Impact of preexisting dengue immunity on Zika virus emergence in a dengue endemic region

Rodríguez-Barraquer, Isabel; Costa, Federico; Nascimento, Eduardo J. M.; Júnior, Nivison Nery; Castanha, Priscila M. S.; Sacramento, Gielson Almeida do; Cruz, Jaqueline S.; Carvalho, Mayara; Olivera, Daiana De; Hagan, José E.; Adhikarla, Haritha; Wunder, Elsio A.; Coêlho, Danilo F.; Azar, Sasha R.; Rossi, Shannan L.; Vasilakis, Nikos; Weaver, Scott C.; Ribeiro, Guilherme S.; Balmaseda, Ángel; Harris, Eva; Nogueira, Maurício Lacerda; Reis, Mitermayer Galvão dos; Marques, Ernesto T. A.; Cummings, Derek A. T.; Ko, Albert Icksang

doi:10.1126/science.aav6618

Cited by 219 publications

(242 citation statements)

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“…An in vitro study showed enhancement of ZIKV replication in the presence of DENV antibodies (23). However, clinical cohort and case control studies of individuals in dengue endemic regions suggest the opposite, that pre-existing dengue immunity reduces the risk of symptomatic ZIKV infection and congenital ZIKV syndrome (13, 14, 26). Pantoja et al .…”

Section: Discussionmentioning

confidence: 99%

Cross-Protection Against Zika Virus Infection Conferred by a Live Attenuated Japanese Encephalitis SA14-14-2 Vaccine

Wang

Zhen

Turtle

et al. 2020

Preprint

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24Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are closely related 25 mosquito-borne flaviviruses. Japanese encephalitis (JE) vaccine SA14-14-2 has been in 26 the Chinese national Expanded Program on Immunization since 2007. The recent 27 recognition of severe disease syndromes associated with ZIKV, and the identification of 28 ZIKV from mosquitoes in China, prompts an urgent need to investigate the potential 29 interaction between the two. In this study, we showed that SA14-14-2 is protective against 30 ZIKV infection in mice. JE vaccine SA14-14-2 triggered both Th1 and Th2 cross-reactive 31 immune responses to ZIKV; however, it was cellular immunity that predominantly 32 mediated cross-protection against ZIKV infection. Passive transfer of immune sera did not 33 result in significant cross-protection, but did mediate antibody dependent enhancement in 34 vitro, though this did not have an adverse impact on survival. This study suggests that 35 SA14-14-2 vaccine can protect against ZIKV through a cross-reactive T cell response. 36This is vital information in terms of ZIKV prevention or precaution in those ZIKV-affected 37 regions where JEV circulates or SA14-14-2 is in widespread use, and opens a promising 38 avenue into developing a novel bivalent vaccine against both ZIKV and JEV. 40Importance 43 Japanese encephalitis is a controllable disease in many countries in Asia, especially in 44 China, where many people have Japanese encephalitis virus (JEV) immunity due to 45 extensive JEV vaccination campaigns or natural exposure. Live-attenuated SA14-14-2 46 strain is a safe and effective vaccine recommended by the World Health Organization and 47 has been vaccinated more than 600 million doses since 1989. As the prevalence of Zika 48 virus (ZIKV) and rising risk in above regions, the cross-reactive immune response 49 between these two antigenically closely related flaviviruses, JEV and ZIKV, should also be 50 fully recognized, which is presumed to be based on those ambiguous cross-reactive 51 immunity between dengue virus and ZIKV. In this study, we found that JEV SA14-14-2 52 vaccine conferred cross-protection against ZIKV challenge in mice, which is mainly due to 53 cellular immunity rather than neutralizing antibody response. However, specific protective 54 components or cooperation between components warrant to be explored in subsequent 55 experiments. In conclusion, this study can provide important evidence for those who live in 56 JEV-endemic areas and are at risk for ZIKV infection.57 4 Introduction 58 Recently, Zika virus (ZIKV) has caused devastating outbreaks of fetal congenital 59 malformations in South and Central America and now transmitted in more than 70 60 countries, including many previously unaffected regions. ZIKV infection during pregnancy 61 increases the risk of neurological disorders in newborns (1), such as microcephaly. In 62 adults, ZIKV causes Guillain-Barré syndrome and other neurologic disorders (2). So far, 63 no specific vaccine or antiviral for prevention and treatment of Z...

