DVI OCTOBER 2014 NEWSLETTER

In This Issue Exclusive Interview with Dr. Maria Rose Capeding

DVI 2014 Americas Dengue Prevention Board Meeting DVI Editorial on Dengue Vaccine Candidate Ph3 Trial Dr. Giovanini Coelho on Dengue Epidemics in Brazil

Updates on dengue vaccine candidates and more…

www.denguevaccines.org

@preventdengue

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DVI OCTOBER 2014 NEWSLETTER Dear all,

Welcome to the October issue of the DVI newsletter. A major event this last quarter was the publication by Dr. Capeding et al. on the safety and efficacy of the Sanofi Pasteur vaccine candidate in Asia (CYD14) and the press release by the pharmaceutical company about the safety and efficacy of their second Phase 3 study (CYD15) in Latin America. With this in mind, the DVI Dengue Champion Spotlight features Dr. Capeding, Head of the Department of Dengue at the Research Institute for Tropical Medicine in the Philippines, for her leadership in the CYD14 trial. In an interview with DVI, she kindly shares her views on dengue, dengue vaccines, and the trial’s results. We wish to congratulate her and her whole team for this accomplishment and commitment to fighting dengue. This edition also includes DVI updates, such as the publication of the meeting report from our Latin America Dengue Prevention Board meeting, which focused on integration of vaccine and vector-control, and the publication of a DVI editorial titled “A new chapter for dengue vaccines with an unwritten ending,” which we published in the Transactions of the Royal Society for Tropical Medicine and Hygiene journal. Additionally, we share an international news roundup on the CYD14 results, offering the perspectives of different major outlets that covered the update. We also put together an overview of the status of other dengue vaccine candidates in clinical trials. You will find in this issue as well first-hand testimonials from the field in dengue-endemic countries. We asked Dr. Giovanini Coelho, Coordinator of the National Program for Dengue Control in Brazil and a member of our Dengue Prevention Board, to describe his experience with dengue outbreaks. Last but not least, we revisit these past months’ dengue events and workshops. Specifically, we highlight the PAHO State of the Art Dengue Meeting and the Dengue Vaccine Effectiveness Workshop, both held in Washington DC, and the Bucaramanga (Colombia) workshop on dengue, where DVI presented. We also list upcoming events related to dengue for your reference.

We hope you enjoy our newsletter and wish to thank you for your support of our activities. Yours Sincerely,

Georges Thiry

Acting Director for DVI

Dengue Champion Spotlight: Maria Rose Capeding

An Exclusive Interview with DVI

Dr. Capeding led the first Phase 3 trial ever completed for a dengue vaccine candidate. The results of this trial in Asia (involving Sanofi Pasteur’s dengue vaccine candidate) were published this summer, July 11, in The Lancet. DVI captures her thoughts about dengue and the trial in the following interview. Can you briefly tell us about yourself, your scientific career? I am a practicing pediatrician with subspecialty in infectious diseases and the Head of the Department of Dengue at the Research Institute for Tropical Medicine, the research arm

of the Department of Health and referral center for infectious diseases in my country, the Philippines. I'm also the head of the Department of Microbiology. How did you get involved with dengue? Dengue is endemic in my country. It is one of the most prevalent factors behind the high number of hospitalization here. I also had a personal connection to dengue. My son got infected with dengue when he was a medical student. As a mother, this was one of my worst experiences and I can identify with the pain of dengue and the burden of the disease for many others. One of the worst things about my son being sick with dengue was the uncertainty of what would happen during that time. You really don't know what's going to happen. Was he going to go into shock? Was he going to bleed? He did end up with dengue hemorrhagic fever. He started getting low blood pressure and I was extremely anxious and worried. The worst of this disease is its unpredictability. This causes much burden. I have also had colleagues, other doctors, who have contracted dengue and they seriously thought that they were going to die. The pain is agonizing and you just don't know how bad it will get. How would you convey the global burden of dengue? How is it a global public health threat, given its low mortality rate relative to diseases like malaria? Dengue is a major international public health concern. There is no specific treatment or effective prevention measures for dengue. It's a health priority in many countries of Latin America and Asia where epidemics occur regularly, but, also look at Japan… In recent weeks it had a case of dengue after 60 years of being free of this disease. What are the major complexities of dengue challenging the R&D of a vaccine to prevent this disease?

