COVID-19 infection, reinfection, and the transition to endemicity

Understanding the protection conferred by previous infection against repeat infection, illness, and severe disease is key to projecting the future epidemiology of COVID-19 and to guiding vaccine policy decisions. In The Lancet, The COVID-19 Forecasting Team¹ report data from a systematic review and meta-analysis of 65 studies from 19 different countries estimating the reduction in COVID-19 risk among individuals with previous SARS-CoV-2 infection, compared with those without a previous infection. Although there have been several previous systematic reviews that address this question, the current study adds substantial new information through the inclusion of an analysis of the change in protection conferred by previous infection with time since infection and an analysis stratified by SARS-CoV-2 variant. This analysis is particularly important following the emergence of the omicron variant in late 2021, with rapid spread globally. Currently, in most parts of the world, COVID-19 is dominated by different omicron sublineages, with ongoing emergence of new sublineages demonstrating the importance of potential immune escape.²

The COVID-19 Forecasting Team¹ found a high level of protection against reinfection and symptomatic disease for ancestral, alpha, beta, and delta variants (mean pooled estimate >82%) but substantially lower protection (approximately 45%) for the omicron BA.1 variant. Protection against severe disease was high for all variants evaluated (>85% at 40 weeks). Protection against reinfection with alpha, beta, and delta variants waned over time but remained higher than 75% at 40 weeks. By contrast, protection against reinfection by omicron BA.1 waned more rapidly, decreasing to 36% at 40 weeks. The data available for the omicron sublineages BA.2, BA.4, and BA.5, although limited, suggested that protection against these sublineages was lower if the past infection was with a pre-omicron variant compared with omicron; however, reinfection of those with a past omicron infection was higher for BA.4 and BA.5, highlighting the ongoing importance of immune evasion as a selective pressure driving the emergence of new subvariants.

The key limitations of this study include the small number of studies done in low-income and middle-income countries, many of which have had high rates of SARS-CoV-2 infection, and the scarce data available on omicron BA.4 and BA.5 and other emerging sublineages. In addition, studies are needed with longer-term follow-up for the effects of waning protection and the protection conferred by repeated infections with different variants.

The immune escape properties of omicron BA.1 were first detected by routine monitoring of population-level reinfection trends on the basis of epidemiological data.³ Although molecular surveillance and immunological analyses are essential for understanding the mechanisms underpinning immune evasion,⁴ the public health implications of viral evolution are fundamentally an epidemiological question. In the context of high population-level immunity, novel approaches are needed for sustained surveillance to assess the epidemiological consequences of new SARS-CoV-2 variants and sublineages, as well as mechanisms to support these platforms and ensure representation of low-income and middle-income countries. Potential approaches could include systematic repeated community testing, such as the innovative Office for National Statistics study in the UK,⁵ repeated analyses of routinely collected large datasets,⁶ and longitudinal cohort studies.⁷ Routine monitoring for changes in epidemiological trends, such as disease severity and repeated infection with different variants in populations with well characterised immune histories, will be essential to maintain alongside platforms for ongoing molecular characterisation of the evolving virus.

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Although it is impossible to predict the long-term trajectory of SARS-CoV-2 circulation with certainty, the short duration of immunity combined with high transmissibility of the omicron variant and its sublineages hint that SARS-CoV-2 may not experience the kind of dynamic resonance that drives annual influenza epidemics.⁸ Although seasonal factors are likely to drive some variation in SARS-CoV-2 incidence throughout the year, the ratio of the peak incidence to the trough could be much closer to 1. Furthermore, in the long run, most infections will occur in people with strong protection against severe disease because of previous infection, vaccination, or both. Together, these results suggests that, similar to other human coronaviruses, there might be a low seasonal hospitalisation burden associated with SARS-CoV-2.

The high and sustained levels of protection conferred by previous infection against severe disease have important implications for COVID-19 vaccine policy. By September, 2021, global SARS-CoV-2 seroprevalence was estimated at 59%, with substantial variation in the proportion of immunity induced by infection or vaccination in different settings.⁹ Seroprevalence in Africa was estimated at 87% in December, 2021, largely as a result of infection.⁹ High levels of immunity are an important contributor to the lower levels of severity observed with infection caused by emerging omicron subvariants.¹⁰ As SARS-CoV-2 epidemiology shifts to more stable circulation patterns in the context of high levels of immunity, studies of the burden and cost of SARS-CoV-2 infection and risk groups for severe disease are needed to guide rational vaccination policy and decisions around prioritisation in relation to other vaccine-preventable diseases.