Zika Virus-Immune Plasmas from Symptomatic and Asymptomatic Individuals Enhance Zika Pathogenesis in Adult and Pregnant Mice

Abstract

Preexisting immunity against dengue virus or West Nile virus was previously reported to mediate antibody-dependent enhancement (ADE) of Zika virus (ZIKV) infection in a mouse model. We show here that ZIKV-immune plasma samples from both symptomatic and asymptomatic individuals mediated ZIKV ADE of infection in vitro and in mice. In a lethal infection model with a viral inoculum 10 times higher, both ADE and protection were observed, depending on the amount of infused immune plasma. In a vertical-transmission model, ZIKV-immune plasma infused to timed pregnant mice increased fetal demise and decreased the body weight of surviving fetuses. Depletion of IgG from an immune plasma abolished ADE of infection, and the presence of purified IgG alone mediated ADE of infection. Higher viral loads and proinflammatory cytokines were detected in mice treated with ZIKV-immune plasma samples compared to those receiving control plasma. Together, these data show that passive immunization with homotypic ZIKV antibodies, depending on the concentration, could either worsen or limit a subsequent ZIKV infection. IMPORTANCE Antibody-dependent enhancement (ADE) of virus infection is common to many viruses and is problematic when plasma antibody levels decline to subneutralizing concentrations. ADE of infection is especially important among flaviviruses, many of which are the cause of global health problems. Recently, human plasma samples immune to heterologous flaviviruses were shown to promote Zika virus (ZIKV) infection. Here we showed in immunocompromised mouse models that homologous immune plasma samples protect mice from subsequent infection at high antibody concentrations but that they mediate ADE of infection and increase ZIKV pathogenesis in adult mice and fetal demise during pregnancy at low concentrations.

Impact of flavivirus vaccine-induced immunity on primary Zika virus antibody response in humans

“…An extremely important finding of our study is the fact that this infection enhancement can be potently suppressed by the presence of IgM antibodies (Figs 4 and 5), and this ability may be crucial in the early phase of flavivirus infections, when potentially enhancing antibodies already pre-exist or are strongly boostered. The in vivo relevance of an anti-ADE effect of IgM antibodies was recently shown in a mouse study with Zika virus, demonstrating that IgG-mediated ADE can be weakened by the presence of IgM [67]. Mechanistically, low-avidity Zika-virus specific IgG (as present early after infection, see also Fig 6B) might be sterically blocked by large pentameric IgM antibodies.…”

The SARS-CoV-2 receptor-binding domain elicits a potent neutralizing response without antibody-dependent enhancement

“…One concern associated with coronavirus vaccines is the possibility that anti-S-protein antibodies could increase the efficiency of infection of cells, such as alveolar macrophages, expressing Fc receptors, for example FcγRI (CD64) or FcγRII (CD32). This undesirable antibody-dependent enhancement (ADE) has been well characterized in tissue-culture studies of several flaviviruses including Zika virus (ZIKV) and dengue virus (Shim et al, 2019). To evaluate this possibility for SARS-CoV-2, SARS2-PV were mixed with pooled day-0 or day-40 serum at the indicated serial dilutions, and the resulting virus/sera mixtures were incubated with HEK293T cells transfected to express rat FcγRI.…”

“…As observed with flaviviruses, there is a qualitative difference between ADE mediated by neutralizing and by non-neutralizing antibodies (Dejnirattisai et al, 2010;Shim et al, 2019;. In the case of neutralizing antibodies, ADE is a consequence of insufficient coating of the virion surface, due to lower affinity or concentration of the antibody.…”

Passive immunisation of convalescent human anti-Zika plasma protects against challenge with New World Zika virus in cynomolgus macaques

“…The caveat for any intervention strategy must be that if only partial protection was attained by vaccination where otherwise naïve subjects still became infected where a ZIKV neutralising antibody response was generated but failed to deliver complete protection from infection, potentiation of subsequent infections where boosts in anti-ZIKV titres that may be deleterious could result in adverse outcomes. Low level or non-neutralisation titres in the context of homotypic ZIKV ADE potentiating ZIKV pathogenesis is thus both a complex and important area 30 , which may need factoring into the regulatory understanding of both beneficial and deleterious responses. Further studies of ZIKV immunisation should address this issue encompassing the broadest range of anti-ZIKV antibody responses, both in terms of quality as well as quantity, to enable differentiation between protective and potentially harmful anti-ZIKV responses that could be elicited by vaccination.…”