Risk of SARS-CoV-2 reinfection after natural infection
Authors: Rosemary J Boyton, Daniel M Altmann
Journal: The Lancet (2021)

Since the start of the COVID-19 pandemic, the question of potential reinfection has been ever present. Although there has been much debate about potential reliance on herd immunity through natural infection, human coronaviruses are well adapted to subvert immunity1Park A Iwasaki A Type I and type III interferons - induction, signaling, evasion, and application to combat COVID-19.Cell Host Microbe. 2020; 27: 870-878Summary Full Text Full Text PDF PubMed Scopus (583) Google Scholar and reinfection occurs for seasonal coronaviruses (229E, OC43, NL63, and HKU1) that cause the common cold due to ephemeral immunity that is poorly protective between infections.2Edridge AWD Kaczorowska J Hoste ACR et al.Seasonal coronavirus protective immunity is short-lasting.Nat Med. 2020; 26: 1691-1693Crossref PubMed Scopus (474) Google Scholar Furthermore, detailed mapping of immune parameters in cohorts such as health-care workers emphasises the heterogeneity of immune responsiveness to SARS-CoV-2, from those with high neutralising antibody titres and broad T-cell repertoires, to the minority with barely detectable immunity.3Reynolds CJ Swadling L Gibbons JM et al.Discordant neutralizing antibody and T cell responses in asymptomatic and mild SARS-CoV-2 infection.Sci Immunol. 2020; 5eabf3698Crossref PubMed Scopus (0) Google Scholar These very low levels of immunity after infection would be hard to equate with protection from reinfection. Furthermore, among the longitudinal studies that have investigated waning antibody levels against SARS-CoV-2, responses have been found to last for 6 months or longer; although, depending on which components of the antibody repertoire are assayed, a substantial minority serorevert to negativity.4Manisty C Treibel TA Jensen M et al.Time series analysis and mechanistic modelling of heterogeneity and sero-reversion in antibody responses to mild SARS-CoV-2 infection.EBioMedicine. 2021; 65103259Summary Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 5Hall V Foulkes S Charlett A et al.Do antibody positive healthcare workers have lower SARS-CoV-2 infection rates than antibody negative healthcare workers? Large multi-centre prospective cohort study (the SIREN study), England: June to November 2020.medRxiv. 2021; (published online Jan 15.) (preprint).https://doi.org/10.1101/2021.01.13.21249642v1Google Scholar Despite the substantial advances in all aspects of COVID-19 analysis and data collection over the past year, calculation of the risk of reinfection has been difficult and there are two key reasons for this. The most obvious reason for difficulty is that most individuals around the world who became infected during the first wave of the pandemic did not access a PCR or antibody test and were not admitted to or treated in hospital, and so are not included in many COVID-19 datasets. The second reason is that scientific journals require specific evidence for formal reporting of reinfection, leading to probable under-reporting. For instance, peer reviewers and editors have required evidence from individuals who tested positive by PCR, then recovered and became negative by PCR, and then subsequently tested positive by a second PCR test, with distinct sequenced viral isolates on each occasion.6To KK-W Hung IF-N Ip J et al.Coronavirus disease 2019 (COVID-19) re-infection by a phylogenetically distinct severe acute respiratory syndrome coronavirus 2 strain confirmed by whole genome sequencing.Clin Infect Dis. 2020; (published online Aug 25.)https://doi.org/10.1093/cid/ciaa1275Crossref Scopus (433) Google Scholar Outside of a research cohort setting, such evidence gathering is rarely achievable and potential confounders exist to reinfection analysis. For example, a minority of individuals can harbour a reservoir of persistent SARS-CoV-2 in the gut,7Robbiani DF Gaebler C Muecksch F et al.Convergent antibody responses to SARS-CoV-2 in convalescent individuals.Nature. 2020; 584: 437-442Crossref PubMed Scopus (1250) Google Scholar such that distinguishing between true reinfection as opposed to recurrence of the original infection is challenging. A study of health-care workers in Sergipe, Brazil, indicated a relatively high rate of reinfections correlated with the lowest antibody responses,8Dos Santos LA Filho PGdG Silva AMF et al.Recurrent COVID-19 including evidence of reinfection and enhanced severity in thirty Brazilian healthcare workers.J Infect. 2021; (published online Feb 9.)https://doi.org/10.1016/j.jinf.2021.01.020PubMed Google Scholar but in most cases the researchers could not confirm de-novo reinfection. From that study, the investigators estimated risk of reinfection to be approximately 7%.8Dos Santos LA Filho PGdG Silva AMF et al.Recurrent COVID-19 including evidence of reinfection and enhanced severity in thirty Brazilian healthcare workers.J Infect. 2021; (published online Feb 9.)https://doi.org/10.1016/j.jinf.2021.01.020PubMed Google Scholar In The Lancet, Christian Hansen and colleagues report their population study of a Danish cohort investigating the risk of becoming positive for SARS-CoV-2 by PCR for the second time, presumed to indicate reinfection.9Hansen CH Michlmayr D Gubbels SM Mølbak K Ethelberg S Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study.Lancet. 2021; (published March 17.)https://doi.org/10.1016/S0140-6736(21)00575-4Summary Full Text Full Text PDF PubMed Scopus (431) Google Scholar The study makes use of data from Denmark's national PCR-testing strategy whereby approximately 4 million people took 10·6 million PCR tests. