BREAKING Dengue News! Study Shows That SARS-CoV-2 Antibodies From Natural Infections Or Vaccines Cross-React And Enhance Dengue Infection!

Dengue News: Dengue fever, a mosquito-borne viral disease, continues to afflict populations in tropical and subtropical regions worldwide. With more than 120 countries grappling with the endemicity of dengue, Asia shoulders the brunt of this global burden. In recent years, the COVID-19 pandemic has inadvertently impacted dengue cases, causing significant surges in many countries. The resurgence of dengue, particularly in countries like India, Bangladesh, Singapore, Malaysia, and others, has raised questions about potential interactions between dengue and the SARS-CoV-2 virus, which causes COVID-19.


 
Dengue virus (DENV), a member of the Flaviviridae family with a genome size of approximately 11kb, has four serotypes (DENV 1-4) that each contain multiple distinct genotypes. Infection with any serotype can result in a spectrum of symptoms, from mild fever to severe forms such as Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS). Primary infection with one serotype provides lifelong immunity against that specific serotype but only partial immunity against the others. Heterotypic secondary infections, those involving different serotypes, can lead to more severe symptoms, often due to higher viral loads facilitated by a phenomenon known as Antibody-dependent Enhancement (ADE).
 
ADE occurs when sub-neutralizing antibodies from a previous infection bind to DENV virions, facilitating Fc receptor (FcR)-mediated viral entry into cells with Fc receptors. This process occurs when the number of bound antibodies is insufficient to neutralize the virus but enough to promote stable attachment to Fc receptors, enabling enhanced viral entry. Notably, serological cross-reactivity between SARS-CoV-2 and DENV has been observed, primarily affecting dengue diagnostics. However, the clinical implications of this cross-reactivity remained unclear. Previous studies and previous Dengue News reports showed varying results, with some suggesting that cross-reactive antibodies may inhibit dengue infection, while others indicated no significant impact.
 
In this context, a groundbreaking study was conducted by researchers from the Translational Health Science and Technology Institute, Faridabad, Delhi-India to explore the relationship between SARS-CoV-2 antibodies and dengue infection, shedding light on potential ADE mechanisms. The study aimed to determine if antibodies generated in response to SARS-CoV-2, either through natural infection or vaccination, could cross-react with DENV and enhance dengue infection. This study represents a critical step towards understanding the interaction between these two viruses and has significant implications for the development and deployment of SARS-CoV-2 vaccines in regions where dengue is endemic.
 
Research Findings
The study's findings are multifaceted and underscore the complex interplay between SARS-CoV-2 antibodies and dengue infection.
 
-Cross-reactivity of SARS-CoV-2 Antibodies with Dengue Virus: Using a range of techniques, including confocal microscopy, it was observed that antibodies directed against the SARS-CoV-2 spike protein and receptor-binding domain (RBD) demonstrated significant cross-reactivity with the Dengue Virus (DEN V-2).
 
-SARS-CoV-2 Convalescent Plasma Enhances Dengue Infection In-Vitro: The study investigated the impact of SARS-CoV-2 convalescent plasma samples on DENV-2 infection in K562 and U937 cells. It found that a substantial proportion of convalescent COVID-19 patient plasma samples significantly enhanced DENV-2 infection in both cell types. This observation was consistent across different waves of the pandemic, including the pre-delta and omicron waves. Furthermore, the study showed that the neutralizing antibody titers against SARS-CoV-2 in these samples did not correlate with the observed enhancement of DENV-2 infection.
 
-Monoclonal and Polyclonal Antibodies Raised Against SARS-CoV-2 Enhance Dengue Virus Infection: To rule out the influence of pre-existing anti-DENV antibodies, commercially available monoclonal and polyclonal antibodies raised against the SARS-CoV-2 spike protein and RBD were tested. Interestingly, all these antibodies enhanced DENV-2 infection in cell-based assays, reinforcing the notion that antibodies targeting SARS-CoV-2 can cross-react with DENV and facilitate ADE.
 
-In-Silico Analysis of Antibody Interaction: The study also employed in-silico methods to investigate the cross-reactivity of SARS-CoV-2 antibodies with DENV-2 E-protein. Several SARS-CoV-2 antibodies were evaluated for their interactions with DENV-2 E-protein, and the results pointed to specific residues and epitopes that could be involved in this interaction.
 
-Time-Dependent Enhancement: A time-course analysis revealed that antibodies from SARS-CoV-2 convalescent plasma and immunized animal sera exhibited a time-dependent enhancement of DENV-2 infection. This suggests that the interaction between these antibodies and the virus might evolve over time, further complicating the dynamics of the immune response.
 
Implications and Future Directions
The study's findings have profound implications for public health and vaccine development, particularly in regions where both dengue and SARS-CoV-2 are prevalent. Here are some key takeaways and potential areas for future research:
 
-Relevance to Vaccination Strategies: The cross-reactivity of SARS-CoV-2 antibodies with DENV raises questions about vaccination strategies in dengue-endemic areas. Considering the potential for ADE, policymakers and healthcare professionals may need to tailor their vaccine deployment strategies to mitigate the risk of enhanced dengue infection in individuals with pre-existing SARS-CoV-2 immunity.
 
-SARS-CoV-2 Vaccine and Dengue Co-Infections: The study provides a glimpse into the complex interactions between SARS-CoV-2 and DENV. It also underscores the importance of monitoring and understanding the implications of co-infections, such as dengue and COVID-19. The study reported higher case fatality rates in co-infected individuals, further emphasizing the need for vigilance in managing dual infections.
 
-Therapeutic and Prophylactic Opportunities: The identification of specific residues and epitopes involved in the cross-reactivity between SARS-CoV-2 antibodies and DENV-2 E-protein opens doors to potential therapeutic and prophylactic interventions. Targeting these epitopes with tailored treatments could help mitigate the risk of enhanced dengue infection in individuals with pre-existing SARS-CoV-2 immunity.
 
-Mechanistic Insights: The study acknowledges that further research is needed to gain a comprehensive understanding of the mechanisms underlying ADE of DENV-2 infection by SARS-CoV-2 antibodies. Differentiating between extrinsic and intrinsic pathways and elucidating the exact cellular and molecular processes involved could provide valuable insights for therapeutic strategies.
 
Conclusion
The study's groundbreaking findings emphasize the complex interplay between SARS-CoV-2 antibodies and dengue infection, shedding light on the potential for antibody-dependent enhancement. These insights have significant implications for vaccine development, deployment strategies, and public health measures, particularly in regions where dengue is endemic. Further research is essential to unravel the mechanistic intricacies of this interaction and to explore therapeutic avenues that could help mitigate the risks associated with co-infections. As the world continues to combat infectious diseases, such studies contribute to our growing understanding of the multifaceted dynamics of viral infections and immunity.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2023.10.09.557914v1
 
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