Estimating population immunity to SARS-CoV-2 by random sampling from primary and secondary healthcare in Scotland,...

As the COVID-19 pandemic has ended, the global focus has shifted from "pandemic response" to "long-term management". With no ongoing nationwide serosurveillance studies, our understanding of the level of immunity in the general population has diminished. In this study, we screened random samples from a biorepository serving the largest health board in Scotland for antibodies against SARS-CoV-2 to define the current immunological landscape, informing vaccine strategies going forward.

997 pseudonymized serum samples were obtained from NHS Greater Glasgow and Clyde (NHS GGC) biorepository in May 2024, along with associated data for age, sex, and COVID-19 vaccine history. Samples spanned ages from 19 to 98 years, with 59.0% female and 41.0% male, and 39.1% from primary healthcare (GP practices) and 61.0% from secondary healthcare (hospitals). Anti-SARS-CoV-2 receptor binding domain (RBD)-specific antibodies were measured by enzyme-linked immunosorbent assay (ELISA), while neutralising antibodies were quantified using HIV(SARS-CoV-2) pseudotype-based virus neutralisation assay (PVNA). ELISAs measured both total IgG and IgG4-mediated responses. Pseudotypes were prepared bearing spike proteins from vaccine antigens B.1 and XBB.1.5, contemporaneous circulating variants KP.3.1.1 and LB.1, and the emerging variant XEC. Samples were grouped by number of COVID-19 vaccine doses received (from no vaccination to ≥8 doses) and 12 samples from each group were screened by ELISA and PVNA.

The random selection of 1000 samples provided a broad cross-section of the population derived from patients with a range of individual vaccine histories, from those having received no COVID-19 vaccines to those having received 8 or more doses. The number of doses received increased with age, from a mean age of ∼40 for those having received one dose to a mean age of 77-78 for those having received 7 or 8 doses. While total IgG responses were similar across each of the groups, irrespective of vaccine history, repeated exposure to mRNA-based vaccines elicited an increase in SARS-CoV-2-specific IgG4. Neutralising antibody titres against the vaccine antigens B.1 and XBB.1.5 increased with age, reaching maximum geometric mean titres of 5610 (95% CI, 2773-11,349) for B.1 and 4577 (1832-11,440) for XBB.1.5 in those receiving 8 doses. In all groups, titres measured against the KP.3.1.1, LB.1 and XEC were significantly lower, consistent with the emergence of immune evasive variants over time. Cross-neutralisation of KP.3.1.1 was limited to maxima of 145 (62.2-336) and 187 (83.8-418) in the 7 and 8 dose groups, while titres against XEC were 105 (47-233) and 90.9 (48.1-172) respectively.

In the absence of systematic COVID-19 serosurveillance, random sampling of sera from biorepositories associated with major health boards can generate valuable data about the level of immunity in the general population, informing estimates of vaccine effectiveness and antigen selection.

United Kingdom Medical Research Council and Genotype-to-Phenotype National Virology Consortium.