Abstract
BackgroundZika virus has recently spread to South- and Central America, causing congenital birth defects and neurological complications. Many people at risk are flavivirus pre-immune due to prior infections with other flaviviruses (e.g. dengue virus) or flavivirus vaccinations. Since pre-existing cross-reactive immunity can potentially modulate antibody responses to Zika virus infection and may affect the outcome of disease, we analyzed fine-specificity as well as virus-neutralizing and infection-enhancing activities of antibodies induced by a primary Zika virus infection in flavivirus-naïve as well as yellow fever- and/or tick-borne encephalitis-vaccinated individuals.MethodologyAntibodies in sera from convalescent Zika patients with and without vaccine-induced immunity were assessed by ELISA with respect to Zika virus-specificity and flavivirus cross-reactivity. Functional analyses included virus neutralization and infection-enhancement. The contribution of IgM and cross-reactive antibodies to these properties was determined by depletion experiments.Principal findingsPre-existing flavivirus immunity had a strong influence on the antibody response in primary Zika virus infections, resulting in higher titers of broadly flavivirus cross-reactive antibodies and slightly lower levels of Zika virus-specific IgM. Antibody-dependent enhancement (ADE) of Zika virus was mediated by sub-neutralizing concentrations of specific IgG but not by cross-reactive antibodies. This effect was potently counteracted by the presence of neutralizing IgM. Broadly cross-reactive antibodies were able to both neutralize and enhance infection of dengue virus but not Zika virus, indicating a different exposure of conserved sequence elements in the two viruses.ConclusionsOur data point to an important role of flavivirus-specific IgM during the transient early stages of infection, by contributing substantially to neutralization and by counteracting ADE. In addition, our results highlight structural differences between strains of Zika and dengue viruses that are used for analyzing infection-enhancement by cross-reactive antibodies. These findings underscore the possible impact of specific antibody patterns on flavivirus disease and vaccination efficacy.
Highlights
Epidemics of infections with Zika virus, a mosquito-borne flavivirus, first emerged in Pacific islands (Yap 2007, French Polynesia 2013) followed by a big outbreak in South and Central America starting in 2015 [1, 2]
Our data point to an important role of flavivirus-specific IgM during the transient early stages of infection, by contributing substantially to neutralization and by counteracting Antibody-dependent enhancement (ADE)
These findings underscore the possible impact of specific antibody patterns on flavivirus disease and vaccination efficacy
Summary
Epidemics of infections with Zika virus, a mosquito-borne flavivirus, first emerged in Pacific islands (Yap 2007, French Polynesia 2013) followed by a big outbreak in South and Central America starting in 2015 [1, 2]. In sequential infections with different flaviviruses, anamnestic responses to shared epitopes can lead to the phenomenon of original antigenic sin, resulting in a strong boost of cross-reactive antibodies at the expense of type-specific antibodies to the newly infecting virus [7, 8] This situation can occur in regions where two or more flaviviruses co-circulate, such as the four dengue viruses in all tropical and sub-tropical regions around the world or dengue and Zika viruses in South and Central America or Southeast Asia [9, 10], or as a result of immunization with different flavivirus vaccines [11,12,13]. Since pre-existing cross-reactive immunity can potentially modulate antibody responses to Zika virus infection and may affect the outcome of disease, we analyzed fine-specificity as well as virus-neutralizing and infection-enhancing activities of antibodies induced by a primary Zika virus infection in flavivirus-naïve as well as yellow fever- and/or tick-borne encephalitisvaccinated individuals
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