The durability of immunity against reinfection by SARS-CoV-2: a comparative evolutionary study

Abstract

Background: Among the most consequential unknowns of the devastating COVID-19 pandemic are the durability of immunity and time to likely reinfection. There are limited direct data on SARS-CoV-2 long-term immune responses and reinfection. The aim of this study is to use data on the durability of immunity among evolutionarily close coronavirus relatives of SARS-CoV-2 to estimate times to reinfection by a comparative evolutionary analysis of related viruses SARS-CoV, MERS-CoV, human coronavirus (HCoV)-229E, HCoV-OC43, and HCoV-NL63.

Methods: We conducted phylogenetic analyses of the S, M, and ORF1b genes to reconstruct a maximum-likelihood molecular phylogeny of human-infecting coronaviruses. This phylogeny enabled comparative analyses of peak-normalised nucleocapsid protein, spike protein, and whole-virus lysate IgG antibody optical density levels, in conjunction with reinfection data on endemic human-infecting coronaviruses. We performed ancestral and descendent states analyses to estimate the expected declines in antibody levels over time, the probabilities of reinfection based on antibody level, and the anticipated times to reinfection after recovery under conditions of endemic transmission for SARS-CoV-2, as well as the other human-infecting coronaviruses.

Findings: We obtained antibody optical density data for six human-infecting coronaviruses, extending from 128 days to 28 years after infection between 1984 and 2020. These data provided a means to estimate profiles of the typical antibody decline and probabilities of reinfection over time under endemic conditions. Reinfection by SARS-CoV-2 under endemic conditions would likely occur between 3 months and 5·1 years after peak antibody response, with a median of 16 months. This protection is less than half the duration revealed for the endemic coronaviruses circulating among humans (5-95% quantiles 15 months to 10 years for HCoV-OC43, 31 months to 12 years for HCoV-NL63, and 16 months to 12 years for HCoV-229E). For SARS-CoV, the 5-95% quantiles were 4 months to 6 years, whereas the 95% quantiles for MERS-CoV were inconsistent by dataset.

Interpretation: The timeframe for reinfection is fundamental to numerous aspects of public health decision making. As the COVID-19 pandemic continues, reinfection is likely to become increasingly common. Maintaining public health measures that curb transmission-including among individuals who were previously infected with SARS-CoV-2-coupled with persistent efforts to accelerate vaccination worldwide is critical to the prevention of COVID-19 morbidity and mortality.

Funding: US National Science Foundation.

Figure 1

Evolutionary divergences, peak-normalised coronavirus anti-spike protein IgG antibody levels, daily probabilities of infection given antibody level, and probabilities of reinfection for human-infecting coronaviruses SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-NL63, and HCoV-229E (A) Phylogenetic chronogram of the evolutionary divergence of human-infecting coronaviruses relative to the most recent common ancestor. Bootstrap support was 100% for all nodes on this phylogeny. Peak-normalised antibody levels with fitted exponential waning (B–G) to a phylogenetically informed (B–D) or empirically determined baseline (E–G), in days from peak antibody level at 3 months. Daily probabilities of infection given peak-normalised S IgG antibody levels (H–M) from phylogenetically informed estimates (H–J) or from a maximum-likelihood fit of a linear-logistic model of probability of infection given antibody level (K–M). (N–S) Daily probability (curve with relative gradient from grey [low], to red [moderate], to yellow [high] for each virus) of reinfection over time, and central 90% interval of the reinfection day (black dashed vertical lines). Curves each correspond to parameters estimated from datasets 1–6., , , , , , HCoV=human coronavirus.

Figure 2

Evolutionary divergences of human-infecting coronaviruses and estimated half-lives of antibody decline to baseline 3 months after infection by human-infecting coronaviruses. Estimated half-life to baseline for SARS-CoV-2 and other human-infecting coronaviruses are colour coded by dataset. The estimated half-lives resulting from analyses of datasets 1–6 are plotted in comparison to the mean half-life to baseline across all coronaviruses (dashed vertical line). HCoV=human coronavirus.

Figure 3

Probability of remaining free of reinfection over time and median times to reinfection for human-infecting coronaviruses SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-NL63, and HCoV-229E. Probability of remaining free of reinfection (curves) and median times to reinfection (black dashed vertical line) resulting from analyses of datasets 1–6, in days from peak antibody level at 3 months. HCoV=human coronavirus.