qualified

producers in developing countries that can: (1) acquire the

technology to produce them; (2) produce enough number of

doses at affordable costs; and (3) be appropriately trained in

production, quality control, and regulatory processes.

There is a dearth of institutions with the capacity to transfer

technology to local producers and/or provide continuous assistance in

process research, physicochemical characterization, and quality

control/quality assurance. The IVI, with its new research

laboratories occupying 211,713 square feet of floor space, aims

to become such an institution. The IVI has established a

laboratory dedicated to process research under strictly controlled

Good Laboratory Practices (GLP) conditions for the production of

clinical lots of selected vaccines and for training staff from

producers in selected developing countries who will be ultimately

responsible for large scale manufacturing. The laboratories are

being equipped with modern physicochemical methods that

allow biological products to be characterized with a high degree

of precision. In addition, the IVI is establishing a laboratory for

humoral immunology that will conduct a range of serological

assays to measure the impact of candidate vaccines in

experimental animals and humans. These assays need to be

validated and to be robust and reproducible, thus this laboratory

will also be devoted to the standardization and validation of these

assays. In the area of technology transfer, the IVI has provided

39

Dr. Aldo Tagliabue, Deputy Director for Laboratory Sciences, and Mr. Rodney Carbis, IVI Senior Scientist, at an IVI laboratory.

Introduction

assistance to vaccine producers in China, Indonesia, India,

Vietnam, and Pakistan. This assistance has focused on

upgrading the production quality of existing vaccines, as well as

the transfer of technologies for the production of newer

generation vaccines. These programs take advantage of the IVI’s

international network of vaccine developers and producers,

which serve as sources of new technologies, as well as of the

IVI’s in-house expertise in providing the hands-on assistance

necessary for a successful technology transfer. Specific activities

carried out by the laboratories for Vaccine Development and

Process Research, Humoral Immunology, and the Technology

Transfer Program are described in this section.

A second major challenge is posed by the rapid expansion of

immunization programs worldwide. To cope with it, the

development of safer and more effective immunization delivery

systems are becoming increasingly important. So far, with few

exceptions, most vaccines are administered as part of routine

childhood immunization programs. Today, over 100 million

children are immunized every year throughout the world. It is

estimated that 1.2 billion vaccine injections are performed every

year, and the number of antigens routinely administered is

increasing rapidly. The fact that many vaccines are administered

parenterally necessitates the presence of a health-care

professional to perform the injection. At the same time, it is

anticipated that the majority of new vaccines that will be available

in the next few years will be injectable and the number of

immunization injections could increase to some 3.5 billion a year.

Worryingly, unsafe injection practices may be spreading

diseases such as hepatitis B and C, and HIV. Allegations of

adverse vaccine-related effects that are not rapidly and

effectively evaluated and dealt with can undermine confidence in

a vaccine, and ultimately, have dramatic consequences for

immunization coverage and disease incidence. Immunization via

the oral route offers obvious advantages. Only a few vaccines,

such as those against polio, cholera, and typhoid fever, are

licensed for oral administration. However, diverse antigen

delivery systems are now being developed for the administration

of non-living and living vaccine antigens to mucosal surfaces and

protective vaccine antigens are even being expressed in

transgenic plants, which would then be administered as edible

vaccines. The IVI has established a laboratory of Mucosal

Immunology for the research and development of vaccines that

can be administered via the mucosal surfaces. Specific activities

launched by this laboratory are also described in this section. At

the same time, recent advances in microbial genetics and

immunology have opened the way towards a revolution in

“Vaccinology”. Based on an improved understanding of

microbial pathogenesis and of host defense mechanisms, new

vaccine strategies are now emerging against pathogens for

which conventional vaccine approaches have not worked. To

fully participate in this ongoing revolution, the IVI is establishing

laboratories of Cellular Immunology and Molecular Microbiology.

Research projects being undertaken in these laboratories are

also described in this section.

Finally, a third major immediate public-health threat for the

world in general and the Asia Pacific region in particular is the

emergence of new deadly diseases whose spread will not be

halted by national boundaries. More than thirty new diseases

have emerged or been identified for the first time in the last three

decades, most notoriously HIV/AIDS which now affects around

40 million people. The need for strengthened surveillance, early

identification, and monitoring of emerging infectious diseases in

the Asia Pacific region has been especially heightened by the

recent emergence of bird flu and Severe Acute Respiratory

Syndrome (SARS). The economic and political impact of these

epidemics has been enormous for the countries affected. More

worrying, a virulent new strain of influenza, for example, could

spread much more rapidly than SARS, which is not especially

contagious in comparison to other respiratory diseases, with

even more dramatic consequences. Recent developments in the

fields of molecular epidemiology and population genetics offer

new possibilities for the early identification of hypervirulent

isolates that have been responsible for epidemics across the

world. The IVI wishes to become a major player in the prevention

of potential epidemics of pathogenic infectious diseases through

the establishment of a state-of-the-art laboratory of molecular

epidemiology within its Molecular Microbiology department.

These programs are further described in this section.

The work of the Division of Laboratory Sciences began in early

2004, with orders of equipment, the establishment of safety and

other procedures, and the recruitment of staff. Although research

in this division has barely started, the work in the division is

already taking place. While the laboratory program at the IVI has

been designed to complement and synergize with the IVI’s

already well-established epidemiological and field research

programs, it has also been conceived to participate in the

advances in vaccinology that will contribute to the panel of

clinically available vaccines in the next twenty years.

Introduction

40

BackgroundAs mentioned in the report on the DOMI Shigellosis Program,

existing conjugate and live attenuated Shigella vaccine

candidates have been either difficult to produce on a large scale

or have rendered disappointing results when tested in Shigella

endemic areas. In order to help overcome these obstacles, as its

first in-house vaccine development project, the IVI has initiated

the manufacture of a Shigella vaccine prototype.

This vaccine is based on an old technology developed by

Levenson et al. in the 1970s. The technology is based on

attaching the Shigella O antigen to bacterial ribosomes. The

association of the antigen with the ribosome converts it from T-

cell independent to T-cell dependent, and the ribosome also acts

as an adjuvant that amplifies the immune response to the O

antigen. The vaccine produced by Levenson et al. was shown to

be immunogenic and protective in animal models. Ribosomal

vaccine development was halted, however, due to contamination

with lipopolysaccharide (LPS), which results in excessive

pyrogenicity. In 2000, a new approach was jointly conceived by

the IVI, Institut Pasteur, and the Walter Reed Army Institute of

Research (WRAIR) to reduce the LPS content of this vaccine.

Shigella mutant (msbB) seed strains expressing low LPS activity

were constructed at Institut Pasteur. WRAIR was responsible for

process development (including pyrogenicity tests in animals) for

clinical-grade batches of this vaccine for human testing.

Unfortunately, a shift in WRAIR’sdevelopment portfolio resulted

in the ribosomal vaccine project being abandoned. In 2003, the

IVI has taken on the challenge of a Shigella ribosomal vaccine as

the first developmental project for its new laboratories.

Progress in 2003-2004During the end of 2003 and first half of 2004, fermentation and

optimization of the growth of S. flexneri 2a and S. sonnei strains

were performed at a three-litre scale. Very high cell yields on semi-

defined media (without the addition of any animal components)

were achieved with both strains. Furthermore, downstream

processing to develop the vaccine at a laboratory scale was

launched. A cell disruption procedure has been developed and

shown to be efficient at the laboratory scale, using equipment that

is scalable to production size. A methodology for separating cell

debris from ribosomes has been tested and a methodology for

removing LPS has been developed and validated. Currently only

wild strains have been used in feasibility studies, but as a parallel

strategy the S. flexneri 2a msbB mutant will also be examined as

a candidate vaccine seed strain. A crude ribosomal preparation

has been made to demonstrate feasibility, and characterization of

this and future preparations will follow. Finally, an enzyme-linked

immunosorbent assay (ELISA) is being developed for quantifying

the antigen for in-process and final lot testing. The ELISA uses

polyclonal antiserum against purified LPS of S. flexneri 2a and S.

sonnei obtained from rabbits.

41

Mr. Hyun Jang of the IVI tests laboratory equipment.

Vaccine Development and Process Research

Future Activities

Future activities are directed at optimizing the manufacturing

process, initially at the laboratory scale, then once consistency is

established, on a pilot scale, and finally for full-scale production.

Assays will be developed to monitor and control the manufacturing

process and ensure the final lot meets all the required specifications.

Control testing and final lot requirements will be agreed to, and

perhaps developed with, the appropriate national regulatory

authorities. The vaccine will be tested for safety and immunogenicity

in appropriate animal models at the IVI. Large-scale manufacturing

will be performed under appropriate Good Manufacturing Practices

(GMP) guidelines in order to produce clinical lots for testing in Phase I

and Phase II trials. After the successful completion of all clinical trials

and the demonstration of manufacturing consistency, the technology

will be transferred to selected vaccine producers willing to

manufacture the vaccine at affordable prices for developing countries.

