Homologous & heterologous COVID-19 vaccine priming schedules: an analysis of systemic & mucosal immunity

Most two dose vaccination schedules, including UK-licensed SARS-CoV2 vaccinations, are licensed as homologous schedules. At the point of UK emergency licensure of the first two SARS-CoV2 vaccines, global demand for vaccine outstripped supply. National immunisation programmes faced logistical challenges to ensure sufficient doses of the same vaccine could be distributed to each person in the manufacturer-recommended timeframe. Two randomised control trials (Com-COV1 and Com-COV2) assessed safety, tolerability and non-inferiority of humoral immunogenicity of heterologous priming schedules using vaccines available to the UK immunisation program – AstraZeneca, Pfizer, Moderna and Novavax. Heterologous schedules are more reactogenic than their equivalent homologous schedules, however, all schedules are tolerable and without safety concern. Not all heterologous schedules are non-inferior to their relevant homologous schedule in terms of serum anti-SARS-CoV2 spike binding IgG, but they do always achieve a robust immunological response at least as large as the least immunogenic schedule studied (homologous AstraZeneca), which has proven efficacy against both severe disease and symptomatic infection. Differences between vaccine platforms are also qualitative with clear differences in the capability of each schedule to produce neutralising responses. T-cell responses differ markedly with the greatest responses seen in those receiving heterologous schedules with AstraZeneca as the first dose. Increasing priming interval from one to three months resulted in a modest increase in antibody response and a decrease in cellular response. Mucosal responses were evaluated as an exploratory endpoint. There was no evidence that mucosal anti-SARS-CoV2 spike IgA was induced by intramuscular vaccination. There is evidence that nasal mucosal responses can occur in the absence of systemic responses, possibly due to asymptomatic mucosal SARS-CoV2 exposure. Existing mucosal IgA responses against seasonal coronaviruses may confer some degree of protection against SARS-CoV2 infection. These results support the use of heterologous schedules as viable alternatives to homologous schedules and support flexibility in priming interval. They have informed UK and global immunisation policy. There is a need for alternative vaccination strategies, such as mucosally delivered vaccines, which induce mucosal responses that may reduce transmission.