Medina, Liana Odette
Lehrer, Axel
Biomed Science (Tropical Medicine)
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Zika Virus (ZIKV) is a positive sense, single stranded RNA virus that for many years was not associated with severe clinical symptoms. However, it became a public health threat following an epidemic in French Polynesia 2013–2014 that resulted in neurological complications associated with infection. Ebola virus (EBOV) on the other hand is a negative sense, single stranded RNA virus with case fatality rates in outbreaks reaching 90%. Between 2013 and 2016 an outbreak of an unprecedented scale occurred in West Africa with almost 30,000 people infected and over 11,000 fatalities were reported. There are currently no vaccines or therapeutics approved for ZIKV while the first EBOV vaccine, Ervebo (rVSVG-ZEBOV-GP), was approved in November 2019 by the European Commission. Another candidate vaccine against EBOV combining two different virally vectored approaches is in advanced clinical trials. Several different vaccine platforms are being used to develop additional strategies to prevent infections with these viruses, mostly based on recombinant viral vectors. However, virally vectored vaccines have shown significant safety risks, particularly in immunocompromised populations. Recombinant subunit vaccines have recently been put into use against several viral infections, such as Engerix-B and Recombivax HB against Hepatitis B virus, FluBlok against seasonal influenza, and GARDASIL and CERVARIX against human papilloma virus. Vaccines made using this versatile platform have high safety profiles and are relatively easy to manufacture and scale up. Using a recombinant subunit platform consisting of antigens produced in Drosophila melanogaster S2 cells, we have developed vaccine candidates for ZIKV and EBOV. The efficacy of our recombinant subunits against EBOV has been evaluated in a guinea pig and non-human primate (NHP) model, while the efficacy of our ZIKV vaccine has been evaluated in immunocompetent mice and NHPs. In our ZIKV NHP model, high neutralizing antibody titers were seen in all protected cynomolgus macaques, and passive transfer demonstrated that plasma from these NHPs was sufficient to protect against viremia in mice subsequently infected with ZIKV. Taken together these data demonstrate the immunogenicity and protective efficacy of the recombinant subunit vaccine candidate against ZIKV in NHPs and highlights the importance of neutralizing antibodies in protection against ZIKV infection, validating their potential to serve as a correlate of protection. Vaccine candidates containing the EBOV glycoprotein with or without matrix proteins Viral Protein 24 and Viral Protein 40, formulated with several different adjuvants were tested in mice, guinea pigs and NHPs for immunogenicity and efficacy against lethal EBOV challenge. We also evaluated bi- and trivalent formulations in guinea pigs and NHPs in an effort to develop multivalent filovirus vaccines. The results demonstrated that the monovalent vaccine candidates engendered high titers of antigen-specific antibodies in immunized animals, and two of these vaccine candidates afforded complete or nearly complete protection against lethal challenge. All vaccine candidates were able to elicit virus-specific anti-GP IgG titers in all species tested, but high antibody titers were also seen in animals not protected from viral challenge. Cell-mediated immunity was analyzed in samples taken from vaccinated NHPs with the goal of discovering responses that correlated with protection, and exploring cross-reactive responses to direct development of future formulations. While we were able to find vaccine specific cell-mediated immune responses, we so far were unable to correlate presence or absence or magnitude of these responses with vaccine efficacy.
Immunology, Virology, Filovirus, Vaccine Development
113 pages
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