Ultimately this technology could become a platform technology for the

development of vaccines against a wide range of pathogens of great

public-health importance.

The goals of the Vaccine Development and Process Research Program for its Shigella ribosomal vaccineproject are:

To develop a manufacturing process for a Shigella ribosomal vaccine that can be scaled up and easily produced by

vaccine manufacturers in developing countries.

To develop a manufacturing process that specifically addresses the removal of endotoxins.

To demonstrate consistency of manufacture on a laboratory scale.

With the assistance of partner vaccine producers, to scale up the process to pilot (100 litres) and eventually production

scale (1,000 litres).

To produce vaccine lots and validate production facilities.

To develop assays for in-process control and final lot release.

To perform clinical trials with vaccine lots used in validation studies.

To transfer the vaccine technology, including the training of quality control and production staff, to partner vaccine

producers.

Vaccine Development and Process Research

42

BackgroundAs an alternative to the parenteral administration of vaccines,

mucosal vaccination offers obvious safety advantages since it

eliminates the risks of blood-borne infections due to unsterile

needles. Mucosally administered vaccines are generally more

readily accepted than injectable vaccines, and as the current

global polio eradication initiative is demonstrating, offer large

logistic advantages for immunization programs.

Mucosal cells, whether of the digestive, respiratory, or

reproductive systems, are constantly exposed to antigens of

microbial, environmental, or food origin and require an effective

defense system. The mucosal immune system covers over 400

square meters of tissue in humans and the cellular mass far

exceeds the total lymphoid cells found in the bone marrow,

thymus, spleen, and lymph nodes combined. Immune cells

stimulated at one mucosal surface induce local as well as

systemic protection, thus providing the potential for vaccines to

be used for a broad spectrum of infectious diseases.

The successful experience with the oral, trivalent attenuated

Sabin polio virus vaccine, which is the driving force in the global

polio eradication effort, triggered research to develop and license

other mucosal vaccines. Examples include Ty21a, a live oral

typhoid vaccine, CVD 103-HgR, a live oral cholera vaccine, and

whole-cell based killed oral cholera vaccines, as well as nasal

formulations of influenza vaccine. Furthermore, aerosolized

administration of measles vaccine has attracted interest as a

technology for accelerating measles control and elimination

efforts worldwide. The Mucosal Immunology Laboratory was

established to expand on these successes through the research

and development of mucosal vaccines that target infectious

diseases of great public-health importance.

Transcutaneous immunization (TCI) will be the second major

area of research for the Mucosal Immunology Laboratory. TCI,

the simple introduction of antigens to the host using a topical

application to intact skin, may have profound implications for

immunization programs, both for their safety and effectiveness.

From the point of view of safety, TCI is a simple, needle-free

vaccine delivery system with the potential to eliminate the risks

associated with injection devices. The feasibility of TCI is based

on the skin’s role as a potent immunologic site. Hydrating the

skin allows the vaccine to penetrate to the Langerhans cells,

potent antigen-presenting cells found in the superficial layers of

skin. Langerhans cells are abundant in the skin, present in 25%

of the surface area, and are highly phagocytic, eliciting co-

stimulatory molecules and cytokines. Pre-clinical studies have

shown that TCI is able to induce priming and secondary humoral

immune responses, without signs of local or systemic toxicity.

Progress in 2003-2004The first six months of 2004 have been dedicated to setting up

the Mucosal Immunology Laboratory with the equipment, animal

facility, and assays necessary to initiate mucosal immunology

studies. These include:

43

Mucosal Immunology

Dr. Mi-na Kweon, Chief of Mucosal Immunology, working at an IVI laboratory.

Warm and cold rooms, carbon dioxide incubators, balances,

freeze dry apparatus, glassware preparations, autoclave,

ELISA and ELISPOT readers, FACS, an automated Flow

Cytometry Sorter, Confocal Laser Scanning Microscope, and

a real-time PCR system.

An animal facility equipped with one hundred cages and water

bottles for mice.

A method to purify dendritic cells from the spleen and large

intestine. This method will be used to characterize mucosal

dendritic cells after rectal vaccination and rectal inflammation.

A method for studying transcutaneous immunization and

purification of Langerhans cells. This method is now being

used to measure immune responses in mice immunized with

tetanus toxoid antigen together with cholera toxin as a

mucosal adjuvant through the skin.

Future ActivitiesRoles of Dendritic Cells in the Mucosal Immune System

The Mucosal Immunology Laboratory will focus its research

on determining the roles of mucosal dendritic cells in the

development of intestinal inflammation, infection, and allergic

reactions. Dendritic cells are antigen presenting cells that are

likely to be pivotal in the balance between a person’s tolerance

and active immunity to food antigens, pathogenic organisms,

and commensal microorganisms. Specific goals of the laboratory

are to clarify (1) the distinct features of the colonic dendritic cells

in terms of cell subsets and cytokine production and (2) the exact

role of colonic dendritic cells in the development of diseases of

the large intestine.

Transcutaneous Immunization Against Enteric Diseases

As mentioned above, vaccination through the skin is

particularly advantageous, as the epidermis is replete with

Langerhans cells. However, the exact role of Langerhans cells in

inducing mucosal immune responses needs to be clarified. The

goals of the Mucosal Immunology Laboratory in this field are to

better understand (1) how Langerhans cells migrate to the

mucosal compartment after antigen uptake, (2) what other cells

are involved, and (3) whether transcutaneous vaccination is

effective in preventing enteric infections such as Salmonella

typhi and Shigella.

Animal Models for the Development of Mucosal Shigella Vaccines

Many mutant and recombinant Shigella strains have been

developed and tested as candidate vaccines, however, none of

them has yet proven to be sufficiently immunogenic in children

living in the developing world. A major obstacle to optimizing and

rationalizing the preclinical stages of Shigella live-attenuated

vaccine candidates is the lack of an appropriate animal model.

Shigella species do not cause acute rectocolitis in mice, even

upon straight intra-rectal or intra-colonic inoculation. Although a

model of jejunal invasion by Shigella in newborn mice following

intragastric inoculation has recently been developed, this model

does not permit immunological and vaccination studies. Thus,

the Mucosal Immunology Laboratory, in close collaboration with

Professor Sansonetti’s group at Institut Pasteur, will be

conducting research to develop alternative shigellosis murine

models for pre-clinical screening of Shigella vaccine candidates.

The objectives of the Mucosal Immunology Laboratory are:

To facilitate the development of mucosal vaccines by characterizing the mucosal immune system, specifically, to determine

the roles of mucosal dendritic cells in the development of intestinal inflammation, infection, and immunity.

To develop strategies for mucosal vaccines by developing new mucosal vaccines targeting M cells and by establishing

efficient and novel delivery routes for mucosal vaccines, such as transcutaneous immunization.

To develop animal models for mucosal vaccine development.

Mucosal Immunology

44

BackgroundThe Cellular Immunology Laboratory was initiated in March

2004 to conduct studies on the molecular processes involved in

the immunological recognition of microbial antigens and in the

differentiation of cells that mediate effector mechanisms. This

knowledge is required for the rational design of many new

vaccines. Whereas antibody responses are sufficient to protect

against infections by many pathogens such as pneumococci or

meningococci, cellular responses may be needed to prevent

diseases caused by intracellular microorganisms such as

viruses, chlamydiae, certain bacteria, or parasites (e.g.,

toxoplasma, malaria, leishmania). If, as some studies suggest,

CD4 T helper (Th-1) cells are required for the clearance of such

infected cells, vaccines directed against intracellular

microorganisms should induce this pattern of response.

Furthermore, vaccines inducing long-term protection are also

critical to sustaining immunization programs in developing

countries, where re-vaccination constitutes a financial and

programmatic challenge. Long-term protection can be achieved

through the induction of immunological memory. Memory B and

T cells do not prevent infection per se, but they quickly proliferate

and differentiate into effectors upon re-exposure to pathogens.

This rapid recall response is critical in controlling the extent of

infection and preventing disease. There are still many questions,

however, about the role of immunological memory in protecting

against infections. The underlying molecular mechanisms that

induce and sustain immunological memory are also a major

research target of this laboratory.

Progress in 2003-2004The first six months of 2004 have been devoted to equipping

the Cellular Immunology Laboratory and setting up the systems

and assays necessary to measure cellular immune responses.

These include:

A flow cytometry assay with four-color staining to detect the

phenotypes of memory cells (Figure 1).

A proliferation assay based upon the reduction of tetrazolium

salts for determining in vitro cell proliferative activity using

antigenic stimulants or mitogens as positive controls.