I would mention three: (1) the 4 serotypes of dengue virus, requiring a vaccine that must protect against all four, in other words, a vaccine that is tetravalent; (2) the lack of an animal model; and, (3) the theoretical risk of imunopotentiation, that is, a patient who got infected more than once may develop more severe manifestations of dengue, hence there’s the need for a large scale clinical trials. How do you see the future of dengue worldwide? I think we have a working vaccine. I'm quite pleased with the results and the future of dengue will hopefully involve a combination of the use of this vaccine with existing vector-control strategies. I do believe that countries must continue their vector control strategies to control dengue and complement the use of the vaccine. What are the implications of this trial for the dengue research community? Researchers worldwide have been working on a dengue for more than 60 years and for the first time we have a potential candidate that shows great promise. This takes us closer to bringing a first vaccine against dengue to the world. How would you explain the variability of protection against each serotype observed for this candidate? How would it affect the benefits of the use of this vaccine in different dengue-endemic countries? Serotype 2 has been a challenge, but the prerelease of the findings from the CYD15 (the Sanofi Phase 3 second trial, which took place in Latin America) shows that the vaccine can prevent against it. We must remember that the 4 serotypes circulate and one serotype may be predominant during this season and another during the next, but, still, they co-circulate. And this vaccine protects against all 4 serotypes. I am sure the research program on dengue continues, at the moment we must focus on the dengue chimeric vaccine to become the world's first vaccine against this disease. Being in different areas, though, and with different age groups and regional characteristics, how do you view these trials together? How do you compare them? The important thing to point out here is the consistency of the results. The Latin American results are consistent with what we found in Asia. Both studies met their primary clinical endpoint with significant findings on reduction of dengue severe disease and reduction in the number of hospitalizations. How can you extrapolate these findings to other regions and countries, like Africa, India, and China? Both CYD14 and CYD15 provide further evidence of this candidate’s impact on protecting those at risk from dengue in a broad population and in various epidemiological environments. Likewise, we have comprehensive data from clinical trials conducted in fifteen countries involving 40000 children, adolescents and adults. Now that the results are published, how do they affect the decision to use this vaccine? What are the next steps? What questions do you consider to be crucial for the

community and public health officials to ask themselves before this vaccine is introduced? It is important to consider the vaccine efficacy rate and the results from both Asia and Latin America bolster the evidence of the vaccine's efficacy and safety and the impact they could have in protecting those at risk from dengue especially in dengue-endemic countries. One must consider the safety data from the numerous clinical trials and no safety signal to date; this will be the basis for submissions to the health authorities in countries where dengue is a public health priority. We have a vaccine with good safety profile, safety data reviewed by an Independent Data Management Committee (IDMC) for any safety signals. What has excited you the most, personally, about leading this trial? I am very pleased with the results from the efficacy study, as a resident in a country where dengue is a major public health problem, as a clinician who takes care of the health of children and as a mother whose biggest nightmare was having a son sick with dengue. I look forward to having the world's first vaccine against dengue become a reality. I am truly happy.

New DVI Report on Americas Dengue Prevention

Board Meeting Focused on Integrating Control Strategies

This year’s Americas Dengue Prevention Board (DPB) convened in Mexico City from March 25–26. The meeting’s objective was to assess the feasibility and benefits of integrating dengue vector-control strategies with a future dengue vaccine. DVI compiled a summary of the discussions and recommendations from the Board in a new report you can access here. The meeting brought together vaccine and vector control experts, researchers, representatives of ministries of health and vaccine manufacturers from different countries who brainstormed to answer:

Assuming a dengue vaccine is licensed and introduced, how could a country integrate prevention of dengue through a vaccination program with existing or new vector control methodologies?

This question is crucial to raise awareness about the urgency of new approaches to fight dengue in light of the recent spike in infections, which shows that vector control, alone, cannot effectively prevent dengue outbreaks. The discussions took into consideration new developments in dengue surveillance, progress with vaccine candidates, the increasing community engagement in vector control and results from mathematical modeling of the impacts that integrating dengue prevention strategies would have on dengue incidence, to underscore the need to evaluate dengue prevention and control strategies comprehensively and in line with a forthcoming dengue vaccine.

“Several novel vector control tools are, or are soon to be, available (new insecticides, genetic and biologic control, spatial repellents and lethal traps) and these hold promise for greater impact on disease transmission. A dengue vaccine is also expected in the coming years. Approaches that integrate both vector control and vaccination hold the best promise for prevention and control.”

As the report captures, the meeting first evaluated vector control efforts in Latin American countries, including Mexico, Nicaragua, Paraguay, Colombia, Venezuela, Argentina, Costa Rica, Brazil and Puerto Rico. Participants also assessed new technologies and partnerships for vector control, dengue vaccine candidates’ developments, and new mathematical models.

The Board concluded the event by identifying the requirements needed to effectively integrate vaccination and vector control. Some of these requirements consisted of generating baseline data to evaluate the additive effects of a vaccine; strengthening capacity for monitoring and evaluation; and standardizing entomological indicators to ease comparisons between countries. The requirements fall into four main areas of focus as the Board identified during the meeting: (1) criteria for selection of study site and study design; (2) communication and coordination with other sectors; (3) standardization of entomological surveillance; and (4) development of policies for vector control. We invite you to read the Board’s recommendations in detail here. These conversations are critical to generate consensus at all levels about the need for a dengue vaccine. By creating an enabling and participatory communication environment, DVI is working hard to help support the introduction of a future dengue vaccine.

About Dengue Prevention Boards

In 2007, PDVI (Pediatric Dengue Vaccine Initiative—DVI’s precursor) established two regional DPBs — one for Asia and one for the Americas. Members of the Boards include medical and public health experts, opinion leaders and policy makers from countries in their respective regions. They meet once a year to advise on dengue surveillance, diagnostics, vaccine introduction and communications.

All reports on DPB meetings are published on the DVI website to inform stakeholders on their content and conclusions and consensus. Dengue is an important and rapidly spreading vector-borne viral disease of humans, with over half of the world’s population living in areas of risk and an estimated 400 million infections annually.

DVI Publishes Editorial in TRSTMH on Sanofi’s Dengue Vaccine Candidate Phase 3 Trial in Asia

Titled, “New chapter unfolding in the fight against dengue with an unwritten ending,” the Dengue Vaccine Initiative’s (DVI) editorial just published in the October issue of Transactions of the Royal Society of Tropical Medicine and Hygiene discusses the results of Sanofi’s dengue vaccine candidate Phase 3 trial in Asia. DVI experts explain that while these results show promising indications that a safe dengue vaccine is technically feasible, key questions remain that need to be addressed.

“Dengue is the most common and fastest growing mosquito-borne viral disease. […] The good news is, a vaccine is forthcoming. While this represents a new chapter in the fight against dengue, as it brings hope for a more sustainable strategy to prevent and control this disease, the ending is yet to be written.”

DVI is committed to following the progress of the Sanofi and other dengue vaccine candidates, as it works to lay the foundation for the adoption and rollout of a licensed dengue vaccine.

Access the editorial here.

