Omicron BA.2.86 cross- neutralising activity in community sera from the UK

WHO recommends that SARS-CoV-2 vaccine antigens should target circulating variants.1WHOStatement on the antigen composition of COVID-19 vaccines.https://www.who.int/news/item/18-05-2023-statement-on-the-antigen-composition-of-covid-19-vaccinesDate: May, 2023Date accessed: September 19, 2023Google Scholar The emergent Omicron BA.2.86 variant displays 61 amino acid mutations relative to the ancestral B.1 lineage used in first-generation vaccines.2jbloomlabNew 2nd generation BA2 variant.https://github.com/jbloomlab/new_2nd_gen_BA2_variant/blob/main/spike_aa_muts_relative_to_Wuhan-Hu-1.csvDate: August, 2023Date accessed: September 19, 2023Google Scholar Many of these mutations are predicted to affect neutralisation;3Yang S Yu Y Jian F et al.Antigenicity and infectivity characterisation of SARS-CoV-2 BA.2.86.Lancet Infect Dis. 2023; 23: e457-e459Summary Full Text Full Text PDF Scopus (0) Google Scholar hence, there is an urgent need for data on existing cross-protective immunity in the general population, as well as vaccine effectiveness of available XBB.1.5-based vaccines. We screened sera derived from a UK single-centre cohort of healthy vaccinated individuals from the DOVE study (appendix pp 1–2);4Davis C Logan N Tyson G et al.Reduced neutralisation of the delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination.PLoS Path. 2021; 17e1010022Crossref Scopus (86) Google Scholar participants were a median age of 52 years (range 29–66) and, of the 36 participants, 20 (56%) were female and 16 (44%) were male. Participants received four doses of vaccine: two doses of ChAdOx1 (AstraZeneca), or BNT162b2 (Pfizer–BioNTech), or mRNA-1273 (Moderna) in early 2021, followed by a booster dose of BNT162b2 or mRNA-1273 in late 2021. A second booster (bivalent Comirnaty [Pfizer] or Spikevax [Moderna] B.1 plus BA.1) was administered in late 2022. Samples were collected approximately 1 month before the first booster and 9 months after the second booster to assess current levels of immunity before the autumn and winter 2023 vaccine campaign. After the first booster, sera displayed high neutralising activity against the vaccine antigen (B.1; figure A). Relative to B.1, cross-neutralisation of BA.1, BQ.1.1, and XBB.1.16 was reduced by 6·1-fold, 10·3-fold, and 30·9-fold, respectively (figure A). Sera after the first booster also neutralised XBB.1.5 and BA.2.86 but reduced by 19·3-fold and 18·1-fold, respectively, relative to B.1 (figure A). After the second booster, sera displayed enhanced cross-neutralisation of all variants relative to B.1 (when compared with sera obtained following the first booster; figure B). The bivalent booster (B.1 plus BA.1) elicited good neutralising activity against BA.1 (1·7-fold reduction relative to B.1), and cross-neutralised BQ.1.1 (4·5-fold), and XBB.1.16 (10·2-fold; figure B). Crucially, sera collected 9 months after the second booster displayed enhanced cross-neutralising activity against both XBB.1.5 and BA.2.86; reductions of 4.7-fold and 9.4-fold, respectively, relative to B.1. Neutralising activity against B.1 and BA.1 after the first booster (figure C) and the second booster (figure D) highlighted enhanced neutralising activity against BA.1 (Spearman's r=0·8374). Neutralisation against XBB.1.5 and BA.2.86 after the first booster (figure E) and the second booster (figure F) revealed a modest relationship between XBB.1.5 and BA.2.86 neutralisation, suggesting that a strong XBB.1.5 response will cross-protect against BA.2.86. However, some participants were noted to have low neutralisation against XBB.1.16 (ten [28%] of 36), BA.2.86 (16 [44%] of 36), and XBB.1.5 (five [14%] of 36). 25 of 36 study participants reported positive lateral flow tests during the BQ.1.1 (n=21) and XBB.1.5 (n=4) waves. If this cohort of healthy individuals is representative of the broader community where hybrid immunity dominates, then existing, modest neutralising activity against XBB.1.5 and related variants will offer cross-neutralising activity against BA.2.86. Further, we can expect that XBB.1.5-based vaccines should trigger the expansion of existing B cells that will enhance cross-protection against BA.2.86 and its descendants. BJW, NL, SS, CD, PA, MJH, JG, AH, DLR, and ECT conceptualised the study. ECT and BJW designed the study. TM and JH oversaw patient recruitment. CD and PA prepared the samples. NL and SS oversaw data collection. PO was the project administrator. BJW oversaw data analysis. BJW and ECT wrote the original draft of the manuscript. BJW, MJH, JG, AH, DLR, and ECT wrote, reviewed, and edited subsequent drafts. All authors had full access to the data in the study and had final responsibility for the decision to submit for publication. We declare no competing interests. AH has received unrelated grant funding from UKRI, Wellcome Trust, MRC, BSAC, and MRF. ECT, JG and RO have received grant income from UKRI/MRC. Data can be made available upon reasonable request to the corresponding author. The study was funded by the MRC CVR Preparedness platform (MC_UU_00034/6). Download .pdf (.2 MB) Help with pdf files Supplementary appendix