ELISA for the detection of human cytokines. The assays will

be used to test the concentration of cytokines from in vitro

supernatant cultures or samples from clinical trials.

Future ActivitiesTwo major projects will be launched to assess cell-mediated

immune responses against enteric pathogens. The first, in

collaboration with Gothenburg University, Sweden, and

Chonnam National University, Korea, will investigate the

importance of CD8 natural killer cells in protecting against V.

cholerae. A second project will measure cell-mediated immune

45

Cellular Immunology

IVI scientific staff doing research in the Cellular Immunology Laboratory.

Naive cells

responses (e.g., changes in cell-mediated immunity and

memory-cell phenotype after vaccination) of volunteers orally

immunized with a live, genetically attenuated Salmonella typhi

strain ZH9, produced by Microscience.

In order to develop the cell-line related assays required to

study the pathogenesis of intracellular bacteria and some

viruses, a cell culture laboratory will be established.

The Cellular Immunology Laboratory will also continue to set

up the following systems and assays: proliferation assay (non-

radioisotope); ELISPOT for the detection of antibody or cytokine

secreting cells; cytometric bead array (CBA) for the detection of

Th1/Th2 cytokines, inflammatory cytokines, and chemokines;

real-time PCR tests for the molecules involved in signaling

pathways; methods for sub-grouping cells after sorting based on

surface phenotype using FACSaria (cell sorter); and the

production of dendritic cells from CD14 derived monocytes.

The objectives of the Cellular Immunology Laboratory are:

To elucidate the cell-mediated immunological mechanisms involved in protection against infections by bacteria

and viruses.

To investigate the underlying mechanisms generating B cell memory responses.

Cellular Immunology

46

Figure 1. CD4 effector memory cells.

BackgroundThe Humoral Immunology Laboratory was established at the

IVI in 2004 to support both disease burden studies and vaccine

development and evaluation activities through the development,

standardization, and validation of assays measuring humoral

immune responses. Laboratory assays as surrogates of

protective immunity are often essential to the approval of

vaccines or to prove that the vaccine can be manufactured to the

same immunological potency. New Hib, pneumocococcal, and

meningococcal conjugate vaccines are good examples of this. It

is essential that the antibody surrogate is based upon a well-

standardized and accepted immune correlate and that the

biological basis of protection is well understood; for example,

neutralization of toxin or opsonophagocytosis of bacteria. The IVI

is developing its laboratory capacity to support its translational

research program by establishing appropriate assays to

demonstrate the immunological potency of vaccines

manufactured by partner producers, as well as evaluating the

humoral immune responses from vaccinated individuals in the

DOMI program’s large demonstration projects for typhoid and

cholera vaccines.

An accurate assessment of the disease burden of infectious

diseases is critical for prioritizing efforts and providing rational

evidence to policymakers of the feasibility and impact of

introducing new vaccine tools into public-health programs. The

availability of accurate, low-cost serological assays for diseases

of the poor may provide improved disease burden estimates and

allow more accurate evaluations of specific disease control

measures, such as drug therapy and vaccines. The situation is

particularly difficult for diseases such as typhoid fever. For

typhoid, although diagnosis is established using a bacterial

culture from biological samples, such as blood or bone-marrow,

culture-based diagnosis has several limitations. One such

limitation is the need for a large blood sample (5 ml), which is

particularly difficult to obtain from young children, and the

variability of the sample depending on the number of days the

specimen was obtained after the onset of illness. Despite the fact

that there are several rapid assays for typhoid fever, including

Felix/Widal, Tubex, and Typhidot, improvements are needed.

The Humoral Immunology Laboratory will be working to improve

current serologic diagnostic assays for evaluating typhoid

infection.

Progress in 2003-2004

Cholera Toxin and LPS Content in WC Cholera Vaccines

In order to facilitate the use of the oral WC cholera vaccine

produced by Vabiotech in Vietnam, the IVI is transferring the

cholera vaccine manufacturing technology from this company to

a number of qualified local manufacturers in Asia, including

BioFarma in Indonesia and Shantha Biotechnics in India (see the

Technology Transfer Program). To assure that the quality control

procedures used by these and other manufacturers of the

vaccine comply with WHO recommendations, the Humoral

47

Humoral Immunology

IVI scientist Dr. Cheol-heui Yun and Prof. Jan Holmgren work on an experiment in Sweden.

Immunology Laboratory will be running three different assays

with the bulk vaccine, namely: (1) a vibriocidal assay for

measuring seroresponses in vaccinees, (2) GM-1 ELISA for

quantitatively measuring the content of whole cholera toxin in the

vaccines, and (3) an LPS inhibition ELISA for measuring the

cholera LPS content in the vaccines. In order to set up the

assays at IVI, staff were trained at Gothenburg University,

Sweden. The GM-1 ELISA has already been set-up at the IVI

laboratories and samples from VaBiotech in Vietnam have been

tested for cholera toxin content. Both the vibrocidal and LPS

inhibition ELISA assays are currently being set up.

Sero-diagnostic Assays for Typhoid Fever

A training course in the three currently available sero-

diagnostic assays was held at the IVI. Samples from surveillance

at a DOMI typhoid field site were analyzed. Head-to-head

comparisons of the three assays, Felix/Widal, Tubex, and

Typhidot, are ongoing using standard parameters, including

sensitivity, specificity, likelihood ratios, and positive and negative

predictive values.

Future Activities

Evaluation of Immune Response to Bacterial Polysaccharide Antigens

For several bacteria the polysaccharide (PS) capsule is an

important determinant of virulence. Serum antibody to the PS

capsule confers protection against encapsulated bacteria by

activating complement-mediated bacteriolysis and/or

opsonization. Most PS vaccines are safe and effective in older

children and adults. However, most PS vaccines are also poor

immunogens in young infants and fail to induce immunological

Humoral Immunology

48

The objectives of the Humoral Immunology Laboratory are:

To establish a reference laboratory for the standardization and validation of serological assays of antibodies against

encapsulated bacteria.

To evaluate humoral immune responses to bacterial polysaccharide antigens.

To develop new low-cost rapid diagnostic tests for targeted infections.

IVI staff working in the Humoral Immunology Laboratory.

memory at all ages. In addition, immune hyporesponsiveness is

observed after repeated vaccination with some PS vaccines

(e.g., group C polysaccharide meningococcal vaccine), which

may represent a problem for individuals requiring long-term

protection. Finally, PS vaccines against encapsulated respiratory

bacteria induce only transient or no protection against bacterial

colonization. To improve current PS vaccines, it is important to

understand the immune responses to bacterial PS antigens. The

Humoral Immunology Laboratory will investigate various types of

model PS antigens, such as LPS of Gram-negative bacteria

(Salmonella typhi, Vibrio cholerae, Escherichia coli, Helicobacter

pylori, etc.), lipoteichoic acid (LTA) of Gram-positive bacteria

(Streptococcus pneumoniae, Staphylococcus aureus, Bacilus

subtilis, etc.), and the capsule PS of S. typhi (Vi) and S.

pneumoniae (serotype-specific PS and C-PS). The project will be

supported for the next three years with a US$ 100,000 grant from

the Korea Research Institute of Bioscience and Biotechnology

(KRIBB).

Reference Laboratory

To complement the translational research programs on

pneumococcal and typhoid fever vaccines, the Humoral

Immunology Laboratory will be setting up a reference laboratory

to: (1) standardize and validate IgG ELISA to measure serotype-

specific antibodies in serum for pneumococcal conjugate and Vi

vaccines, (2) standardize and validate an opsonophagocytic-

killing assay to measure functional antibodies induced by

pneumococcal conjugate vaccines, and (3) establish assays for

serotyping invasive pneumococcal strains.

49

50

BackgroundRecent developments in the fields of molecular epidemiology

and population genetics have altered our perspective on how to

classify the bacteria that cause invasive disease. Molecular

epidemiological studies based on multilocus enzyme

electrophoresis (MLEE) and multilocus sequence typing (MLST)

have demonstrated that, while certain bacterial pathogens such

as Salmonella, Shigella, Vibrio cholerae, and meningococci are

genotypically diverse, specific complexes of related hypervirulent

isolates have been responsible for epidemics across the world.

Horizontal genetic exchange occurs continually within

populations of pathogenic bacteria. This not only provides the

mechanism by which hypervirulent isolates continue to emerge,

through the acquisition of genes that enhance pathogenicity, but

also facilitates the exchange of genes that encode variable

antigens. The latter has important implications for the design of

vaccines because the organism has the ability to switch antigen

genes within the pathogen’s gene pool and thereby evade the

immune response. Molecular epidemiology provides a tool to

predict epidemics caused by hypervirulent clones and to monitor

the effectiveness of vaccination programs.

