Vaccine-induced correlate of protection against fatal COVID-19 in the old and frail during waves of neutralization resistant variants of concern

Background To inform future preventive measures including repeated vaccinations, we have searched for a clinically useful immune correlate of protection against fatal Covid-19 among nursing homes residents. Methods We performed repeated capillary blood sampling with analysis of S-binding IgG in an open cohort study with inclusion of nursing home residents in Sweden. We analyzed immunological and registry data collected from September 2021 with end of follow-up 31 August 2022. The study period included implementation of the 3rd and 4th mRNA monovalent vaccine doses and Omicron virus waves. Findings A total of 3012 nursing home residents with median age 86 were enrolled. The 3rd mRNA dose elicited a 99-fold relative increase of S-binding IgG among 2606 blood-sampled individuals and corresponding increase of neutralizing antibodies. The 4th mRNA vaccine dose boosted the levels 3.8-fold. Half-life of S-binding IgG was 72 days. A total 528 residents acquired their first SARS-CoV-2 infection after the 3rd or the 4th vaccine dose and the 30-day mortality was 9.1%. We found no indication that levels of vaccine-induced antibodies protected against infection with Omicron VOCs. In contrast, the risk of death was inversely correlated to levels of S-directed IgG below the 20th percentile. The risk plateaued at population average above lower 35th percentile of S-binding IgG. Interpretation In the absence of neutralizing antibodies that protection from infection, quantification of S-binding IgG post vaccination may be useful to identify the most vulnerable for fatal Covid-19 among the oldest and frailest. This information is of importance for future strategies to protect vulnerable populations against neutralization resistant variants of concern. Funding Swedish Research Council, SciLife, Knut and Alice Wallenberg Foundation and Vinnova. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project was funded by grants from the Swedish Research Council (2020-06235 to MNEF, 2021-04665 to CA and 2020-05782 to JK), SciLifeLab reseach programs funded by Knut and Alice Wallenberg (VC2021-0018 and VC2022-0008 to MNEF, VC2022-0028 to MNEF and AJ and VC2021-0026 to JK), and Swedish Healthcare Regions (VISARENORR968921, RV-970105 and RV-982630 to AJ). J.N. is a Wallenberg Center for Molecular Medicine Associated Researcher. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Swedish Ethical Review Authority (decisions 2020-01653 and 2021-00055 including amendments 2021-01397, 2021-02328,2021-03937 and 2022-00564-02). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript