DVI JANUARY 2015 NEWSLETTER

In This Issue Dengue Vaccine Candidates in Review Exclusive Interview with Dr. Luis Villar

Mr. Gates on Dengue Vaccines in ASTMH DVI Asia-Pacific Dengue Prevention Board 2014 Meeting

Research Students Interview on Strategic Demand Forecasting and more…

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DVI JANUARY 2015 NEWSLETTER Dear all,

Welcome to our first edition of 2015.

On behalf of DVI, I would like to wish you all a happy, healthy and prosperous New Year!

Our newsletter presents an overview of the status of development of dengue vaccine candidates as per the end of 2014. A major event was the publication “Efficacy of a Tetravalent Dengue Vaccine in Children in Latin America” published in the New England Journal of Medicine on November 3rd by Villar et al. Dr. Villar was the study’s lead investigator and is Head of the Clinical Epidemiology Unit at the University of Santander, Colombia. He is our Dengue Champion. In an exclusive interview with DVI, he shares his views on the trial and dengue vaccines.

We also highlight two DVI meetings. The first one is the DVI Asia-Pacific Dengue Prevention Board meeting held in Seoul on November 21 and 22. This two-day meeting gathered dengue specialists from ten countries in the region, officers from their ministries of health, and representatives from the pharmaceutical industry. We deeply appreciate all participants for such a stimulating and collaborative discussion on dengue vaccine introduction. The second meeting gathered representatives from seven National Regulatory Authorities (NRAs). It was held in Beijing from Nov 24-26, in conjunction with the Developing Country Vaccine Regulators’ Network (DCVRN) meeting organized by WHO.

This edition also includes an exclusive interview on the work of two researchers, Marta Wilson-Barthes and Cristina Garcia from DVI member IVAC (International Vaccine Access Center at the Johns Hopkins Bloomberg School of Public Health), on dengue vaccine demand forecasting in Brazil.

Lastly, we summarize the recent 63rd annual American Society of Tropical Medicine and Hygiene (ASTMH) convention in New Orleans, including Mr. Bill Gates’s comments on dengue during his keynote speech, and list upcoming dengue-related events for your reference.

It is with deep appreciation to the dengue vaccine community that I leave my position as DVI’s Acting Director, effective January 7, 2015. I wish to express my sincere gratitude for the opportunity offered to have worked with knowledgeable and hardworking dengue researchers and advocates. My two years with DVI have been invaluable personally and professionally and I would like to commend the consortium’s work, wishing them continued success and contributions to the fight against dengue. My replacement will be announced in our website, via email, and DVI social media.

We hope you enjoy reading our newsletter and wish to thank you for your continued interest and support of our activities.

Sincerely yours,

Georges Thiry

DVI Acting Director

DVI Dengue Champion Spotlight: Dr. Luis Ángel Villar Centeno

This issue of the DVI Dengue Champion Spotlight features Dr. Luis Villar, the lead investigator in the second Phase III trial ever completed for a dengue vaccine candidate. The results of this trial in Latin America (referred to as CYD15) that evaluated the Sanofi Pasteur’s dengue vaccine candidate, were published November 3rd in the New England Journal of Medicine.

DVI dedicates this section to Dr. Villar for his and his team’s contribution to dengue research and below we report a conversation we had with him on dengue and the trial.

Tell us about yourself: how did you start your career in epidemiology and clinical studies? Why and how did you become interested in dengue?

Twenty years ago, after completing my training in infectious diseases I returned to my city Bucaramanga, Colombia. A national dengue outbreak was unfolding and Bucaramanga was one of the hot spots. For the first time in the country, severe dengue cases started to emerge, raising medical uncertainty and several questions by my university research group. Some of these questions focused on defining dengue diagnostics using clinical skills in febrile cases and on predicting early complications of the disease. It was in this context that I came to understand the importance of developing studies on the clinical epidemiology of dengue.

From your experience, how do people (the general public) perceive and deal with dengue in Latin America?

