Improved antibody breadth with an extended primary dose interval of COVID-19 vaccine is overcome by boosters

Jessica I Ahmed ¹ Samantha J Krosta ¹ Mandy N Reimer ¹ Winnie Cheung ¹ Christine Mesa ¹ Carmen Lopez ¹ Rayeil J Chua ¹ Farah Alsattari ¹ Alyssia Robinson ¹ Kathy Manguiat ¹ Naima Jahan ² Bernard Abrenica ¹ Angela Harris ¹ Karla Cachero ¹ Rissa Fabia ¹ Jonathan Walker ¹ Myo Minn Oo ² Derek Stein ^2,3 Hezhao Ji ^1,2 Ruey-Chyi Su ^1,2 Paul J Mclaren ^1,2 Lyle McKinnon ^2,4 T Blake Ball ^1,2 Heidi Wood ¹ John Kim ¹ Sandra Kiazyk ^1,2 Catherine Card ^1,2*

• ¹ National Microbiology Laboratory, Public Health Agency of Canada (PHAC), Winnipeg, Manitoba, Canada
• ² Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada
• ³ Cadham Provincial Laboratory, Winnipeg, Manitoba, Canada
• ⁴ Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa

During rollout of mRNA-based COVID-19 vaccines, several jurisdictions extended the interval between the first and second doses to prioritize wider population access to limited vaccine supply. This study evaluated the effects of an extended dose interval on development of antibody and cell-mediated responses following the primary dose series and a subsequent booster dose. An extended dose interval was associated with improved breadth of neutralizing antibody responses against both ancestral and early SARS-CoV-2 variants, but not Omicron variants. Dose interval had no impact on the development of antigen-specific memory T cell responses, the memory or T helper phenotypes of responding T cells or cytokine production. Importantly, the effects of the primary dose interval on immune outcomes were no longer evident after a third dose of mRNA vaccine, indicating that the short-term immunological benefits of an extended dose interval are transient in the context of subsequent exposures. However, in addition to the public health benefits of wider population access to COVID-19 vaccines, the short-term immunological benefits of extending the dose interval may have been sustained in the absence of boosters. These findings underscore the importance of evaluating dosing intervals during the development of future vaccine candidates.