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Section: Discussionmentioning

confidence: 99%

Cross-Protection Against Zika Virus Infection Conferred by a Live Attenuated Japanese Encephalitis SA14-14-2 Vaccine

Wang

Zhen

Turtle

et al. 2020

Preprint

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“…Differences were also observed in B-cells and T-cells activation and cytokines and chemokines profile (24). Our previous results have been recently validated in a metanalysis using most of the NHP available data (32) and more relevant, in two studies presenting real settings of humans living in DENV-endemic areas (32-34). In this work, we aimed to establish the contribution of different DENV convalescent periods (3 months or early and 12 months or middle convalescent periods) on the immune response and disease course after ZIKV infection.…”

Section: Discussionmentioning

confidence: 61%

“…However, playing a significant role controlling ZIKV viremia and liver damage happens only after a middle-convalescent period of approximately 12 months, but not too early (3 months) or too late (2.8 years) after the primary DENV infection. Interestingly a recent report showed that the IgG3 levels (a marker of recent DENV infection) were positively associated with risk of infection by ZIKV (34). In humans, this fact correlates with our finding in NHPs that a shorter period of DENV immunity may not provide same level of protection against ZIKV replication.…”

Section: Discussionmentioning

confidence: 99%

Significant control of Zika infection in macaques depends on the elapsing time after dengue exposure

Serrano-Collazo

Pantoja

et al. 2019

Preprint

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29Prior exposure to a single serotype of dengue virus (DENV) predisposes individuals to severe 30 disease upon secondary heterologous DENV infection. Here we show that the length of time 31 between DENV/Zika (ZIKV) infections has a qualitative impact on controlling ZIKV replication. 32We identified limited but significant differences in the magnitude of the early humoral immune 33 response associated with a period of twelve months but not three months of DENV 34 convalescence. However, their role limiting ZIKV replication is not conclusive. There was no 35 evidence of in vivo antibody-dependent amplification of ZIKV by DENV immunity in any group. 36We are also showing that the significant differences among groups may be linked to a pre-37 existing polyfunctional CD4+ T cells response (increased IFN-g and Cd107a before ZIKV 38 infection) and to an early and continuous expansion of the CD4+ effector memory cells early on 39 after ZIKV infection. Those significant differences were associated with a period of 12 months 40 after DENV infection that were not observed in a span of 3-months. These results suggest that 41 there is a window of optimal cross-protection between ZIKV and DENV with significant 42 consequences. These results have pivotal implications while interpreting ZIKV pathogenesis in 43 flavivirus-experimented populations, diagnostic results interpretation and vaccine designs 44 among others. 45 46 Author Summary 47impact on controlling the ZIKV infection. In this study, as in our prior work we did not observe 100 evidence of ZIKV disease enhancement associated with prior DENV exposure. We also 101 confirmed that the significant differences among groups are mediated by the pre-existence of a 102 robust effector memory T cell (TEM) and cytotoxic activity mainly mediated by CD4 + T cells 103 more than qualitative differences in the humoral immune response. However, by conducting a 104 detailed study of the ZIKV-neutralizing titers vs. ZIKV RNAemia at early time points after 105 infection, we were able to determine a possible contribution of the neutralizing antibodies 106 limiting the ZIKV replication at 7 days after infection in the animals with 12 months but not 3 107 months of DENV immunity or in the control group. Overall, we demonstrated that exposure to 108 ZIKV 12 months after DENV infection afford a high level of T cell-mediated cross protection than 109 it was observed at the 3-month span. Based on our previous study we believe this protection 110 wanes as macaques exposed to ZIKV 2.8 years after DENV were not afforded this protection. 111These results suggest that there is a window of optimal T cell cross-protection between ZIKV 112 and DENV. 113 114 Results 115