People in Latin America perceive dengue as a highly serious disease, knowing that it can be mortal and fearing its effects. Generally people deal with the disease by visiting healthcare centers. Dengue is one of the most important public health issues in Colombia. To offer the best attention possible we need to improve our health system and give timely responses to avoid further complications. How would you describe the global burden of dengue? How is it a global public health threat, when, as some argue, it has a relatively low mortality rate?

Dengue is a threat to nearly half of the world’s population. It is a healthcare priority in many Latin American and Asian countries where epidemics occur regularly. The WHO estimates up to 100 million infections per year, but the overall number of people infected with dengue globally is not fully known. Each year, 500,000 people, including children, are affected with dengue hemorrhagic fever (DHF), the severe form of the disease. Dengue is underreported because the disease is often misdiagnosed due to a large spectrum of clinical symptoms from mild non-specific illness to life threatening complications and because of the limitations of the surveillance systems. The mortality rate is also underreported due to the same limitations mentioned. Timely access to appropriate health care is critical to reduce the risk of mortality in case of severe dengue. Why invest in a dengue vaccine? Why is it important?

There is a significant and continually growing public health need for effective interventions against dengue. A safe, effective and affordable dengue vaccine would represent a major advance for the control of the disease.

Currently, there is no specific treatment available for dengue. DHF is a leading cause of hospitalization, placing tremendous pressure on health systems and straining medical resources resulting in significant economic and social impact. Undoubtedly, a vaccine against dengue will be a key part of the overall strategy for dengue control.

What are the major challenges for the R&D of a dengue vaccine? Why has it taken so many decades to develop dengue vaccines? Why has the process accelerated in recent years?

The following have generally been identified as the main challenges for the research and development of dengue vaccines:

Lack of animal model for the disease, requiring clinical studies. Four different viral serotypes, requiring a vaccine that must protect against all four. Theoretical risk of immunopotentiation after sequential infections, tetravalent vaccine is

needed. Live attenuated vaccine technology to optimize protection. No known correlate of protection, large efficacy studies are needed.

I would add that, since dengue is such a complex disease, it requires testing the vaccine in geographically different populations, with different epidemiological environments, varying prevalence of the 4 serotypes, and diverse age groups. As progress has been made in the development of dengue vaccines, and, according to the results of the studies, additional questions and challenges have emerged. These include the differential efficacy among serotypes; the efficacy between naive and pre-immune population; efficacy against overall disease versus severe disease; the role of the immune cellular response, genetic determinants, among other.

The Sanofi Pasteur dengue vaccine has been characterized by more than a decade at preclinical and Phase I/II clinical levels, in which satisfactory reactogenicity and immunogenicity were demonstrated. In recent years, research has accelerated the process of vaccine development, as they have completed the phase II studies and in 2014, the large scale Phase III efficacy trials that were conducted in 10 endemic countries of Asia and Latin America, demonstrated safety, satisfactory reactogenicity and efficacy over the 25-month period of the active surveillance phase and a 4-year long term follow up is ongoing.

What are the main conclusions of the trial? What are the implications of this trial for the dengue research community? Of its results?

The data from the overall clinical program, Phase I, II and III and especially from this efficacy trial support the fact that this dengue vaccine has the potential to provide an important public health benefit as part of the comprehensive strategy for dengue control, in dengue endemic countries. The results of the first efficacy study in Latin America, are particularly relevant for the scientific community, the sample size allowed with robust data demonstrate the efficacy of the vaccine against the 4 serotypes and confirmed the favorable safety profile.

How would you explain the variability in protection by serotype and serostatus? What implications can the heterogeneity of vaccine efficacy by serotype and serostatus at baseline have from a programmatic perspective?

This subject is being studied. There are many hypotheses regarding this question. We still don’t have a specific answer.

What are your thoughts on the Asian and Latin American trials, when viewed together? Are they comparable, being in such different regions? If so, how are they comparable?

The two efficacy Phase III trials are comparable considering that they have the same design, the same objectives, and the same primary endpoint. Their surveillance systems were similar. The main differences were the age group (the trial in Asia included younger children between the ages of 2 -14 and in Latin America it included children and adolescents of between ages 9 – 16) and the sample size (10,275 participants in Asia and 20,869 in Latin America). Both Asia and Latin America had all 4 serotypes during the phase of active surveillance, in which efficacy was determined.