State of the Art for the Prevention and Control of Dengue in the Americas

PAHO (Pan-American Health Organization), through the Dengue Regional Program, organized the Meeting on the State of the Art for the Prevention and Control of Dengue in the Americas, held May 28-29, 2014 in Washington DC to examine achievements and challenges over the past 10 years of implementation of the IMS-Dengue strategy (Integrated Management Strategy for the Prevention and Control of dengue) and engage stakeholders in a discussion of future steps. Sessions on initiatives evolving in the Americas, including vaccines and vaccine development, the economic impact of dengue, and emerging technologies for vector control were also included.

The meeting’s main objectives were to: (1) review currently available knowledge of and experiences for surveillance, detection, diagnosis, management, treatment, and prevention of dengue; (2) derive conclusions and recommendations that will help the Dengue Regional Program to modify and update its strategies and technical cooperation plans, as well as its role in the prevention and control of dengue in the Americas; (3) learn from the experiences of countries in the Americas who have been focusing on generating knowledge through research and practice, of how to better approach dengue in the 21st century; and (4) review preliminary results of a systematic review of the published literature for each component of the IMS-Dengue strategy to identify research opportunities and gaps.

For more information click here.

Dengue Epidemics in Brazil: Lessons Learned

By: Giovanini Evelim Coelho - General Coordinator of the National Dengue Control Program/Ministry of Health, Brazil

The reintroduction of the dengue virus in Brazil during the 1980s led to the transmission of the disease in the country for the past 28 years. Aspects related to climatic conditions and the infrastructure of the cities, such as irregular garbage collection and water supplying, associated with the absence of effective control measures for the vector, Aedes aegypti, have all contributed for the current hyperendemic/epidemic scenario observed in the country.

Between the years of 2000 and 2012, dengue consolidated itself as one of the biggest challenges regarding public health in Brazil. Currently the population is exposed to the

four serotypes that are circulating in all the regions of the country. During this period, we observed important changes in the disease epidemiology, highlighted by a higher number of hospitalizations with shifts in disease severity towards children and the elderly. In this scenario, the maintenance and improvement of prevention and control measures, with the development of states and municipalities capacity for response during dengue epidemics became a priority to the Ministry of Health.

The National Dengue Control Program (PNCD) instituted in 2002 has been promoting diverse initiatives aimed at the strengthening epidemiologic surveillance, vector control strategies, patient’s management and population’s communication and mobilization. All these components are part of the contingency plans elaborated by the three spheres of the Public Health System (SUS) management of Brazil.

Dengue is a mandatory notifiable disease and the surveillance system is present in all

5570 municipalities of the country. Among its characteristics, we highlight the use of standardized instruments for data collection with a common information system and a wide laboratory network for diagnostics and identification of circulating serotypes of the virus. This has been allowing a better knowing of the disease’s epidemiological aspects such as the detection of epidemic processes, identification of changes in the pattern of affected people’s age groups and the description of the seasonality of the transmission between different geographic regions.

Aimed at the improvement of the vector control activities, the Aedes aegypti Infestation Index Rapid Survey (LIRAa) was developed. This methodology identifies in a short period of time the areas with the higher indices of residential mosquito infestation and its predominant breeding sites in a representative sample of the municipalities. Its information permits the aiming of the control measures into the most critical areas with a possibility of the population’s mobilization for adoption of preventing methods in their own home environment, and the managers’ mobilization for structural problems solving, such as regularization of garbage collection and water supply.

The reduction of mortality due to dengue is the main goal of PNCD. During epidemic periods, the health facilities experience an overwhelming increase in the number of patients searching for care. Strategies to increase the patients’ access include are numerous, including the adoption of extended working hours of health units and the utilization of tents for intravenous fluid therapy to prevent hypovolemic shock. The use of a risk classification protocol is widespread and highlights the importance of alarm signals. The training of health professionals, doctors and nurses is a strategic component that has evolved in its methodology, focusing on the spread of knowledge in a high scale, such as the use of distance education supported by universities and the Ministry of Health.

