At Tuesday’s sessions of the National Foundation for Infectious Diseases Annual Conference on Vaccine Research, vaccine scientists were moderately hopeful about developing an effective Zika virus vaccine. Their hope stems both from precedent and from the relatively simplicity of Zika virus: several effective vaccines for related flaviviruses have been developed, and there appears to be only one serotype of Zika virus, unlike, for example, dengue virus, which has four types.
Colonel Paul B. Keiser, MD, Walter Reed Army Institute of Research, described the other flavivirus vaccines and the lessons they offer for Zika. Yellow fever vaccine has been used since the 1930s and is exceptionally effective, although it does present serious risks to certain individuals. An inactivated vaccine for tick-borne encephalitis has been available in Europe since the 1970s. This vaccine doesn’t have the effectiveness profile of yellow fever vaccine and must be given in a three-dose series with boosters every 3-5 years. The Japanese encephalitis vaccine is another model for Zika vaccine: it is formalin inactivated and given generally in a three-dose series. (China uses a live JE vaccine.)
Keiser raised many questions that may influence Zika vaccine development efforts: Is vaccine efficacy more important to the individual than to the herd? How long does immunity need to last? How long will the current Zika epidemic last? How long would an epidemic last in temperate regions? Will we need to vaccinate pregnant women? Are the pathogenic effects of Zika due to the virus itself or to the immune response to infection? And, of course, sponsors and funders will be very interested whether a Zika virus vaccine will be commercially viable.
Different groups are taking varying approaches to developing a Zika virus vaccine; Keiser noted than an inactivated vaccine, a subunit/peptide vaccine, a live attenuated virus vaccine, and a DNA vaccine are currently in development.
Scientists at Walter Reed are building an inactivated vaccine, so Keiser was keen to develop a case for that approach. Inactivated vaccines are faster and less expensive to develop than other types, and, based on success with other flaviviruses vaccines, he thinks this type of vaccine should work. A key, however, will be using the right inactivation technique and an effective dosing/adjuvant strategy. The main disadvantage of pursuing the inactivated approach is that immunity will likely be short-lived.
Testing the vaccine will present further questions. Keiser raised the possibility that efficacy could be demonstrated in a challenge trial, meaning that during the trial, researchers would attempt to infect those vaccinated with Zika virus. Early malaria vaccine candidates are often tested this way. Given that Zika virus illness is usually mild, this might be a reasonable model. A challenge trial could accelerate development efforts in that it could eliminate ineffective vaccine candidates before larger-scale trials begin. But Zika virus is difficult to detect in the blood after infection, and so end points for a challenge trial might be difficult to define and measure. But the main disadvantage to a challenge trial is that Zika virus infection seems to be associated with Guillain-Barré Syndrome (GBS). Keiser noted that we don’t know anything about the pathophysiology of GBS associated with Zika (is it the virus that causes GBS or the immune response to the infection that causes it?). A challenge test, given this uncertainty, might be too risky.
Barney S. Graham, MD, PhD, is also working on a Zika virus vaccine at the National Institute of Allergy and Infectious Diseases (NIAID). His model is a DNA vaccine, using a virus-like particle capsid for Zika virus. His group was able to use their work on a chikungunya vaccine to accelerate their Zika vaccine work. They have designed a Phase 1 trial that could be launched in 3-4 months in Sao Paulo, Brazil.
Questions from the audience drew a connection with Monday’s conference session about lessons learned from Ebola vaccine trials during the 2014-15 West African epidemic. Keiser said the lesson he drew is that the lack of publicly funded advanced vaccine development is an impediment to epidemic response. Graham noted, looking ahead to the next emerging pandemic, that we should be developing more basic scientific knowledge about the virus families that can infect humans. For some of these families, he said, research is less than preliminary: it just hasn’t been done. He suggested large-scale efforts to solve the structures of prototypical viruses in each family, to understand their pathogenicity, and to develop human monoclonal antibodies for them. These kinds of broad steps could mean a faster response to vaccine needs for the next pandemic.