Neutralising immunity to omicron sublineages BQ.1.1, XBB, and XBB.1.5 in healthy adults is boosted by bivalent BA.1-containing mRNA vaccination and previous Omicron infection

The global COVID-19 landscape is increasingly complex; emerging new variants rapidly cause waves of infection in people with variably induced immunity. Most individuals now have so-called hybrid immunity from both infection and vaccination. However, sequential infecting variants, induction of immunity, and subsequent waning are interlinked, and immune protection against new variants is unclear. In the UK, the Living with COVID-19 strategy is based on the assumption that high population hybrid immunity will continue to blunt the severity and duration of COVID-19 waves. What happened in Singapore in late 2022 suggests that this might be a fragile assumption. Omicron subvariant XBB caused more than 45 000 cases, including more than 36 000 primary infections, despite vaccination rates of more than 90%; admissions and deaths rose marginally.1Tan CY Chiew CJ Pang D et al.Protective immunity of SARS-CoV-2 infection and vaccines against medically attended symptomatic omicron BA.4, BA.5, and XBB reinfections in Singapore: a national cohort study.Lancet Infect Dis. 2023; (published online March 13.)https://doi.org/10.1016/S1473-3099(23)00060-9Summary Full Text Full Text PDF Scopus (5) Google Scholar, 2Goh AXC Chae S-R Chiew CJ et al.Characteristics of the omicron XBB subvariant wave in Singapore.Lancet. 2023; 401: 1261-1262Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar One study on reinfection cases in Singapore in The Lancet Infectious Diseases reported that hybrid immunity from vaccination and infection with pre-omicron variants did not confer protection against XBB reinfection.1Tan CY Chiew CJ Pang D et al.Protective immunity of SARS-CoV-2 infection and vaccines against medically attended symptomatic omicron BA.4, BA.5, and XBB reinfections in Singapore: a national cohort study.Lancet Infect Dis. 2023; (published online March 13.)https://doi.org/10.1016/S1473-3099(23)00060-9Summary Full Text Full Text PDF Scopus (5) Google Scholar Although it is tempting to assign causation to immune memory,3Boyton RJ Altmann DM Imprinted hybrid immunity against XBB reinfection.Lancet Infect Dis. 2023; (published online March 13.)https//doi/org/10.1016/S1473-3099(23)00138-XSummary Full Text Full Text PDF PubMed Scopus (1) Google Scholar this observation is underpinned by marked population heterogeneity including: differing early infection exposure, waning, or antigenic distance between inducing and re-challenge variants. During the autumn of 2022, both the US Centers for Disease Control and Prevention and the UK's Joint Committee on Vaccination and Immunisation recommended the targeted deployment of bivalent mRNA vaccines containing BA.1 as fourth doses from August 2022.4Gov.UKGoogle ScholarJCVI advises an autumn COVID-19 vaccine booster.https://www.gov.uk/government/news/jcvi-advises-an-autumn-covid-19-vaccine-boosterDate: 2023Date accessed: April 25, 2023Google Scholar After our earlier reports on enhanced neutralising immunity against omicron BA.1 after a third dose of monovalent vaccine,5Wu M Wall EC Carr EJ et al.Three-dose vaccination elicits neutralising antibodies against omicron.Lancet. 2022; 399: 715-717Summary Full Text Full Text PDF PubMed Scopus (52) Google Scholar we hypothesised that a low-level, pre-existing neutralising capacity to omicron subvariants BQ.1.1, XBB, and XBB.1.5 would be enhanced by encounters with the omicron subvariant Spike through bivalent vaccination or infection, or both. We used our live-virus assay to measure neutralising antibody titres before and after fourth doses of bivalent vaccines containing both ancestral and BA.1 subvariants (Pfizer and BioNTech BNT original and and omicron BA.1) in 85 individuals, and mRNA1273.214 (Moderna)4Gov.UKGoogle ScholarJCVI advises an autumn COVID-19 vaccine booster.https://www.gov.uk/government/news/jcvi-advises-an-autumn-covid-19-vaccine-boosterDate: 