From the beginning, PATH’s Japanese encephalitis (JE) vaccine project emphasized that countries need data for decision-making. Data such as JE incidence, measures of cost-effectiveness, estimates of the long-term cost of vaccination, modeling of the potential impact of vaccination, and modeling the potential impact of JE vaccine introduction on other established Expanded Programme on Immunization (EPI) vaccines are needed to make sound decisions regarding JE vaccine introduction.
At the same time, the cost, time, and logistical challenges associated with conducting surveillance or collecting these other data may be prohibitive. This means that every country may not need its own detailed data. Although public health decisions should be based on country-specific data as much as possible, the JE project showed the potential and value of regularly sharing high-quality data between neighbors in order to make decisions on new vaccine uptake. In other words, the data does not need to be perfect, complete, or country-specific for a country to make well-informed, evidence-based decisions.
A group of boys in Nepal crowd together, small fingers raised to show the ink markings on them, indicating that they have received their vaccinations. Photo: PATH/Rocky Prajapati.
Laying a foundation for decision-making through disease surveillance
Assessing a country’s disease burden through surveillance is the first and most important step for decision-making about vaccine introduction. JE surveillance, however, is complicated by many factors. First, JE is only one of several causes of acute encephalitis syndrome (AES), and it has no specific clinical presentation compared to other causes of AES. Second, a JE diagnosis can only be made through either laboratory testing of cerebrospinal fluid, which may be difficult to collect in some settings, or testing serum samples taken during both the acute and recovery phases of illness. For countries lacking laboratory capacity, equipment, or trained personnel, these diagnostic methods present several challenges. Additionally, the JE virus has cross-reactivity with other regional flaviviruses, such as dengue and West Nile viruses, that may be co-circulating at the same time in the same areas, resulting in diagnostic errors. Finally, a lack of reporting standards can prevent the collection of standardized and useful data. Overcoming these challenges to provide enough surveillance data for decision-making was an important part of PATH’s JE project.
To address diagnostic challenges, PATH worked with partners to develop WHO JE surveillance standards, evaluated and supported development of JE diagnostic tests with several manufacturers, and helped support establishment of and standards for regional JE laboratory networks. The global team of partners assisted in the evaluation of sensitivity and specificity across diagnostic kits and the development of a validation panel to assist national level use of in-house diagnostic kits. Importantly, the partners worked with national programs in collaboration with WHO regional offices to begin or enhance JE surveillance. Increased surveillance efforts led by the US Centers for Disease Control and Prevention (CDC) in Bangladesh, Cambodia, China, India, and Nepal provided insights into the burden of JE disease to inform decision-making on immunization. One key lesson from enhancing country surveillance was that JE disease burden involves not only the acute disease, but also its devastating sequelae, including long-term disability—an important factor when considering the potential value and impact of a JE vaccine.
Using surveillance to assess a country’s disease burden is the first and most important step for vaccine introduction decision-making.
Building in-country surveillance capacity allowed governments to generate data to answer a critical question—whether their country would benefit from introducing a JE vaccine. Having a good surveillance system in place before vaccine introduction also enabled disease burden monitoring after introduction to determine vaccine impact. One of the challenges of the JE project, however, was that not every country had the capacity to conduct nationwide disease surveillance. Often, countries only had surveillance in a handful of hospitals. Frequently, these hospitals were in urban settings as opposed to the rural settings where JE occurred more frequently. Others only had syndromic AES surveillance, with no way to confirm the proportion of cases caused by JE. Some had no surveillance at all.
At the same time, WHO, CDC, PATH, and other JE experts knew that vaccination would likely be beneficial for most countries in the JE-endemic region based on data from neighboring countries and/or the presence of the principal vector mosquito and similar ecology, geography, and agricultural practices. WHO, CDC, and PATH’s JE team also helped countries determine the likelihood that JE virus transmission is occurring by investigating AES outbreaks. Although these types of data are not perfect and are often incomplete, they may provide a compelling-enough picture of likely disease burden to inform vaccine decisionmaking. WHO has recognized that JE surveillance data does not have to be complete or perfect before making the decision to introduce JE vaccination, which WHO recommends that countries integrate into routine immunization in all areas where JE is recognized as a public health priority or is likely present due to environmental factors.
In order to decide with data, programs must have data to use—but when enough regional and global contextual evidence exists, routine national surveillance is not necessary to justify action.
Building confidence through clinical trials
Vials of vaccine sit in front of a health worker who is administering JE vaccine in Nepal. Photo: PATH/Rocky Prajapati.
A mainstay of developing and introducing any new vaccine is ensuring its safety, efficacy, and ideally, co-administration feasibility with data from clinical trials. When PATH began working with the Chengdu Institute of Biological Products (CDIBP) to attain WHO prequalification of the live attenuated JE vaccine, CD-JEV, and help countries make decisions about introduction, the team knew that the decision-making would require data.