The campaigns for communication and mobilization of the population have evolved to focus on the differences observed in the epidemiology and characteristics of the public among the

different regions of the country. This allowed informing each particular target group (health professionals, managers, etc.) and geographic areas according to its entomological singularities.

Due to the absence of effective control measures, the Ministry of Health has supported the development of research in alternative vector and disease control methods. Standing out are the Wolbachia bacteria effectiveness evaluation studies on the prevention of dengue, the use of traps for the development of a new entomological index, large scale use of screens impregnated with insecticides in the households, identification of contingency plans triggering alarms, and preparation studies for the introduction of dengue vaccines in the future.

In all these efforts, the Ministry of Health has searched for partnerships with international organizations such as the World Health Organization (WHO/OMS) and Dengue Vaccine Initiative (DVI).

International News Roundup:

Results from Sanofi Pasteur’s Dengue Vaccine Candidate Phase 3 Study in Asia

Several outlets across the globe reported on the publication of the results of Sanofi Pasteur’s dengue vaccine candidate phase 3 trial in Asia. Titled “Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomized, observer-masked, placebo-controlled trial” the data were released in July in The Lancet.

As DVI explained in July in a blog that examines the results and in a response statement including a WHO Q&A on the matter, the trial, conducted in 10,275 children in Indonesia, Malaysia, the Philippines, Thailand, and Vietnam, showed moderate efficacy of 57% against any virologically-confirmed dengue. Results show that efficacy against serotypes 1, 2, 3, and 4 is 50%, 35%, 78% and 75%, respectively. Vaccine efficacy was statistically significant for all serotypes except serotype 2. In exploratory analyses, results showed a 67% efficacy against hospitalization due to severe dengue or dengue hemorrhagic fever. Additionally, vaccinated children were found to be at reduced risk of severe disease (based on a definition by an independent data monitoring committee) with a vaccine efficacy of 81%. Here we compile headlines, statements, blog posts, and multimedia from different major international outlets to reflect on different perspectives of the update. We want to highlight that this is by no means an exhaustive list, but with the information below we seek to share with you a range of different viewpoints on this topic.

Reactions

A point raised in multiple publications was that Sanofi Pasteur’s vaccine shows promise in preventing dengue disease and represents an important milestone in the dengue research field as the first candidate to have completed a Phase 3 trial. At the same time, several sources agreed that the efficacy at reducing dengue infection is moderate and further studies are necessary to better evaluate this vaccine’s performance:

BBC (UK): “Experts say though the long-awaited study is promising, vaccines with greater effectiveness are crucial.” Bloomberg (USA): “The most advanced experimental vaccine against dengue protected some children against the disease in a study, though a more effective weapon may still be needed to curb the most widespread mosquito-borne infection.” Top Santé (France): “The first vaccine will be a step forward, but certainly not a panacea.” Dr. Lance Gordon, Director for Neglected Infectious Diseases in the Global Health Program of the Bill and Melinda Gates Foundation called the trial “a potential breakthrough in the fight against dengue fever” in his post in Impatient Optimists. Dr. Seth Berkeley, CEO of the GAVI Alliance, stated that: “This brings us a step closer to making dengue fever a vaccine-preventable disease.”

Topics for further examination Many news articles also mentioned the limitations of the study and cautioned from drawing definitive conclusions from the results, particularly in regards to efficacy and efficiency, DENV2 or serotype 2, protection, age, travel, and dosage. 1. Efficacy and efficiency

