Recombinant Zika Virus Subunits Are Immunogenic and Efficacious in Mice

ABSTRACT Following the 2015 Zika virus (ZIKV) outbreaks in the South Pacific, Caribbean, and Americas, ZIKV has emerged as a serious threat due to its association with infantile microcephaly and other neurologic disorders. Despite an international effort to develop a safe and effective vaccine to co...

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Autores principales:	Albert To, Liana O. Medina, Kenji O. Mfuh, Michael M. Lieberman, Teri Ann S. Wong, Madhuri Namekar, Eileen Nakano, Chih-Yun Lai, Mukesh Kumar, Vivek R. Nerurkar, Axel T. Lehrer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	recombinant subunit vaccine Zika virus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/fb364bc8a3c247729518337769478019
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spelling	oai:doaj.org-article:fb364bc8a3c2477295183377694780192021-11-15T15:22:01ZRecombinant Zika Virus Subunits Are Immunogenic and Efficacious in Mice10.1128/mSphere.00576-172379-5042https://doaj.org/article/fb364bc8a3c2477295183377694780192018-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00576-17https://doaj.org/toc/2379-5042ABSTRACT Following the 2015 Zika virus (ZIKV) outbreaks in the South Pacific, Caribbean, and Americas, ZIKV has emerged as a serious threat due to its association with infantile microcephaly and other neurologic disorders. Despite an international effort to develop a safe and effective vaccine to combat congenital Zika syndrome and ZIKV infection, only DNA and mRNA vaccines encoding the precursor membrane (prM) and envelope (E) proteins, an inactivated-ZIKV vaccine, and a measles virus-based ZIKV vaccine are currently in phase I or II (prM/E DNA) clinical trials. A ZIKV vaccine based on a nonreplicating, recombinant subunit platform offers a higher safety profile than other ZIKV vaccine candidates but is still highly immunogenic, inducing high virus-neutralizing antibody titers. Here, we describe the production and purification of Drosophila melanogaster S2 insect cell-derived, soluble ZIKV E protein and evaluate its immunogenicity and efficacy in three different mouse strains. As expected, significant virus-specific antibody titers were observed when using formulations containing clinically relevant adjuvants. Immunized mice challenged with live virus demonstrate inhibition of virus replication. Importantly, plaque reduction neutralization tests (PRNTs) indicate the high-titer production of neutralizing antibodies, a correlate of protection in the defense against ZIKV infection. ZIKV challenge of immunocompetent mice led to full protection against viremia with two doses of adjuvanted vaccine candidates. These data demonstrate a proof of concept and establish recombinant subunit immunogens as an effective vaccine candidate against ZIKV infection. IMPORTANCE The recent outbreaks of Zika virus (ZIKV) infection in French Polynesia, the Caribbean, and the Americas have highlighted the severe neuropathological sequelae that such an infection may cause. The development of a safe, effective ZIKV vaccine is critical for several reasons: (i) the difficulty in diagnosing an active infection due to common nonspecific symptoms, (ii) the lack of a specific antiviral therapy, and (iii) the potentially devastating pathological effects of in utero infection. Moreover, a vaccine with an excellent safety profile, such as a nonreplicating, noninfectious vaccine, would be ideal for high-risk people (e.g., pregnant women, immunocompromised patients, and elderly individuals). This report describes the development of a recombinant subunit protein vaccine candidate derived from stably transformed insect cells expressing the ZIKV envelope protein in vitro, the primary antigen to which effective virus-neutralizing antibodies are engendered by immunized animals for several other flaviviruses; the vaccine candidate elicits effective virus-neutralizing antibodies against ZIKV and provides protection against ZIKV infection in mice.Albert ToLiana O. MedinaKenji O. MfuhMichael M. LiebermanTeri Ann S. WongMadhuri NamekarEileen NakanoChih-Yun LaiMukesh KumarVivek R. NerurkarAxel T. LehrerAmerican Society for MicrobiologyarticlerecombinantsubunitvaccineZika virusMicrobiologyQR1-502ENmSphere, Vol 3, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	recombinant subunit vaccine Zika virus Microbiology QR1-502
