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V3. Studies of treatment and prevention of viral infections
Oral Abstract Submission
Brett W. Jagger, MD, PhD
Infectious Diseases Fellow
Washington University
St. Louis, MO
Disclosure: Nothing to disclose
Kimberly A. Dowd, PhD
Associate Scientist
National Institutes of Health
Bethesda, MD
Disclosure: NIH: Employee, K.A.D. is named as inventor on U.S. government-owned patent application(s) for ZIKV DNA vaccine technology.
Pritesh Desai, PhD
Postdoctoral Research Associate
Washington University
St. Louis, MO
Disclosure: Nothing to disclose
Barney S. Graham, MD, PhD
Deputy Director
National Institutes of Health
Bethesda, MD
Disclosure: NIH: Employee, B.S.G. is named as inventor on U.S. government-owned patent application(s) for ZIKV DNA vaccine technology.
Theodore C. Pierson, PhD
Chief
National Institutes of Health
Bethesda, MD
Disclosure: NIH: Employee, T.C.P. is named as inventor on U.S. government-owned patent application(s) for ZIKV DNA vaccine technology.
Michael S. Diamond, MD, PhD
Herbert S. Gasser Professor
Washington University
St. Louis, MO
Disclosure: Moderna: Advisor or Review Panel member, M.S.D. is a member of the Scientific Advisory Board for Moderna.
Background :
Zika virus (ZIKV) caused an epidemic of microcephaly and congenital malformations in 2015-2016, prompting the development of ZIKV vaccines. Plasmid DNA and modified mRNA lipid nanoparticle-encapsulated (mRNA-LNP) vaccines were among the first to reach human clinical trials, where their evaluation is ongoing. Few studies have evaluated vaccine efficacy in the setting of infection during pregnancy, and there is an open question around antibody-dependent enhancement (ADE) of flaviviral disease due to cross-reactive fusion loop epitope (FLE) antibodies.
Methods :
Female C57BL/6J mice and human STAT2 knock-in (hSTAT2-KI) mice were immunized with plasmid DNA (VRC5283) or mRNA-LNP (Moderna Inc.) vaccines encoding the ZIKV prM-E genes. Antibody responses were assayed, and immunized mice were mated and WT mice were transiently immunocompromised by administration of interferon blocking antibody, followed by ZIKV challenge. 1 week post-infection, ZIKV burden was measured via qRT-PCR. ZIKV-specific memory B cell (MBC), long lived plasma cell (LLPC), and CD8+ T cell vaccine responses were also assayed.
Results :
VRC5283 and mRNA-LNP vaccines were highly immunogenic, eliciting serum neutralizing EC50 responses > 1:10,000, and markedly reduced placental ZIKV burden and fetal transmission. An improved mRNA-LNP construct with higher immunogenicity correlated with reduced placental viral burden. Significantly, an FLE-mutant mRNA-LNP vaccine yielded comparable EC50 responses without compromising vaccine efficacy; sera from these mice did not enhance dengue virus infection in vitro. Both VRC5283 and mRNA-LNP vaccines elicited MBC, LLPC, and CD8+ T cell responses, although MBC and LLPC responses were greater after mRNA-LNP immunization. Surprisingly, low-level ZIKV infection of the placenta and a minority of fetal heads was observed despite robust neutralizing antibody responses, which was not seen in the immunocompetent hSTAT2-KI model.
Conclusion :
Nucleic acid vaccines were highly immunogenic and protective against vertical ZIKV transmission during pregnancy in mice. These data support and inform the ongoing clinical development of these vaccines in humans.