El Tiempo Latino (USA): “In the most recent test, conducted in more than 10,000 children between 2 and 14 years in Indonesia, Malaysia, Thailand, Philippines and Vietnam, the vaccine

efficacy improved to 56%. The most common vaccines, such as measles and polio, have an efficiency of over 95%” 2. Serotype 2 Globo (Brazil): “To infectologist, Alexandre Barbosa, a professor at the Faculty of Medicine of the University of the State of São Paulo (UNESP), the low level of protection against serotype 2 could mean that the number of occurrences of this serotype infections during the study was not sufficient to accurately assess the degree of protection.” The Star (Malaysia): “The Health Ministry is looking at a higher overall protection rate against all four dengue serotypes before deciding on a proposed vaccine for the disease.” Deutsche Welle (Germany): “A disappointing result, Wilder-Smith said, adding that in many parts of the world serotype 2 is the most frequent dengue type.” [Wilder-Smith was involved in an earlier phase of developing the potential vaccine, but not in the recent Phase 3 study.] 3. Age Reuters (UK): “It offered poor protection to young children - who are most at risk from dengue - and proved notably inefficient in tackling one of the viral disease's four strains.” 4. Traveler Vaccine Radio Australia: “Unsurprisingly, protection was higher in those who have already been exposed to dengue, suggesting that the vaccine would be most helpful in countries at risk, rather than a vaccine for travelers.” 5. Number of Administrations Science Codex (USA): "Perhaps the most interesting finding of this trial was that efficacy after at least one dose was almost as high as that after three doses…Because three doses 6 months apart is an inconvenient and costly immunization schedule for scale up in national programs, the question of whether sufficient efficacy can be achieved with a lower number of doses deserves further assessment." 6. Next Steps Reuters (UK): “Sanofi expects to submit regulatory applications for the world's first dengue vaccine in the first quarter of 2015 and the French drug maker could start selling the first batches at the end of that year, CEO Chris Viehbacher said on Thursday.” Business Inquirer (Philippines): “According to Sanofi Pasteur dengue vaccine head Guillaume Leroy, the company intends to make the vaccine available first in countries suffering the most from dengue. Leroy added that the price would only be determined after discussions with the WHO and the countries interested in purchasing the vaccine. In the country, Leroy said Sanofi Pasteur will provide the DOH all necessary data about the vaccine and apply for a license.” 7. Vaccine Market Radio Australia (Australia): [Interview with Annelies Wilder-Smith is a professor of Infectious Diseases at Singapore's Lee Kong Chian School of Medicine]

“Are you confident that these vaccines will be commercially viable?” WILDER-SMITH: “It's a very complex question. It really depends on the country, on the epidemiological levels of dengue in that particular country and it depends on the final pricing that Sanofi Pasteur will put on this vaccine.” Bloomberg (USA) “Leroy said it’s too early to talk about the price Sanofi will charge for the vaccine. The company may sell the three-dose course for about $30 in developing nations and about $150 for travelers from rich countries, Deutsche Bank’s Clark estimates.” As outlets continue to cover more vaccine developments, we invite you to stay informed via DVI’s Facebook Page and @preventdengue

A Look at Preliminary Data of Final Phase 3

Trial: Sanofi's Dengue Vaccine Candidate

Sanofi Pasteur published a press release with preliminary results of their second Phase 3 trial of its candidate dengue vaccine. The trial was conducted in Brazil, Colombia, Honduras, Mexico, and Puerto Rico and involved 20,875 children and teenagers aged 9 to 16.

The announcement follows a series of updates made through the year about a previous similar Phase 3 trial conducted in Indonesia, Malaysia, the Philippines, Thailand, and Vietnam, with 10,275 children and teenagers aged 2 to 14. A little less than two months ago, on July 10th, Capeding et al published a manuscript in The Lancet with the detailed Asia findings.

With this update, the dengue research community again awaits with anticipation the publication of the key results, which would move us closer to assessing the public health utility of this vaccine candidate and its potential in reducing the burden of dengue.

