Antibody responses to circulating strains provide the greatest protection against SARS-CoV-2 infection

A CITF-supported study, published in Vaccines, suggested that higher antibody levels do not guarantee protection against COVID-19. Levels of antibodies to the original strain are not a reliable indicator to determine the need for or timing of booster dosing. Having received a bivalent vaccine (combining the original and Omicron strains) was associated with lack of a breakthrough infection during the Omicron BA.4/5 waves of the pandemic. Hybrid immunity (vaccine-induced and infection-acquired) was also associated with protection from further infections. The study was led by Dr. Sharon Walmsley (University of Toronto and University Health Network) in collaboration with Dr. Anne-Claude Gingras, Dr. Allison McGeer (both University of Toronto and Sinai Health System), and the STOP-CoV Team.

Key findings:

• Higher antibody levels decreased the risk of breakthrough infections during the Delta and Omicron BA.1/2 waves of infection, but not during the Omicron BA.4/5 wave.
• The older cohort was less likely to have a breakthrough infection at all time points of the study, which potentially could be related to behavioural differences and better adherence to public health recommendations.
• Those who received a bivalent vaccine (combining the original and Omicron strains) and had a SARS-CoV-2 infection had greater protection from a second infection during the later Omicron BA.4/5 and XBB waves.
• This study was unable to determine an antibody threshold level that could protect against infection or be used to guide vaccine booster schedules.

STOPCoV is a decentralized, non-randomized, longitudinal, observational, prospective cohort study initially planned to follow participants for 48 weeks after an initial two-dose COVID-19 vaccine series, with an optional study extension continued as a 96-week follow-up.

This study (n = 1,286) compared antibody responses in an older (≥70 years) cohort with those in a younger cohort (aged 30–50 years). The correlates of breakthrough infection were explored in 983 eligible participants (769 aged 70 or older and 214 aged 30-50 years old). The participants provided self-reported information through an online portal on their initial vaccine series, any subsequent booster doses, and their experiences with COVID-19 infections. They also provided dried blood spots for antibody testing using ELISA. Statistical analysis explored the correlates of breakthrough infection.

For the younger cohort, 0, 1, 2, 3 or 4 booster doses were received by 30 (12%), 81 (33%), 90 (36%), 41 (16.5%) and 6 (2.4%) participants, respectively, over the 96-week study period. The corresponding numbers for the older cohort are 37 (5%), 96 (13%), 143 (19.5%), 377 (51.2%,) and 82 (11%). In total, 318 (32%) had received one bivalent (original/Omicron) booster, including 37 (15%) of the younger and 281 (38%) of the older cohort.

In conclusion, antibody levels based on the ancestral strain cannot be used to determine the need for or timing of booster dosing. Although there was an association between higher antibody levels and a reduced risk of breakthrough infection in the early waves of the pandemic, this decreased with time and with the emergence of SARS-CoV-2 variant strains. There was a strong association between receiving a bivalent original/Omicron vaccine and lack of a breakthrough infection during the Omicron BA.4/5 waves of the pandemic, suggesting that receiving vaccines that match the circulating variants may provide the greatest protection. This supports recommendations on their use in an era of vaccine fatigue. Hybrid immunity was also associated with reduced risk of further infections.