Vaccine protection against Zika virus from Brazil - PubMed (original) (raw)

. 2016 Aug 25;536(7617):474-8.

doi: 10.1038/nature18952. Epub 2016 Jun 28.

Peter Abbink, Jean Pierre S Peron, Paolo M de A Zanotto, M Justin Iampietro, Alexander Badamchi-Zadeh, Michael Boyd, David Ng'ang'a, Marinela Kirilova, Ramya Nityanandam, Noe B Mercado, Zhenfeng Li, Edward T Moseley, Christine A Bricault, Erica N Borducchi, Patricia B Giglio, David Jetton, George Neubauer, Joseph P Nkolola, Lori F Maxfield, Rafael A De La Barrera, Richard G Jarman, Kenneth H Eckels, Nelson L Michael, Stephen J Thomas, Dan H Barouch

Vaccine protection against Zika virus from Brazil

Rafael A Larocca et al. Nature. 2016.

Abstract

Zika virus (ZIKV) is a flavivirus that is responsible for the current epidemic in Brazil and the Americas. ZIKV has been causally associated with fetal microcephaly, intrauterine growth restriction, and other birth defects in both humans and mice. The rapid development of a safe and effective ZIKV vaccine is a global health priority, but very little is currently known about ZIKV immunology and mechanisms of immune protection. Here we show that a single immunization with a plasmid DNA vaccine or a purified inactivated virus vaccine provides complete protection in susceptible mice against challenge with a strain of ZIKV involved in the outbreak in northeast Brazil. This ZIKV strain has recently been shown to cross the placenta and to induce fetal microcephaly and other congenital malformations in mice. We produced DNA vaccines expressing ZIKV pre-membrane and envelope (prM-Env), as well as a series of deletion mutants. The prM-Env DNA vaccine, but not the deletion mutants, afforded complete protection against ZIKV, as measured by absence of detectable viraemia following challenge, and protective efficacy correlated with Env-specific antibody titers. Adoptive transfer of purified IgG from vaccinated mice conferred passive protection, and depletion of CD4 and CD8 T lymphocytes in vaccinated mice did not abrogate this protection. These data demonstrate that protection against ZIKV challenge can be achieved by single-shot subunit and inactivated virus vaccines in mice and that Env-specific antibody titers represent key immunologic correlates of protection. Our findings suggest that the development of a ZIKV vaccine for humans is likely to be achievable.

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Figures

Extended Data Figure 1

Extended Data Figure 1. ZIKV maximum likelihood phylogenetic tree

The ZIKV-BR and ZIKV-PR challenge isolates are depicted with red arrows.

Extended Data Figure 2

Extended Data Figure 2. ZIKV amino acid sequence comparisons

Number of and percentage amino acid differences in the polyprotein are shown for the following ZIKV isolates: Brazil/ZKV2015 (Brazil strain; ZIKV-BR challenge stock), PRVABC59 (Puerto Rico strain; ZIKV-PR challenge stock), BeH815744 (Brazil strain; immunogen design), H/PF/2013 (French Polynesian strain), and MR766 (African strain).

Extended Data Figure 3

Extended Data Figure 3. prM-specific antibody responses in DNA vaccinated mice

In the experiment described in Figure 2, humoral immune responses were assessed at week 3 following vaccination by prM-specific ELISA. Red bars reflect medians.

Extended Data Figure 4

Extended Data Figure 4. Immunogenicity and protective efficacy of prM-Env DNA vaccine in SJL mice

SJL mice (N=5/group) received a single immunization by the i.m. route with 50 µg full-length prM-Env DNA vaccine or a sham vaccine and were challenged at week 4 by the i.v. route with 105 VP (102 PFU) ZIKV-BR. Humoral immune responses were assessed at week 3 following vaccination by Env-specific ELISA (top). Red bars reflect medians. Serum viral loads are shown following ZIKV-BR challenge (bottom).