The Results

As DVI previously reported in a blog post from September, the data prerelease indicates that the trial showed efficacy of 60.8 percent of reduction of dengue disease cases. Sanofi also announced that efficacy in this trial in Latin America was demonstrated for all serotypes, with 50.3 percent for serotype 1, 42.3 percent for serotype 2, 74.0 percent for serotype 3, and 77.7 percent for serotype 4. The study conducted in Asia showed an efficacy of 56.6 percent against any virologically-confirmed dengue and efficacy against serotypes 1, 2, 3, and 4, of 50 percent, 35 percent, 78.4 percent and 75.3 percent, respectively. In Asia, vaccine efficacy was not statistically significant for serotype 2. The Latin American trial remained consistent with previous trials of this candidate in that no safety concerns were observed. Sanofi also reported a significant reduction of the risk of hospitalization by 80.3 percent in Latin America, remaining consistent with a similar observation made in the Asian trial, where results showed a reduction by 67.2 percent.

What Does this Mean?

The data prerelease provides an insight into the Latin American Phase 3 trial. The results confirm the feasibility of protection against dengue by vaccination, including severe disease. However, the detailed data are required in order to fully assess the benefits, limitations, and further unknowns of this vaccine candidate in preventing and controlling dengue. The more complete results will also allow for in depth examination to better understand the heterogeneities in vaccine performance in Sanofi’s two Phase 3 trials.

For example, why does the protection against serotype 2 tend to be low? Is the difference in age groups between both trials important in explaining the results of the efficacy of the vaccine? How do regional differences affect the analysis of viewing this data together?

Without the results of CYD15 being in the public domain, comparisons will be limited. Questions still remain, but as the last stage of this Phase 3 clinical trial, we are closer to deepening our knowledge on dengue vaccines and uncovering future challenges and their potential solutions.

What’s next?

Once the complete data are publicly available this year in November, as predicted by Sanofi, the World Health Organization (WHO) will provide an independent assessment, as done for the Phase 3 study in Asia. Following licensure by a functional National Regulatory Authority (NRA), the WHO Strategic Advisory Group of Experts (SAGE) on immunization will advise WHO on the public health utility of the vaccine.

Update of Dengue Vaccines Currently in Clinical Trial

There are currently 5 tetravalent DENV candidate vaccines in clinical evaluation. Three of the vaccines are live attenuated tetravalent (LATV) 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).

The Sanofi Pasteur live attenuated tetravalent dengue vaccine CYD is a chimeric vaccine based on the yellow fever 17D vaccine. The vaccine is administered subcutaneously in 3 doses over a 12-month period (0, 6, and 12 month). It has completed two Phase 3 efficacy trials, one in Asia and one in Latin America. These trials build upon the data from the Phase 2b efficacy trial conducted in Thailand that showed an overall efficacy of the vaccine to protect against symptomatic dengue of 30.2% with no significant protection against DENV-2. The Phase 3 trial in Asia enrolled 10,275 children 2 – 14 years of age from 5 different countries. The vaccine achieved 56.7% efficacy against symptomatic dengue and a 67% reduction in hospitalization. The second Phase 3 trial enrolled 20,875 children 9 – 16 years of age in five countries in Latin America. The vaccine achieved an overall efficacy of 61% against symptomatic dengue and an efficacy against hospitalization of 80%.

The LATV vaccine produced by Takeda is also a chimeric vaccine but is based on a live attenuated DENV-2 virus as opposed to the YF 17D vaccine. The vaccine is administered in 2 doses given 3 months apart. A recently completed phase 1 clinical trial evaluated 2 different dose formulations and 2 different routes of administration of the vaccine in flavivirus-naïve adults. The vaccine was well tolerated and 47% to 71% of subjects seroconverted to all four DENV serotypes, depending on dose and route of administration, following 2 doses of the vaccine. The vaccine is currently undergoing Phase 1 and Phase 2 clinical trials in dengue-endemic areas.

