Reduced risk of SARS-CoV-2 infection among household contacts with recent vaccination and past COVID-19 infection: results from two multi-site case-ascertained household transmission studies

Background COVID-19 vaccines reduce the risk of severe disease, but it is less clear what effect vaccines have on reducing the risk of infection in high contact settings like households, alone or in combination with prior infection. Methods Households with an individual who tested positive for SARS-CoV-2 during Sep 2021–May 2023 were screened nationwide and at 7 sentinel sites and enrolled if the index case’s illness onset was ≤6 days prior. Household members had daily self-collected nasal swabs tested by RT-PCR for SARS-CoV-2. COVID-19 vaccination status was assessed by plausible self-report (with date) or vaccination records. Prior infection was assessed by self-reported prior testing and by anti-nucleocapsid antibodies presence at enrollment. The effects of prior immunity, including vaccination, prior infection, or hybrid immunity (both vaccination and prior infection) on SARS-CoV-2 infection risk among household contacts were assessed by robust, clustered multivariable Poisson regression. Findings There were 1,532 contacts from 905 households included in this analysis. Of these, 67% were enrolled May–November 2022, when Omicron BA.4/5 predominated. Most contacts (89%) had some immunity to SARS-CoV-2 at the time of household exposure: 8% had immunity from prior infection alone, 51% from vaccination alone, and 29% had hybrid immunity. Sixty percent of contacts tested SARS-CoV-2-positive during follow-up. The risk of SARS-CoV-2 infection was not significantly reduced by vaccination but was reduced among those with prior infection considering such immunity separately (adjusted relative risk 0.83; 95% confidence interval: 0.77, 0.90); however, when accounting for both sources of immunity, only contacts with vaccination and prior infection had significantly reduced risk of infection (aRR: 0.81, 95% CI: 0.70, 0.93). The risk of infection was lower when the last immunizing event (vaccination or infection) occurred ≤6 months before COVID-19 affected the household (aRR: 0.69, 95% CI: 0.57, 0.83). Interpretation Immunity from COVID-19 vaccination and prior infection was synergistic in protecting household contacts from SARS-CoV-2 infection. These data support COVID-19 vaccination, even for those who have been previously infected. Evidence before this study We searched PubMed using the terms (“hybrid immunity” or “natural immunity”) AND (“SARS-CoV-2” or COVID*) in October of 2023 to identify previous research into the role of hybrid immunity (defined as immunity from prior infection and vaccination) in susceptibility to SARS-CoV-2 infections. We reviewed 512 articles for estimates of the association between hybrid immunity and susceptibility to illness, infection, or reinfection in humans. Multiple previous meta-analyses were identified, including a meta-regression from 2023 finding that hybrid immunity was associated with 61% reduction in risk of infection compared to immune-naïve individuals 6 months after the immunizing event. The estimates included in this meta-regression were all published before June of 2022, prior to the widespread circulation of Omicron BA.4, BA.5, or recombinant lineages, and none reported on the risk of infection in a setting of household exposures. Added value of the study In a pair of multi-site case-ascertained household transmission investigations with the majority of enrollments occurring during the Omicron BA4/5 predominant periods, the risk of infection among household contacts of a person with SARS-CoV-2 infection was high. In a study design with systematic, daily testing of household contacts regardless of symptoms, serological verification of prior infection, and vaccine verification, the primary result of analyses of infection risk among household contacts was that this risk was lowest among those with hybrid immunity. The estimate of the magnitude of this protection was lower than in previous reports of protection in other settings. Implications of all the available evidence The risk of SARS-CoV-2 infection among household contacts was lowest among those with hybrid immunity, compared to those with no previous immunity, vaccination alone, or previous infection alone. These findings underscore the importance of staying updated with COVID-19 vaccinations, even for individuals with prior infection. ### Competing Interest Statement HQM, JGP, and EAB receive research support from CSL Seqirus unrelated to this work. CGG reports grants from Campbell Alliance/Syneos, the National Institutes of Health, the Food and Drug Administration, the Agency for Health Care Research and Quality and Sanofi-Pasteur, and consultation fees from Merck. ### Funding Statement These research studies were supported the Centers for Disease Control and Prevention (CDC) by contracts 75D30121C11656 (jointly funded by CDC and the US Food and Drug Administration, awarded to Vanderbilt University Medical Center) and 75D30121C11571 (awarded to Westat). ### 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: Study activities were reviewed and approved by Vanderbilt University and sites participating (with Vanderbilt University serving as the Institutional Review Board) in the sentinel approach and the Westat Institutional Review Board in the national approach (see 45 C.F.R. part 46.114; 21 C.F.R. part 56.114). 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors