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

  1. Prince Baffour Tonto
  2. Sebastian Gallon
  3. Reem Alatrash
  4. Wei-Kung Wang
  5. Bobby Brooke Herrera

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Abstract

Widespread yellow fever virus (YFV) immunity in Sub-Saharan Africa may mitigate orthoflavivirus outbreaks. Here, we investigate whether pre-existing YFV-17D immunity confers cross-protection against dengue virus serotype 2 (DENV-2) in a murine model. IFNAR1 -/- mice immunized with YFV-17D exhibited significantly reduced DENV-2 viremia, weight loss, and disease severity, with improved survival compared to YFV-naïve controls. Mechanistic studies revealed that cross-protection was mediated by heterologous T cell responses rather than cross-neutralizing antibodies. Depletion of T cells in YFV-17D-immune mice prior to DENV-2 challenge resulted in increased viremia, weight loss, and disease severity, underscoring the protective role of YFV-17D-elicited T cell immunity. Furthermore, YFV-17D-specific T cells displayed cytotoxicity against DENV NS3- and NS5-pulsed cells, demonstrating their functional role in viral control. These findings highlight the critical contribution of heterologous T cell immunity in YFV-17D-mediated protection against DENV-2 and suggest that vaccines designed to elicit T cell responses could enhance cross-protection against orthoflavivirus infections.

Article activity feed

  1. Rapid Reviews Infectious Diseases

    Anurag Adhikari, Sujan Shresta, Pradhan Aunji

    Review 4: "Pre-existing YFV-17D Immunity Mediates T Cell Cross-protection Against DENV-2 Infection"

    Overall, reviewers commended the preprint's contribution to understanding immune response across flaviviruses.

  3. Rapid Reviews Infectious Diseases

    Strength of evidence

    Reviewer(s): A Durbin (Johns Hopkins University) | 📒📒📒 ◻️◻️
    S Biering & V Kril (UC San Diego) | 📒📒📒◻️◻️
    E E Ooi (Duke-NUS Medical School) | 📘📘📘📘📘
    A Adhikari & S Shresta & P Aunji (La Jolla Institute for Immunology) | 📗📗📗📗◻️

  4. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/15473676.

    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.

  5. Version published to 10.1101/2025.04.16.649113v1 on bioRxiv