Editorial: The challenge of dengue vaccine development and introduction

The Bill and Melinda Gates Foundation recently awarded a 55 million dollar grant to the paediatric dengue vaccine initiative (PDVI). The grant is very much needed to accelerate the development and introduction of a dengue vaccine. Dengue, especially its more sinister forms dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), is a frightening disease. This mosquito-borne illness strikes suddenly, causing ‘break-bone’ fever with the risk of capillary leakage, bleeding and death. An estimated 50 million dengue infections occur annually, including 500 000 cases of DHF/DSS, with 24 000 deaths mostly in children. The burden is greatest in tropical Asia where dengue is a leading cause of paediatric hospitalization. Before 1970, only nine countries were reporting DHF epidemics, a number which has since increased more than fourfold (World Health Organization 2000). In recent years, several Latin American countries have been experiencing dengue outbreaks with serious consequences. The battle against dengue has focused on improving recognition and case management. The need for differentiation from other causes of fever and the lack of clinical predictors of severe disease complicate diagnosis. During the dengue season, particularly during outbreaks that occur every 3–4 years, health care facilities are inundated by fearful parents bringing in febrile children for evaluation and admission. Due to the progressive nature of the illness, repeated assessments over a period of about 3–7 days of fever are necessary. Lenient hospitalization policies allow close observation and improve outcome but use up precious resources. The illness is particularly cruel in that complications usually occur just as the patient starts to defervesce. The cornerstone of management is closely monitored intravenous fluid replacement. Where skilled staff and facilities are available, the case-fatality rate has been brought down to <1% but remains as high as 10–30% in poor countries or during outbreaks. The occurrence of repeat dengue episodes aggravates the situation. The virus has four serotypes and infection with one provides life-long immunity against that same but not the other serotypes. Not only do repeated episodes occur but the risk of severe illness is increased at least 15-fold during secondary compared with primary infections (Halstead 1980). Various mechanisms have been suggested to explain this phenomenon. Enhancement of virus replication in mononuclear cells by antibodies from a previous heterologous dengue virus infection has been demonstrated (Halstead 1988). Most recently, investigators have suggested that increased T-cell activation and apoptosis may contribute to the systemic disturbances leading to DHF (Mongkolsapaya et al. 2003). The impact of dengue is not only in terms of suffering from disease and death. Dengue imposes an economic burden including private expenditures for medical care and time taken from work to look after ill family members; government costs for provision of treatment and control activities; and lost revenue from tourism and industry. Currently, there is no sustainable preventive approach against dengue. Community-based mosquito control projects have succeeded on a small scale but national programmes have only been effective under strong central government supervision. Vector control has not provided wide-spread and long-lasting results. Vaccination offers greater hope as an effective and sustainable strategy (Jacobs 2000). Several multivalent dengue vaccines are in various stages of development but none of them is close to licensure (Halstead & Deen 2002). A live attenuated vaccine is thought to be the most promising design. Live attenuated viral vaccines actively replicate in the host resulting in an array of wild virus-like antigens, which could potentially provoke a response similar to natural immunity. Intracellular replication of the virus elicits strong cytotoxic T-cell responses. Long-term memory T-cells and immunity are exceptionally durable and complete immunization may be achieved with few doses (Monath et al. 2002). Live attenuated tetravalent dengue vaccines are being developed either through multiple passages of the virus in animal tissues and cell cultures (Bhamarapravati & Sutee 2000; Kanesa-thasan et al. 2001) or through viral mutations combined with chimerization. The main advantage of the latter technology is its potential to stabilize the genetic composition of a vaccine strain and reduce the risk of generating variants. Several chimeric dengue vaccine candidates have been constructed by replacing the premembrane and envelope genes of a dengue or the 17D yellow fever virus with those of another dengue virus serotype (Huang et al. 2000; Durbin et al. 2001; Guirkhoo et al. 2001; Markoff et al. 2002). As a result of the possibility of immunization-mediated enhanced disease, the current goal is to produce solid immunity against all four dengue serotypes with one or two vaccine doses. Much more research is needed to understand the pathophysiology of severe dengue disease and the implications for dengue immunization. The absence of an appropriate animal model disadvantages the development of dengue vaccine candidates. Even if mice and monkeys can be infected by dengue viruses, they do not manifest disease and although fever is sometimes seen in monkeys, they do not develop the severe illness seen in humans. Another challenge in dengue research is the lack of a good correlate of immunity. The plaque reduction neutralization test, which is an antibody assay, is perhaps the current most reliable marker of protection against dengue. Studies are underway to develop a standardized plaque reduction neutralization assay and an international standard antibody preparation for calibration of serological assays. Although