Oligomeric state of the ZIKV E protein defines protective immune responses

Metz, Stefan; Thomas, Ashlie; Brackbill, Alex; Forsberg, John‐Gunnar; Miley, Michael J.; López, César A.; Lazear, Helen M.; Tian, Shaomin; Silva, Aravinda M. de

doi:10.1038/s41467-019-12677-6

Cited by 25 publications

(29 citation statements)

References 29 publications

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“…For instance antigenic epitopes present on the surface of E protein, which consists of domains I, II, and III, are both linear and quaternary and immune activation to E generates antibodies that are largely neutralizing against the virus of same type (50-52). In the context of immune responses to E protein, antibodies that are neutralizing are better generated by the quaternary structures of E protein dimers, compared to the monomeric form of the protein (53). Moreover some E dimer epitopes are conserved across related flaviviruses and evoke antibodies that are cross-neutralizing to flaviviruses of differing serocomplexes, for example antibodies that can neutralize both DENV and ZIKV (54,55).…”

Section: Flavivirus Cross-reactive Antibody Responsesmentioning

confidence: 99%

Cross-Reactive Immunity Among Flaviviruses

2020

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Flaviviruses consist of significant human pathogens responsible for hundreds of millions of infections each year. Their antigenic relationships generate immune responses that are cross-reactive to multiple flaviviruses and their widespread and overlapping geographical distributions, coupled with increases in vaccination coverage, increase the likelihood of exposure to multiple flaviviruses. Depending on the antigenic properties of the viruses to which a person is exposed, flavivirus cross-reactivity can be beneficial or could promote immune pathologies. In this review we describe our knowledge of the functional immune outcomes that arise from varied flaviviral immune statuses. The cross-reactive antibody and T cell immune responses that are protective versus pathological are also addressed.

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Section: Flavivirus Cross-reactive Antibody Responsesmentioning

confidence: 99%

Cross-Reactive Immunity Among Flaviviruses

2020

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“…The hAd5-ZKV vaccine candidate developed here included known human ZIKV T and B cell epitopes [69][70][71]. The inclusion of both T cell and B cell epitopes into this vaccine allowed for for the induction of the adaptive immune response and the potential for long-term memory.…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity and Efficacy of a Recombinant Human Adenovirus Type 5 Vaccine against Zika Virus

et al. 2020

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Zika virus (ZIKV) is a significant public health concern due to the pathogen's ability to be transmitted by either mosquito bite or sexual transmission, allowing spread to occur throughout the world. The potential consequences of ZIKV infection to human health, specifically neonates, necessitates the development of a safe and effective Zika virus vaccine. Here, we developed an intranasal Zika vaccine based upon the replication-deficient human adenovirus serotype 5 (hAd5) expressing ZIKV pre-membrane and envelope protein (hAd5-ZKV). The hAd5-ZKV vaccine is able to induce both cell-mediated and humoral immune responses to ZIKV epitopes. Importantly, this vaccine generated CD8 + T cells specific for a dominant ZIKV T cell epitope and is shown to be protective against a ZIKV challenge by using a pre-clinical model of ZIKV disease. We also demonstrate that the vaccine expresses pre-membrane and envelope protein in a confirmation recognized by ZIKV experienced individuals. Our studies demonstrate that this adenovirus-based vaccine expressing ZIKV proteins is immunogenic and protective in mice, and it encodes ZIKV proteins in a conformation recognized by the human antibody repertoire.The development of a ZIKV vaccine is urgent due to the speed of ZIKV spread in susceptible populations, as well as the range of diseases caused by infection [5]. According to the World Health Organization (WHO), a majority of individuals who are infected with ZIKV are asymptomatic, but those with a mild clinical form of the disease report symptoms including fever, rash, conjunctivitis, and muscle and joint pain, all of which typically last less than a week. While these symptoms are rarely debilitating, complications of Zika virus disease can include Guillain-Barré syndrome. Zika-induced microcephaly and congenital abnormalities are generally classified as congenital Zika syndrome (CZS), which is also a potential complication in the developing fetuses of pregnant women [4,6-10]. These risks, combined with the explosive outbreaks that occurred at Yap Island in 2007 [11], French Polynesia in 2013 [12], and Brazil in 2015-16 [13], underscore the need to control the spread of ZIKV. However, there are no current FDA-approved vaccines available to control infection.Harnessing the power of both arms of the adaptive immune response improves vaccine potency and efficacy while reducing opportunities of viral escape. Current data from both naturally acquired human infection and mouse models of ZIKV disease indicate that protection from disease is multi-faceted (reviewed in [14][15][16][17][18]). Both small and large animal models of ZIKV infection have demonstrated that the Zika-specific CD8 + and CD4 + T cell response is necessary and sufficient to protect against a lethal ZIKV challenge [19][20][21][22]. As has been demonstrated previously for multiple flavivirus infections [23-25], ZIKV-specific polyclonal and monoclonal neutralizing antibody responses can protect mice and nonhuman primates from mortality and severe disease. There is also a role fo...

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“…Recently, a characterization of two dimeric E antigens was published, dimerization was achieved by the A264C mutation or replacing the E transmembrane domain with the FC fragment of a human IgG (40). While this manuscript was under preparation, two other articles reported development and evaluation of dimer-based subunit vaccines similar to that described in here (41,42). The authors showed that in all three cases the antigens were able to induce in mice the production of neutralizing antibodies.…”

Section: Discussionmentioning

confidence: 99%

Zika virus-like particles bearing covalent dimer of envelope protein protect mice from lethal challenge

Lorenzo

Tandavanitj

Doig

et al. 2020

Preprint

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Zika virus (ZIKV) envelope (E) protein is the major target of neutralizing antibodies in infected host, and thus represents a candidate of interest for vaccine design. However, a major concern in the development of vaccines against ZIKV and the related dengue virus is the induction of cross-reactive poorly neutralizing antibodies that can cause antibody-dependent enhancement (ADE) of infection. This risk necessitates particular care in vaccine design. Specifically, the engineered immunogens should have their cross-reactive epitopes masked, and they should be optimized for eliciting virus-specific strongly neutralizing antibodies upon vaccination. Here, we developed ZIKV subunit- and virus-like particle (VLP)-based vaccines displaying E in its wild type form, or E locked in a covalently linked dimeric (cvD) conformation to enhance the exposure of E dimers to the immune system. Compared with their wild-type derivatives, cvD immunogens elicited antibody with higher capacity of neutralizing virus infection of cultured cells. More importantly, these immunogens protected animals from lethal challenge with both the African and Asian lineages of ZIKV, impairing virus dissemination to brain and sexual organs. Moreover, the locked conformation of E reduced the exposure of epitopes recognized by cross-reactive antibodies and therefore showed a lower potential to induce ADE in vitro. Our data demonstrated a higher efficacy of the VLPs in comparison with the soluble dimer and support VLP-cvD as a promising ZIKV vaccine.

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Oligomeric state of the ZIKV E protein defines protective immune responses

Cited by 25 publications

References 29 publications

Cross-Reactive Immunity Among Flaviviruses

Cross-Reactive Immunity Among Flaviviruses

Immunogenicity and Efficacy of a Recombinant Human Adenovirus Type 5 Vaccine against Zika Virus

Zika virus-like particles bearing covalent dimer of envelope protein protect mice from lethal challenge

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