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Review 2: "SARS-CoV-2 Antibodies Cross-React and Enhance Dengue Infection"

Reviewers find the preprint's in vitro evidence for SARS-CoV-2 antibody enhancement of dengue infection potentially informative but advise corroborating with clinical and epidemiological data.

Published onNov 15, 2023
Review 2: "SARS-CoV-2 Antibodies Cross-React and Enhance Dengue Infection"
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key-enterThis Pub is a Review of
SARS-CoV-2 antibodies cross-react and enhance dengue infection
SARS-CoV-2 antibodies cross-react and enhance dengue infection

Abstract Dengue disease is highly prevalent in tropical and subtropical regions worldwide. However, its pathogenesis is still incompletely understood, particularly in comparison to other endemic viruses. Antibody-dependent enhancement (ADE) is a well-known phenomenon for dengue viruses. Given the recent surge in dengue cases and potential cross-reactivity with SARS-CoV-2 antibodies, this study explores the impact of anti-SARS-CoV-2 antibodies on DENV-2 infection.The study assessed the cross-reactivity of SARS-CoV-2 antibodies with the DENV-2 Virus. Human convalescent plasma samples collected during different waves of COVID-19 and monoclonal and polyclonal antibodies raised against SARS-CoV-2 were examined for their potential to cause ADE of DENV-2 infection using cell-based assays. The study found that anti-SARS-CoV-2 antibodies acquired from natural infection in humans or through experimental immunization in animals were cross-reactive with DENV-2 and had the potential to enhance DENV-2 infection in K562 and U937 cells. In-silico and in-vitro studies indicated a strong interaction between SARS-CoV-2 antibodies and DENV-2 E-protein, providing a molecular basis for these findings. This study is the first to demonstrate that anti-SARS-CoV-2 antibodies can cross-react with DENV-2 and can enhance its infection through ADE. These findings have implications for SARS-CoV-2 vaccine development and deployment strategies in regions where dengue is endemic.Summary Antibodies against SARS-CoV-2 (RBD and Spike) showed significant cross reactivity with DENV-2 (E protein). Also, anti-SARS-CoV-2-commercial antibodies, immunised animal sera and 46 human convalescent plasma samples (from different waves of pandemic) demonstrated antibody-dependent enhancement (ADE) of DENV-2 infection.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



Antibody dependent enhancement is a complex phenomenon that can be impacted by a number of different parameters that occur during virus infections. The authors of the manuscript claim that antibodies from SARS-CoV-2 infections can enhance dengue virus infections in cell culture systems. 

Antibody-dependent enhancement (ADE) of infection occurs when antibodies from a previous virus infection facilitate viral entry into host cells and enhance viral infection in these cells during subsequent virus infections. The prototype example of this phenomenon is with the four dengue virus serotypes and secondary infections, but ADE has also been observed with Coronaviruses (e.g., feline infectious peritonitis virus) and other viruses. Whether ADE can occur between distantly related viruses remains unclear. Here, Jakhar et al. use cell culture systems and immune sera from convalescent COVID-19 patients to address whether SARS2 immunity affects the outcome of dengue virus serotype 2 infection. Overall, this is an interesting study that may yield some insight but the main claims are not strongly justified by the methods and data. I believe there are a few scientific issues and several aspects of the manuscript that need to be addressed to facilitate understanding by the reader. 

The most important issue is that there is extensive literature that exists to demonstrate that an antibody-dependent effect in vitro does not represent or predict ADE of disease in vivo without additional proof of a role for the antibody in the pathogenesis of a more severe outcome. As a result, the results presented herein need to be interpreted with caution and will require rigorous follow-up to establish the veracity of what is being claimed: that SARS2 antibodies can enhance dengue virus infections. At a minimum more details are needed on the neutralizing antibody titers against both SARS2 and dengue virus in the patient serum samples used in this study. Similarly, more information is needed on how samples were diluted for ADE assays. This is critical to establish a stoichiometric threshold for the antibody concentration needed to observe ADE. Similarly, for experiments in which monoclonal antibodies were used to demonstrate ADE, it will be very informative to generate LALA versions to see if this abrogates the enhancing effect. As a result, there are additional experiments required to rigorously establish whether or not this is likely to be happening during human infections. 

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