The secret journey of an effective vaccine

How a global public-private collaboration has successfully rolled back a little-known but devastating disease.

The children were lined up in rows after rows. They were unconscious, wracked by high fever and seizures, many lying in pools of their own urine or vomit, having to share far too few hospital beds. They all suffered from the “brain fever” that unleashed devastation in this rural corner of India’s Andhra Pradesh state every rainy season, and the local authorities had asked for help.

More than fifteen years after she walked through that hospital ward, Julie Jacobson, formerly of PATH and the Bill & Melinda Gates Foundation, still tears up when describing what she saw. “It was completely and totally overwhelming,” she recalls. “What is going on here?” she remembers thinking. “This is a medical emergency!”

The “brain fever” was Japanese encephalitis, or JE, a mainly tropical disease that was then little known outside of specialized health circles. Endemic in 24 countries in Asia and the Pacific, JE strikes in rural areas, home to rice paddies that are breeding grounds for the mosquitoes transmitting the virus, and to the pigs and wading birds that carry it. This puts over 3 billion people at risk of infection.

Most JE victims are children. Two thirds of those who develop the disease either die or are left disabled for the rest of their lives. Some can no longer walk or talk. Others go blind or are left with severe neurological damage. Even children deemed to have “recovered” are often very far from being fine, unable to recognize their family or flying into incontrollable fits of rage. “JE takes away the person,” Julie Jacobson points out. “And that’s just devastating.” Even more devastating was the knowledge that this was preventable. “We don’t have a lot of solvable problems,” says Julie Jacobson. “But this was one of them.”

Although solvable, it was not easy. Rolling back JE required putting together a solid plan and bringing together a global coalition of public and private partners. With support from the Bill & Melinda Gates Foundation, PATH got on the case. First, the JE disease burden needed to be better mapped. Estimates put the number of cases at 70,000 a year, but the true burden of disease was unclear. Japanese encephalitis is tricky to diagnose. Its array of possible symptoms, from seizures, confusion and headaches to high fever and diarrhea, overlap with other diseases’, and cases were grossly underreported. In addition, blood tests were often misleading, because the antibody response can take weeks to manifest and is cross reactive with other closely related viruses, such as the West Nile and Dengue viruses. Initially, PATH worked closely with the World Health Organization (WHO), the U.S. Centers for Disease Control and Prevention (CDC) and private partners to develop better diagnostics, guidelines and surveillance networks.

With no cure available and no way to eradicate the virus, identifying a safe, effective, easy-to-use and affordable vaccine that could be supplied in large quantities was an essential part of the strategy. JE vaccines were available, but the main technology, which involved injecting the JE virus into mice, harvesting their brains and inactivating the virus, was difficult to scale to protect the millions of people who needed it, and there were concerns over safety. The vaccine was also unaffordable for many countries where JE was endemic and required three doses, significantly complicating administration.

Looking at possible alternatives, PATH came across a vaccine known as SA 14-14-2 or CD-JEV, which was made in China and had been used to immunize some 200 million Chinese children since the 1980s. Julie Jacobson took a team of experts to Chengdu Institute of Biological Products, a subsidiary of China National Biotech Group, which manufactured the vaccine. Cultivated from hamsters’ kidney cells, the live vaccine required only a single dose and was safe. It was also much more affordable than other vaccines.

To supply the vaccine through international procurement agencies, however, the manufacturer had to obtain pre-qualification from the WHO, a stamp of approval confirming that the vaccine and its production met international quality, safety and efficacy standards. No Chinese vaccine manufacturer had ever gone through that process. Production also needed to be scaled up.

When the Chinese team was told that their vaccine could protect millions of children across Asia, the response was swift. “Of course, we’ll do it. Whatever you need.” Over the following six years, Chengdu Institute of Biological Products, working in tandem with PATH, the WHO and Chinese health authorities, invested over US$ 100 million to upgrade and expand manufacturing facilities, revise production and safety standards, and train their staff. Procedures were revamped to adopt internationally acceptable standard operating procedures and manufacturing practices. Clinical trials were conducted and data collected in other countries to demonstrate that the vaccine was safe and effective in other contexts. At the same time, the Chinese manufacturer agreed to provide the vaccine to the poorest countries at an initial price of less than 25 cents a dose—at least 15 times less than alternative vaccines.

A Game Changer

On October 9, 2013, Chengdu Institute became the first Chinese manufacturer to obtain WHO prequalification for a vaccine. This was a milestone. Not only did an effective, safe and affordable JE vaccine become available internationally, but the Chinese National Regulatory Authority also met stringent WHO prequalification guidelines. This created momentum for other Chinese vaccines to be prequalified, which would turn China into a global supplier of high-quality, affordable vaccines, particularly in the developing world.

