Widespread Japanese encephalitis (JE) vaccination is, first and foremost, a public health solution to JE control. PATH’s JE project sought to prioritize public health benefit when identifying and advancing a JE vaccine for global use. Because public health was always the primary goal, the project had a remarkable impact on communities suffering from JE.
Finding a JE vaccine that could be optimized for use in a public health setting was an important driver of the JE project’s priorities and strategies. And because price, logistics, ease of use, long-term immune protection, and time required are all important factors in determining public health benefit, solutions that are the simplest to deliver are usually the ones with the highest public health benefit. Therefore, our second lesson learned is to prioritize both public health benefit and simplicity as the foremost goals when developing, identifying, evaluating, or delivering vaccines for public health use.
A young student from Myanmar showing his proof of immunization during a JE vaccination campaign. Photo: PATH/Thet Htoo.
Finding a safe, effective, and affordable vaccine
After listening to country decision-makers and learning more about the JE burden and need for a vaccine, PATH conducted a landscape analysis of vaccine manufacturers. The goal was to develop or identify a vaccine that was safe, effective, and had a minimal impact on the existing cold chain. In addition, the vaccine had to be affordable for low- and lower-middle-income countries without donor support. Several inactivated JE vaccines derived from infected mouse brains were used in various countries, but these had safety concerns, required numerous doses, and were unaffordable in many JE-endemic countries—all major obstacles for a public health solution.
After several months of research, a simple solution emerged.
The team identified that one JE-endemic country, China, had developed an effective live attenuated vaccine that met many of the public health requirements. The Chengdu Institute of Biological Products’ (CDIBP’s) SA 14-14-2 vaccine—now referred to as CD-JEV—had safely and effectively protected 200 million Chinese children over nearly 20 years. It only required one dose for lifelong immunity. Most importantly, CDIBP was willing to work with PATH and other global partners to make this vaccine more available for public health benefit.
The first obstacle was gaining international approval so that countries other than China could readily use the CDIBP vaccine. CD-JEV was not widely used outside of China and, because it did not initially meet international manufacturing standards, it could not be procured using global funding mechanisms. In fact, no Chinese vaccine had previously achieved the World Health Organization’s (WHO) prequalification, an international signal of quality and safety.
Facilitating China's entrance into the global vaccine market
To be procured through international mechanisms like WHO, UNICEF, other United Nations associated health programs, and Gavi, the Vaccine Alliance, vaccines need to be WHO prequalified. Prequalification required a strong evidence base regarding the vaccine’s safety, efficacy, and manufacturing quality and was an important step in providing CD-JEV to low- and lower-middle-income countries. PATH partnered with CDIBP and other partners to build the evidence base and take the steps needed for prequalification. PATH supported capacity building, demand forecasting, contingency planning, construction of a new manufacturing facility, and development of a Quality Management System and a Pharmacovigilance System.
New facility construction immediately tripled CDIBP’s vaccine production capacity. In addition, this new facility was deemed compliant with Good Manufacturing Practices (GMP), a system for ensuring vaccines are consistently produced and controlled according to international quality standards. In 2012, CDIBP began producing CD-JEV in its new facility, which underwent comprehensive inspections to ensure the vaccine and manufacturing site met international standards. One of the requirements for prequalification was a “bridging” clinical trial, a scientific study that shows that the vaccine made in the new GMP-compliant facility had the same efficacy, safety, and quality of the vaccine made in the previous manufacturing facility and used in previous clinical studies.
Alongside efforts to build the evidence for prequalification, PATH continued to perform demonstration projects and post-licensure clinical trials outside of China. This was done to leverage buy-in from JE-endemic countries and increase product confidence in China’s first WHO-prequalified vaccine. Although China has been exporting several vaccines to low-income countries for decades through bilateral aid programs, changing global perception of vaccine quality was an important step.
To help facilitate these demonstration projects, PATH secured millions of CD-JEV doses that could be donated to countries. CDIBP provided these vaccines as part of a collaborative agreement whereby PATH provided CDIBP with technical assistance in strengthening and increasing its vaccine manufacturing capabilities in exchange for access to this donated vaccine. In addition, CDIBP agreed to provide CD-JEV at a lower price to several JE-endemic low- and lower-middle-income countries. By demonstrating the safety, effectiveness, quality, and value of CD-JEV in JE-endemic countries, these projects and trials laid the groundwork for countries to introduce the vaccine.
