Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease

Abstract

SUMMARY The emergence of Zika virus (ZIKV) and its association with congenital malformations has prompted the rapid development of vaccines. Although efficacy with nucleic acid or inactivated viral vaccine platforms has been established in animals, no study has addressed protection during pregnancy. We tested in mice two vaccine platforms, a lipid nanoparticle-encapsulated modified mRNA vaccine encoding ZIKV prM and E genes and a live-attenuated ZIKV strain encoding an NS1 protein without glycosylation, for their ability to protect against transmission to the fetus. Vaccinated dams challenged with a heterologous ZIKV strain at embryo day 6 (E6) and evaluated at E13 showed markedly diminished levels of viral RNA in maternal, placental, and fetal tissues, which resulted in protection against placental damage and fetal demise. As modified mRNA and live-attenuated vaccine platforms can restrict in utero transmission of ZIKV in mice, their further development in humans to prevent congenital ZIKV syndrome is warranted.

Zika virus–related neurotropic flaviviruses infect human placental explants and cause fetal demise in mice

“…S1A ), we harvested fetuses only from healthy-appearing dams and euthanized any pregnant dams exhibiting hunched posture or lethargy. Similar to studies of congenital ZIKV infection ( 7, 29 ), we inoculated mice on E6.5 to allow time for peripheral viral replication so that peak viremia would coincide with placentation. However, to confirm that congenital infection occurs even after placentation, we also performed separate experiments with the neurotropic flaviviruses (WNV and POWV) where we inoculated dams subcutaneously on E9.5 ( Fig.…”

mRNA vaccines — a new era in vaccinology

“…Notably, this report showed that antibody-dependent enhancement of secondary infection with a heterologous flavivirus, a major concern for dengue and Zika virus vaccines, could be diminished by removing a cross-reactive epitope in the E protein. A recent follow-up study evaluated the same vaccine in a model of maternal vaccination and fetal infection 112 . Two immunizations reduced Zika virus infection in fetal mice by several orders of magnitude and completely rescued a defect in fetal viability.…”

“…This level of reactogenicity appears to be similar to that of more traditional vaccine formats 113,114 . Finally, the Zika virus vaccine described by Richner et al 85,112 is also entering clinical evaluation in a combined phase I/II trial (NCT03014089). Future studies that apply nucleoside-modified mRNA–LNP vaccines against a greater diversity of antigens will reveal the extent to which this strategy is broadly applicable to infectious disease vaccines.…”

Zika virus vaccines

“…In mouse pregnancy models, these mRNA vaccines prevented fetal demise, whereas fetal resorption was observed in non-immunized infected pregnant mice. However, levels of ZIKV RNA could still be detected in maternal spleen and brain as well as in placenta and in the fetal head in immunized mice 56 .As these results were obtained in the immunocompromised mouse model, which supports increased viral replication, it remains to be determined if viral replication would be observed in immunocompetent animal models. The first-in-human, phase I/II clinical trial led by Moderna Therapeutics is currently ongoing to assess the safety and immunogenicity of escalating doses of prM-ENV mRNA (NCT03014089) (Table 1).…”