Immune response and immunological MEMORY against SARS-CoV-2: impact of viral variants, vaccination, and protection against reinfection

"Our previous investigations revealed that: - The 4th mRNA vaccine dose qualitatively and quantitatively restores the level of immunity, but does not surpass s the levels reached after the third doses (1, 2). - Hybrid immunity confers advantage on long-term humoral and cellular immunity, but limits the diversification of RBD-specific memory B cells as compared to vaccination-induced immunity, highlighting the immune imprinting - Fc-mediated function and anti-S IgG4 levels are strongly impacted by additional immunization conferred by breakthrough infection or new vaccination. Today, the HAS recommends administering a booster dose of a bivalent vaccine to i) individuals at high risk of developing severe disease (immunosuppressed individuals) and to ii) individuals living in proximity to or in regular contact with immunocompromised or vulnerable individuals, such as healthcare and medico-social professionals. This dose should be administered regardless of the number of previous boosters received. Still, the HAS emphasized on the importance of adhering to the recommended intervals between boosters: 3 months for individuals aged 80 and over and immunocompromised individuals and 6 months for others. For individuals who have already been infected with SARS-CoV-2, the HAS recommends an additional dose, provided there is a minimum interval of 3 months after the infection. Yet, the impact of repeated vaccination and/or immunization on immunity is not really understood. While repeated immunization is thought to improve immune response, data in the context of SARSCoV-2, CMV, and HCoV for example, reported that repeated exposure to viral antigens from vaccination or infection may promote immune tolerance or exhaustion (3-8). Some studies also reported that frequent and repeated vaccination did not negatively impact immune memory parameters (9). Thus, how repeated exposures to SARS-CoV-2 antigens influence immune protection against past, current and future variants deserve further investigation. In this context, the main objective of the ANRS 0154 extension study is to pursue the immunomonitoring of our cohort, to generate an unprecedented longitudinal dataset of the SARSCoV-2 immune memory and determine how it is influenced by the repetition of breakthrough infections and booster vaccinations. We will study how the repetition of immune challenges by viral and/or vaccinal antigens influences antiviral immunity at the individual level. For this we will selected 10 subjects bearing the HLA-A2:01 genotype, who where repeatedly immunized of the course of the pandemic (at least 7 antigen exposures in 36 months, for whom PBMC and sera were collected at least 10 times each). "