Early Omicron infection is associated with increased reinfection risk in older adults in long-term care and retirement facilities

Abstract

Background: Older adults are at increased risk of SARS-CoV-2 Omicron infection and severe disease, especially those in congregate living settings, despite high SARS-CoV-2 vaccine coverage. It is unclear whether hybrid immunity (combined vaccination and infection) after one Omicron infection provides increased protection against subsequent Omicron reinfection in older adults.

Methods: Incidence of SARS-CoV-2 Omicron infection was examined in 750 vaccinated residents of long-term care and retirement homes in the observational cohort COVID in Long-Term Care Study in Ontario, Canada, within a 75-day period (July to September 2022). Risk of infection was assessed by Cox proportional hazards regression. Serum anti-spike and anti-RBD SARS-CoV-2 IgG and IgA antibodies, microneutralization titres, and spike-specific T cell memory responses, were examined in a subset of 318 residents within the preceding three months.

Findings: 133 of 750 participants (17.7%) had a PCR-confirmed Omicron infection during the observation period. Increased infection risk was associated with prior Omicron infection (at 9-29 days: 47.67 [23.73-95.76]), and this was not attributed to days since fourth vaccination (1.00 [1.00-1.01]) or residence outbreaks (>6 compared to ≤6: 0.95 [0.37-2.41]). Instead, reinfected participants had lower serum neutralizing antibodies to ancestral and Omicron BA.1 SARS-CoV-2, and lower anti-RBD IgG and IgA antibodies, after their initial Omicron infection.

Interpretation: Counterintuitively, SARS-CoV-2 Omicron infection was associated with increased risk of Omicron reinfection in residents of long-term care and retirement homes. Less robust humoral hybrid immune responses in older adults may contribute to risk of Omicron reinfection.

Funding: COVID-19 Immunity Task Force of the Public Health Agency of Canada.

Keywords: COVID-19; Hybrid immunity; Older adults; Omicron; SARS-CoV-2.

Fig. 1

SARS-CoV-2 Omicron infection incidence and risk. In Panel A, time to SARS-CoV-2 Omicron infection from July 1 through September 13, 2022, was estimated in individuals with one prior Omicron infection (i.e., between December 15, 2021 and June 30, 2022, with no pre-Omicron infections), one pre-Omicron infection (i.e., infection prior to December 15, 2021), multiple prior infections (i.e., prior to and/or between December 15, 2021 and July 1, 2022), and no prior infections (i.e., no infections between March 2020 and June 30, 2022), by means of the Kaplan–Meier method. Statistical significance between the curves was determined by log-rank test. Shading around the mean line indicates the 95% confidence interval. The dotted horizontal-vertical line indicates 50% cumulative incidence. In Panel B, the Cox proportional-hazards regression model was used to estimate hazard ratios of Omicron infection between July 1 and September 13, 2022, with the baseline hazard on July 1, 2022. Variables (age, sex, previous infection, mRNA vaccine combination, residence type, number of outbreaks, clinical frailty scale, time since fourth vaccination) reflect characteristics at baseline, with adjustments for study site. The hazard ratios are presented with 95% confidence intervals based on robust standard errors.

Fig. 2

Overview of the study cohort. An overview of the study cohort by participant infection history and blood collections is shown in Panel A by flow chart and Panel B as a timeline.

Fig. 3

Serum antibody levels in residents of long-term care and retirement facilities in context of hybrid immunity. Ancestral anti-spike and anti-RBD (receptor binding domain) IgG and IgA antibody levels were measured by ELISA in serum samples collected within three months prior to the start of the observation period (i.e., collected between April 1 and June 30 before the July 1 to September 13, 2022 observation period). Panel A shows data according to Omicron infection history prior to July 1, 2022. Panel B stratifies data by Omicron infection outcome between July 1 and September 13 in individuals with no prior Omicron infection from panel A. Panel C stratifies data by Omicron reinfection outcome between July 1 and September 13 in individuals with prior Omicron infection from panel A. Each data point indicates an individual participant. Data are presented as box and whisker plots, minimum to maximum, with the center line at the median. Dotted lines indicate cutoff thresholds. Statistical significance was assessed by Mann–Whitney U test. All P-values are shown.

Fig. 4

Serum anti-SARS-CoV-2 microneutralization titres in residents of long-term care and retirement facilities in context of hybrid immunity. Microneutralization titres (MNT₅₀) of ancestral and Omicron BA.1 anti-SARS-CoV-2 antibodies in serum samples collected within three months prior to the start of the observation period (i.e., collected between April 1 and June 30 before the July 1 to September 13, 2022 observation period). Panel A shows data according to Omicron infection history prior to July 1, 2022. Panel B stratifies data by Omicron infection outcome between July 1 and September 13 in individuals with no prior Omicron infection from panel A. Panel C stratifies data by Omicron reinfection outcome between July 1 and September 13 in individuals with prior Omicron infection from panel A. Dotted lines indicate cutoff thresholds. Each data point indicates an individual participant. Data are presented on a log2 scale as box and whisker plots, minimum to maximum, with the center line at the median. Dotted lines indicate cutoff thresholds. Statistical significance was assessed by Mann–Whitney U test. All P-values are shown.

Fig. 5

Memory T cell recall responses to SARS-CoV-2 spike protein in residents of long-term care and retirement facilities in context of hybrid immunity. Memory T cell recall responses to SARS-CoV-2 complete ancestral spike protein, immunodominant regions of ancestral spike protein (ancestral-ID), and complete Omicron BA.1 spike protein in whole blood were assessed by an Activation-Induced Marker (AIM) flow cytometry assay within three months prior to the observation period (i.e., collected between April 1 and June 30 before the July 1 to September 13, 2022 observation period). Panel A shows data according to Omicron infection history prior to July 1, 2022. Panel B stratifies data by Omicron infection outcome between July 1 and September 13 in individuals with no prior Omicron infection from panel A. Panel C stratifies data by Omicron reinfection outcome between July 1 and September 13 in individuals with prior Omicron infection from panel A. Data are plotted on a log10 scale. Each data point indicates an individual participant. Data are presented as box and whisker plots, minimum to maximum, with the center line at the median. Statistical significance was assessed by Mann–Whitney U test. All P-values are shown.

Fig. 6

Humoral responses to SARS-CoV-2 vaccination and Omicron infections. In Panel A, post-vaccination neutralizing antibodies against ancestral SARS-CoV-2 were measured after two and three mRNA vaccine doses and prior to future Omicron BA.1/2 and BA.5 infection outcomes. Humoral responses were examined in Panels B to D in serum samples collected after the observation period baseline and Omicron BA.5 infections. Ancestral anti-spike and anti-RBD (receptor binding domain) IgG and IgA antibody levels were measured by ELISA. Neutralizing antibodies against ancestral and Omicron BA.1 anti-SARS-CoV-2 were assessed by microneutralization assays (MNT₅₀). Each data point indicates an individual participant. Data are presented as box and whisker plots, minimum to maximum, with the center line at the median. Data in Panels A and B are presented on a log2 scale. Dotted lines indicate cutoff thresholds. Statistical significance was assessed by Kruskal–Wallis test with Dunn's multiple comparisons test. P values are only shown for post-hoc comparisons of statistical significance.