The U.S. National Institutes of Health has two LATV candidate vaccines (TV003 and TV005) currently under evaluation. Both vaccines have been well tolerated and are highly immunogenic. TV003 induced a tetravalent neutralizing antibody response in 74% of vaccinees and TV005 and TV005 induced a tetravalent neutralizing response in 90% of vaccinees following a single

subcutaneous dose. Both candidates are undergoing Phase 2 clinical trial in dengue-endemic areas to determine the final formulation to be evaluated in Phase 3 efficacy trials.

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.

GSK is developing a purified inactivated tetravalent DENV vaccine. The company completed a proof of concept study and is currently evaluating 2 doses of the vaccine given one month apart with different novel adjuvants.

Second International Course in Bucaramanga on Integral Interventions for Dengue

This year, the International Course on Integral Interventions for Dengue, the second of its kind, was held in Bucaramanga, Colombia. The course objective was to provide useful tools and updates on implementation and strengthening of the integrated strategies for dengue prevention and control (or “Estrategia de Gestión Integrada,” EGI). Emphasis was placed on its main components: surveillance, laboratory diagnosis, case management, and vector control. The course included three symposia: (1) preparedness for emergence of Chikungunya; (2) determinants and predictors of the dengue severity, and (3) evidence for decision-making on vaccine introduction in dengue endemic regions. DVI was asked to present the symposium on the last topic focusing on the data needed to estimate the potential impact of dengue vaccine introduction in different scenarios. This session included presentations of preliminary data from epidemiological and economic studies in DVI sites by the DVI/IVI (International Vaccine Institute) scientists, Jacqueline Lim, Jung Seok, Lee, and Mabel Carabali and the modeling work by Dr. Ira Longini from University of Florida. The 4-day event covered topics through plenary sessions and focus group discussions. Participants included dengue researchers from Colombia, dengue experts from the Americas, members of the Colombian Ministry of Health and specialists from PAHO.

For more information click here and here.

Dengue Vaccine Effectiveness Workshop

A workshop was held in June 2014 in the PAHO headquarters in Washington DC with experts in vaccine evaluation and outcomes research, in dengue epidemiology, and diagnostics and outcomes research. The objective of the meeting was to develop recommendations pertinent to the evaluation of dengue vaccine effectiveness in post-licensure studies, for vaccines that have demonstrated acceptable safety and efficacy in Phase 3 trials. Workshop participants identified the most desirable study methods, study designs, and endpoint indicators that would allow for the determination of dengue vaccine effectiveness at preventing disease, including herd protection, and developed recommendations for what dengue surveillance systems should measure in order to determine

dengue vaccine effectiveness, and how country-level dengue surveillance can be used to guide dengue prevention and control in an era of dengue vaccination.

The workshop responded to the expectation that several countries will want to conduct vaccine effectiveness evaluations either before or after wide scale vaccine introduction. Vaccine effectiveness studies are planned in Mexico, Brazil, Colombia, and several Southeast Asian countries. However, for several reasons, effectiveness studies are likely to be limited both in number and in scope. Therefore, to derive maximum benefit from these studies it is critical for study design to be carefully considered. Specifically, studies should have the capability of measuring desirable endpoints, and definitions and indicators should be standardized across studies where possible. This will ensure a maximum of comparability and contribute to a greater understanding of vaccine performance.

For more click here.

Events

Asian Congress of Pediatric Infectious Diseases, October 12-15, 2014, Beijing,

China. 4th Pan-American Dengue Research Network Meeting: October 19-22, Belem, Brazil.

4th International Conference on Vaccines and Vaccination: September 24-26, Valencia, Spain.

World Vaccine Congress Europe, October 13-15, Brussels, Belgium. World Health Summit: October 21-23. Berlin, Germany.

63rd American Society of Tropical Medicine and Hygiene Annual Meeting: November 2-6. New Orleans, USA.

Asia Dengue Prevention Board Meeting: November 21-22, Seoul, South Korea (by invitation only).

15TH Developing Country Vaccine Regulators’ Network Meeting: November 24-28, Beijing, China (by invitation only).

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.

www.denguevaccines.org

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