What questions do you think health specialists and ministries of health should ask themselves if they seek to introduce this vaccine, if licensed?

The first considerations of a safe vaccine with moderate overall efficacy should be age group in which to introduce the vaccine, the groups for the catch up, and the preparation of the pharmacovigilance system. Post vaccine licensure and introduction, more investigations will be required on the impact on dengue burden, dengue related health care utilization, vaccine performance, vaccine safety and effectiveness, and the implementation of the vaccine pharmacovigilance system.

What are the main lessons that you learned from leading this trial? What has excited you the most, personally, about leading this trial?

While conducting this trial, I appreciated the necessity of multi-centric studies to respond to clinical epidemiology research questions. The participation of researchers in 22 centers in 5 countries made possible the number of cases to evaluate the efficacy of this vaccine. Another major lesson was the application of a rigorous protocol in all the involved research centers to obtain valid results was a valuable lesson.

Personally I found pleasing the active, responsible and altruistic participation of the volunteers in the study. This is evidence that research can be empowered by people’s generosity and welfare.

2014 Dengue Vaccine Candidates in Review

2014 was a productive year in the dengue vaccine field. We highlight major developments of the five tetravalent DENV candidate vaccines currently undergoing clinical studies. Three of the vaccines are live attenuated tetravalent vaccines (Sanofi Pasteur, Takeda, and the U.S. National Institutes of Health), one is a sub-unit protein vaccine (Merck & Co.), and the fifth is a purified inactivated vaccine (GSK). Below we describe their status as of the end of 2014:

Foto credit: Esther Havens

GlaxoSmithKline/Fiocruz/Walter Reed is developing a tetravalent dengue vaccine candidate named DPIV (dengue whole virus inactivated purified vaccine), adjuvanted with AS01 or AS03, given in 2 doses, 4 weeks apart. The target profile aims to fit within the Expanded Program on Immunization (EPI) schedule and to be used for rapid deployment in the army.

In a Phase 1 study with 160 volunteers exposed to 1 of 4 DPIV formulations, the usual range and types of adverse events were noted in all groups, and most were grade 1 or 2. In a Phase I trial in the USA, with 100 subjects (90% naïve for dengue) who received the vaccine with varying doses of Alum, ASO1 or ASO3, high seroconversion to all four dengue virus serotypes was noted with the AS01 and AS03 adjuvanted formulations and high dose AlOH formulation. The ASO3 formulation was about 100X more immunogenic based on GMTs.

The same study design in Puerto Rico, where a large proportion of subjects had antibodies against dengue from previous infection (‘primed’), showed waning levels of GMTs at 7 month in dengue-naive subjects but no waning in primed volunteers. A new study planned for March 2015 will specifically look at the dosing regimen in dengue-naïve recipients. A final formulation will be selected and trials will proceed by age de-escalation, to generate efficacy data in primed and naïve subjects.

Merck & Co. is developing a sub-unit protein tetravalent vaccine using recombinant envelope protein expressed in an insect cell system. The vaccine contains recombinant E protein from the 4 DENV serotypes and will be administered as 3 intramuscular injections given 1 month apart. The vaccine is currently in a Phase 1 clinical trial in Australia.

NIH/ Butantan is developing a live attenuated tetravalent dengue vaccine comprised of full-length DENV-1, DENV-3, DENV-4 and a chimeric DENV–2 vaccine (TV003 and TV005). In Phase I trials, all adverse events were found to be mild. A mild, asymptomatic vaccine-associated rash actually correlated with a tetravalent immune response. Vaccinees were completely protected against infection with a second dose of vaccine given at 6 months and only a minimal antibody boost, indicating the vaccine induces sterilizing immunity was induced for at least 6 months. .

Challenge studies in human volunteers with an under-attenuated DENV-2, showed that a single dose of TV003 completed protected 14/14 volunteers from viremia, rash and neutropenia induced by the challenge virus.

