key: cord-1003941-snrlpyu0 authors: Vivaldi, G.; Jolliffe, D. A.; Faustini, S.; Holt, H.; Perdek, N.; Talaei, M.; Tydeman, F.; Chambers, E. S.; Cai, W.; Li, W.; Gibbons, J. M.; Pade, C.; McKnight, A.; Shaheen, S. O.; Richter, A. G.; Martineau, A. R. title: Correlation between post-vaccination titres of combined IgG, IgA, and IgM anti-Spike antibodies and protection against breakthrough SARS-CoV-2 infection: a population-based longitudinal study (COVIDENCE UK) date: 2022-02-13 journal: nan DOI: 10.1101/2022.02.11.22270667 sha: 34c3ceeee201a3c33a02574580b6258b5662cd23 doc_id: 1003941 cord_uid: snrlpyu0 In this population-based cohort of 7530 adults, combined IgG/A/M anti-Spike titres measured after SARS-CoV-2 vaccination were predictive of protection against breakthrough SARS-CoV-2 infection. Discrimination was significantly improved by adjustment for factors influencing risk of SARS-CoV-2 exposure including household overcrowding, public transport use, and visits to indoor public places. Identifying a robust correlate of vaccine-induced protection against SARS-CoV-2 could provide insights into mechanisms of protective immune responses and accelerate licensure for candidate SARS-CoV-2 vaccines. 1 Here, we explore the predictive strength of a new marker-combined IgG, IgA, and IgM responses to the SARS-CoV-2 trimeric spike glycoprotein (anti-Spike IgG/A/M)-which can be assayed in dried blood spots at low cost. We hypothesised that anti-Spike IgG/A/M titres would correlate positively with authentic virus neutralising antibody titres, and that higher titres would therefore associate with reduced risk of breakthrough infection in vaccinated individuals. COVIDENCE UK is a prospective, longitudinal, population-based observational study of COVID-19 in the UK general population, launched on May 1, 2020 (https://www.qmul.ac.uk/covidence). Inclusion criteria were age 16 years or older and UK residence at enrolment, with no exclusion criteria. Participants were asked to complete an online baseline questionnaire and monthly follow-up questionnaires to capture information on SARS-CoV-2 vaccine status, incident SARS-CoV-2 infection, and a wide range of potential determinants of vaccine response and SARS-CoV-2 exposure. Further details on . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint After enrolment into COVIDENCE UK, participants were invited to take part in a postvaccination antibody study. The additional inclusion criterion for this study was having received a full primary course of SARS-CoV-2 vaccination (ie, two vaccine doses, or one dose of a onedose regimen). Fully vaccinated participants were sent a kit containing instructions, lancets, and blood spot collection cards, which were returned to the study team and analysed at the Clinical Immunology Service, Institute of Immunology and Immunotherapy of the University of Birmingham (Birmingham, UK). Semi-quantitative determination of antibody titres in dried blood spot eluates was done using a commercially available ELISA that detects anti-Spike is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 13, 2022. ; https://doi.org/10.1101/2022.02.11.22270667 doi: medRxiv preprint public transport, or to or from other households). Finally, we compared the area under the ROC curve between the minimally and fully adjusted models using Stata's roccomp command. Statistical analyses were done using Stata/MP (version 17.0) and GraphPad Prism (version 9.1.2). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 13, 2022. ; https://doi.org/10.1101/2022.02.11.22270667 doi: medRxiv preprint significantly so among BNT162b2 recipients (figure C). Adjustment for factors influencing SARS-CoV-2 exposure significantly improved discrimination of the models overall (p<0.0001) and by vaccine type (ChAdOx1: p<0.0001; BNT162b1: p=0.0012; figure C). In this analysis of a large population-based study, we show a strong correlation between anti-Spike IgG/A/M and neutralising antibody titres, and a far weaker correlation between anti-Spike IgG/A/M titres and S peptide-stimulated whole blood IFN-γ responses. Anti-Spike IgG/A/M titres were modestly predictive of breakthrough SARS-CoV-2 infection in the first 6-7 months after full vaccination, with discrimination significantly improved by including key exposure variables, such as sharing a home with schoolchildren or working-age adults. Previous studies have shown strong correlations between post-vaccination antibody titres and vaccine efficacy, 2,5 and some have estimated anti-Spike IgG thresholds of protection for different vaccines. 4, 5, 11 However, these thresholds can differ by the mechanism generating the antibodies, 11 and may be less accurate for mild or asymptomatic infections. 4 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 13, 2022. ; https://doi.org/10.1101/2022.02.11.22270667 doi: medRxiv preprint interactions with other households. Finally, we used a sensitive CE-marked, validated assay that extends beyond IgG and captures combined antibody responses. A limitation of our study is that our findings are limited to recipients of ChAdOx1 and BNT162b2 vaccines, although these are two of the most widely administered vaccines and operate via different mechanisms. We also lacked statistical power in our analysis of breakthrough and HH contributed to data management. GV did the statistical analysis, with input from ARM. GV and ARM wrote the first draft of the report. All authors revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. ARM had final responsibility for the decision to submit for publication. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 13, 2022. A correlate of protection for SARS-CoV-2 vaccines is urgently needed Evidence for antibody as a protective correlate for COVID-19 vaccines Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK) Determinants of pre-vaccination antibody responses to SARS-CoV-2: a population-based longitudinal study (COVIDENCE UK). medRxiv 2022 It is made available under a perpetuity.is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted February 13, 2022.