Progress in microbial genetics and advances in genetic

engineering are an essential part of the ongoing vaccine

revolution. Identifying the molecular basis of virulence and the

microbial antigens essential for inducing successful defense

mechanisms in the host enables the construction of “intelligent”

vaccines, such as genetically engineered, attenuated micro-

organisms or live vectors carrying foreign genes relevant for

protection. For example, the identification of virulence genes in

Shigella, enterotoxigenic E. coli, S. typhi, and V. cholerae has

led, through selective deletion of these virulence genes, to the

production of attenuated strains, and thus of live candidate

vaccines. Such attenuated strains can also be used as vectors

that carry foreign genes in their bacterial genomes. Deciphering

the entire genomes of the most important human pathogens has

also had a marked impact on vaccine development. Genes of

specific interest for vaccine design are identified by a

computerized analysis of genomic sequences and searching for

sequence homologies between different microorganisms. The

Molecular Microbiology Department has been established to

tackle the problems of vaccine development using state-of-the-

art techniques of molecular biology and bioinformatics, and is

divided in two laboratories: Molecular Epidemiology and

Molecular Vaccinology.

Progress in 2003-2004

Establishment of the Molecular Microbiology Department

The department was established by the appointment of Doctor

Jongsik Chun from the School of Biological Sciences, Seoul

National University (SNU), as acting Head in April 2004. Doctor

Chun leads the Laboratory of Bacteriology and Bioinformatics at

Overall work flow for the Molecular Microbiology Department

Molecular Microbiology

SNU. Necessary equipment for the long-term storage of

cultures, molecular typing, microbiology, molecular biology, and

bioinformatics has been ordered. All laboratory functions are

expected to be operational by the end of 2004.

Molecular Epidemiology of Vibrio choleraeVibrio cholerae O1 El Tor strains isolated from the DOMI site

in Mozambique were shown to have a distinctive genomic

feature that differs from other pandemic strains. In order to

understand the identity of these unusual strains, MLST analysis

was employed. A total of nine loci were chosen and are being

sequenced in collaboration with ICDDR,B in Bangladesh. This

information will be used to elucidate the genomic features and

evolutionary origin of these vibrios.

Future ActivitiesMolecular Epidemiology Laboratory

Culture collection: A culture collection system will be

established at the IVI, in order to create an IVI bio-bank. All

biological and logging information will be incorporated and

maintained in an integrated database management system.

Reference laboratory for the molecular epidemiology of

pathogens: The following methods will be established:

automated ribotyping, pulsed field gel electrophoresis (PFGE),

microarray diagnosis, variable number tandem repeats analysis

(VNTR), antimicrobial susceptibility, and general microbiological

diagnosis.

Bioinformatics: A bioinformatics unit will be established to

create an integrated database management system for the

Laboratory Sciences Division. A multi-user, intranet-based

computer server will be generated to store information on

biological resources in the IVI bio-bank (Strains, DNA, sera,

blood, etc.) and to provide sophisticated bio-data analysis in a

user-friendly interface.

Molecular Vaccinology Laboratory

Genetic and functional analysis of virulence factors of

infectious diseases: Many Gram-negative bacterial pathogens

use a type III secretion system to inject virulence factors through

the host cell membrane. The Laboratory of Molecular

Vaccinology will focus on virulence factor(s) involved in the

down-regulation of the immune response. A number of

techniques will be employed: construction of a knock-out

mutation of each virulence factor gene, complemented strain

construction, infectivity and dissemination tests of mutants,

purification of each virulence factor, and biochemical and cellular

analysis of the purified virulence factors.

Analysis of the DNA sequence of virulence plasmids:

Virulence factors, their secretion apparatus, and their regulators

are carried by an extrachromosomal plasmid in some pathogens.

These plasmids are large (50-200 kb), exist in a small number of

copies, and are composed of multiple-origin DNA fragments,

including insert sequences. Virulence plasmids of pathogens will

be collected and their DNA sequences analyzed.

Development of live genetically-attenuated vaccines against

shigellosis: Besides the development of sub-unit vaccines (see

Vaccine Development and Process Research), the IVI is also

interested in the development of improved live-attenuated

vaccine candidates against shigellosis. Using the knowledge

acquired from the research on virulence factors, the Laboratory

of Molecular Vaccinology will focus on the construction of

genetically modified strains and the characterization of these

strains by a number of tests (infectivity, dissemination, and rabbit

and mouse models), which could lead to the development of new

vaccine candidates against Shigella.

The objectives of the Molecular Microbiology Department are:

To establish a world-class standard culture collection.

To establish a state-of-the-art reference laboratory for the molecular epidemiology of pathogens.

To establish a state-of-the-art laboratory for molecular vaccinology.

To establish a laboratory for bioinformatics.

51

52

BackgroundThe introduction and routine use of a vaccine in developing

countries requires a reliable supply of the vaccine at a

reasonable price. For vaccines of importance to developing

countries this will probably require that vaccines be produced by

international manufacturers and by manufacturers in developing

countries.

The quality control and regulatory practices that govern

vaccine production are not optimal in some developing countries.

For this reason, developing countries may be reluctant to obtain

vaccines from other developing countries unless the

manufacturers and their national regulatory authorities (NRA) are

WHO pre-qualified.

The production of vaccines by developing country manufacturers

is dependent on whether these producers have access to

production technologies. For this to happen, there are different

models that can be followed, ranging from an alliance with

established vaccine manufacturers or academic institutions to a

complex series of partnerships with developers and sub-

contractors. These models have rarely been successful in the past.

Implementing the successful and sustainable transfer of vaccine

technologies while honoring patent rights is the goal of the

Technology Transfer Program. It is the intention of the IVI to

thoroughly and continuously train the staff of vaccine manufacturing

partners in production procedures and quality-control testing for any

vaccine that the IVI transfers to developing countries. It is also the

goal of the IVI to work with the appropriate NRAs and to train their

staff in the appropriate vaccine quality-control and release

procedures. Training will take place at the manufacturer’s facility,

the NRA, and on some occasions, at the IVI.

Progress in 2003-2004The IVI is currently transferring manufacturing technology for

killed, oral cholera vaccine, owned by VaBiotech in Vietnam, to

Shantha Biotechnics of India, to BioFarma of Indonesia, and to

Sinovac of China. VaBiotech has been manufacturing cholera

Technology Transfer Program

From left to right, Dr. Aldo Tagliabue (IVI), Dr. Luis Jodar (IVI), Dr. John D. Clemens (IVI), Mr. Varaprasad Reddy (Shantha Biotechnics), and Mr. Rodney Carbis (IVI) inIndia for the Technology Transfer Program.

Killed oral WC cholera vaccine to BioFarma

in Indonesia

Killed oral WC cholera vaccine to Shantha

Biotechnics in India

Killed oral WC cholera vaccine to Sinovac Biotech

in China

Typhoid Vi vaccine to BioFarma in Indonesia

Typhoid Vi vaccine to Shantha Biotechnics in India

Typhoid Vi vaccine to Amson Vaccines & Pharma

in Pakistan

53

vaccine for several years and produces the vaccine for the EPI in

Vietnam, but does not export to any other country. For this

reason, the IVI is also providing assistance to VaBiotech and the

Vietnamese NRA to upgrade the quality of production and

regulation of this vaccine to meet WHO standards. The IVI is

also providing assistance with the transfer of Vi polysaccharide

vaccine to both BioFarma and Shantha, as well as to Amson in

Pakistan.

Future ActivitiesThe Technology Transfer Program will complete the transfer of

cholera and Vi vaccine technologies as described above, and will

begin technology transfer initiatives for both cholera and typhoid

vaccines to other countries. Specific plans are as follows:

Complete and submit to regulatory authorities in India the

documentation required for importing the Vietnamese killed,

WC cholera vaccine in preparation for an upcoming cholera

field trial.

Train IVI scientists in cholera vaccine control assays with a

view to the future training at the IVI of appropriate people from

developing country manufacturers in these assays.

Develop in-house at the IVI a standardized ELISA for the

quantification of antibodies to typhoid Vi vaccine.

Develop a licensing agreement with NIH (U.S.) for typhoid Vi

vaccine technology and Vi conjugation technology for future

technology transfers to developing countries.

Recruit staff to perform technology transfers and training.

Train IVI staff in cholera and typhoid Vi vaccine production and

control testing.

The goals of the Technology Transfer Program are:

To obtain suitable vaccine technologies that can be transferred to manufacturers in developing countries and to review the

suitability of these technologies for transfer.

To hold discussions with selected vaccine manufacturers and the appropriate national regulatory authorities regarding the

introduction of new vaccines.

To train IVI staff in production and quality-control procedures and to provide training in production and quality control to

partner vaccine producers and national regulatory authorities.

