Flavivirus vaccines: Innovate, invest, implement

World Immunization Week 2016 is April 24–30. Coincidentally, on April 4 the Philippines launched a dengue immunization program targeting more than 1 million schoolchildren using the world's first dengue vaccine, CYD-TDV (Dengvaxia®). It took more than 20 years of research and development, including two Phase 3 clinical trials involving over 35,000 participants aged 2–16 years, for this new vaccine to reach approval—first in Mexico, the Philippines and Brazil in December 2015, then El Salvador in February 2016, with several other countries in the process of regulatory review. Over the past five decades, from being present in only a few countries, dengue is now endemic in more than 100 tropical and subtropical countries and is a major public health problem in Asia, Latin America and Africa. TheWorldHealth Organization (WHO) reports an estimated 390million dengue infections every year, with 500,000 hospitalizations and 25,000 deaths. The causative agent, dengue virus, exists in four serotypes. Recovery from infection with one serotype usually results in lifelong immunity against that serotype, but not the others, while subsequent infections with other serotypes can lead to severe dengue, including the life-threatening dengue hemorrhagic fever. One possible explanation is antibody-dependent enhancement (ADE) when nonneutralizing antiviral antibodies help the virus gain entry into host cells and increase viral infectivity, although other immune components may also play a role. It is thus crucial for a dengue vaccine to induce immunity against all four serotypes concurrently. CYD-TDV is a live attenuated, tetravalent, chimeric vaccine that is built on the backbone of the yellow fever 17D vaccine strain, which has been commercially available since the 1950s. Using DNA recombination technology, the pre-membrane (prM) and envelope (E) genes of 17D strain are replacedwith those from each of the four dengue serotypes. In clinical trials, CYD-TDV was capable of inducing immunity against all four dengue serotypes, and resulted in 80% reduction in hospitalization and 90% reduction in severe dengue. Dengue virus and yellow fever virus both belong to the genus Flavivirus that also includes West Nile virus (WNV) and Zika virus (ZIKV)—all of which can be transmitted by the mosquito Aedes aegypti that thrives in tropical and subtropical climates worldwide. There is only one ZIKV serotype, but unlike dengue, less is known about ZIKV pathogenesis. Because ZIKV infections generally produce mild influenza-like symptoms, the disease has been neglected for decades until the recent major outbreaks when the virus was suspected of being linked to serious neurological disorders, including Guillain– Barré syndrome (GBS) and fetal microcephaly. The current ZIKV outbreak started in 2015 in Brazil, spread quickly to several countries in Latin America, and is predicted to reach most of the Americas later in 2016. The WHO declared a global emergency in February 2016, and several research groups have rushed into developing a Zika vaccine.