Zika virus pathogenesis in rhesus macaques is unaffected by pre-existing immunity to dengue virus

Pantoja, Petraleigh; Pérez-Guzmán, Erick X.; Rodríguez, Idia V.; White, Laura; González, Olga; Crisanta, Serrano,; Giavedoni, Luis D.; Hodara, Vida; Cruz, Lorna; Arana, Teresa; Martínez, Melween I.; Hassert, Mariah; Brien, James D.; Pinto, Amelia K.; Silva, Aravinda M. de; Sariol, Carlos A.

doi:10.1038/ncomms15674

Cited by 176 publications

(228 citation statements)

References 57 publications

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“…Previous studies have suggested that DENV-specific antibodies can increase ZIKV replication in vitro and in mice (28–30), but studies in primates have to date not replicated these findings (31, 32). Dedicated studies of ZIKV vaccines in DENV-exposed animals and humans are therefore warranted.…”

Section: Discussionmentioning

confidence: 98%

Durability and correlates of vaccine protection against Zika virus in rhesus monkeys

et al. 2017

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An effective Zika virus (ZIKV) vaccine will require long-term durable protection. Several ZIKV vaccine candidates have demonstrated protective efficacy in nonhuman primates, but such studies have typically involved ZIKV challenge shortly following vaccination at peak immunity. In this study, we show that a single immunization with an adenovirus vector-based vaccine, as well as two immunizations with a purified inactivated virus vaccine, afforded robust protection against ZIKV challenge in rhesus monkeys at 1 year following vaccination. In contrast, two immunizations with an optimized DNA vaccine, which provided complete protection at peak immunity, resulted in reduced protective efficacy at 1 year that was associated with declining neutralizing antibody titers to sub-protective levels. These data define a microneutralization log titer of 2.0-2.1 as the threshold required for durable protection against ZIKV challenge in this model. Moreover, our findings demonstrate that protection against ZIKV challenge in rhesus monkeys is possible for at least 1 year with a single-shot vaccine.

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Section: Discussionmentioning

confidence: 98%

Durability and correlates of vaccine protection against Zika virus in rhesus monkeys

et al. 2017

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“…Recent data in HLA transgenic mice demonstrated that ZIKV challenge following immunization of mice with ZIKV-specific and ZIKV/DENV cross-reactive epitopes elicited CD8 ϩ T cell responses that reduced infectious ZIKV levels, and CD8 ϩ T cell depletions confirmed that CD8 ϩ T cells mediated this protection (29). In addition, a recent paper has shown that Zika virus pathogenesis in rhesus macaques is unaffected by preexisting immunity to dengue virus (33). Together, these data underline important implications for ZIKV vaccine development.…”

Section: Discussionmentioning

confidence: 83%

Prior Dengue Virus Exposure Shapes T Cell Immunity to Zika Virus in Humans

Grifoni

Pham

Sidney

et al. 2017

J Virol

155

214

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While progress has been made in characterizing humoral immunity to Zika virus (ZIKV) in humans, little is known regarding the corresponding T cell responses to ZIKV. Here, we investigate the kinetics and viral epitopes targeted by T cells responding to ZIKV and address the critical question of whether preexisting dengue virus (DENV) T cell immunity modulates these responses. We find that memory T cell responses elicited by prior infection with DENV or vaccination with tetravalent dengue attenuated vaccines (TDLAV) recognize ZIKV-derived peptides. This cross-reactivity is explained by the sequence similarity of the two viruses, as the ZIKV peptides recognized by DENV-elicited memory T cells are identical or highly conserved in DENV and ZIKV. DENV exposure prior to ZIKV infection also influences the timing and magnitude of the T cell response. ZIKV-reactive T cells in the acute phase of infection are detected earlier and in greater magnitude in DENV-immune patients. Conversely, the frequency of ZIKV-reactive T cells continues to rise in the convalescent phase in DENV-naive donors but declines in DENV-preexposed donors, compatible with more efficient control of ZIKV replication and/or clearance of ZIKV antigen. The quality of responses is also influenced by previous DENV exposure, and ZIKV-specific CD8 T cells from DENV-preexposed donors selectively upregulated granzyme B and PD1, unlike DENV-naive donors. Finally, we discovered that ZIKV

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“…To what extent cross-enhancement contributes to the pathogenesis of Zika or dengue infections in humans is still unresolved. So far, studies in rhesus macaques did not find an influence of previous infections with dengue or yellow fever viruses on Zika virus pathogenesis [133,134], although in vitro ADE was clearly demonstrable with the sera from these animals. Possible effects of pre-existing flavivirus immunity on the teratogenic potential of Zika virus infections have not yet been analyzed in non-human primates (NHPs).…”

Section: Antibody-dependent Enhancementmentioning

confidence: 91%

The bright and the dark side of human antibody responses to flaviviruses: lessons for vaccine design

et al. 2017

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Zika and dengue viruses belong to the Flavivirus genus, a close group of antigenically related viruses that cause significant arthropod‐transmitted diseases throughout the globe. Although infection by a given flavivirus is thought to confer lifelong protection, some of the patient's antibodies cross‐react with other flaviviruses without cross‐neutralizing. The original antigenic sin phenomenon may amplify such antibodies upon subsequent heterologous flavivirus infection, potentially aggravating disease by antibody‐dependent enhancement (ADE). The most striking example is provided by the four different dengue viruses, where infection by one serotype appears to predispose to more severe disease upon infection by a second one. A similar effect was postulated for sequential infections with Zika and dengue viruses. In this review, we analyze the molecular determinants of the dual antibody response to flavivirus infection or vaccination in humans. We highlight the role of conserved partially cryptic epitopes giving rise to cross‐reacting and poorly neutralizing, ADE‐prone antibodies. We end by proposing a strategy for developing an epitope‐focused vaccine approach to avoid eliciting undesirable antibodies while focusing the immune system on producing protective antibodies only.

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Zika virus pathogenesis in rhesus macaques is unaffected by pre-existing immunity to dengue virus

Cited by 176 publications

References 57 publications

Durability and correlates of vaccine protection against Zika virus in rhesus monkeys

Durability and correlates of vaccine protection against Zika virus in rhesus monkeys

Prior Dengue Virus Exposure Shapes T Cell Immunity to Zika Virus in Humans

The bright and the dark side of human antibody responses to flaviviruses: lessons for vaccine design

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