In 2013, WHO prequalified CD-JEV—the first-ever prequalification for a vaccine made in China. Prequalification opened the door for CD-JEV to be supported by Gavi for introduction in low-income countries. Just as important, the prequalification symbolized China’s entry as a contributor to the global vaccine market and as a benefactor of global public health.
Ensuring affordability
While partners were working to increase vaccine availability through WHO prequalification, PATH and CDIBP addressed another key bottleneck in vaccine access—affordability. If the vaccine was prequalified but remained unaffordable for the countries that needed it, it would be difficult to achieve public health impact. Early in the JE project, PATH negotiated with the manufacturer to secure a maximum public-sector price for the vaccine for the JE-endemic region. This public health pricing mechanism, which is in place until 2033, allows vaccine introduction in countries with limited public health resources, while still supporting CDIBP’s business goals even in the absence of support from other donors such as Gavi.
No Chinese vaccine had previously achieved the World Health Organization’s (WHO) prequalification, an international signal of quality and safety.
Achieving a vaccine price that was sustainable for CDIBP and low- and lower-middle-income countries alike was a critical step. Providing a vaccine for widespread public health impact should not have a negative financial impact on a manufacturer; instead, it should have both public health impact and a positive business impact to keep private-sector partners engaged. Through the pricing agreement, PATH and CDIBP opened new markets for CD-JEV, increased access to the vaccine for many countries, and ensured a sustainable supply for the foreseeable future.
While Gavi-eligible countries now benefit from Gavi support for JE vaccination, the price negotiations greatly benefited several low- and middle-income countries in the JE-endemic region before Gavi support was available, and the low price will continue to benefit non-Gavi-eligible, Gavi-graduated, and middle-income countries who do not receive donor support for childhood vaccination programs.
PATH also supported CDIBP through demand forecasting projections, which provided useful data for the manufacturer and global partners like Gavi.
Prioritizing public health and sustainability
A child receives a JE vaccination in China. Photo: Bill & Melinda Gates Foundation.
PATH’s JE project showed the potential benefits of multi-sector partnerships that prioritize vaccines for low- and lower-middle-income countries. Vaccine manufacturers may be hesitant to invest in vaccines for low-income countries, where profits will be minimal, unless another group—like a donor, non-profit, or public institution—are committed to sharing the investment. Although PATH prioritized public health and the availability of vaccine for low-income countries throughout this project, the partnership also sought to maintain an acceptable profit margin that would keep CDIBP engaged in producing vaccine for international export.
Country Spotlight: China
In addition to its leadership role in developing and distributing the CD-JEV vaccine, China was an early leader in national JE control. A highly JE-endemic country, the first clinical case of JE in China was confirmed in 1943. A national JE case reporting system was established in 1951, and in the decades that followed, China saw several major JE epidemics.
The first use of JE vaccine in China was with an earlier, inactivated mouse brain-derived vaccine that was licensed in 1968. Development of the live attenuated SA14-14-2 vaccine (CD-JEV) began in the 1970s under the leadership of Dr. Yu Yongxin at the National Institutes for Food and Drug Control. In the early 1980s, his team transferred the vaccine technology to the Chengdu Institute of Biological Products (CDIBP), one of several vaccine manufacturing institutes in China, for further development. After undergoing safety and efficacy testing, CD-JEV was licensed in China in 1988. Because of its improved safety and fewer required doses compared to the inactivated vaccine, it was introduced in immunization programs starting in 16 provinces and gradually expanded to the national EPI starting in 2008, with over 200 million children vaccinated in a 20-year period.⁴
Due to the commitment of Chinese health authorities and CDIBP to reducing JE’s toll through vaccination, JE incidence in China decreased from 21 cases per 100,000 in 1971 to an estimated 0.12 cases per 100,000 in 2011. Later, this same commitment by CDIBP would help make CD-JEV available to save lives not just in China, but across the entire JE-endemic region in Asia and the Western Pacific.
⁴ Gao X, Li X, Li X, et al. Vaccine strategies for the control and prevention of Japanese encephalitis in mainland China, 1951-2011. PLoS Neglected Tropical Diseases. 2014;8(8):e3015. doi: 10.1371/journal.pntd.0003015.
This is the second lesson in Approaching vaccination from end to end: Five lessons from more than 15 years of advancing Japanese encephalitis vaccination, a report developed PATH's Center for Vaccine Innovation and Access.