In order to achieve WHO prequalification, attain licensure and introduction in individual countries, inform immunization schedules, and transition from other JE vaccines, PATH and partners conducted seven clinical trials with CD-JEV in three JE-endemic countries.
Because most of the safety and efficacy studies needed for prequalification had already been completed both within and outside of China, a lot-to-lot consistency study, conducted in Bangladesh, was the only additional trial required for WHO prequalification. This trial showed that the vaccine made in the new CDIBP manufacturing facility was as safe and immunogenic as the vaccine from the previous facility.⁵ Before conducting that trial, however, PATH also led four other trials looking at CD-JEV co-administration with other vaccines, duration of protection, and transition from the mouse brain vaccine. PATH knew the results would be crucial for safety as well as country decision-making based on concerns about a then-unfamiliar product. Introducing a new vaccine into a country’s EPI requires carving out a safe, effective, and logical space for the new vaccine into an already crowded schedule, and an important factor for finding the right place is ensuring that the new vaccine can be safely co-administered with other routine vaccines. This is an especially critical factor when live attenuated vaccines are being administered at the same time. The team needed to ensure that the new vaccine would not disrupt the schedules or effectiveness of existing vaccines—especially those driving global initiatives like measles control or polio elimination.
Table 1. CD-JEV clinical trials conducted by PATH.
After the first five trials, PATH conducted two additional studies. One ensured the safety and immunogenicity of CD-JEV when co-administered with measles-mumps-rubella vaccine in the Philippines, and another confirmed the duration of protection of CD-JEV in Bangladesh after the initial trial for WHO prequalification.
All of the clinical trials provided important evidence on safety, immunogenicity, and co-administration that not only resulted in the WHO decision to prequalify CD-JEV in 2013, but also supported countries’ decisions to introduce the vaccine in their national immunization programs.
Vaccine safety and efficacy trials and effectiveness studies, however, do not need to be performed in every country considering JE vaccine introduction. Building an evidence base through a limited number of high-quality clinical trials and studies can go a long way to inform decision-makers in many countries.
Informing country strategies with cost-effectiveness analyses
Although immunization is recognized as one of the most cost-effective health interventions available, many countries have limited resources to invest in new vaccines. When faced with competing priorities and limited funds, evidence from economic evaluations can help determine appropriate resource allocation and strategy designs.
Early in the project, PATH worked directly with two countries to conduct cost-effectiveness analyses of CD-JEV before the public-sector pricing agreement was in place. In 2006, the team worked with local investigators in Andhra Pradesh, India, to compare the cost-effectiveness of (1) two strategies: a one-time catch-up campaign or a catch-up campaign combined with routine immunization; and (2) two vaccines: an inactivated, mouse brain–derived JE vaccine and the live attenuated CD-JEV vaccine. Results showed that the WHO-recommended JE vaccine introduction strategy (catch-up campaigns, plus routine immunization) using CD-JEV would be highly cost-effective.⁶ By contrast, this same strategy using the inactivated, mouse brain–derived JE vaccine would not be cost-effective. Given limited resources, immunization strategies targeting only high-risk areas were found to be more cost-effective than vaccinating nationwide. Nationwide strategies may have been more economically favorable with current pricing, but at the time of the analysis CD-JEV’s public sector price was not available.
Similarly, PATH and the Cambodian government launched a study in 2007 to analyze costeffectiveness of JE vaccines in Cambodia. The results also supported a catch-up campaign combined with routine immunization, which helped guide decision-making and inform Cambodia’s JE immunization strategy.⁷ A key result from Cambodia’s analysis was that initial campaigns would have greater impact by targeting wider age ranges, leading Cambodia to conduct campaigns up to 15 years of age before transitioning into routine JE immunization.
Other cost-effectiveness analyses led by the International Vaccine Institute and partners in China,⁸ Indonesia,⁹ and other countries added to the regional knowledge base of the cost-effectiveness of JE immunization strategies.
When faced with competing priorities and limited funds, evidence from economic evaluations can help determine appropriate resource allocation and strategy designs.
Disseminating data for decision-making
Data helps countries make the best, most effective decisions, but for it to be useful, it must reach decision-makers. Disseminating the data and sharing information with the right audiences were key elements of PATH’s JE project from the start. Data must be clearly and appropriately communicated to decision-makers and influencers in a timely manner.
