Antibody dependent enhancement – a dark horse against a Zika virus vaccine

With Zika virus causally associated with microcephaly and other birth defects, a vaccine is urgently needed. Fortunately, a recent study shows promise for a Zika virus vaccine, and other candidates are in development. While this news is rightfully celebrated, vaccination for flaviviruses such as Zika and Dengue virus is not simple due to a phenomenon known as antibody dependent enhancement (ADE). Studies show that Dengue antibodies can enhance Zika virus infection.  The consequences of this are severe and have the potential to exacerbate the disease.

What is ADE?

The immune system produces neutralizing antibodies after infection or vaccination. These antibodies bind to the surface proteins of a virus to block infection. ADE occurs when antibodies that neutralize one virus can bind to, but do not block the infection of a similar virus.

ADE is most commonly observed for Dengue virus. There are 4 serotypes of Dengue virus, which contain closely related but distinct surface proteins. Infection with one serotype typically results in mild symptoms. However, if an individual is subsequently infected with another Dengue serotype, the immune system will produce antibodies to the first. These antibodies bind to but do not always block infection of the other serotypes. This results in antibody-mediated uptake into cells that Dengue virus does not normally infect. This can result in a more severe form of disease such as Dengue hemorrhagic fever or Dengue shock syndrome.

Dengue antibodies can promote ADE of Zika virus

Not only do antibodies to Dengue virus promote ADE of other Dengue virus serotypes, but also a recent report indicates that Dengue virus antibodies can enhance Zika virus infection. The authors tested what effect Dengue neutralizing antibodies or serum from Dengue virus patients had on Zika virus in cell culture. In the absence of antibody, Zika virus poorly infected the cells, but when Zika virus was incubated with Dengue serum or neutralizing antibodies, Zika virus robustly infected these cells, indicating ADE. While the physiological relevance of this finding requires confirmation in animal models of infection, researchers should take the implications seriously.

Implications for vaccine design

Dengvaxia is a recently approved vaccine for Dengue virus. Scientists should therefore test if serum from people vaccinated with Dengvaxia promotes ADE of Zika virus. It would be a tragic consequence if preventing one disease increased the severity of another. It also stands to reason that if Dengue virus antibodies can promote ADE of Zika virus, that Zika virus antibodies could promote ADE of Dengue virus. If this is the case, vaccination against Zika virus could increase the incidence of Dengue hemorrhagic fever or Dengue shock syndrome. This possibility needs to be considered and tested in Zika vaccine animal models before any human trials begin in areas where both viruses are endemic.

Other studies should test whether people with prior exposure to Dengue virus are more likely to have severe outcomes of Zika virus infection and vice versa. Knowing whether or not ADE occurs in animals can then inform vaccine and therapeutic design. While the need for a Zika virus vaccine is vital, the consequences of ADE are severe and deserve immediate consideration.

Featured image is from Carlos Reusser Monsalvez, shared via public domain.