Extended Data Figure 5

Extended Data Figure 5. Protective efficacy of prM-Env DNA vaccine in C57BL/6 mice

C57BL/6 mice (N=5/group) received a single immunization by the i.m. route with 50 µg full-length prM-Env DNA vaccine or a sham vaccine and were challenged at week 4 by the i.v. route with 105 VP (102 PFU) ZIKV-BR or ZIKV-PR. Serum viral loads are shown following challenge.

Extended Data Figure 6

Extended Data Figure 6. Protective efficacy of various DNA vaccines in C57BL/6 mice

C57BL/6 mice (N=5/group) received a single immunization by the i.m. route with 50 µg various DNA vaccines and were challenged at week 4 by the i.v. route with 105 VP (102 PFU) ZIKV-BR. Serum viral loads are shown following challenge.

Extended Data Figure 7

Extended Data Figure 7. Adoptive transfer of low titers of Env-specific IgG

Serum viral loads in mice that received adoptive transfer of low titers of Env-specific IgG (as defined in Figure 3a) and were then challenged with ZIKV-BR.

Extended Data Figure 8

Extended Data Figure 8. CD4+ and CD8+ T lymphocyte depletion

CD4+ and/or CD8+ T lymphocyte depletion following mAb treatment of prM-Env DNA vaccinated Balb/c mice.

Figure 1

Figure 1. Production and immunogenicity of DNA vaccines

(a) Schema of ZIKV prM-Env immunogens and deletion mutants. (b) Western blot of transgene expression from (1) prM-Env, (2) prM-Env.dTM, (3) prM-Env.dStem, (4) Env, (5) Env.dTM, (6) Env.dStem, and (7) sham DNA vaccines transfected in 293T cells. Balb/c mice (N=5/group) received a single immunization with 50 µg of these DNA vaccines by the i.m. route. (c) Humoral immune responses were assessed at week 3 following vaccination by Env-specific ELISA. Red bars reflect medians. Cellular immune responses were assessed by (d) IFN-γ ELISPOT assays and (e) multiparameter intracellular cytokine staining assays. Error bars reflect s.e.m.

Figure 2

Figure 2. Protective efficacy of DNA vaccines

(a) Balb/c mice (N=5 or 10/group) received a single immunization by the i.m. route with 50 µg full-length prM-Env DNA vaccine or a sham vaccine and were challenged at week 4 by the i.v. route with 105 VP (102 PFU) ZIKV-BR or ZIKV-PR. Serum viral loads are shown. (b) Mice (N=5/group) received a single immunization with 50 µg of various DNA vaccines and were challenged with ZIKV-BR. Correlates of (c) protective efficacy and (d) day 3 viral loads are shown. Red bars reflect medians. P-values reflect t-tests and Spearman rank-correlation tests.

Figure 3

Figure 3. Mechanistic studies

(a) Env-specific serum antibody titers in recipient Balb/c mice (N=5/group) following adoptive transfer of varying amounts (high, mid, low) of IgG purified from serum from prM-Env DNA vaccinated mice or naïve mice (sham). (b) Correlates of protective efficacy. (c) Serum viral loads in mice that received adoptive transfer of purified IgG from vaccinated mice and were challenged with ZIKV-BR. (d) Serum viral loads in prM-Env DNA vaccinated mice that were depleted of CD4+ and/or CD8+ T lymphocytes prior to challenge with ZIKV-BR. Red bars reflect medians. P-values reflect t-tests.

Figure 4

Figure 4. Immunogenicity and protective efficacy of PIV vaccine

Balb/c mice (N=5/group) received a single immunization by the i.m. or s.q. route with 1 µg PIV vaccine with alum or alum alone and were challenged at week 4 by the i.v. route with 105 VP (102 PFU) ZIKV-BR. (a) Humoral immune responses were assessed at week 3 following vaccination by Env-specific ELISA. (b) Correlates of protective efficacy. (c) Serum viral loads are shown following ZIKV-BR challenge. Red bars reflect medians. P-values reflect t-tests.

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