A stepwise Phase II trial in adults is now underway in Brazil in dengue naïve and exposed individuals. Immunogenicity and safety data from a 1 dose protocol is expected shortly. Once II results are available, the trial will progress to Phase III in 2015. A separate Phase II is expected to enroll 240 subjects in Thailand in December 2014 for a head to head comparison of TV003 and TV005 (DENV-2 component given at a dose of 104 PFU vs 103 PFU in TV003) and if there are no safety concerns, the trial will age de-escalate with TV005 down to children 1 year of age.

Sanofi Pasteur is completing clinical testing with a live attenuated tetravalent recombinant chimeric vaccine, named CYD-TDV, using a yellow fever backbone in which thirty thousand individuals have been enrolled.

Safety and efficacy results from the first 25 months of follow-up in Phase III clinical trial from Asia were published in July 2014, and from the Americas in November 2014, involving Indonesia, Vietnam, Thailand, the Philippines, and Malaysia in Asia and, in the Americas, Brazil, Mexico, Puerto Rico, Columbia, and Honduras. Vaccine efficacy was measured against symptomatic virologically-confirmed dengue, irrespective of disease severity or serotype, occurring after 28 days post-third injection.

The Phase III trials targeted ages 2-14 years in Asia; and 9 – 16 years in the Americas. Three doses of CYD-TDV were given and 0, 6 and 12 months. Efficacy and safety were measured over one year post-third injection. Safety will ultimately be tracked for up to 6 years for hospitalized cases.

Results from the Phase III trial in Asia: efficacy data were derived from 10,275 subjects and immunogenicity data from a subset of 2000 subjects. Study compliance was high (98.8% for 3 doses) with 0.8% drop out over 2 years and 2.1% excluded from per-protocol efficacy.

Primary endpoint analysis shows that efficacy, post-dose 3, was statistically significant against any serotype at 56.5% (43.8 – 66.4). And efficacy against the WHO 1997 definition of dengue hemorrhagic fever (DHF) was 88.5% (58.2 - 97.9). Point estimates of serotype-specific efficacy ranged from 35.0% for DENV-2, to 78.4% for DENV-3, and was statistically significant for all serotypes but 2. Likewise, country-specific efficacy ranged from 51.1% in Vietnam to 79.0% in Malaysia but differences were not statistically significant.

A trend of lower efficacy was noted in participants of younger age and in those who did not have measurable antibodies to dengue before the first vaccine dose was administered. The observed safety profile in the first 13 months of follow-up post-dose 3 shown no adverse events. Immune responses were good after a first dose and did not increase much with additional doses.

Results from the Phase III trial in the Americas: in the Americas, a larger sample size was necessary because the attack rate is lower. 20,869 subjects were enrolled for efficacy and 2,000 for immunogenicity.

Primary endpoint analysis shows that efficacy, post-dose 3, was statistically significant against any serotype. Vaccine efficacy against symptomatic virologically-confirmed dengue was 60.8% (52.0 - 68.0).

Point estimates of serotype-specific efficacy ranged from 42.3% for DENV-2, to 77.7% for DENV-4 and were all statistically significant. Likewise, country-specific efficacy ranged from 31.3% in Mexico (where there was a higher proportion of seronegatives) to 77.5% in Brazil but differences were not statistically significant. Intention-to-treat analyses show 80.3% (64.7–89.5) efficacy against hospitalization, and 95.0% (64.9–99.9) against 1997 WHO DHF criteria. A trend was noted for higher efficacy in seropositives than seronegatives (83.7% vs 43.2%). As in Asia, the observed safety profile in the first 13 months of follow up after the 3rd dose was acceptable.

Takeda is developing a live attenuated tetravalent recombinant chimeric vaccine using an attenuated DENV–2 backbone. Approximately 600 individuals have received the study vaccine to date, including about 200 children under 12 years. In addition, a number of studies are ongoing to better ascertain the role of cell immunity.

Clinical development has reached Phase II, currently evaluating safety, tolerability and immunity at 1.5 to 45 years in Puerto Rico, Colombia, Singapore, and Thailand, with 246 subjects receiving the study vaccine subcutaneously in 2 doses, 90 days apart. The study looks at a high and low dose formulation. So far, the safety profile of both formulations is encouraging with no serious adverse events (AEs), no dengue-like symptoms, and no meaningful blood chemistry of hematological changes. Results also show that the candidate vaccine induces high level of neutralizing antibodies and seroconversion ≥80% to all four dengue virus serotypes, after two doses, in endemic populations. A pivotal efficacy study, among others, are in preparation for launch in 2015.

