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Review 1: "Primary Exposure to Zika Virus Increases Risk of Symptomatic Dengue Virus Infection with Serotypes 2, 3, and 4 but not Serotype 1"

Overall, the reviewer found the study to be well-designed with strong evidence to support the claims.

Published onJun 28, 2024
Review 1: "Primary Exposure to Zika Virus Increases Risk of Symptomatic Dengue Virus Infection with Serotypes 2, 3, and 4 but not Serotype 1"
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Primary exposure to Zika virus increases risk of symptomatic dengue virus infection with serotypes 2, 3, and 4 but not serotype 1
Primary exposure to Zika virus increases risk of symptomatic dengue virus infection with serotypes 2, 3, and 4 but not serotype 1
Description

ABSTRACT Infection with any of the four dengue virus serotypes (DENV1-4) can protect against or enhance subsequent dengue depending on pre-existing antibodies and the subsequent infecting serotype. Additionally, primary infection with the related flavivirus Zika virus (ZIKV) has been shown to increase DENV2 disease. Here, we measured how prior DENV and ZIKV immunity influenced risk of disease caused by all four serotypes in a pediatric Nicaraguan cohort. Of 3,412 participants in 2022, 10.6% experienced symptomatic DENV infections caused by DENV1 (n=139), DENV4 (n=133), DENV3 (n=54), DENV2 (n=9), or an undetermined serotype (n=39). Longitudinal clinical and serological data were used to define infection histories, and generalized linear and additive models adjusted for age, sex, time since the last infection, cohort year, and repeat measurements were used to predict disease risk. Compared to flavivirus-naïve participants, primary ZIKV infection increased disease risk of DENV4 (relative risk = 2.62, 95% confidence interval: 1.48-4.63) and DENV3 (2.90, 1.34-6.27) but not DENV1 (1.20, 0.72-1.99). Primary DENV infection or a DENV followed by ZIKV infection also increased DENV4 risk. We re-analyzed 19 years of cohort data and demonstrated that prior flavivirus-immunity and pre- existing antibody titer differentially affected disease risk for incoming serotypes, increasing risk of DENV2 and DENV4, protecting against DENV1, and protecting at high titers but enhancing at low titers against DENV3. We thus find that prior ZIKV infection, like prior DENV infection, increases risk of certain DENV serotypes. Cross-reactivity among flaviviruses should be carefully considered when assessing vaccine safety and efficacy.One-Sentence Summary Dengue disease risk is differentially modulated depending on pre- existing immunity to dengue and Zika virus infections and the secondary infecting serotype.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review: Zambrana J V et al. claimed that primary ZIKV infection enhances risk of subsequent dengue disease in a serotype-dependent manner. In addition, they showed that the order of sequential DENV and ZIKV infections (DENV-ZIKV vs. ZIKV-DENV) modulate disease outcome differently. Finally, most infection histories generated protective and enhancing antibodies that influence the infection outcome depending on the antibody titer (Low vs. high), except for primary ZIKV infection.

The authors tracked Dengue and Zika virus (DENV and ZIKV) infection histories of a large Nicaraguan pediatric cohort to determine how prior DENV and ZIKV infection can influence the risk of disease outcome (Asymptomatic and/or symptomatic infection and severe) following subsequent infections by each of the four DENV serotypes. The authors claimed that primary ZIKV infection enhances risk of subsequent dengue disease in a serotype-dependent manner. In addition, they showed that the order of sequential DENV and ZIKV infections (DENV-ZIKV vs. ZIKV-DENV) modulate disease outcome differently. Finally, most infection histories generated protective and enhancing antibodies that influence the infection outcome depending on the antibody titer (Low vs. high).

The data used in this study come from a well-known cohort of thousands of children tracked since 2004 in Nicaragua. The study presents evidences showing the complexity of the immune responses to DENV and ZIKV infections and their clinical outcomes. The study is outstanding for human research (more than 10 groups of infection histories), especially considering the challenges in tracking infection histories in humans. The authors tackled an important subject in the field, emphasizing the importance of understanding cross-reactive immune responses among flaviviruses, particularly antibodies, for ensuring vaccine safety and efficacy. All points claimed by the authors are well-justified and presented in the results. The methodologies used are well-established approaches, (i.e iELISA to determine the antibody titers), strengthening the results. The discussion provided by the authors is clear and highlights the strength and limitations of the study.

Overall, this study has strong evidences to support the main claims from a pediatric cohort (<18 years old) and should be considered conclusive in that context.

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