Deconstructing the protective immunity of yellow fever virus 17D to inform flavivirus vaccine design

Project Information

Yellow4FLAVI

Grant agreement ID: 101137459

DOI

10.3030/101137459

EC signature date 14 November 2023

Start date 1 January 2024

End date 31 December 2028

Funded under

• Health

Total cost

€ 8 544 780,75

EU contribution

€ 8 544 780,75

Coordinated by

INSTITUT PASTEUR
France

Periodic Reporting for period 1 - Yellow4FLAVI (Deconstructing the protective immunity of yellow fever virus 17D to inform flavivirus vaccine design)

Reporting period: 2024-01-01 to 2025-06-30

Summary of the context and overall objectives of the project

Flaviviruses—including Zika, dengue, West Nile, and yellow fever—are mosquito-borne pathogens of increasing global concern. Their spread is rising due to climate change and urbanization, leading to the emergence of new outbreaks in regions such as Europe, where record numbers of local cases have been reported. In August 2025, the European Centre for Disease Prevention and Control warned that West Nile virus could become “the new normal” for Europe. Many flaviviruses lack effective vaccines, and even for yellow fever vaccine, the immune mechanisms underlying its exceptional protection remain incompletely understood.
Yellow4FLAVI’s mission is to unlock the immune “blueprint” of the yellow fever vaccine (YF17D)—one of humanity’s most successful vaccines—in order to correlate the virus structure with its immunogenicity and guide the design of safer, next-generation flavivirus vaccines. The project aims to tailor vaccines to a diverse population with co-circulation of Flaviviruses and maximize public trust through robust, science-based risk communication.
Yellow4FLAVI leverages advanced technologies: cryo-electron microscopy, super-resolution microscopy, spatial transcriptomics, high-dimensional spectral flow cytometry, single-cell RNA sequencing, advanced cell engineering, and animal/clinical and social studies, both in Europe and in dengue-endemic Colombia. This comprehensive approach tracks events from the very first molecular and cellular responses at the vaccine injection site to community perceptions of vaccination.
Social acceptance is crucial for vaccine success. The project incorporates comparative quantitative and qualitative social studies on vaccine hesitancy in Germany and Colombia, which will enable developing context-adapted, evidence-based communication methods.
Main objectives:
1. To understand how the structure of the virus affects how the immune system recognizes it, to help design better vaccines.
2. To find out what factors in people influence how well they respond to the YF17D vaccine and how long their protection lasts.
3. To create clear and effective ways to share information about new vaccines.
By fostering partnerships across Europe and South America, Yellow4FLAVI accelerates data and sample sharing and strengthens responses to viral threats amplified by climate change. Ultimately, the project aims to provide robust scientific and societal foundations for future pandemic preparedness.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Structural studies of yellow fever virus have generated valuable insights into how the virus is recognized—and neutralized—by the immune system. In addition, the development of hybrid viruses combining elements of West Nile and Usutu viruses has provided new tools for studying immune cross-reactivity, critical for the rational design of broadly protective vaccines.
Key discoveries have emerged in predicting and understanding vaccine responses. Detailed analysis of clinical trial participants identified early blood biomarkers—including elevated levels of the chemokine CXCL10 and specific helper T cell subsets—that help predict individual responsiveness to the yellow fever vaccine. Furthermore, it was revealed that individuals vaccinated for the first time with YF17D retain an important subclass of protective IgM antibodies for many years. Those previously exposed to related flaviviruses, such as tick-borne encephalitis (TBE) vaccine, displayed a different antibody profile dominated by cross-reactive but less-potent antibodies suggesting a negative impact of prior exposure to other Flaviviruses.
The project’s collaborative work includes recruiting cohorts in Colombia (targeting dengue-exposed individuals), Germany, and Italy (targeting West Nile–exposed individuals). Advanced imaging and skin explant studies have begun mapping the earliest vaccine–immune cell interactions at the site of injection. Newly developed laboratory models—such as a mouse model for antibody-dependent enhancement—are enabling the testing and optimization of vaccine safety for vulnerable populations.
Social science research conducted through focus groups in Germany and Colombia has provided new understanding of public attitudes and worries regarding novel vaccine technologies. This work will contribute directly to the creation of communication methods that match the needs and concerns of different communities, thus helping lay the groundwork for greater public trust and vaccine acceptance.
Together, these efforts strengthen the scientific foundation for safer and more broadly applicable flavivirus vaccines, while ensuring that the challenges of acceptance, protection of vulnerable groups, and international collaboration are met.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Yellow4FLAVI is advancing the field on multiple levels. The project has identified new early biomarkers that may allow accurate prediction of vaccine response before traditional immunity develops. The discovery that long-term protection in yellow fever vaccine recipients is sustained by IgM antibodies, and that prior exposure to other flaviviruses alters this profile, provides new understanding of how immunity operates across different populations. This is critical for designing future vaccines that are both broadly protective and safe and to establish adapted calendars of vaccination.
The generation of hybrid viruses and innovative laboratory models—such as a dedicated ADE mouse model—represents an advance over existing preclinical tools, enabling a deeper exploration of both effectiveness and risks of vaccine candidates. The design of specific antigens offers a toolbox to both analyze in depth the immune response to the vaccine and generate specific diagnostic tools. The spatial mapping of early immune responses at the injection site, made possible by advanced imaging and spatial transcriptomics, yields fundamental insights into the mechanisms underpinning potent and durable immunity.
The project’s cross-country qualitative social research into vaccine hesitancy will lead to the co-creation of tailored messaging and engagement strategies, an approach rarely integrated in vaccine R&D projects.

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