Primary exposure to Zika virus increases risk of symptomatic dengue virus infection with serotypes 2, 3, and 4 but not serotype 1

  1. Jose Victor Zambrana
  2. Chloe M. Hasund
  3. Rosemary A. Aogo
  4. Sandra Bos
  5. Sonia Arguello
  6. Karla Gonzalez
  7. Damaris Collado
  8. Tatiana Miranda
  9. Guillermina Kuan
  10. Aubree Gordon
  11. Angel Balmaseda
  12. Leah Katzelnick
  13. Eva Harris

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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.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/10393624.

    Does the introduction explain the objective of the research presented in the preprint? Yes The introduction clearly explains the objective of the study by presenting information on how antibody titers can be cross-reactive that are both neutralizing and increase the risk of infection. This is further built upon in how the paper describes the implication of previous DENV or ZIKV infections and the increased risk they pose.
    Are the methods well-suited for this research? Somewhat appropriate The methods and materials that were described were thorough and properly executed and produced a solid foundation on which one would be able to generate meaningful discourse. The methods could be further enhanced if the study design had accounted for potential confounding variables that may have been prevalent during the time of the study that was being observed.
    Are the conclusions supported by the data? Highly supported
    Are the data presentations, including visualizations, well-suited to represent the data? Somewhat appropriate and clear
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Somewhat clearly
    Is the preprint likely to advance academic knowledge? Somewhat likely
    Would it benefit from language editing? No
    Would you recommend this preprint to others? Yes, it's of high quality
    Is it ready for attention from an editor, publisher or broader audience? Yes, after minor changes

    Competing interests

    The author declares that they have no competing interests.

  2. Version published to 10.1101/2023.11.29.23299187v1 on medRxiv