2023Date accessed: April 25, 2023Google Scholar in 107 individuals (table), enrolled in the University College London Hospital and Francis Crick Institute Legacy study (NCT04750356). The Legacy study was approved by London Camden and Kings Cross Health Research Authority Research and Ethics committee (20/HRA/4717).TableDemographic summary of participants in the Legacy study included the analysis of fourth dose BA.1-containing bivalent vaccine responsesBNT162b2 and BA1 (N=85)mRNA1273.214 (N=107)p valueSexFemale64 (75%)75 (70%)0·48Male21 (25%)31 (29%)..Unknown01 (1%)..Age, years51 (43–56)53 (42–58)0·23Unknown01 (1%)..Anti-N IgG at latest visitNegative9 (11%)17 (16%)0·97Positive41 (48%)79 (74%)..Unknown35 (41%)11 (10%)..Time of serum sample, number of days before dose 45 (2–14)4 (1–13)0·79Time of serum sample, number of days after dose 424 (19–59)19 (15–25)0·0004Data shown as n (%) or median (IQR). The p values were calculated using a Pearson's χ2 test, a Wilcoxon rank sum test, or Fisher's exact test. Open table in a new tab Data shown as n (%) or median (IQR). The p values were calculated using a Pearson's χ2 test, a Wilcoxon rank sum test, or Fisher's exact test. Firstly, we assessed neutralising antibody titres before and 3 weeks after bivalent vaccine dose against variants including BQ.1.1, XBB, and XBB.1.5 (figure A; table). We found that for ancestral and delta variants, as well as omicron BA.1, BA.2, and BA.5, median post-dose neutralising antibody titres were above the quantitative range (2560-fold diluted serum inhibited more than 50% of the viral infection in vitro, McNemar χ2 p=1·25 × 10–8 for ancestral, 1·45 × 10–10 for delta, 2·00 × 10–13 for BA.1, 5·92 × 10–10 for BA.2, and 8·11 × 10–10 for BA.5). Median BQ.1.1, XBB, and XBB.1.5 neutralising antibody titres were increased after bivalent fourth doses (median fold-change 3·6 [95% CI 2·8–5·1] for BQ.1.1, 3·9 [3·2–4·6] for XBB, and 3·0 [2·3–3·5] for XBB.1.5). Unlike other reports,6Yue C Song W Wang L et al.ACE2 binding and antibody evasion in enhanced transmissibility of XBB.1.5.Lancet Infect Dis. 2023; 23: 278-280Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar we found a post-dose difference between median neutralising antibody titres against XBB and XBB.1.5 (figure A), with XBB.1.5 neutralised less effectively than XBB (median fold-reduction 1·69 [1·5–1·85], Wilcoxon signed rank p<2·2 × 10–16). Peak post-fourth dose titres were highest in participants with previous infection exposure (anti-nucleocapsid IgG+ group; figure B; appendix p 1). Before the fourth doses, we found that eight (7%) of 110 individuals in the anti-nucleocapsid IgG positive group had pre-fourth dose titres against XBB.1.5 of less than 40, compared with three (27%) of 11 of IgG negative individuals (Fisher's test p=0·06). We then defined a sub-cohort of participants whose only Spike exposure was through vaccination, and compared them with vaccinated participants whose first infection was an omicron subvariant after three vaccinations. We found fourth antigenic encounters resulted in broadly similar peak neutralising antibody titres against all variants of concern tested (appendix p 2). Finally, we examined whether either bivalent vaccine formulation affected post-fourth dose titres. In anti-N negative individuals, we found similar titres between BNT162b2 and BA.1 combined, and mRNA1273.214 (Wilcoxon all variants tested p>0·05; appendix p 3). Substantial concern was generated by early data in vitro that suggested immune evasion by omicron subvariants XBB, XBB.1.5, and BQ.1.1 (appendix pp 17–21).7Hoffmann M Arora P Nehlmeier I et al.Profound neutralization evasion and augmented host cell entry are hallmarks of the fast-spreading SARS-CoV-2 lineage XBB.1.5.Cell Mol Immunol. 2023; 20: 419-422Crossref PubMed Scopus (6) Google Scholar However, these data are not easily generalised: firstly, they universally use pseudovirus constructs, with variable replication of virion size or spike density, or both; secondly, many use cell lines overexpressing ACE2 that risk underestimating neutralisation;8Pinto D Park Y-J Beltramello M et al.Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody.Nature. 2020; 583: 290-295Crossref PubMed Scopus (1057) Google Scholar and thirdly, the serum samples used reflect local protocols and exposure that might not be widely applicable.6Yue C Song W Wang L et al.ACE2 binding and antibody evasion in enhanced transmissibility of XBB.1.5.Lancet Infect Dis. 2023; 23: 278-280Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar This variability has led to calls for WHO-level assay standardisation.9Knezevic I Mattiuzzo G Page M et al.WHO International Standard for evaluation of the antibody response to COVID-19 vaccines: call for urgent action by the scientific community.Lancet Microbe. 2022; 3: e235-e240Summary Full Text Full Text PDF PubMed Scopus (60) Google Scholar Reassuringly, using a high-throughput live virus assay, we found that bivalent mRNA BA.1-containing vaccines substantially increased cross-reactive neutralising immunity against then yet-to-emerge omicron subvariants, including XBB.1.5, at titres that are compatible with a low risk of systemic illness.10Cromer D Steain M Reynaldi A et al.Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis.Lancet Microbe. 2022; 3: e52-e61Summary Full Text Full Text PDF PubMed Scopus (235) Google Scholar Cross-reactivity was similarly increased by fourth exposures as either infection or vaccination. Our data thus provide a partial explanation for the substantial difference between what happened subsequently in Singapore and the UK with regards to XBB infections, including a substantially smaller-than-expected peak of severe COVID-19 across the UK in the winter of 2022–23. The joint policy of targeted bivalent vaccination and early access to antivirals for at-risk individuals provided complementary protection to the widespread hybrid population immunity after earlier BA.1, BA.2, and BA.5 waves, and underpinned the living with COVID-19 strategy. All authors declare they have no competing interests. All data (anonymised) and full R code to produce all figures and statistical analysis presented in this Correspondence are available online on Github: https://github.com/davidlvb/Crick-UCLH-Legacy-XBB-2023-03. This study was sponsored by University College London Hospitals. This study was undertaken at University College London Hospitals and University College London, which received a proportion of funding from the National Institute for Health Research University College London Hospitals Biomedical Research Centre and Clinical Research Facility. ECW, VL, and BW are supported by the Biomedical Research Centre funding scheme. This study was supported jointly by the Biomedical Research Centre and core funding from the Francis Crick Institute, which receives its funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust. DLVB and RB are additionally supported by the Genotype-to-Phenotype (G2P) National Virology Consortium via UK Research and Innovation and the UK Medical Research Council. The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding authors had full access to all the data and the final responsibility to submit for publication. Download .pdf (2.6 MB) Help with pdf files Supplementary appendix Protective immunity of SARS-CoV-2 infection and vaccines against medically attended symptomatic omicron BA.4, BA.5, and XBB reinfections in Singapore: a national cohort studyProtection against XBB reinfection conferred by a previous omicron infection with vaccination was lower and waned faster than protection against BA.4 or BA.5 reinfection, which is indicative of the greater immune evasiveness of the XBB sublineage. Although severe COVID-19 is uncommon, populations remain vulnerable to future reinfection waves from emerging SARS-CoV-2 variants despite high rates of vaccination and infection, as reflected by substantially higher reinfection rates during Singapore's XBB wave than during the previous BA.5-driven wave. Full-Text PDF