Purified Inactivated Zika Vaccine Candidates Afford Protection against Lethal Challenge in Mice

Abstract

In response to the 2016 global public health emergency of international concern announced by the World Health Organization surrounding Zika virus (ZIKV) outbreaks, we developed a purified inactivated Zika virus vaccine (PIZV) candidate from ZIKV strain PRVABC59, isolated during the outbreak in 2015. The virus isolate was plaque purified, creating six sub-isolated virus stocks, two of which were selected to generate PIZV candidates for preclinical immunogenicity and efficacy evaluation in mice. The alum-adjuvanted PIZV candidates were highly immunogenic in both CD-1 and AG129 mice after a 2-dose immunization. Further, AG129 mice receiving 2 doses of PIZV formulated with alum were fully protected against lethal ZIKV challenge and mouse immune sera elicited by the PIZV candidates were capable of neutralizing ZIKVs of both African and Asian genetic lineages in vitro. Additionally, passive immunization of naïve mice with ZIKV-immune serum showed strong positive correlation between neutralizing ZIKV antibody (NAb) titers and protection against lethal challenge. This study supported advancement of the PIZV candidate toward clinical development.

Complete Protection in Macaques Conferred by Purified Inactivated Zika Vaccine: Defining a Correlate of Protection

“…www.nature.com/scientificreports www.nature.com/scientificreports/ to correlate with protection [23][24][25] . Further supporting this correlate of protection, it has been reported that passive transfer of Zika neutralizing monoclonal antibodies or antisera from vaccinated humans and animals to mice is sufficient to protect against ZIKV challenge 16,17,21,26 . Adoptive transfer of serum from immunized mice fully protected against viremia, while splenocytes from the same donors provided marginal protection 27 demonstrating that the mechanism of protection against ZIKV infection is antibody mediated.…”

“…www.nature.com/scientificreports www.nature.com/scientificreports/ Neutralizing antibodies directed against the envelope (E) protein have been identified as correlates of protection for vaccines Japanese encephalitis virus (JEV), yellow fever virus, and tickborne encephalitis viruses 4 . Other laboratories using different vaccine platforms (DNA, RNA, inactivated virus, protein subunit, adenovirus-vectored, VLP) have reported induction of ZIKV-specific neutralizing antibodies that conferred protection against live ZIKV challenge in animal models [6][7][8][16][17][18][19][20][21][22] . These data support ZIKV E-specific neutralizing antibodies as a mechanism of protection against ZIKV infection.…”

“…In flavivirus vaccine development, neutralizing antibody titers that can confer protection against viremia have be reported in animal models using several different assay methods: microneutralization (MNT), RVP, and plaque reduction neutralization (PRNT). Studies of other candidate ZIKV vaccines have demonstrated that a neutralizing antibody titer as low as 100, using a MNT assay, or a titer of 1,000 using an RVP assay can confer protection against viremia in animal models 6,16,22 . These results are qualitatively similar to those of licensed vaccines against flaviviruses such as JEV, where a neutralizing antibody titer of >10 (as measured by PRNT) is considered To determine the correlate of protection, the neutralizing antibody titers (log 10 EC50) of infected (positive for vRNA at any given timepoint) and protected (negative for vRNA) macaques were plotted.…”

“…While ZIKV exists as three genotypes (West African, East African and Asian), they all behave as a single serotype 28,29 . Our previous studies demonstrated that PIZV is capable of eliciting antibodies that neutralize both African and Asian ZIKV isolates in vitro 16 . Others have shown that the magnitude or duration of viremia in unvaccinated macaques challenged with ZIKV isolates from Brazil or Puerto Rico is similar 6 , and that vaccinated macaques are protected against challenge with heterologous ZIKV strains 13,21,30 .…”

“…The purified inactivated Zika vaccine (PIZV) has previously been evaluated in mouse models and was immunogenic in AG129 and CD1 mice and protected AG129 mice against lethal ZIKV challenge 16 . In those studies, Baldwin et al demonstrated that neutralizing antibodies correlate with protection in AG129 mice.…”