Reducing the priming dose of a SARS CoV-2 vaccine improves vaccine-elicited immunity

Abstract

Abstract SARS-CoV-2 caused a global pandemic that has killed over 2 million people. While several vaccine candidates have received emergency use authorization, there is still limited vaccine availability and lack of knowledge on optimal vaccine dosing. A recent AstraZeneca vaccine study with an adenovirus vector suggested that priming with a low dose (LD) is superior than priming with a standard dose (SD). We extended these results to a murine vaccination model to further understand the mechanism of how limiting the priming dose affects vaccine-elicited immunity. We first primed C57BL/6 mice intramuscularly with an adenovirus-based vaccine expressing SARS CoV-2 spike (Ad5-spike), either with a LD (106 PFU) or a SD (109 PFU), followed by a SD boost three weeks later. An initial priming with a SD resulted in a higher magnitude of adaptive immune responses relative to an initial priming with a LD, consistent with the notion that adaptive responses are proportional to the priming antigen dose. However, T cell responses generated by a LD prime exhibited more rapid central memory differentiation, suggesting that they could display improved recall expansion following subsequent booster immunization. Interestingly, mice that were primed with a LD exhibited significantly more potent anamnestic T cell responses upon boosting, relative to mice that were primed and boosted with a SD. Antibody responses were also significantly improved in the LD/SD vaccine regimen. Overall, our data suggest that limiting the priming dose may offer a substantial long-term benefit for SARS CoV-2 vaccines. These findings may be useful for improving vaccine availability and also for the rational design of prime-boost vaccine regimens for SARS CoV-2 and other diseases.