Advocacy and communication efforts included translating results from surveillance studies, clinical trials, and cost-effectiveness analyses into clear and simple messages for various audiences; including messages in published materials and media resources; conference and workshop presentations, and policy briefs; and working with clinical trial teams to provide guidance and support on communicating trial results to the media. One key lesson from dissemination efforts was realizing the importance of highlighting JE’s regional and country-specific impact. Because JE is a regional disease and the disease burden is much lower than many other global diseases, it was largely underappreciated by global funding agencies and international health agencies. However, in an individual country, JE’s impact can be catastrophic. These findings needed to be aggregated and communicated upward to country decision-makers and global funders who support new vaccine introduction. In order to decide with data, decision-makers must have access to and understand the data.
In order to decide with data, decision-makers must have access to and understand the data.
Using the evidence
Data should always be an essential part of decision-making for public health interventions such as vaccines. However, it is neither feasible nor necessary for every country to have the highest possible levels of country-specific disease surveillance and vaccine data. A strong foundation of regional and global data on disease surveillance, vaccine safety and efficacy, and cost-effectiveness—with some country-specific verification—may be enough for a country to implement a cost-effective, lifesaving, and sustainable vaccination program. The benefit of introducing a new vaccine based on non-country-specific data usually outweighs the cost of failing to introduce the vaccine while waiting for perfect data.
Country Spotlight: Phillipines
The burden of JE in the Philippines has been recognized for over a decade. In 2008, a national surveillance program was established to monitor cases of acute encephalitis syndrome. Disease patterns indicate that transmission in the Philippines is variable yet widespread; people living in rural regions with rice or pig farming—two of the largest agricultural outputs in the Philippines—are generally at highest risk. The Research Institute of Tropical Medicine (RITM), located in Manila, was an early and crucial partner in the JE project, recognizing the potential of CD-JEV vaccination for the Philippines. In partnership with RITM, PATH conducted three clinical trials with CD-JEV in the Philippines, vaccinating more than 1,200 children with no vaccine-related adverse events—crucial research that contributed to the WHO approval and recommendation of CD-JEV for use in all JE-endemic countries.
On a national level, data from the surveillance program and clinical trials also informed decision-making within the Department of Health (DOH). The National Immunization Program needed more information to evaluate options for CD-JEV delivery strategies—including routine nationwide vaccination only, a one-time nationwide campaign followed by routine vaccination, or subnational campaigns in high-risk regions followed by routine vaccination. To estimate the costs and benefits of each strategy, PATH conducted a cost-effectiveness analysis comparing these options. With this additional evidence to inform decision-making, in March 2019, the DOH conducted subnational immunization campaigns in four high-risk regions, vaccinating half a million children under the age of 15. Following the conclusion of the campaigns, the DOH is now evaluating the possibility of introducing the JE vaccine into its routine immunization program. PATH has provided continued support to the DOH through campaign planning and evaluation, vaccine provision, and additional cost-effectiveness analysis.
Finally, the Philippines also demonstrated the importance of communicating and disseminating data for building trust and fighting vaccine misinformation. After the completion of the most recent clinical study with CD-JEV, PATH and RITM hosted a meeting in Manila in October 2018 to present and explain the results to trial participants, their families, and other local and national stakeholders.
At the October 2018 community meeting, a presenter from RITM followed each presentation with a quiz. The answers were unanimous: Is the vaccine safe? “YES!” Is it effective? “YES!” Photo: PATH/Jodi Feser.
⁵ Zaman K, Naser AM, Power M, Yaich M, Zhang L, Ginsburg AS et al. Lot-to-lot consistency of live attenuated SA 14-14-2 Japanese encephalitis vaccine manufactured in a good manufacturing practice facility and non-inferiority with respect to an earlier product. Vaccine. 2014;32(46):6061–6066.
⁶ Suraratdecha C, Jacobson J, Sivalenka S, Narahari D. A cost-effectiveness analysis of strategies for controlling Japanese encephalitis in Andhra Pradesh, India. Journal of Pharmaceutical Finance, Economics & Policy. 2006;15(1):21–40.
⁷ Touch S, Suraratdecha C, Samnang C, et al. A cost-effectiveness analysis of Japanese encephalitis vaccine in Cambodia. Vaccine. 2010;28(29):4593-4599.
⁸ Ding D, Kilgore PE, Clemens JD, et al. Cost–effectiveness of routine immunization to control Japanese encephalitis in Shanghai, China. Bulletin of the World Health Organization. 2003;81(5):334-342.
⁹ Liu W, Clemens JD, Kari K, Xu ZY. Cost–effectiveness of Japanese encephalitis (JE) immunization in Bali, Indonesia. Vaccine. 2008;26(35):4456-4460.
This is the fourth lesson in Approaching vaccination from end to end: Five lessons from more than 15 years of advancing Japanese encephalitis vaccination, a report developed by PATH's Center for Vaccine Innovation and Access.