Interview with IVAC Research Students: How Strategic Demand Forecasting Helps in Planning

for Vaccine Introduction

Strategic planning for vaccine introduction requires credible information about target populations, distribution, administration, efficacy and safety, and costs. Strategic demand forecasting (SDF) helps in overall strategic planning for vaccine introduction by allowing stakeholders to consider a variety of introduction scenarios that take into account this information.

A successful introduction of a vaccine is possible when the motivations of all three groups of stakeholders – industry, countries, and funding partners – overlap. SDFs reveal the decision spaces within which this overlap occurs and the factors that bear influence within this space.

Interview: Research Students’ Perspectives on working with SDF in Brazil In the beginning of this year, IVAC (International Vaccine Access Center) partnered with the Brazilian Federal Ministry of Health to project the demand and supply of a dengue vaccine in Brazil. The vaccine in study is the 1 dose live attenuated tetravalent vaccine being developed by Brazil’s Butantan Research Institute and utilizes the NIH technology. The Butantan dengue vaccine would be the first dengue vaccine developed by the Institute for production in Brazil and eventually outside.

Two graduate students from Johns Hopkins are working with IVAC’s Director of Economics and Finance, Dr. Dagna Constenla, to gather data for the SDF model. They were based in Brazil for the 2014 summer and share their experience in an interview with DVI.

Can you tell us about yourselves and how you became involved with dengue research?

My name is Cristina Garcia and I’m a third year PhD student studying international health. I’m interested in transferring interventions for infectious disease control like vaccines into public health

programs and policies through research that generates evidence for policy purposes. I hope to use my experience in Brazil to continue working on modeling the changing dengue epidemiological pattern and the impact of a dengue vaccine in Brazil as part of my dissertation.

My name is Marta Wilson-Barthes. I’m completing a Master’s of Science in Public Health at Johns Hopkins with a focus on international health and global disease control. I’ve worked with IVAC and Dr. Constenla on the strategic demand forecasting model and will be writing my thesis on these results.

Can you describe your work in Brazil?

This summer we gathered demographic, epidemiological, product and program cost data and information about rollout scenarios from the Federal District in Brasilia and five states across Brazil: Goiás, Minas Gerais, Pernambuco, Rio de Janeiro and São Paulo. These data are used to create a demand forecast model to analyze dengue vaccine introduction scenarios and their associated costs in Brazil. The model is based on a series of assumptions that are determined from Ministry of Health data and from stakeholder information that we collected, including national dengue specialists, officials from ministries of health, vaccine manufacturers and funding partners.

What is the objective of your research?

We are looking to estimate the potential demand for the Butantan dengue vaccine in Brazil and the costs associated with this demand. We will link disease impact information to the current model to estimate the impact of dengue based on various vaccine introduction scenarios. This study is vital to estimate the potential demand of the dengue vaccine in the Brazilian context, to help with financing decisions for the accelerated introduction of the dengue vaccine.

It’s crucial to address, in particular, who should be vaccinated and when. The disease pattern is different in Brazil compared to that in Asia, for example, and it’s hard to generalize. Also, keep in mind that Brazil is a country of over 200 million people and dengue in this country is primarily a disease of adults. Effective vaccination campaigns will depend on specific knowledge from each dengue-endemic state. This is why we aim to gain as comprehensive a picture of the disease distribution from as many states as possible.

Why did you focus on the Butantan dengue vaccine candidate?

The Butantan Research Institute is a public, government supported research laboratory affiliated to the São Paulo State Secretary of Health. It is unique in that once its vaccine is licensed, it will be sold directly to the Ministry of Health at a lower price per dose than would a private, for-profit manufacturer. Currently, Butantan provides the Ministry of Health with an estimated 150 million doses of vaccines per year. The Institute has a strong R&D program and guides its development effort to produce efficacious and safe biologicals, using technologies that take into account affordable costs.

