PREreview of Pre-existing YFV-17D immunity mediates T cell cross-protection against DENV-2 infection

This paper investigates whether pre-existing immunity to the YFV-17D vaccine confers cross-protection against Dengue Virus serotype 2 (DENV 2) in a murine model. 

The investigators used IFNAR-/- mice to show that YFV-17D immunization reduced DENV-2 viremia significantly, with differences in weight loss, disease severity and improved survival compared to YFV naive mice. Mechanistic experiments demonstrated that this cross-protection is mediated by T cell responses rather than cross-neutralizing antibodies. Depletion of T cells abrogates protection, and YFV-17D-specific T cells display cytotoxicity against DENV NS3 and NS5-pulsed cells. The findings of this study highlight the importance of heterologous T cell immunity in orthoflavirus cross-protection and suggest implications for vaccine design.

This study sought to address questions regarding the impact of pre-existing flavivirus immunity on disease outcomes, especially in regions where multiple orthoflavivirus co-circulate. The methodologies used are robust, combining in vivo challenge, T cell depletion, antibody neutralization/ADE assays, and cytotoxicity assays to dissect the mechanisms of cross-protection. The findings are relevant for vaccine development and strategies in endemic regions and could help explain epidemiological patterns of flavivirus outbreaks.

Major considerations

Real-world practice vs the immunization regimen used in the study: Two doses of the YFV-17D were administered, whereas current guidelines recommend a single dose in humans. Although the authors describe the rationale for using two doses, the potential impact on translational relevance and immune response requires further clarification. A single-dose group could have been included to better model real-world vaccination scenarios.

Mouse models limitations:  Though necessary for robust DENV infection, the use of IFNAR-/- mice may not fully recapitulate human immune responses. The investigators acknowledge this limitation, but the implications for generalizability, especially regarding the role of T cells and vaccine-induced immunity, should be more deeply discussed.

Incomplete clinical data reporting: The results mention a mouse in the CD4 depletion group that died without further explanation (in the section describing T cells contributing to cross protection against DENV-2, page 6). Additional details regarding the cause of death and whether it was related to the experiment, infection, or depletion protocol should be provided for full transparency.

Minor considerations

Data presentation: In the weight-loss results, only average values are provided. Including ranges (min and max values) would allow for better assessment of variability and overlap between groups.

Opportunities for improvement

Modeling Real-world Vaccination: Including a single-dose group to compare with the current human vaccination schedule and assess durability of cross-protection.

Conclusion

This manuscript provides compelling evidence that YFV-17D-induced T cell immunity can mediate cross-protection against DENV-2 in a murine model, independent of cross-neutralizing antibodies. The work is methodologically sound and addresses an important question with clear implications for vaccine design and public health. Addressing the outlined considerations, particularly regarding immunization regimens, model limitations, and data reporting-will further strengthen the manuscript and its translational relevance.

Competing interests

The authors declare that they have no competing interests.

Use of Artificial Intelligence (AI)

The authors declare that they used generative AI to come up with new ideas for their review.