SARS-CoV-2 Vaccine-Induced Antibodies Protect Against Omicron Breakthrough Infection

Abstract

Background: The SARS-CoV-2 Omicron variant quickly spread globally, also in regions with high vaccination coverage. Vaccine-induced immunity protects against severe disease, however, the understanding of immunological requirements for protection against Omicron breakthrough infection is limited.

Methods: A matched case-control study was conducted to characterize Omicron breakthrough infections in triple-vaccinated individuals from the ENFORCE cohort. Omicron spike-specific IgG levels, ACE2-blocking antibody titers, and T cell responses were evaluated in samples collected prior to a positive (case) or negative (control) PCR test. Pre- to post-infection nucleocapsid IgG levels among cases were determined to investigate seroconversion.

Findings: A total of 482 cases with Omicron breakthrough infection were matched with 482 uninfected controls. Omicron spike-specific IgG levels were significantly lower in cases compared to controls (geometric mean ratio [95% CI] for BA.2: 0·83 [0·73–0·95], P=0·006). Multivariable logistic regression showed significant associations between high antibody levels and lower odds of Omicron breakthrough infection (adjusted odds ratio [95% CI] for BA.2 spike-specific IgG: 0·65 [0·48–0·88], P=0·006 and BA.2 ACE2-blocking antibodies: 0·46 [0·30–0·69], P=0·0002). A sex-stratified analysis revealed that these associations were more pronounced for females than males. No significant differences in frequency of spike-specific T cells were observed. Nucleocapsid IgG seroconversion occurred in 96·9% of cases and we found no correlation between vaccine-induced immunity and seroconversion.

Interpretation: High levels of vaccine-induced antibodies provide partial protection against Omicron breakthrough infections. This is important knowledge to further characterize a threshold for protection against new emerging variants and to estimate the necessity and timing of booster vaccination.

Funding: ENFORCE has received a grant from the Danish Ministry of Health (SUM).

Declaration of Interest: NBS declares to have served as an investigator in clinical trials sponsored by Pfizer, Gilead, and Bavarian Nordic. HN declares to have been on advisory boards for GSK and MSD. TB declares receipt of unrestricted grants from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Foundation, Erik and Susanna Olesen’s Charitable Fund, GSK, Pfizer, Gilead Sciences, and MSD; and being advisory board member for GSK, Pfizer, Gilead Sciences, MSD, Janssen, and Astra Zeneca; and being principal investigator on clinical trials conducted by Pfizer, Boehringer Ingelheim, Gilead Sciences, MSD, Roche, Novartis, Kancera AB, Bavarian Nordic, and Janssen; and being board member on Pentabase; and receiving consulting fees from GSK and Pfizer; and receiving honorarium for lectures from GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, Abbvie, Astra Zeneca, and Bavarian Nordic; and receiving donation of trial medication (baricitinib) from Eli Lilly. MT declares to be on a Data Safety Monitoring Board for ImmunoCore clinical trial, testing a bispecific T cell engager in people living with HIV. The remaining authors declare no competing interests.

Ethical Approval: The study involved human participants and the protocol was approved by the Danish Medicines Agency (#2020-006003-42) and the National Committee on Health Research Ethics (#1-10-72-337-20). All participants provided written informed consent.

Keywords: SARS-CoV-2, Omicron, COVID-19, Breakthrough Infection, Antibodies, Vaccination, Seroconversion, Case-Control