In the event other dengue vaccine candidates are licensed before Butantan’s, our model will be taking these into account to better help Brazil determine the potential demand and associated costs of introducing different dengue vaccines. Introducing the vaccine in different populations would require different strategies, supply needs, and costs. All of these factors are the heart of the model.

How did you gather these data?

We developed surveys for officials at the federal, state, and municipal levels of the ministry of health. These surveys guided the 40 interviews we conducted during our time in Brazil. We also continue to

gather data from the Brazilian reporting systems, DATASUS and SINAN, and key publications from Brazilian dengue experts, many of whom we interviewed.

Our conversations with Butantan manufacturers have been invaluable during our research since they provide direct information on vaccine costs and trial results. We were also very fortunate to work closely with Dr. Giovanini Coelho, our partner and Coordinator of the National Dengue Control Program, who provided immense technical and logistical support to stakeholder interviews, and many other local stakeholders in Brazil. Our fieldwork in Brazil was a highly collaborative effort between the ministry of health and Johns Hopkins University.

What was the perception of a dengue vaccine in Brazil?

The desire for a dengue vaccine is unanimous throughout the country. Everyone has been affected by dengue on some level or knows someone who has. It is a national problem that is not going away and the desire for a solution is a national health concern. You see and feel this both in increased research and in daily public life.

What have been the main challenges of this project?

The size of the country and its epidemiological diversity. Because of the climate-related geography and population movements, each state has different dengue serotypes circulating at any one time compared to its neighbor, and the strength of each health system varies from state to state and even within states. This makes it almost impossible to anticipate when or where the next epidemic will occur.

Politics has been another challenge. In many parts of Brazil dengue has become a political issue and each state has its own priorities and perspectives on the best strategy for controlling dengue. The federal government provides guidelines and resources, but implementation responsibilities lie with the states and municipalities.

Brazil’s decentralized health system, for its many strengths, also poses challenges for standard disease detection and control efforts. And while the interest in dengue control is high across states, logistical priorities for and management of control efforts, and where funding and resources should be applied, differs between states. Some states can provide the necessary financial and human resources needed to meet, and even at times exceed, the federal guidelines. But, other states lack the resources to adequately implement the federal guidelines. Additionally, some states are concerned with patient surveillance and treatment while others hold a higher interest in vector control while others are more concerned with receiving the vaccine as soon as possible. These differences in resource availability and priorities are attributable to both population differences and varying political interests.

What can you say about the timing of your study, which coincided with the World Cup in Brazil?

It was an added perk to be able to perform fieldwork during the World Cup. Luckily, it was Brazil’s winter, which is a low dengue transmission season. Surveillance activities were ongoing and included regimented case detection, screening, notification, and vector control. Public health communication efforts were definitely ramped up in host cities.

How would your describe your experience interviewing dengue experts and others involved in the project?

Because of the high stake in dengue control and prevention, everyone was interested in participating in the research. Since the bulk of our interviews were with ministry personnel, much of our

information was about policy and implementation. This was a challenge in the sense that economic data on health budget and dengue surveillance and immunization program costs were not always available.

Any specific takeaways that you want to mention?

We are honored to have had the opportunity to work, and continue to work, with such a strong and driven network of people in Brazil. The country is incredibly driven and committed to understanding this disease and seeing that a vaccine is introduced in the most efficient and beneficial way possible for the country at large.

We have to remember that his in unchartered territory. We are working with a product that is completely new and a disease that is incredibly complex and, in some way, unpredictable. We need to ensure that a thorough and comprehensive understanding of the vaccine supports the external desire for a solution. We hope this research contributes to that progress.

Mr. Bill Gates Highlights Developments in Dengue Vaccines at ASTMH Meeting

This past November kicked-off with a much anticipated event for tropical disease scientists, researchers, and health specialists alike: the annual conference of the American Society of Tropical Medicine and Hygiene (ASTMH) – an international organization promoting global health through prevention and control of infectious diseases. Held in New Orleans from November 1-6, the convention gathered thousands who presented and attended symposia, special interest workshops, and poster sessions on diseases from Ebola, malaria, typhoid, to dengue.

