Delayed reinforcement of costimulation improves the efficacy of mRNA vaccines in mice
Sarah Sanchez, Tanushree Dangi, Bakare Awakoaiye, Min Han Lew, Nahid Irani, Slim Fourati, Pablo Penaloza-MacMaster
Sarah Sanchez, Tanushree Dangi, Bakare Awakoaiye, Min Han Lew, Nahid Irani, Slim Fourati, Pablo Penaloza-MacMaster
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Research Article Immunology

Delayed reinforcement of costimulation improves the efficacy of mRNA vaccines in mice

Abstract

mRNA vaccines have demonstrated efficacy during the COVID-19 pandemic and are now being investigated for multiple diseases. However, concerns linger about the durability of immune responses, and the high incidence of breakthrough infections among vaccinated individuals highlights the need for improved mRNA vaccines. In this study, we investigated the effects of reinforcing costimulation via 4-1BB, a member of the TNF receptor superfamily, on immune responses elicited by mRNA vaccines. We first immunized mice with mRNA vaccines, followed by treatment with 4-1BB costimulatory antibodies to reinforce the 4-1BB pathway at different time points after vaccination. Consistent with prior studies, reinforcing 4-1BB costimulation on the day of vaccination did not result in a substantial improvement in vaccine responses. However, reinforcing 4-1BB costimulation on day 4 after vaccination, when 4-1BB expression levels were highest, resulted in a profound improvement in CD8+ T cell responses associated with enhanced protection against pathogen challenges. A similar clinical benefit was observed in a therapeutic cancer vaccine model. We also report time-dependent effects with OX40, another costimulatory molecule of the TNF receptor superfamily. These findings demonstrate that delayed reinforcement of costimulation may exert an immunologic benefit, providing insights for the development of more effective mRNA vaccines for infectious diseases and cancer.

Authors

Sarah Sanchez, Tanushree Dangi, Bakare Awakoaiye, Min Han Lew, Nahid Irani, Slim Fourati, Pablo Penaloza-MacMaster

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Figure 4

Reinforcing 4-1BB costimulation 4 days after mRNA vaccination induces sterilizing protection against pathogen challenges.

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Reinforcing 4-1BB costimulation 4 days after mRNA vaccination induces st...
(A) Experimental outline to examine whether treatment with α4-1BB on day 4 improves immune protection conferred by an mRNA-LCMV vaccine. (B) Summary of LCMV Cl-13 loads in the spleen on day 7 after challenge. On day 14 after vaccination, mice were challenged i.v. with LCMV Cl-13 (2 × 106 PFU) and viral loads were quantified in Vero-E6 monolayers. (C) Experimental outline to examine whether treatment with α4-1BB on day 4 improves immune protection conferred by an mRNA-OVA vaccine. (D) Summary of LM-OVA bacterial loads in the spleen on day 3 after challenge. On day 14 after vaccination, mRNA-OVA–vaccinated mice were challenged i.v. with a supralethal dose of LM-OVA (1 × 107 CFU) and bacterial loads were quantified in agar plates. In the challenge experiments, mice were immunized with 3 μg of the respective vaccine followed by treatment with 50 μg of α4-1BB or control antibodies on day 4. LCMV Cl-13 challenge data are from 2 experiments, one with n = 5 per group/experiment and one with n = 4 per group/experiment. Data from the LM-OVA challenge experiment are from one experiment, n = 4–5 per group. The control vaccines were still able to confer partial protection, relative to no vaccination (mean LCMV Cl-13 viral loads in unvaccinated mice = 1.3 × 107 PFU/g; mean LM-OVA loads in unvaccinated mice = 1.1 × 106 CFU/g). Indicated P values in B and D were calculated by the Mann-Whitney test.