SARS-CoV-2 vaccine(The Scientific and Technological Research Council of Turkey)

Understanding humoral and T cell responses to SARS-CoV-2 immunisations is important for informing seasonal COVID-19 vaccine recommendations in the elderly. Existing protection against emerging strains may vary based on vaccination and infection history. Using a longitudinal cohort of healthy seniors (65-80 years), we investigated the magnitude and quality of T cell and antibody responses after multiple SARS-CoV-2 vaccine doses and repeated infections.

Samples were collected at six consecutive time points from Dec 2020 to May 2024, covering up to six doses of mRNA vaccines. Vaccination and infection records were retrieved from national health registries and questionnaires. Frequency and polyfunctionality of T cell responses and neutralising antibodies (NAbs) to the B.1 strain and several Omicron variants were determined, as well as anti-spike, -nucleocapsid, and -membrane protein IgG levels.

After three vaccine doses, the quantity and quality of CD4 and CD8 spike-specific T cell responses remained stable throughout the study period spanning 2.5 years and up to three additional booster doses. About 60% of participants reported at least one infection over this time period. Samples from early 2022 showed cross-reactivity to emerging Omicron variants (XBB.1.5/BA.2.86) and CD4 T cell responses strongly correlated between newer SARS-CoV-2 strains and B.1. By contrast, NAb titres against B.1 remained high but were reduced against newer variants. Spike IgG levels plateaued over time while membrane protein IgG levels revealed unreported infections.

The quality and quantity of spike-specific T cell responses were maintained over several years and three doses of the original B.1 vaccine generated good T cell cross-reactivity against future strains. This suggests that overall, healthy older adults have robust cellular protection against severe COVID-19. NAbs were more strain-specific with reduced neutralisation of newer variants, consistent with immune imprinting and antigenic drift, suggesting that updated vaccines may be necessary for vulnerable individuals.

Despite currently available commercial COVID-19 vaccines, a COVID-19 vaccine that can offer greater and broader protection with minimal side effects is needed. The parainfluenza virus 5 (PIV5)-vectored intranasal COVID-19 vaccine (CVXGA) expressing the spike (S) protein is a promising next generation COVID-19 vaccine that has been shown to be safe and efficacious in Phase 1 and 2a clinical studies. Here, we conducted the preclinical studies to evaluate the immunogenicity and efficacy of CVXGA50, an updated PIV5-vectored COVID-19 vaccine expressing the S protein of the Omicron KP.2 variant. In contrast to the PIV5-based CVXGA1 COVID vaccine expressing the WA1 S protein, which induced high levels of IgG and neutralizing antibodies (nAb) in mice, CVXGA50 elicited lower levels of serum S-specific IgG and undetectable nAb in naïve and pre-immune mouse models. However, a robust cellular immune response was detected in CVXGA50 immunized mouse models. Despite the poor serum antibody responses, CVXGA50 completely protected against homologous KP.2 challenge virus replication in the lungs of K18-hACE2 mice, as well as heterologous WA1 lethal challenge, suggesting that the nAb response is not the major protective mechanism for CVXGA50 intranasal vaccine. KP.2 mRNA vaccine elicited a high level of serum S-specific IgG and nAb response, but it was not superior to CVXGA50 in preventing challenge virus replication. In contrast to the mouse model, CVXGA50 elicited high levels of serum S-IgG and nAb in naïve and pre-immune hamsters and offered complete protection against KP.2 challenge, reflecting species-specific antibody responses. One Sentence Summary: PIV5-vectored SARS-CoV-2 KP.2 intranasal vaccine protects against homologous and heterologous challenge in the mouse and hamster animal models even though it did not generate a robust serum antibody response in the mouse models.