Dubbed #TropMed14, the conference, proved to be fruitful for dengue specialists, with three events in particular. First, keynote speaker, Mr. Bill Gates, highlighted dengue fever early on during his address as an example of a disease that has spread widely during the last decades and that calls for urgent intervention that will halt this trend. Mr. Gates welcomed recent dengue vaccine developments, emphasizing Sanofi Pasteur efforts in completing Phase III trials. Mr. Gates called the vaccine candidate a “powerful tool” that, preventing up to 80% of dengue hospitalizations, “could play a key role as one of the tools that would really bring the result counts down.” Mr. Gates ended his speech with an optimistic note, saying there is still much more the scientific community can do to fight diseases. He also underscored that the efforts to improve global health require increased investment in research and development: “The only way to stay ahead of the natural evolution of

infectious diseases is to stay fully invested in the R&D pipeline for new drugs, new vaccines, new diagnostics and innovative approaches to vector control.”

Another major dengue event took place on Monday evening: the presentation of the results of Sanofi Pasteur’s dengue vaccine candidate Phase 3 efficacy trial in Latin America, published on the same day in the New England Journal of Medicine by L. Villar et al. Remaining consistent with the previous Phase III trial in Asia, the Latin American trial met its primary endpoint. The presentation concluded with a Q&A between a panel of dengue experts and the audience.

Other dengue presentations given during this ASTMH conference included a session on dengue vaccines and presentations of the candidates in the pipeline and their latest developments, and interesting sessions focusing on immunology, epidemiology, and pathogenesis.

Watch the full speech here.

Asia-Pacific Dengue Prevention Board 2014 Meeting

On November 21 and 22, DVI convened a meeting of the Asia Pacific Dengue Prevention Board (APDPB) in Seoul, Korea, gathering dengue specialists from ten countries in the region, officers from their ministries of health, and representatives from the pharmaceutical industry. The objective of the meeting was to review the CYD-TDV dengue vaccine candidate Phase III clinical trial results published by Capeding et al. in July and Villar et al. in November of this year; the progress of other candidate’s clinical development; and the mathematical modeling of the potential impact of vaccination on dengue. Attendees from the ten countries each presented the current dengue fever

situation in their homeland and, lastly, together revisited the ‘Points for Consideration’ DVI document developed in 2012 by the Asia-Pacific and Americas Dengue Prevention Boards, in view of new data available, updates in the dengue vaccine field, and the current epidemiology of dengue in their respective countries. They also shared perspectives on the prospects for dengue vaccine introduction and use in their countries, including integration with vector control, and highlighted specific challenges and needs for decisions.

The two-day meeting concluded with a set of considerations and recommendations from the Board, including how the complexities around modeling dengue and the potential impacts of vaccination in conjunction with vector-control strategies emphasizes the importance of ongoing interactions between dengue experts and modelers and that differences between countries will require country-tailored dengue vaccine policies and implementation strategies, among others.

The complete Board considerations and recommendations will be published in a full report of the meeting in the DVI website, under “Resources” and social media channels. We will also send an email to subscribers once the report is published.

National Regulatory Authority (NRA) 2014 Meeting

One of DVI’s initiatives, the DVI Regulatory project, was conceptualized by Luis da Silva and Richard Mahoney and was launched in Brasilia, Brazil, in April 2013 by Liliana Chocarro, Senior Regulatory Advisor for DVI. The aim of this project is to strengthen the capacity of NRA from countries likely to be the first to review a file of a dengue vaccine. Below, Dr. Chocarro reports progress made since the Brasilia meeting.

The DVI NRA meeting on November 24-26, 2014 in Beijing was the fourth face-to-face meeting of these National Regulatory Agencies (NRAs) organized by DVI. The meeting was attended by representatives from the NRAs of Brazil, Indonesia, Malaysia, Mexico, Philippines and Thailand, Dr. Nora Dellepiane and Dr. Joachim Hombach from WHO, Dr. Georges Thiry, the Acting Director of DVI, and Dr. Liliana Chocarro, Chair of the meeting. Regrettably, representatives from the NRA from Colombia could not attend.