To produce small scale lots at partner vaccine producers under IVI supervision.

To assist with obtaining and/or developing all the appropriate documentation for licensing the new vaccine in the specified

country.

Training and Capacity Building

IVI Scientific Publications

Administration and Finance

Organizational Chart

Financial Statements

Donors to the IVI

Korea Support Committee

International Collaborators

Board of Trustees

Building Success

Training on the Clinical Evaluation of Vaccines

For the past four years, the IVI has conducted annual training

courses for professionals in developing countries on the clinical

evaluation of vaccines. The sponsors for these courses have

been the Rockefeller Foundation, GlaxoSmithKline, Sartorius,

and Becton-Dickenson. In 2004, the IVI hosted at its new

headquarters its fourth annual course for a group of participants

that included health professionals from Australia, Bangladesh,

Cambodia, China, India, Indonesia, South Korea, Malaysia,

Nepal, Pakistan, the Philippines, Singapore, Taiwan, Thailand,

and Vietnam. The course aimed at strengthening the overall

vaccinology capacity of countries from the Asia-Pacific region by

providing participants with a comprehensive overview of the

vaccine continuum, from vaccine development, evaluation, and

regulatory principles, to production, introduction, and policy

issues. The new strategy of including representatives from both

developed and developing countries of Asia led to a very fruitful

exchange of perspectives. It is planned that next year’s course

will be followed by a course for the WHO Global Training

Network at the IVI’s headquarters. This course will focus on

evaluating evidence from clinical vaccine trials and will target

national regulatory authorities in developing countries.

Advanced Course in Epidemiologyand Vaccinology at Seoul NationalUniversity

The IVI has established a course on advanced epidemiology

and vaccinology for graduate students at the School of Public

Health at Seoul National University. The course is attended by

approximately thirty students with diverse backgrounds, including

medical and pharmaceutical graduates, nurses, public-health

specialists, and scientists from the private sector. The course

aims to provide students with knowledge and skills that will

enable them to make valuable contributions to vaccine research

and immunization programs. It bridges the disciplines of

epidemiology, laboratory sciences, and public health and policy

Training and Capacity Building

55

Participants in the Fourth International Advanced Course on Vaccinology in the Asia-Pacific region in March 2004.

in order to train or retrain students who wish to work directly on a

multidisciplinary practical approach to the control of infectious

diseases through immunization programs. The goal is to equip

students with specialized skills that will facilitate a career in the

control of infectious diseases as staff of health ministries,

regional or local health departments, national or international

disease control agencies, international aid organisations, or

universities.

By the end of this course, students will have acquired a basic

understanding and knowledge of contemporary vaccinology and

will be able to: (1) demonstrate a basic knowledge and

understanding of the principles underlying immunological and

56

Training and Capacity Building

molecular biological techniques as they are applied to vaccine

development and research; (2) demonstrate an advanced

knowledge and understanding of the role of epidemiology and its

contribution to vaccine introduction; (3) demonstrate knowledge of

methods for the pre-licensure clinical evaluation of experimental

vaccines leading to product licensure and registration; (4)

demonstrate knowledge of methods for post-marketing

assessments of vaccine safety and effectiveness; (5) understand

the principles and approaches to the economic analyses of

vaccines and their impact; and (6) demonstrate knowledge of the

key issues confronting the development of vaccines against

several key pathogens affecting Asian populations.

57

Ali M., Wagatsuma Y., Emch M., Breiman R.F. 2003. Use of a

geographic information system for defining spatial risk for

dengue transmission in Bangladesh: role for Aedes

albopictus in an urban outbreak. American Journal of

Tropical Medicine and Hygiene 69(6):634-40.

Blum L.S., Nahar N. 2004. Cultural and social context of

dysentery: implications for the introduction of a new vaccine.

Journal of Health, Population and Nutrition 22(2):159-69.

Bresee J., Fang Z.Y., Wang B., Nelson E.A., Tam J., Soenarto Y.,

Wilopo S.A., Kilgore P., et al. 2004. Asian Rotavirus

Surveillance Network. First report from the Asian Rotavirus

Surveillance Network. Emerging Infectious Diseases

10(6):988-95.

Butraporn P., Pach A., Pack R.P., Masngarmmeung R., Maton

T., Sri-aroon P., Nyamete A., Chaicumpa W. 2004. The

health belief model and factors relating to potential use of a

vaccine for shigellosis in Kaeng Koi district, Saraburi

province, Thailand. Journal of Health, Population and

Nutrition 22(2):170-81.

Chowdhury A., Ishibashi M., Thiem V.D., Tuyet D.T., Tung T.V.,

Chien B.T., von Seidlein L., Canh do G., Clemens J., Trach

D.D., Nishibuchi M. 2004. Emergence and serovar transition

of Vibrio parahaemolyticus pandemic strains isolated

during a diarrhea outbreak in Vietnam between 1997 and

1999. Microbiology and Immunology 48(4):319-27.

Clemens J., Savarino S., Abu-Elyazeed R., Safwat M., Rao M.,

Wierzba T., Svennerholm A.M., Holmgren J., Frenck R.,

Park E., Naficy A. 2004. Development of pathogenicity-

driven definitions of outcomes for a field trial of a killed oral

vaccine against enterotoxigenic Escherichia coli in Egypt:

application of an evidence-based method. Journal of

Infectious Diseases 189(12):2299-307.

Clements C.J., Larsen G., Jodar L. 2004. Technologies that make

administration of vaccines safer. Vaccine 22(15-16):2054-8.

Deen J. 2004. The challenge of dengue vaccine development

and introduction[editorial]. Tropical Medicine and

International Health 9(1):1-3.

DeRoeck D., Deen J., Clemens J.D. 2003. Policymakers' views

on dengue fever/dengue haemorrhagic fever and the need

for dengue vaccines in four southeast Asian countries.

Vaccine 22(1):121-9.

Dong B.Q., Tang Z.Z., Lin M., Li C.Y., Tan D.M., Liang D.B., Liao

H.Z., Liu X.Z., Quan Y., Fang J.S., Wu X.H., Qin W.W.,

Kilgore P.E., Kennedy W.A., Xu Z.Y., Clemens J.D. 2004.

[Epidemiologic surveillance for bacterial meningitis in 140

000 children under 5 years of age in Nanning district,

Guangxi province]. Zhonghua Liu Xing Bing Xue Za Zhi

25(5):391-5.

England L., Brenner R., Bhaskar B., Simons-Morton B., Das A.,

Revenis M., Mehta N., Clemens J. 2003. Breastfeeding

practices in a cohort of inner-city women: the role of

contraindications. BMC Public Health 3(1):28-36.

Frenck R.W. Jr., Clemens J. 2003. Helicobacter in the developing

world. Microbes and Infection 5(8):705-13.

Ha S.J., Jeon B.Y., Kim S.C., Kim D.J., Song M.K., Sung Y.C.,

Cho S.N. 2003. Therapeutic effect of DNA vaccines

combined with chemotherapy in a latent infection model

after aerosol infection of mice with Mycobacterium

tuberculosis. Gene Therapy 10(18):1592-9.

Han S.H., Kim J.H., Martin M., Michalek S.M., Nahm M.H. 2003.

Pneumococcal lipoteichoic acid (LTA) is not as potent as

staphylococcal LTA in stimulating toll-like receptor 2.

Infection and Immunity 71(10):5541-8.

Hino A., Kweon M.N., Fujihashi K., McGhee J.R., Kiyono H.

2004. Pathological role of large intestinal IL-12p40 for the

induction of Th2-type allergic diarrhea. American Journal of

Pathology 164(4):1327-35.

Jang M.H., Kweon M.N., Iwatani K., Yamamoto M., Terahara K.,

Sasakawa C., et al. 2004. Intestinal villous M cells: an

antigen entry site in the mucosal epithelium. Proceedings of

IVI Scientific Publications

Publications from July 2003 to July 2004

IVI Scientific Publications

58

the National Academy of Sciences USA 101(16):6110-5.

Jodar L., Butler J., Carlone G., Dagan R., Goldblatt D., Kayhty

H., et al. 2003. Serological criteria for evaluation and

licensure of new pneumococcal conjugate vaccine

formulations for use in infants. Vaccine 21(23):3265-72.

Jodar L., Griffiths E., Feavers I. 2004. Scientific challenges for

the quality control and production of group C meningococcal

conjugate vaccines. Vaccine 22(8):1047-53.

Kaljee L.M., Thiem V.D., von Seidlein L., Genberg B.L., Canh

D.G., Tho L.H., Minh T.T., Kim Thoa L.T., Clemens J.D.,

Trach., D.D. 2004. Healthcare use for diarrhoea and

dysentery in actual and hypothetical cases, Nha Trang, Viet

Nam. Journal of Health, Population and Nutrition 22(2):139-

49.