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“…This is in contrast with in vitro and murine studies that have shown significant enhancement of secondary ZIKV infection in the presence of anti-flavivirus antibodies (12, 15, 53, 54). Whether this is consistent with secondary ZIKV infections in humans is unknown, but recent human cohort studies suggest more similarities with macaques (5, 21, 22, 54). In addition, there was, at most, a minimal difference in peak DENV vRNA load between animals with and without prior ZIKV exposure, suggesting that prior ZIKV exposure may only minimally affect DENV disease, at least in macaques.…”

Section: Discussionmentioning

confidence: 74%

Primary infection with dengue or Zika virus does not affect the severity of heterologous secondary infection in macaques

Breitbach

Newman

Dudley

et al. 2019

Preprint

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33Zika virus (ZIKV) and dengue virus (DENV) are genetically and antigenically related 34 flaviviruses that now co-circulate in much of the tropical and subtropical world. The rapid 35 emergence of ZIKV in the Americas in 2015 and 2016, and its recent associations with 36 Guillain-Barré syndrome, birth defects, and fetal loss have led to the hypothesis that 37 DENV infection induces cross-reactive antibodies that influence the severity of 38 secondary ZIKV infections. It has also been proposed that pre-existing ZIKV immunity 39 3 could affect DENV pathogenesis. We examined outcomes of secondary ZIKV infections 40 in three rhesus and fifteen cynomolgus macaques, as well as secondary DENV-2 41 infections in three additional rhesus macaques up to a year post-primary ZIKV infection. 42 Although cross-binding antibodies were detected prior to secondary infection for all 43 animals and cross-neutralizing antibodies were detected for some animals, previous 44 DENV or ZIKV infection had no apparent effect on the clinical course of heterotypic 45 secondary infections in these animals. All animals had asymptomatic infections and, 46 when compared to controls, did not have significantly perturbed hematological 47 parameters. Rhesus macaques infected with DENV-2 approximately one year after 48 primary ZIKV infection had higher vRNA loads in plasma when compared with serum 49 vRNA loads from ZIKV-naive animals infected with DENV-2, but a differential effect of 50 sample type could not be ruled out. In cynomolgus macaques, the serotype of primary 51 DENV infection did not affect the outcome of secondary ZIKV infection. 52 53 Author summary 54 Pre-existing immunity to one of the four DENV serotypes is known to increase the risk 55 of severe disease upon secondary infection with a different serotype. Due to the 56 antigenic similarities between ZIKV and DENV, it has been proposed that these viruses 57 could interact in a similar fashion. Data from in vitro experiments and murine models 58 suggests that pre-existing immunity to one virus could either enhance or protect against 59 infection with the other. These somewhat contradictory findings highlight the need for 60 immune competent animal models for understanding the role of cross-reactive 61 4 antibodies in flavivirus pathogenesis. We examined secondary ZIKV or DENV infections 62 in rhesus and cynomolgus macaques that had previously been infected with the other 63 virus. We assessed the outcomes of secondary ZIKV or DENV infections by quantifying 64 vRNA loads, clinical and laboratory parameters, body temperature, and weight for each 65 cohort of animals and compared them with control animals. These comparisons 66 demonstrated that within a year of primary infection, secondary infections with either 67 ZIKV or DENV were similar to primary infections and were not associated with 68 enhancement or reduction in severity of disease based on the outcomes that we 69 assessed. 70 71 126 an effective vaccine for ZIKV, as well as the introduction of a tetravalent DENV va...

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Impact of preexisting dengue immunity on Zika virus emergence in a dengue endemic region

Cited by 219 publications

References 43 publications

Cross-Protection Against Zika Virus Infection Conferred by a Live Attenuated Japanese Encephalitis SA14-14-2 Vaccine

Cross-Protection Against Zika Virus Infection Conferred by a Live Attenuated Japanese Encephalitis SA14-14-2 Vaccine

Significant control of Zika infection in macaques depends on the elapsing time after dengue exposure

Primary infection with dengue or Zika virus does not affect the severity of heterologous secondary infection in macaques

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