Acute and Post-Acute COVID-19 Outcomes Among Immunologically Naïve Adults During Delta Versus Omicron Waves

Importance The U.S. arrival of the Omicron variant led to a rapid increase in SARS-CoV-2 infections. While numerous studies report characteristics of Omicron infections among vaccinated individuals and/or persons with a prior history of infection, comprehensive data describing infections among immunologically naïve adults is lacking. Objective To examine COVID-19 acute and post-acute clinical outcomes among a well-characterized cohort of unvaccinated and previously uninfected adults who contracted SARS-CoV-2 during the Omicron (BA.1/BA.2) surge, and to compare outcomes with infections that occurred during the Delta wave. Design A prospective cohort undergoing high-resolution symptom and virologic monitoring between June 2021 and September 2022 Setting Multisite recruitment of community-dwelling adults in 8 U.S. states Participants Healthy, unvaccinated adults between 30 to 64 years of age without an immunological history of SARS-CoV-2 who were at high-risk of infection were recruited. Participants were followed for up to 48 weeks, submitting regular COVID-19 symptom surveys and nasal swabs for SARS-CoV-2 PCR testing. Exposure(s) Omicron (BA.1/BA.2 lineages) versus Delta SARS-CoV-2 infection, defined as a positive PCR that occurred during a period when the variant represented ≥50% of circulating SARS-CoV-2 variants in the participant’s geographic region. Main Outcome(s) and Measure(s) The main outcomes examined were the prevalence and severity of acute (≤28 days post-onset) and post-acute (≥5 weeks post-onset) symptoms. Results Among 274 immunologically naïve participants, 166 (61%) contracted SARS-CoV-2. Of these, 137 (83%) and 29 (17%) infections occurred during the Omicron- and Delta-predominant periods, respectively. Asymptomatic infections occurred among 6.7% (95% CI: 3.1%, 12.3%) of Omicron cases and 0.0% (95% CI: 0.0%, 11.9%) of Delta cases. Healthcare utilization among Omicron cases was 79% (95% CI: 43%, 92%, P =0.001) lower relative to Delta cases. Relative to Delta, Omicron infections also experienced a 56% (95% CI: 26%, 74%, P =0.004) and 79% (95% CI: 54%, 91%, P <0.001) reduction in the risk and rate of post-acute symptoms, respectively. Conclusions and Relevance These findings suggest that among previously immunologically naïve adults, few Omicron (BA.1/BA.2) and Delta infections are asymptomatic, and relative to Delta, Omicron infections were less likely to seek healthcare and experience post-acute symptoms. Question What are acute and post-acute outcomes among previously uninfected and unvaccinated adults who contracted Omicron (BA.1/BA.2), and how do these compare with Delta infections? Findings In this prospective cohort of 274 immunologically naïve adults, 166 (61%) contracted SARS-CoV-2, with 9 (5.5%) asymptomatic infections. Compared with Delta, Omicron infections experienced a 79% relative reduction in healthcare utilization, and 56% and 79% relative reductions in the risk and rate of post-acute symptoms (≥5-weeks), respectively. Meaning These findings suggest among immunologically naïve adults, few infections are asymptomatic, and relative to Delta, Omicron infections have lower likelihoods of severe illness and post-acute symptoms. ### Competing Interest Statement MKD has received research support from St. Luke's Wood River Foundation. AW served as an advisory board member for Kyorin Pharmaceutical, and received research support from GSK, Vir Biotechnology, Pfizer, Allovir, Ansun Biopharma and Amazon (all for work outside this study). AH, DH, and FS are employed by and hold equity in Amazon, Inc. JB received research support from GSK and IgM Biosciences (all for work outside this study). MB served as a consultant for Vir Biotechnology, Merck, and Moderna, and received research support from GSK, Vir Biotechnology, Merck, Ridgeback, Amazon, Inc. and Regeneron. SC has consulted for GSK, JP Morgan, Citi, Morgan Stanley, Avalia NZ, Nutcracker Therapeutics, University of California, California State Universities, United Airlines, Adagio, and Roche. ### Funding Statement The current work was funded by the NIH NIAID under awards AI142742 (Cooperative Centers for Human Immunology, CCHI) (S.C.), and a supplement to NIH AI142742. This work was additionally supported in part by LJI Institutional Funds, and the NIAID under K08 award AI135078 (J.M.D.). ### 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 Western Institutional Review Board gave ethical approval for this work. 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 Data are not currently available