Objective: To examine whether SARS-CoV-2 reinfection risk has changed through time in South Africa, in the context of the emergence of the Beta, Delta, and Omicron variants Design: Retrospective analysis of routine epidemiological surveillance data Setting: Line list data on SARS-CoV-2 with specimen receipt dates between 04 March 2020 and 27 November 2021, collected through South Africa's National Notifiable Medical Conditions Surveillance System Participants 2,796,982 individuals with laboratory-confirmed SARS-CoV-2 who had a positive test result at least 90 days prior to 27 November 2021. Individuals having sequential positive tests at least 90 days apart were considered to have suspected reinfections. Main outcome measures: Incidence of suspected reinfections through time; comparison of reinfection rates to the expectation under a null model (approach 1); empirical estimates of the time-varying hazards of infection and reinfection throughout the epidemic (approach 2) Results: 35,670 suspected reinfections were identified among 2,796,982 individuals with laboratory-confirmed SARS-CoV-2 who had a positive test result at least 90 days prior to 27 November 2021. The number of reinfections observed through the end of the third wave was consistent with the null model of no change in reinfection risk (approach 1). Although increases in the hazard of primary infection were observed following the introduction of both the Beta and Delta variants, no corresponding increase was observed in the reinfection hazard (approach 2). Contrary to expectation, the estimated hazard ratio for reinfection versus primary infection was lower during waves driven by the Beta and Delta variants than for the first wave (relative hazard ratio for wave 2 versus wave 1: 0.75 (CI95: 0.59-0.97); for wave 3 versus wave 1:0.71 (CI95: 0.56-0.92)). In contrast, the recent spread of the Omicron variant has been associated with a decrease in the hazard of primary infection and an increase in reinfection hazard. The estimated hazard ratio for reinfection versus primary infection for the period from 1 November 2021 to 27 November 2021 versus wave 1 was 2.39 (CI95: 1.88-3.11). Conclusion: Population-level evidence suggests that the Omicron variant is associated with substantial ability to evade immunity from prior infection. In contrast, there is no population-wide epidemiological evidence of immune escape associated with the Beta or Delta variants. This finding has important implications for public health planning, particularly in countries like South Africa with high rates of immunity from prior infection. Urgent questions remain regarding whether Omicron is also able to evade vaccine-induced immunity and the potential implications of reduced immunity to infection on protection against severe disease and death. ### Competing Interest Statement All authors have completed the ICMJE uniform disclosure form. CC and AvG have received funding from Sanofi Pasteur in the past 36 months. JRCP and KM serve on the Ministerial Advisory Committee on COVID-19 of the South African National Department of Health. The authors have declared no other relationships or activities that could appear to have influenced the submitted work. ### Funding Statement This work was supported by the South African Department of Science and Innovation and the National Research Foundation and the Wellcome Trust (grant number 221003/Z/20/Z) in collaboration with the Foreign, Commonwealth and Development Office, United Kingdom. ### 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: This study has received ethical clearance from University of the Witwatersrand (Clearance certificate number M210752, formerly M160667) and approval under reciprocal review from Stellenbosch University (Project ID 19330, Ethics Reference Number N20/11/074\_RECIP\_WITS\_M160667\_COVID-19). 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 and code will be made available at https://github.com/jrcpulliam/reinfections. The following data are included in the repository: - Counts of reinfections and primary infections by province, age group (5-year bands), and sex (M, F, U) - Daily time series of primary infections and suspected reinfections by specimen receipt date (national) - Model output: posterior samples from the MCMC fitting procedure and simulation results Requests for additional data must be made in writing to the National Institute for Communicable Diseases, South Africa.