Omicron breakthrough infection instills higher and more broadly neutralizing immune responses against SARS-CoV-2 variants than a booster dose alone

A CITF-funded study, published in Mucosal Immunology, found that the breadth and magnitude of T-cell responses were comparable whether individuals with two vaccine doses had a third vaccine dose or an Omicron breakthrough infection. Those with two vaccine doses and an Omicron breakthrough infection produced higher salivary SARS-CoV-2 IgA antibodies against spike and RBD than individuals with three vaccine doses and no breakthrough infection. SARS-CoV-2 IgA antibodies produced after a breakthrough infection also cross-reacted with other variants, including the ancestral SARS-CoV-2 strain and even SARS-CoV-1. This study was led by Dr. Jennifer Gommerman (University of Toronto) in collaboration with other CITF-funded researchers: Dr. Allison McGeer (Sinai Health), Dr. Mario Ostrowski (University of Toronto), Dr. Mark Brockman (Simon Fraser University), Dr. Ciriaco Piccirillo (McGill University), Dr. Caroline Quach (University of Montréal), Dr. Anne-Claude Gingras (University of Toronto), and Dr. Hélène Decaluwe (University of Montréal).

The study’s goal was to compare the immune responses of individuals who had two intramuscular vaccine doses of a Health Canada-approved mRNA vaccine followed by an Omicron breakthrough (BT) infection to individuals with three doses of vaccine (without an Omicron BT infection). Two cohorts of participants were recruited to this study. One cohort included people who had at least two vaccine doses and either did or did not have an Omicron breakthrough infection. The second cohort was formed of health care workers who had experienced an ancestral strain SARS-CoV-2 infection before the advent of vaccines. Those who then received two doses of vaccine and had an Omicron breakthrough infection, as well as those who received a third vaccine without a breakthrough infection were included in the analysis. This study assessed the cellular (T-cell) and humoral (antibody) immune responses following a subsequent Omicron BT infection or a third vaccine dose in both cohorts.

Key findings:

• Previously infection-naïve individuals who were vaccinated with two doses and then experienced an Omicron BT infection had higher and broader neutralizing antibodies to SARS-CoV-2 spike and receptor-binding domain (RBD) than those who received two or three vaccine doses only (and had no infection).
• Individuals who had a SARS-CoV-2 infection before vaccination, then received two doses of vaccine followed by an Omicron BT infection had higher IgG and IgA antibody levels than individuals with two vaccine doses. However, their IgG and IgA antibody levels were comparable to individuals with three vaccine doses and no breakthrough infection.
• In both groups of individuals (individuals who had a previous infection and those without a previous infection), individuals with two vaccine doses who had an Omicron BT infection had comparable cellular T-cell immune responses to those with three vaccine doses.
• Individuals with two vaccine doses and an Omicron BT infection produced higher salivary SARS-CoV-2 IgA antibodies against Spike and RBD than individuals with three doses of vaccine and no BT infection. These salivary SARS-CoV-2 IgA antibodies produced following BT infection also cross-reacted with other variants, including the ancestral SARS-CoV-2 strain and even SARS-CoV-1.

This study highlights the importance of continued booster vaccinations in those with and without previous SARS-CoV-2 infection. The findings suggest that intranasal vaccination, which would mimic mucosal exposure to induce neutralising antibodies in the upper respiratory tract, could be valuable in enhancing and broadening long-lasting immunity to SARS-CoV-2 and its variants.

Participant samples were obtained in 2020 by the CITF-funded study REInfection in COVID-19 Estimation of Risk (RECOVER) and the CoVaRR-Net Biobank (Coronavirus Variants Rapid Response Network). Participants who had an Omicron BT infection had samples collected between December 2021 to January 2022.

In the RECOVER cohort, healthcare workers infected with the ancestral SARS-CoV-2 strain prior to vaccination were recruited through five university hospitals and vaccination centres in the Greater Montreal Area in Quebec following their positive PCR result for SARS-CoV-2 infection. From the CoVaRR-Net Biobank, healthy adults from the Greater Toronto Area in Ontario who had not experienced COVID-19 infection prior to vaccination were recruited and provided blood and saliva samples at the University of Toronto and Unity Health.