Comparison of Omicron breakthrough infection versus monovalent SARS-CoV-2 intramuscular booster reveals differences in mucosal and systemic humoral immunity

Vaccine protection declines over time, necessitating seasonal boosters administered for influenza and now for SARS-CoV-2 as well. In this study, the aim was to assess how immune responses to SARS-CoV-2 are modulated by booster vaccination compared to breakthrough infection. From late 2021 to early 2022, the emergence of the Omicron variant and subsequent breakthrough infections coincided with booster rollout in the provinces of Ontario and Quebec, making this an opportunity to compare exposure routes. Immune responses were compared in two adult cohorts. Participants from the RECOVER cohort were infected by SARS-CoV-2 at the beginning of the pandemic – before getting vaccinated, while participants from the CoVaRR-Net cohort had never been infected prior to vaccination. The main objective was to understand the differences in immunity following different exposure events among these four groups (RECOVER with booster dose versus RECOVER with breakthrough and CoVaRR-Net with booster dose versus CoVaRR-Net with breakthrough). Humoral immune responses (antibodies) against SARS-CoV-2 were measured in the blood and saliva. The function of white blood cells (more specifically, T cells) was also assessed in the blood by measuring a by-product of activated T-cells (interferon-gamma).

Our results show that Omicron breakthrough infection :

1. Triggered stronger and more broadly effective antibody responses in the blood than vaccination alone in people who had not been infected before.
2. Boosted T-cell responses, even in those who had been infected with SARS-CoV-2 before vaccine rollout.
3. Caused an increase in the levels of salivary antibodies that recognize SARS-CoV-2, variants of SARS-CoV-2 and SARS-CoV-1, a distinct Betacoronavirus.

Taken together, these results indicate that there is an added degree of cross-reactivity in antibodies from those who experienced an Omicron breakthrough infection. This increased cross-reactivity allows for the recognition of a distinct Betacoronavirus and suggests that hybrid immunity induces more robust and broader antibody production. Therefore, it may be particularly advantageous to consider multiple routes of antigen exposure as a vaccine strategy to support robust immune responses to evolving SARS-CoV-2 variants and other similar pathogenic threats. Indeed, this study highlights the potential advantages of mucosal SARS-CoV-2 vaccines that would be administered through the mucosal surfaces of the mouth and nasal cavity (which are the first sites of encounter with the virus). This strategy may be able to mimic the benefits of viral exposure without exposing individuals to the risks associated with SARS-CoV-2 infection.

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