Heterologous vs. homologous vaccine regimens: Sulfated lactosyl archaeol (SLA) archaeosome-adjuvanted SARS-CoV-2 spike protein boost following an mRNA/LNP prime induces robust and balanced immune responses

To combat the spread of and disease caused by SARS-CoV-2, mRNA/LNP vaccines were introduced into the clinic in 2020 with tremendous uptake and success. Since then, there have been multiple other SARS-CoV-2 vaccines approved across different countries based on various types of platforms including viral vector, inactivated virus and adjuvanted protein subunit vaccines. This has led to a scenario where there is a high probability of heterologous vaccinations in certain populations, whereby booster doses will differ from the initial vaccine formulations they received. We have previously demonstrated the immunogenicity of sulfated lactosyl archaeol (SLA) archaeosome-adjuvanted protein subunit vaccines and mRNA/LNPs in preclinical models within separate studies. Herein, we compared the immunological outcomes following homologous and heterologous vaccination regimens against SARS-CoV-2 spike based on mRNA/LNPs and/or SLA archaeosome-adjuvanted protein subunit vaccines in a mouse model. The homologous mRNA/LNP regimen induced a strong humoral response consisting of a more balanced IgG1:IgG2c ratio accompanied by robust CD4⁺ and CD8⁺ T cell activation, compared to the homologous protein subunit regimen which led to a dominating IgG1 response with robust CD4⁺ T cell activation only. With the heterologous regimens, the IgG1:IgG2c ratios were reflective of their priming vaccine, a potential impact of immunological imprinting. However, in the heterologous regimens, robust cellular responses were only achieved in animals which had received a priming mRNA/LNP vaccine and not in those which were primed with the adjuvanted protein vaccine. This regimen resulted in superior CD4⁺ T cell activation as compared to the homologous mRNA/LNP regimen, while maintaining similar levels of CD8⁺ T cells. This study illustrates the potential for different immunological profiles to be induced by different heterologous vaccination regimens, which may impact long-term outcomes in human populations, such as the waning immunity observed for SARS-CoV-2.