Human antibody response to Zika and other flaviviruses

Flaviviruses are among the most important human pathogens transmitted by arthropods (mosquitoes and ticks) and include Zika, dengue, yellow fever, West Nile, Japanese encephalitis and tick-borne encephalitis viruses. Some of these viruses have spread dramatically in the past and have conquered new territories, best exemplified by the recent outbreaks of Zika virus infections in Pacific Islands, South- and Central America. Flaviviruses cause a wide spectrum of clinical diseases from mild febrile infections to life threatening conditions. Humans infected with flaviviruses produce antibodies as part of their immune response and these are believed to confer long-lasting immunity to the infecting virus. The protective effect of antibodies is based on their capacity to bind to the surface of infectious virus particles and thereby neutralizing their infectivity. Immune responses, however, are heterogeneous and lead to an array of antibody populations in the blood that react with different parts of the virus. Some of them are very potent in preventing infection but others are ineffective, and there is strong evidence that such poorly neutralizing antibodies are not only non-protective but can even enhance the virus infection of certain cells and lead to severe disease. This phenomenon of antibody-dependent enhancement of infection has been implicated in the most severe forms of dengue virus infections (hemorrhagic dengue fever and dengue shock syndrome) and is now also hypothesized to contribute to transplacental infections of Zika virus and consequently to embryonic malformations such as microcephalies. It is the major goal of this proposal to dissect the different antibody populations in human blood after infections with Zika, dengue, West Nile and tick-borne encephalitis viruses as well as yellow fever and tick-borne encephalitis vaccinations and to determine the balance between neutralizing and infection-enhancing activity. A strong focus will be on a group of antibodies that can react with all flaviviruses but are unable to inhibit infectivity. These have been proposed to be the central culprit in the context of infection- and disease-enhancement but so far there is no comparative information as to which extent they are produced compared to neutralizing antibodies after different flavivirus infections and vaccinations. Such broadly cross-reactive but non-neutralizing antibodies can also be an undesirable result of vaccination and in addition hamper the specific laboratory diagnosis of flavivirus infections. This project will therefore not only have implications for our basic understanding of immune responses to flaviviruses but also impact the design of novel vaccines and diagnostic tests.

Flaviviruses are important human pathogens transmitted by arthropods (mosquitoes and ticks) and include Zika, dengue, yellow fever (YF), West Nile, and tick-borne encephalitis (TBE) viruses. Some of these viruses have spread dramatically in the past and have emerged in new territories, exemplified by the recent outbreaks of Zika in Pacific Islands, South- and Central America. Flaviviruses cause a wide spectrum of clinical diseases from mild febrile infections to life-threatening conditions. There are no specific antiviral drugs for treatment available, but some very effective vaccines are in use for prophylaxis. All flaviviruses are antigenically related, and flavivirus infections and/or vaccinations induce type-specific antibodies (which effectively neutralize the virus and cause long-lived protection) as well as antibodies that cross-react with other flaviviruses and are usually non-protective. Pre-existing flavivirus immunity can modulate immune responses to secondary infections with other flaviviruses or to vaccinations with heterologous vaccines. In our work, we investigated the effect of a prior flavivirus immunity on the antibody responses to a) Zika virus infection and b) TBE vaccination. In both studies, we observed a strong booster of broadly cross-reactive but non-neutralizing IgG antibodies. Of note, in the flavivirus pre-immune TBE-vaccinated cohort, the neutralizing antibody response to TBE virus was even impaired compared to a control cohort, suggesting that the memory response to cross-reactive sites occurred at the expense of the generation of new antibodies capable of neutralizing TBE virus. This phenomenon is referred to as 'original antigenic sin'. No such effect was observed with the pre-immune Zika virus-infected cohort, in which production of Zika virus-specific neutralizing antibodies was similar to that in the nave control group. However, a reduction of newly formed Zika virus-specific IgM antibodies was observed in the pre-immune cohort. An impairment of IgM antibody formation may have important biological consequences, because we showed that they contributed significantly to virus neutralization and prevented infection enhancement by other antibodies. Taken together, our data provide novel insights into the effects of pre-existing cross-reactive immunities on the specificities and functional activities of antibody responses in flavivirus vaccinations as well as infections, enhancing our understanding of flavivirus pathogenesis and the efficacy of vaccines.