Kaljee L.M., Genberg B.L., von Seidlein L., Canh D.G., Kim Thoa

L.T., Thiem V.D., et al. 2004. Acceptability and accessibility

of a shigellosis vaccine in Nha Trang City of Viet Nam.

Journal of Health, Population and Nutrition 22(2):150-8.

Kang J.O., Kim M.N., Kim J., Suh H.S., Yoon Y., Jang S., Chang

C., Choi S., Nyambat B., Kilgore P.E. 2003. [Epidemiologic

trends of rotavirus infection in Republic of Korea, July 1999

through June 2002]. Korean Journal of Laboratory Medicine

23(6):382-7.

Khiem H.B., Huan le D., Phuong N.T., Dang D.H., Hoang do H.,

Phuong le T., Sac P.K., Chien T.M., Tai L.A., Dan N.T.,

Deen J.L., Seidlein L., Clemens J., Trach D.D. 2003. Mass

psychogenic illness following oral cholera immunization in

Ca Mau City, Vietnam. Vaccine 21(31):4527-31.

Kim Y.D., Park J.K. 2004. Comparison of interval estimation for

relative risk ratio with rare events. Korean Communications

in Statistics 11(1):181-188.

Kweon M.N. 2003. The mucosal immune system. BioWave

5(14):1-22.

Lee J.T., Yu S.S., Han E., Kim S., Kim S. 2004. Engineering the

splice acceptor for improved gene expression and viral titer

in an MLV-based retroviral vector. Gene Therapy 11(1):94-9.

Lim S.H., Koe Y.S., Jo D.S., Lee S.J., Hwang P.H., Kilgore P.,

Nyambat B., Kim J.S. 2003. [Pediatrician perspectives on

the evaluation and treatment of acute gastrointestinal

infections, Jeonbuk, South Korea, 2002]. Journal of the

Korean Pediatric Society 46(12):1217-23.

Magpusao N.S., Monteclar A., Deen J.L. 2003. Slow improvement

of clinically-diagnosed dengue haemorrhagic fever case

fatality rates. Tropical Doctor 33(3):156-9.

Park E., Kim Y. 2004. Analysis of longitudinal data in case-

control studies. Biometrika 91(2):321-30.

Park E.J., Takahashi I., Ikeda J., Kawahara K., Okamoto T.,

Kweon M.N., et al. 2003. Clonal expansion of double-

positive intraepithelial lymphocytes by MHC class I-related

chain a expressed in mouse small intestinal epithelium.

Journal of Immunology 171(8):4131-9.

Putnam S., Frenck R., Riddle M., El-Gendy A., Taha N., Pittner

B., Abu-Elyazeed R., Wierzba T., Rao M., Savarino S.,

Clemens J. 2003. Antimicrobial susceptibility trends in

Campylobacter jejuni and Campylobacter coli isolated

from a rural Egyptian pediatric population with diarrhea.

Diagnostic Microbiology and Infectious Diseases 47(4):601-8.

Qadri F., Ahmed T., Wahed M.A., Ahmed F., Bhuiyan N.A.,

Rahman A.S., Clemens J.D., Black R.E., Albert M.J. 2004.

Suppressive effect of zinc on antibody response to cholera

toxin in children given the killed, B subunit-whole cell, oral

cholera vaccine. Vaccine 22(3-4):416-21.

Rao M.R., Abu-Elyazeed R., Savarino S.J., Naficy A.B., Wierzba

T.F., Abdel-Messih I., Shaheen H., Frenck R.W. Jr.,

Svennerholm A.M., Clemens J.D. 2003. High disease

burden of diarrhea due to enterotoxigenic Escherichia coli

among rural Egyptian infants and young children. Journal of

Clinical Microbiology 41(10):4862-4.

Rhie G.E., Roehrl M.H., Mourez M., Collier R.J., Mekalanos J.J.,

Wang J.Y. 2003. A dually active anthrax vaccine that

confers protection against both bacilli and toxins. Proceedings

of the National Academy of Sciences USA 100(19):10925-30.

Ricci S., Macchia G., Ruggiero P., Maggi T., Bossu P., Xu L.,

Medaglini D., Tagliabue A., Hammarstrom L., Pozzi G.,

Boraschi D. 2003. In vivo mucosal delivery of bioactive

human interleukin 1 receptor antagonist produced by

Streptococcus gordonii. BMC Biotechnol 3(15):1472-6.

Samosornsuk S., Jitsanguansuk S., Sirima N., Sudjai S.,

Tapchaisri P., Chompook P., von Seidlein L., Robertson

S.E., Ali M., Clemens J.D., Chaicumpa W. 2004.

59

Preferences for treatment of diarrhoea and dysentery in

Kaengkhoi district, Saraburi province, Thailand. Journal of

Health, Population and Nutrition 22(2):113-8.

Shepard D.S., Suaya J.A., Halstead S.B., Nathan M.B., Gubler

D.J., Mahoney R.T., Wang D.N., Meltzer M.I. 2004. Cost-

effectiveness of a pediatric dengue vaccine. Vaccine 22(9-

10):1275-80.

Simanjuntak C.H., Punjabi N.H., Wangsasaputra F., Nurdin D.,

Pulungsih S.P., Rofiq A., Santoso H., Pujarwoto H.,

Sjahrurachman A., Sudarmono P., von Seidlein L., Acosta

C., Robertson S.E., Ali M., Lee H., Park J., Deen J.L., Agtini

M.D., Clemens J.D. 2004. Diarrhoea episodes and

treatment-seeking behaviour in a slum area of North

Jakarta, Indonesia. Journal of Health, Population and

Nutrition 22(2):119-29.

Sun L.W., Tong Z.L., Li L.H., Zhang J., Chen Q., Zheng L.S., Liu

J., Xie H.P., Wang C.X., Zhang L.J., Ivanoff B., Glass R.I.,

Bresee J.S., Jiang X.I., Kilgore P.E., Fang Z.Y. 2003.

[Surveillance finding on rotavirus in Changchun children's

hospital during July 1998-June 2001]. Zhonghua Liu Xing

Bing Xue Za Zhi 24(11):1010-2.

Sur D., Manna B., Deb A.K., Deen J.L., Danovaro-Holliday M.C.,

von Seidlein L., Clemens J.D., et al. 2004. Factors

associated with reported diarrhoea episodes and treatment-

seeking in an urban slum of Kolkata, India. Journal of

Health, Population and Nutrition 22(2):130-8.

Tagliabue A. 2003. Mucosal delivery of enteric vaccines.

Vaccines: Children & Practice 6:31-4.

Tong Z.L., Ma L., Zhang J., Hou A.C., Zheng L.S., Jin Z.P., Xie

H.P., Ma L., Zhang L.J., Ivanoff B., Glass R.I., Bresee J.S.,

Jiang X.I., Kilgore P.E., Fang Z.Y. 2003. [Epidemiological

study of rotavirus diarrhea in Beijing, China: a hospital-

based surveillance from 1998-2001]. Zhonghua Liu Xing

Bing Xue Za Zhi 24(12):1100-3.

Von Seidlein L., Greenwood B.M. 2003. Mass administrations of

antimalarial drugs. Trends in Parasitology 19(10):452-60.

Vu D.T., Hossain M.M., Nguyen D.S., Nguyen T.H., Rao M.R.,

Do G.C., Naficy A., Nguyen T.K., Acosta C.J., Deen J.L.,

Clemens J.D., Dang D.T. 2003. Coverage and costs of

mass immunization of an oral cholera vaccine in Vietnam.

Journal of Health, Population and Nutrition 21(4):304-8.

Vu D.T., Sethabutr O., von Seidlein L., Tran V.T., Do G.C., Bui

T.C., Le H.T., Lee H., Houng H.S., Hale T.L., Clemens J.D.,

Mason C., Trach D.D. 2004. Detection of Shigella by a PCR

assay targeting the ipaH gene suggests increased

prevalence of shigellosis in Nha Trang, Vietnam. Journal of

Clinical Microbiology 42(5):2031-5.

Wang M., Dong B., Yang J., Li C., Tang D., Tang Z., Ou S., Zeng

J., Zhang J., Wu X., Page A.L., Acosta C. 2003.

[Comparative research of Widal testing with domestic and

international reagents]. Guangxi Journal of Preventive

Medicine 9(5):302-4.

Wang X.Y., von Seidlein L., Robertson S.E., Ma J.C., Han C.Q.,

Zhang Y.L., Lee H.J., Liu W., Ali M., Clemens J.D., Xu Z.Y.

2004. A community-based cluster survey on treatment

preferences for diarrhoea and dysentery in Zhengding

county, Hebei province, China. Journal of Health, Population

and Nutrition 22(2):104-12.

