Increased risk of SARS-CoV-2 reinfection associated with emergence of Omicron in South Africa

We provide two methods for monitoring reinfection trends in routine surveillance data to identify signatures of changes in reinfection risk and apply these approaches to data from South Africa’s severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic to date. Although we found no evidence of increased reinfection risk associated with circulation of the Beta (B.1.351) or Delta (B.1.617.2) variants, we did find clear, population-level evidence to suggest immune evasion by the Omicron (B.1.1.529) variant in previously infected individuals in South Africa. Reinfections occurring between 1 November 2021 and 31 January 2022 were detected in individuals infected in all three previous waves, and there has been an increase in the risk of having a third infection since mid-November 2021. Description Omicron and reinfection risk So far, our experience with pandemic coronavirus has been that the emergence of new variants is not detected until there has been substantial community transmission. Early in November 2021, South African scientists spotted reinfections consistent with the timing of the emergence of the Omicron variant (B.1.1.529). In a population largely untouched by vaccines but widely infected, Pulliam et al. found that Beta or Delta variants rarely caused reinfection. However, after 31 October 2021, individuals were found who had had three experiences of infection (see the Perspective by Zelner and Eisenberg). The culprit was the rapidly emerging Omicron variant, with multiple mutations in the Spike protein. This variant’s chief advantage is its ability to evade naturally acquired immunity. Fortunately, the Omicron variant does not fully evade vaccine-derived immunity, but only those privileged to have been vaccinated can benefit. —CA Analysis of routine surveillance data from South Africa indicates that the Omicron variant of SARS-CoV-2 evades immunity from prior infection. INTRODUCTION Globally, there have been more than 404 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with 5.8 million confirmed deaths as of February 2022. South Africa has experienced four waves of SARS-CoV-2 transmission, with the second, third, and fourth waves being driven by the Beta, Delta, and Omicron variants, respectively. A key question with the emergence of new variants is the extent to which they are able to reinfect those who have had a prior natural infection. RATIONALE We developed two approaches to monitor routine epidemiological surveillance data to determine whether SARS-CoV-2 reinfection risk has changed through time in South Africa in the context of the emergence of the Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529) variants. We analyzed line-list data on positive tests for SARS-CoV-2 with specimen receipt dates between 4 March 2020 and 31 January 2022 collected through South Africa’s National Notifiable Medical Conditions Surveillance System. Individuals having sequential positive tests at least 90 days apart were considered to have suspected reinfections. Our routine monitoring of reinfection risk included comparison of reinfection rates with the expectation under a null model (approach 1) and estimation of the time-varying hazards of infection and reinfection throughout the epidemic (approach 2) based on model-based reconstruction of the susceptible populations eligible for primary and second infections. RESULTS A total of 105,323 suspected reinfections were identified among 2,942,248 individuals with laboratory-confirmed SARS-CoV-2 who had a positive test result at least 90 days before 31 January 2022. The number of reinfections observed through the end of the third wave in September 2021 was consistent with the null model of no change in reinfection risk (approach 1). Although increases in the hazard of primary infection were observed after 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: the relative hazard ratio for wave 2 versus wave 1 was 0.71 [95% confidence interval (95% CI): 0.60 to 0.85]; the relative hazard ratio for wave 3 versus wave 1 was 0.54 (95% CI: 0.45 to 0.64). By contrast, the recent spread of the Omicron variant has been associated with an increase in reinfection hazard coefficient. The estimated relative hazard ratio for reinfection versus primary infection versus wave 1 was 1.75 (95% CI: 1.48 to 2.10) for the period of Omicron emergence (1 November 2021 to 30 November 2021) and 1.70 (95% CI: 1.44 to 2.04) for wave 4 versus wave 1. Individuals with identified reinfections since 1 November 2021 had experienced primary infections in all three prior waves, and an increase in third infections has been detected since mid-November 2021. Many individuals experiencing third infections had second infections during the third (Delta) wave that ended in September 2021, strongly suggesting that these infections resulted from immune evasion rather than waning immunity. CONCLUSION Population-level evidence suggests that the Omicron variant is associated with a marked 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 such as South Africa with high rates of immunity from prior infection. The further development of methods to track reinfection risk during pathogen emergence, including refinements to assess the impact of waning immunity, account for vaccine-derived protection, and monitor the risk of multiple reinfections, will be important for future pandemic preparedness. SARS-CoV-2 reinfection patterns in South Africa. South Africa has experienced four waves of SARS-CoV-2 transmission, each driven by the emergence of a new variant. Reinfection of previously infected individuals was relatively rare through the end of the third wave. Methods developed in South Africa to monitor reinfection trends led to the early detection of increased reinfection risk associated with the Omicron variant.