The meeting included closed sessions for regulators, WHO and DVI, and two separate closed sessions, one with Sanofi Pasteur and one with Takeda. In addition, the scientific sessions were done jointly with the dengue session of the Developing Country Vaccine Regulators’ Network. The agenda of the joint meeting included

presentations from vaccine developers, the USFDA, WHO (Kirsten Vannice, Joachim Hombach) and independent experts. Dr. Ananda Amarasinghe and Dr. Edwin Asturias as well as Dr Kirsten Vannice, made significant contributions regarding the safety and efficacy/effectiveness aspects of dengue vaccines that was greatly appreciated by the attending regulators. Another session addressed the WHO’s regulatory guidance and whether this information requires update. While the guidance was overall still considered accurate, the recommendation was made for an expert group to assess more closely whether updates are needed. During the meeting in Bangkok, Thailand, in 2013, in the context of discussions on joint evaluations of dengue vaccines, it was proposed that the group develop terms of reference to set a platform for sharing information and expertise. A document was developed by DVI, circulated for approval to all participating NRAs, edited by the legal unit of ANVISA and sent to signature by their Directors.

It was agreed that the opportunity of a joint evaluation or consultation among countries regarding the evaluation of registration dossiers and the specific terms for such activity will be discussed on a case by case basis with the relevant companies. This document provides the platform to allow NRAs to work together and share information when these opportunities arise.

DVI will continue its commitment to support the strengthening of the NRA’s capacity. DVI will also provide resources needed for regulatory evaluation by the NRA of dengue vaccines in 2015. A plan of action was discussed with the group, taking into consideration that all seven countries are

expecting to receive registration dossiers and many of them will receive clinical trial applications in 2015.

The DVI regulatory group regrets the departure of Dr. Georges Thiry as Acting Director of DVI. At the end of our meeting, the NRA collectively expressed their gratitude for his efforts and support during these past two years.

Upcoming Events

4th DVI Field's Investigators Meeting: January 26, Seoul, South Korea.

Partnership for Dengue Control (PDC) Vector Control Meeting: February 2-3, Annecy, France.

DVI Americas Dengue Prevention Board Meeting: March 16-17, Bogota, Colombia.

WHO World Immunization Week: April 24-30.

The Dengue Vaccine Initiative is a consortium of four organizations, with the mission to encourage the development and consideration of vaccines to prevent dengue.

The International Vaccine Institute will lead the Consortium and have lead responsibility for the field studies under the Evidence for Decision-Making component of DVI and for preparation of the focal country vaccine introduction cases and the global investment case. IVI is an international organization based in Seoul, Korea, established under treaty, with 40 countries and the WHO as signatories to its charter. IVI’s mission is “to combat infectious diseases through innovations in vaccine design, development and introduction, addressing the needs of people in developing countries”.

The WHO Initiative for Vaccine Research (IVR) will have the lead role in the development of

information and guidance documents, and in regulatory training activities. The unit’s mission is to accelerate the development and optimal use of safe and effective vaccines and technologies, especially in developing countries. IVR has expertise in the fields of product R&D, vaccine manufacturing and regulation, vaccine clinical trials, vaccine introduction, and cost-effectiveness analysis.

The International Vaccine Access Center (of the Johns Hopkins University Bloomberg School of

Public Health) will lead activities related to the financing of dengue vaccine purchase including budget impact analysis and strategic demand forecasting. It will also provide high level support to WHO on

regulatory pathways. The mission of IVAC is to accelerate global access to life-saving vaccines through development and implementation of evidence-based policies.

The Sabin Vaccine Institute, a non-profit organization established in 1994 and headquartered in Washington, DC, will have the lead role in the DVI’s coalition-building, advocacy and communications activities. Sabin’s mission is to save lives by stimulating the development of new vaccines against vaccine preventable and neglected tropical diseases, and by advocating for improved access to vaccines and essential medicines for people throughout the world. Sabin has established coalitions to

raise awareness of important diseases among policymakers and to mobilize funds to combat these diseases through vaccination or other effective prevention and treatment efforts.

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