Prior Zika virus infection can enhance the risk of severe dengue disease, according to a new study, which uses a unique cohort from Nicaragua to confirm previous reports that have suggested the action of cross-reactive antibodies between the two closely related flaviviruses. The findings have important implications for the development, efficacy and safety of Zika vaccines. Furthermore, the insights gained may provide a framework for understanding the interactions between other immunologically complex viruses, including coronaviruses. For nearly the past two decades, subsequent epidemics of dengue (DENV) and Zika virus (ZIKV) - two closely related, mosquito-borne flaviviruses - have wracked the global tropics, infecting hundreds of millions of people annually. While a great deal of research has been conducted to better understand how prior dengue immunity impacts Zika infection, little is known about how immunity through Zika infection or vaccination affects subsequent dengue disease. Leveraging long-running pediatric cohort studies in Nicaragua, Leah Katzelnick and colleagues evaluated Zika immunity's effects on subsequent dengue infections in those that experienced sequential DENV 1-3, ZIKV and DENV2 infections during their respective epidemics since 2004. Similar to prior DENV infection, Katzelnick et al. found that a single ZIKV infection significantly increased the likelihood of symptomatic and severe dengue disease - particularly DENV2. However, unlike subsequent rounds of dengue, which raises DENV antibodies to protective levels and has been shown to imbue modest protection against uncomplicated Zika, the findings indicate that a single DENV infection followed by a case of ZIKV does reduce the future risk of dengue disease. "[The study by] Katzelnick et al. serves as a reminder that issues of co-circulation and cross-immunity should remain in view for understanding transmission dynamics and vaccination," writes Hannah Clapham in a related Perspective.
Adding to interpretations of implications, Katzelnick and co-author Eva Harris write, "Our finding is about flaviviruses and specifically dengue and Zika viruses and dengue disease. Antibody-dependent enhancement (ADE) is a well-established mechanism and cause of severe dengue disease. However, ADE is not a mechanism that has been shown to be important for human coronaviruses, and thus we don't expect that this unusual mechanism would necessarily apply to COVID-19. However, studying immunological cross-reactivity between closely related viruses is always valuable, and will help provide insights into whether natural infection with other human coronaviruses as well as COVID-19 vaccines provide protective immunity or potentially immunity that is associated with pathogenic outcomes. This is why carefully conducted large Phase 3 vaccine studies are critical: they test whether a vaccine works for protecting people (efficacy) as well as whether the vaccine causes any negative side-effects (safety). Post-marketing (Phase 4) studies are also important to conduct to continue monitoring even larger numbers of people receiving the vaccine(s). An additional lesson from our study is that natural ZIKV infection can have long-term negative consequences. Thus, ZIKV vaccines are being engineered to induce a better response as compared to natural ZIKV infection by only inducing potently neutralizing anti-ZIKV antibodies and avoiding inducing enhancing antibodies. This is an important consideration for COVID-19: COVID-19 vaccines can be engineered to induce a better immune response than natural SARS-CoV-2 infection, making them safer and more effective."
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Journal
Science