Wang X.Y., Xu Z., Yao X., Tian M., Zhou L., He L., et al. 2004.

Immune responses of anti-HAV in children vaccinated with

live attenuated and inactivated hepatitis A vaccines. Vaccine

22(15-16):1941-5.

Wu J.H., Wu W.S., Jiang M.B., Zhang G.H., Ren J.Y., Cao H.L.,

Wang X.Y., Xu Z.Y. 2003. [Immune strategy and evaluation

of hepatitis B vaccine]. Chinese Journal of Biology

16(4):247-9.

Yamamoto M., Kweon M.N., Rennert P.D., Takachika T.,

Fujihashi K., McGhee J.R., et al. 2004. Role of gut-

associated lymphoreticular tissues in antigen-specific

intestinal IgA immunity. Journal of Immunology

173(2):762-9.

Yang J., Dong B.Q., Zeng J., Si G.A., Zhang J., Liang G.C.,

Huang H.X., Yang H.H., Ochiai R.L., Danovaro C., Park

J.K., Ali M., Acosta C.J. 2004. [Investigation of resident

environment and health behavior in Hechi city, Guangxi].

Guangxi Journal of Preventive Medicine 10(3):129-31.

Yang J., Dong B., Zeng J., Zhang J., Si G., Zhou T., Zeng H.,

Acosta C., Ali M. 2003. [The use of GIS in typhoid Vi

vaccine trial study]. Guangxi Journal of Preventive Medicine

9(6):321-4.

IVI Scientific Publications

60

Yang J., Dong B., Zeng J., Zhang J., Si G., Zhou T., Zeng H.,

Acosta C., Ali M. 2004. [Use of GIS on epidemiologic study].

Guangxi Journal of Preventive Medicine 10(2):199-21.

Yang J., Wei S., Liu L., Zhang J., Huang L., Wen X., Ochiai R.L.,

Ali M., Acosta C.J. 2004. [Applying verbal autopsy to

determine cause of death aged 5-60 years old in Hechi city].

Chinese Journal of Primary Health Care 18(6):19-20.

Youlong G., Stanton B.F., von Seidlen L., Xueshan F., Nyamette

A. 2004. Perceptions of Shigella and of Shigella vaccine

among rural Chinese: compatibility with Western models of

behavioral change. Southeast Asian Journal of Tropical

Medicine and Public Health 35(1):97-108.

Zeng J., Yang J., Dong B., Zhang J., Liang D., Liang H., Si G.,

Acosta C., Ochiai L. 2004. [A survey of adverse events

following a mass vaccination]. Chinese Journal of Primary

Health Care 18(3):43-4.

Zhang J., Yang J., Dong B., Ali M., Park J.K., Zhou B., Huang X.

2004. [Establishment and use of data management system

in DOMI Hechi project]. Guangxi Medical Journal

26(4):584-5.

Zhang J., Zhou B., Yang J., Dong B., Ali M., Park J.K., Huang H.

2004. [Application of Data Management System in DOMI

Hechi project]. Guangxi Journal of Preventive Medicine

10(2):112-4.

Zhang L.J., Du Z.Q., Zhang Q., Kang H.Y., Zheng L.S., Liu X.M.,

Xie H.P., Yang H.Y., Wang Y.C., Ivanoff B., Glass R.I.,

Bresee J.S., Jiang X., Kilgore P.E., Fang Z.Y. 2004.

[Rotavirus surveillance data from Kunming Children's

Hospital, 1998 - 2001]. Zhonghua Liu Xing Bing Xue Za Zhi

25(5):391-5.

Zhou J.J., Wu W.S., Sun C.M., Dai H.Q., Zhou L., Liu C.B., Cao

H.L., Wang X.Y., Xu Z.Y. 2003. [Long-term evaluation of

immune efficacy among newborns 16 years after HBV

vaccination]. Chinese Journal of Vaccines and Immunization

9(3):129-32.

61

Growing for the FutureThe Administration and Finance division provides logistics

support to the scientific divisions and manages the physical

facilities of the IVI. It is supported by the Accounting Department;

the Human Resources, Travel and Purchasing Departments; the

Computer Services Department; the Library; the Facilities and

Maintenance Department; and the Program Administrative

Department for Translational Research. Additionally, the

Administration and Finance division is supported by a

Government Liaison and Cooperation Unit which looks after

funding and liaison activities with various government ministries

in the host country of South Korea. As the IVI’s activities and

operations grow, and demands increase, the level of

administrative and financial services support will increase

appropriately.

Staff GrowthThe number of staff at the IVI has grown from 17 in 1999 to 79

in June 2004, and the composition of staff has changed

accordingly. In the scientific and technical areas, staff has

increased significantly, from 6 in 1999 to 32 in June 2004.

Scientific and technical support staff increased from 1 in 1999 to

25 in June 2004; administrative support staff has increased from

10 in 1999 to 22 in June 2004.

Revenue GrowthThe IVI’s income has increased from $2.5 million in 1999 to

$10.5 million in 2003. Unrestricted income over this period has

remained at the same yearly level of about $1.45 million, while

restricted project income has increased from $0.68 million in

1999 to $9.1 million in 2003. For further financial details, please

refer to audited financial statements.

Administrative Highlights from June 2003 to June 2004

The IVI moved into its new headquarters building in June

2003, initially occupying the first two floors.

The IVI celebrated its June move with an Inauguration

Symposium titled New Frontiers in Vaccinology Research, a

Scientific Advisory Group Meeting, a meeting of the IVI Board

of Trustees and the Institute Support Council, and played host

to the meeting of the Global Alliance for Vaccine and

Immunization (GAVI) here in Seoul, Korea.

A meeting of the Executive Committee of the Board of Trustees

was held on December 21 and 22, 2003, in Seattle, Washington.

The Division of Laboratory Sciences recruited two senior

positions: a Chief of Mucosal Immunology and a Head of

Vaccine Development. Laboratory equipment started to be

purchased to equip the new laboratories.

Three post-doctoral fellows returned in early 2004 after their

two-year fellowships to assume Research Scientist positions in

the Immunology and Molecular Microbiology laboratories.

Senior staff and key members of the IVI plant a tree in October 2003 to commemorate the sixth anniversary of the IVI.

Administration and Finance

Administration and Finance

62

A joint appointment with the Seoul National University was

made for an acting Head of Molecular Microbiology in 2004.

The Scientific Advisory Group (SAG) held their annual meeting

in Seoul on March 5 and 6, 2004.

A Director for the Pediatric Dengue Vaccine Initiative (PDVI)

was successfully recruited in mid-2004.

Financial Highlights for 2003

The IVI was awarded a $55 million grant over five years (to 2008)

from the Bill & Melinda Gates Foundation for the Pediatric

Dengue Vaccine Initiative (PDVI).

The Korea International Cooperation Agency (KOICA)

provided a grant of approximately $1.5 million over three years

in support of Japanese encephalitis projects in Cambodia,

Vietnam, and Indonesia.

The UBS Foundation awarded the IVI a three-year grant of

$700,000 for studies of paratyphoid fever.

Total revenue received and recognized as income for 2003

was $10.5 million. Compared with revenue in 2002 of $8.8

million, revenue in 2003 reflected a 19% increase.

Unrestricted revenue in 2003 amounted to $1.4 million, while

restricted revenue totaled $9 million.

Operating expenditures increased from $7.7 million in 2002 to

$10 million in 2003, largely due to planned staff increases as a

result of the move to the new headquarters building,

occupancy expenses related to utilities and maintenance in the

new facilities, and an increase in subcontracts that reflect

increases in project funding.

The 2003 year ended with an operating surplus of $851,004.

Current assets make up 96% of total assets, out of which 98%

or $25 million is in the form of cash and bank deposits.

The Institute’s financial position continues to be strong.

Figure 1. Staff Growth from 1999 to2003.

Figure 2. Revenue Growth from1999 to 2003.

63

Organizational Chart

Organizational Chart

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Financial Statements

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Financial Statements

66

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Financial Statements

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Financial Statements

70

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Financial Statements

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Financial Statements

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Donors to the IVICore funding to the IVI is provided by the governments of

Korea and Sweden. In addition, donors from the public and the

private sector provide support for the Institute’s research and

technical assistance activities. The support of the following

donors is gratefully acknowledged:

AusAID

Bill & Melinda Gates Foundation

Children’s Vaccine Program ot PATH

Industry (Aventis Pasteur, Berna Biotech, CJ, Chiron,

GlaxoSmithKline, LG, Merck, Microscience, Nonghyup,

Sartorius, Wyeth)

Japan International Cooperation Agency

Japan Society for the Promotion of Science

Korea International Cooperation Agency (KOICA)

Korea Research Foundation

Korea Research Institute of Bioscience and Biotechnology

Korean Science and Engineering Foundation

Ministry of Education & Human Resource Development,

Republic of Korea

Rockefeller Foundation

Swedish International Development Cooperation Agency

UBS Optimus Foundation

United Nations Development Programme (UNDP)

U.S. National Institutes of Health

Wellcome Trust Labs, Ho Chi Minh city

Korea Support CommitteeA large number of prominent Korean citizens have joined

together to form the Korea Support Committee for the IVI. The

Committee is a vehicle for mobilizing resources within Korea. It is

under the leadership of Korea’s First Lady, Ms. Kwon Yang-suk.