spellingShingle	recombinant subunit vaccine Zika virus Microbiology QR1-502 Albert To Liana O. Medina Kenji O. Mfuh Michael M. Lieberman Teri Ann S. Wong Madhuri Namekar Eileen Nakano Chih-Yun Lai Mukesh Kumar Vivek R. Nerurkar Axel T. Lehrer Recombinant Zika Virus Subunits Are Immunogenic and Efficacious in Mice
description	ABSTRACT Following the 2015 Zika virus (ZIKV) outbreaks in the South Pacific, Caribbean, and Americas, ZIKV has emerged as a serious threat due to its association with infantile microcephaly and other neurologic disorders. Despite an international effort to develop a safe and effective vaccine to combat congenital Zika syndrome and ZIKV infection, only DNA and mRNA vaccines encoding the precursor membrane (prM) and envelope (E) proteins, an inactivated-ZIKV vaccine, and a measles virus-based ZIKV vaccine are currently in phase I or II (prM/E DNA) clinical trials. A ZIKV vaccine based on a nonreplicating, recombinant subunit platform offers a higher safety profile than other ZIKV vaccine candidates but is still highly immunogenic, inducing high virus-neutralizing antibody titers. Here, we describe the production and purification of Drosophila melanogaster S2 insect cell-derived, soluble ZIKV E protein and evaluate its immunogenicity and efficacy in three different mouse strains. As expected, significant virus-specific antibody titers were observed when using formulations containing clinically relevant adjuvants. Immunized mice challenged with live virus demonstrate inhibition of virus replication. Importantly, plaque reduction neutralization tests (PRNTs) indicate the high-titer production of neutralizing antibodies, a correlate of protection in the defense against ZIKV infection. ZIKV challenge of immunocompetent mice led to full protection against viremia with two doses of adjuvanted vaccine candidates. These data demonstrate a proof of concept and establish recombinant subunit immunogens as an effective vaccine candidate against ZIKV infection. IMPORTANCE The recent outbreaks of Zika virus (ZIKV) infection in French Polynesia, the Caribbean, and the Americas have highlighted the severe neuropathological sequelae that such an infection may cause. The development of a safe, effective ZIKV vaccine is critical for several reasons: (i) the difficulty in diagnosing an active infection due to common nonspecific symptoms, (ii) the lack of a specific antiviral therapy, and (iii) the potentially devastating pathological effects of in utero infection. Moreover, a vaccine with an excellent safety profile, such as a nonreplicating, noninfectious vaccine, would be ideal for high-risk people (e.g., pregnant women, immunocompromised patients, and elderly individuals). This report describes the development of a recombinant subunit protein vaccine candidate derived from stably transformed insect cells expressing the ZIKV envelope protein in vitro, the primary antigen to which effective virus-neutralizing antibodies are engendered by immunized animals for several other flaviviruses; the vaccine candidate elicits effective virus-neutralizing antibodies against ZIKV and provides protection against ZIKV infection in mice.
format	article
author	Albert To Liana O. Medina Kenji O. Mfuh Michael M. Lieberman Teri Ann S. Wong Madhuri Namekar Eileen Nakano Chih-Yun Lai Mukesh Kumar Vivek R. Nerurkar Axel T. Lehrer
author_facet	Albert To Liana O. Medina Kenji O. Mfuh Michael M. Lieberman Teri Ann S. Wong Madhuri Namekar Eileen Nakano Chih-Yun Lai Mukesh Kumar Vivek R. Nerurkar Axel T. Lehrer
author_sort	Albert To
title	Recombinant Zika Virus Subunits Are Immunogenic and Efficacious in Mice
title_short	Recombinant Zika Virus Subunits Are Immunogenic and Efficacious in Mice
title_full	Recombinant Zika Virus Subunits Are Immunogenic and Efficacious in Mice
title_fullStr	Recombinant Zika Virus Subunits Are Immunogenic and Efficacious in Mice
title_full_unstemmed	Recombinant Zika Virus Subunits Are Immunogenic and Efficacious in Mice
title_sort	recombinant zika virus subunits are immunogenic and efficacious in mice
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/fb364bc8a3c247729518337769478019
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Recombinant Zika Virus Subunits Are Immunogenic and Efficacious in Mice

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