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Time-dependent enhancement of mRNA vaccines by 4-1BB costimulation
Sarah Sanchez1, Tanushree Dangi1, Bakare Awakoaiye1
1Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Abstract:
mRNA vaccines have demonstrated efficacy against COVID-19. However, concerns regarding waning immunity and breakthrough infections have motivated the development of next-generation vaccines with enhanced efficacy. In this study, we investigated the impact of 4-1BB costimulation on immune responses elicited by mRNA vaccines in mice. We first vaccinated mice with an mRNA vaccine encoding the SARS-CoV-2 spike antigen like the Moderna and Pfizer-BioNTech vaccines, followed by administration of 4-1BB costimulatory antibodies at various times post-vaccination. Administering 4-1BB costimulatory antibodies during the priming phase did not enhance immune responses. However, administering 4-1BB costimulatory antibodies after 96 hours elicited a significant improvement in CD8 T cell responses, leading to enhanced protection against breakthrough infections. A similar improvement in immune responses was observed with multiple mRNA vaccines, including vaccines against common cold coronavirus, human immunodeficiency virus (HIV), and arenavirus. These findings demonstrate a time-dependent effect by 4-1BB costimulation and provide insights for developing improved mRNA vaccines.
Insights
Next-generation mRNA vaccines show improved efficacy. Adding 4-1BB costimulation after 96 hours significantly boosts CD8 T cell responses and protection against infections.
Area of Science:
- Immunology
- Vaccinology
- Molecular Biology
Background:
- mRNA vaccines offer protection against COVID-19 but face challenges like waning immunity.
- Next-generation vaccines are needed to enhance efficacy and address breakthrough infections.
Approach:
- Mice were vaccinated with an mRNA vaccine encoding the SARS-CoV-2 spike antigen.
- 4-1BB costimulatory antibodies were administered at various times post-vaccination.
- Immune responses, particularly CD8 T cell activity, were analyzed.
Key Points:
- Administering 4-1BB costimulation during the priming phase did not improve immune responses.
- Delayed administration of 4-1BB costimulation (after 96 hours) significantly enhanced CD8 T cell responses.
- This approach improved protection against breakthrough infections in mice.
Conclusions:
- 4-1BB costimulation exhibits a time-dependent effect on mRNA vaccine-induced immunity.
- This strategy enhances T cell responses and protection across various mRNA vaccine platforms.
- Findings provide insights for developing improved mRNA vaccines with sustained efficacy.