For many countries where JE was endemic, the cost-benefit equation of immunization was very clear. In line with WHO recommendations, the greatest immediate impact would be realized if catch-up campaigns were conducted in affected areas before rolling the vaccine into routine immunization schedules. Yet the poorest countries with a JE problem still required financial support to launch a mass campaign and then transition to a routine program.

Enter Gavi, the Vaccine Alliance. With few donors familiar with JE and why it should be funded when weighed against other life-saving vaccines, affected countries pushed to have the vaccine included in the Gavi program; an analysis of cost, cases and deaths averted from JE due to vaccination further helped. In December 2013, with the WHO pre-qualification secured, the Gavi Board approved funding for immunization against JE, which covered the cost of the vaccine itself for campaigns, as well as associated expenses such as training, social mobilization and vaccination sessions.

Gavi’s initial funding supported catch-up vaccination campaigns for children aged between 9 months and 15 years old and provided a grant to transition to routine immunization, which local authorities then had to fund themselves. Laos was the first to apply in 2014, followed by Nepal and Cambodia the following year. Unlike Laos and Cambodia, where no JE vaccine had been available except through small donations, Nepal had been conducting immunization in its worst affected zones, but Gavi’s financial support allowed the authorities to expand their program to all endemic areas in the country. In 2015, Gavi started co-financing JE routine immunization as well, conducted in most cases in tandem with measles-rubella (MR) immunization, following which Myanmar became the fourth country to receive financial assistance. By the end of 2017, thanks to Gavi’s support, 17 million children had been vaccinated against JE in Laos, Nepal, Cambodia, Myanmar, and routine immunization is now in place in all four countries. In 2018, Gavi also supported a catch-up campaign in Bali. Vietnam had applied for financial support as well but withdrew after deciding to use a locally-produced vaccine instead.

Fifteen years after the initial grant from the Bill & Melinda Gates Foundation, what has been accomplished? Thanks to the coordinated intervention and advocacy of the Foundation, PATH, Chengdu Institute of Biological Products, Gavi, WHO and its Regional Offices, CDC and UNICEF, 10 countries have improved JE surveillance and control of the disease through the vaccination of some 300 million children; in February 2019, the Philippines started to roll out the JE vaccine. Another two countries—Bhutan and Pakistan—have improved their surveillance and are assessing the need for routine immunization. Without a reliable baseline pre-dating the JE campaign, the exact impact remains difficult to measure. But studies in 31 districts in Nepal indicate that vaccine introduction resulted in a drop of about 80 percent of JE cases and almost 60 percent in all cases of encephalitis.

In spite of this success, there is no room for complacency. Tina Lorenson, senior program officer of Vaccine Delivery at the Bill & Melinda Gates Foundation, sums it up in a few questions. “PATH has done a tremendous job at raising awareness of JE and ensuring production of safe and effective vaccine reaches vulnerable populations. How do we ensure countries and regions will continue to maintain the successes to date? How do we continue to track at risk populations? How do we ensure that vaccine coverage in endemic areas remains high?”

Work indeed remains to be done to improve surveillance and better measure the impact of interventions. More granular data will help refine where vaccination is most needed. National authorities facing competing immunization choices have to decide where to roll out the JE vaccine at the subnational level. Better data would also help make the case for JE immunization in countries such as Bangladesh and Indonesia outside of Bali, where JE is endemic but the vaccine is still not being offered as part of public health programs. Whether a booster dose of the CD-JEV vaccine might be needed to sustain maximum protection over time also requires careful monitoring.

Even in countries where routine immunization is now in place, coverage can still be further improved. Khin Devi Aung, senior program manager at Gavi, points out that in some countries, the vaccination coverage is lower for JE than for MR, even though both vaccines are supposed to be administered at the same time. Why this gap? It is still unclear. Then there is the question of risk management. Continued immunization, particularly in the poorest countries, depends on the uninterrupted supply of a reasonably priced vaccine. Joachim Hombach, the focal point for JE at the WHO headquarters for many years, points out that relying on a single manufacturing facility is not without risks.

And continued, immunization must be. “Once you've made the commitment to vaccination, you have to keep vaccinating because there is no eradication of this virus,” explains Tony Marfin, director of Vaccine Introduction and Impact at PATH. “It's not like smallpox, it's not like polio, which are human-to-human transmitted viruses. Japanese encephalitis is primarily a bird virus, and it continues to stay in the environment because it cycles within birds.”

For Wa Meng, who lost his eldest 13-year-old son to JE, vaccination has been a life saver. When the immunization campaign came to his village of Khonkandone in Laos, he had all his other children vaccinated. The challenge is to ensure that his children’s children will be, too.