Donors to the IVI and the Korea Support Committee

IVI Director Dr. John Clemens thanks Korea’s First Lady, Ms. Kwon Yang-suk.

Australia: The Queensland Institute of Medical Research

Bangladesh: ICDDR,B; Center for Health and Population

Research; Dhaka Shishu Hospital

Belgium: GlaxoSmithKline Biologicals

Cambodia: Communicable Disease Control, Ministry of

Health; Kantha Bopha Children’s Hospital; National

Immunization Program, Ministry of Health; National Pediatric

Hospital

Canada: Health Canada; University of Western Ontario

China: An Hui Province Anti-Epidemic Station; Beijing

Friendship Hospital; Changchun Children’s Hospital; Centers

for Disease Control; Dongnan University School of Public

Health; Fudan University; Guangxi Maternal and Child

Hospital; Guangxi Medical University; Guangxi Province Anti-

Epidemic Center; Guangxi Provincial Hospital; Hebei Province

Anti-Epidemic Station; Jiangsu Province Anti-Epidemic

Station; Kunming Children’s Hospital; Lanzhou Institute of

Biological Products; Lulong County Health and Anti-Epidemic

Center; Ma-An-Shan Hospital; Nanning Second City Hospital;

Sinovac Biotech; Suzhou Medical School; Wuhan Institute of

Biological Products; Wuming County Hospital; Yongning

County Hospital

Egypt: Ministry of Health and Population; U.S. Naval Medical

Research Unit 3; Vacsera

Finland: National Public Health Institute

France: Aventis Pasteur; Epicentre; Institut Pasteur

Germany: Sartorius Group

India: All India Institute of Medical Sciences; Indian Council of

Medical Research; International Center for Genetic

Engineering and Biotechnology; National Institute of Cholera

and Enteric Diseases; Shantha Biotechnics

Indonesia: BioFarma; Centers for Disease Control; Central

Public Health Laboratory; National Institute of Health Research

and Development; Udayana University; U.S. Naval Medical

Research Unit 2

Japan: National Institute of Infectious Diseases; Osaka

University; Research Institute for Microbial Diseases, The

Institute of Medical Science, University of Tokyo.

Korea: Catholic University, St. Paul’s Hospital and St. Mary’s

Hospital; Changwon Fatima Hospital; Chonbuk National

University; Chonbuk Provincial Department of Health; Chonju

Presbyterian Medical Center; Green Cross Reference

Laboratory; Hallym University Medical Center; Hanyang

University Hospital; Inha University Hospital; Cheju National

University Hospital; Jung-Eub Hospital; Korea Research

Institute of Bioscience and Biotechnology; Korea University;

Korea Food and Drug Administration; Korean National Institute

of Health; Kyung Hee University Medical Center; LG Life

Sciences; Namwon Medical Center; Pohang University of

Science and Technology; Pusan National University Hospital;

Samkwang Reference Laboratories; Seoul Clinical

Laboratories; Seoul National University; Samsung Medical

Center; Social Security Research Institute; SoonChunHyang

University Hospital; Ulsan University; Wonkwang University

Medical Center; Yonsei University

International Collaborators

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International Collaborators

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Laos: Mahosot Hospital; National Institute of Public Health,

Ministry of Health

Mongolia: Maternal and Child Health Research Center,

Ministry of Health

Mozambique: Ministry of Health

Pakistan: Aga Khan University; Amson Pharmaceuticals

Philippines: Cebu Institute of Medicine; Research Institute

for Tropical Medicine

Singapore: K.K. Women’s and Children’s Hospital

Sri Lanka: Epidemiology Unit, Ministry of Health; Lady

Ridgeway Hospital

Sweden: Swedish Bacteriological Laboratory; University of

Gothenburg

Switzerland: Berna Biotech; Medecins Sans Frontieres

Thailand: Armed Forces Research Institute of Medical

Sciences; Center for Disease Control, Ministry of Public

Health; Mahidol University

United Kingdom: Wellcome Trust Sanger Institute; Health

Protection Agency; Imperial College London; London School

of Hygiene & Tropical Medicine; Microscience; National

Institute of Biological Standards and Control

United States: Arizona State University; AVANT

Immunotherapeutics; Brandeis University; California Institute

of Technology; Center for Biologics Evaluation and Research,

Food and Drug Administration; Centers for Disease Control

and Prevention; Chiron; Colorado State University; Harvard

University; Johns Hopkins University; Merck; National

Institutes of Health; Naval Medical Research Center; Portland

University; Program for Appropriate Technology in Health;

Purdue University; University of Alabama; University of

California at Berkeley; University of California at Los Angeles;

University of Maryland; University of North Carolina at Chapel

Hill; University of Pennsylvania; University of Rochester

Medical Center; University of Texas Medical Branch at

Galveston; Walter Reed Army Institute of Research;

Washington University; Wayne State University; West Virginia

University; Wyeth

Vietnam: Bach Mai Hospital; Hanoi Health Service; Ha Tay

Province Preventive Medicine Center; Ho Chi Minh Pasteur

Institute; Hue City Hospital; Hue Province Preventive Medicine

Center; Institute of Vaccines and Biological Substances;

Khanh Hoa Provincial Hospital; National Institute of Hygiene

and Epidemiology; National Institute of Pediatrics; Nha Trang

Pasteur Institute; Ninh Hoa District Hospital; Phu Tho Province

Center for Preventive Medicine; Phu Tho Provincial Hospital;

VaBiotech; Wellcome Trust, Center for Tropical Diseases, Ho

Chi Minh City

International: World Health Organization

′

Prof. Samuel Katz - Chairman Professor Emeritus,

Department of Pediatrics, Duke University Medical

Center, Durham, North Carolina, USA

Prof. Jan Holmgren - Vice Chairman Professor,

Department of Medical Microbiology & Immunology,

University of Gothenburg, Gothenburg, Sweden

Prof. Maharaj Krishnan Bhan Secretary,

Department of Biotechnology, Ministry of Science

and Technology, New Delhi, India

Prof. Myung-Hee Chung Vice-President,

Seoul National University, Seoul,

Republic of Korea

Dr. John D. Clemens Director,

International Vaccine Institute, Seoul,

Republic of Korea

Prof. Gordon Dougan Professor,

Center for Molecular Microbiology and Infection,

Department of Biological Science, Imperial College of

Science, Technology and Medicine, London, United Kingdom

Dr. Michel Greco Former President,

Aventis Pasteur, Lyon, France

Prof. Ian David Gust Professor Emeritus,

University of Melbourne, Victoria, Australia

Dr. Nay Htun Professor and Executive Director,

University for Peace, New York, USA

Prof. Paul-Henri Lambert Professor,

Department of Pathology, University of Geneva,

Geneva, Switzerland

Dr. Hanna Maria Nohynek

Department of Vaccines, National Public Health

Institute, Helsinki, Finland

Mr. Joon Oh Director General,

Office of Policy Planning and International

Organizations, Ministry of Foreign Affairs & Trade,

Seoul, Republic of Korea

Dr. Shigeru Omi Regional Director,

WHO Regional Office for the Western

Pacific (WPRO), Manila, The Philippines

Dr. Samlee Plianbangchang Regional Director,

WHO Regional Office for South-East Asia (SEARO),

New Delhi, India

Dr. George Poste Director,

The Biodesign Institute at Arizona State University,

Tempe, Arizona, USA

Prof. Philip K. Russell Professor Emeritus,

Johns Hopkins Bloomberg School of Public Health,

Baltimore, Maryland, USA

Prof. Geoffrey Schild Professor,

Imperial College of Science, Technology, and Medicine,

London, United Kingdom

79

Board of Trustees

From the left to right in the first row, Dr. John D. Clemens, Prof. Samuel L. Katz, Dr. Hanna Maria Nohynek, Prof. Myung-Hee Chung, Dr. Shigeru Omi, Mr. Joon Oh; in the secondrow, Prof. Margaret Liu, Prof. Geoffrey Schild, Dr. Michel Greco, Prof. Ian David Gust, Prof. Philip Russell, Prof. Gordon Dougan, Prof. Jan Holmgren, Prof. Paul Henri Lambert