the absence of an absolute measure of immunity does not preclude the conduct of a phase III efficacy trial, it creates challenges for the ultimate licensure and deployment of a future dengue vaccine. With all these and other unanswered questions, a main focus of the PDVI will be to support basic research. Once a safe and effective vaccine becomes available for wide-scale evaluation, several study design issues will have to be carefully considered and planned. In order for a phase III trial to have sufficient power to measure protective efficacy but not significantly interrupt dengue virus transmission, an individually randomized study of a high-risk age cohort has been suggested. This design would allow randomization, blinding, use of a placebo and measurement of protective efficacy within a specific age group and a single dengue transmission cycle and yet not significantly reduce dengue virus transmission. However, an individually randomized trial would only measure the direct protection provided by the vaccine. In contrast, a cluster-randomized design would allow measurement of both direct and indirect protection (i.e. that from decreased transmission). Furthermore, a cluster-randomized design of a population not restricted to a high-risk age cohort would enable measurement of vaccine efficacy by age group. This is important as immunization logistics including the potential integration of a dengue vaccine into the expanded programme of immunization schedule may require that children be vaccinated before they are at high risk. Unfortunately, in comparison with individually randomized trials, the cluster-randomized design requires a much larger sample size and is consequently much more complex and expensive to conduct and analyse. For example the clusters would have to be geographically discrete to avoid contamination by migrating vector mosquitoes (to measure indirect protection) but sufficiently similar in baseline characteristics to allow comparison. Other design considerations include the primary efficacy endpoint that should be used and how to ensure an adequate sample size to detect differences in this endpoint between the vaccinated and unvaccinated groups. It has been suggested that the primary efficacy endpoint be severe dengue disease requiring hospitalization. This endpoint would have to be defined clearly; should cases be limited to those that fulfil the World Health Organization definition of DHF and DSS or include all those with dengue infection admitted to hospital? To calculate the sample size needed, an estimated incidence of the primary efficacy endpoint in the study population would be required. As incidence varies from year to year, pre-vaccination surveillance of a study population over more than one season would be essential. Hospital-based data are inadequate for these purposes as the absence of a denominator would not allow calculation of accurate incidence. By supporting the surveillance of several study populations in distinct transmission regions, the PDVI would accelerate the availability of potential field sites. In the evaluation of a dengue vaccine in large, partially immune populations exposed to natural infection in dengue-endemic areas, safety issues will be paramount. A major conundrum is differentiating potential vaccine-induced immune enhanced disease from the event to be prevented by vaccination. In the presence of partial protection, it may not be possible to know whether one is observing the effect of vaccine toxicity or the result of incomplete vaccine protection. Thus, vaccine evaluation cannot be limited to conventional criteria. The PDVI could be instrumental in developing and planning for ways to carefully evaluate adverse events. Even with large phase III trials, rare adverse events may not be detected during several transmission cycles and post-licensure surveillance for several years may be necessary. To assuage safety concerns, future post-licensure surveillance could potentially be coordinated by the PDVI. Finally, the licensure of a dengue vaccine would not guarantee its use by those who need it most. Although the greatest morbidity and mortality from dengue occurs in children in developing countries, particularly in Asia, current dengue vaccines are primarily targeted towards adult travellers and Western military personnel. A survey of policymakers in four south-east Asian countries in 2002 revealed an almost uniformly high level of concern about dengue and a great perceived need for a dengue vaccine, suggesting favourable conditions for public and private sector markets (DeRoeck et al. 2003). Once a dengue vaccine is close to licensure, cost-effective analysis comparing vaccination costs with expenditures for treatment and control would assist governments in setting health priorities and making budgetary decisions. Willingness-to-pay and middle-class demand surveys could help convince producers of market viability and help them plan production capacity. Policy and economic information would be helpful in developing innovative financing schemes (for e.g. a multi-tier pricing system). The PDVI has an important role in the continued dialogue with policymakers and in developing private–public sector partnerships to ensure that the vaccine is available to poor children in dengue-endemic countries. In summary, the development of a safe and effective dengue vaccine is long due. Only a concerted effort by vaccine developers and scientists is likely to overcome the many obstacles before a dengue vaccine can be licensed, safely recommended, and eventually implemented. The generous funding received by the PDVI could allow the initiative to be the catalyst towards this endeavour. The PDVI is hosted at the International Vaccine Institute (IVI) in Seoul, Korea. The views expressed here are solely of the author and do not reflect those of the PDVI nor the IVI.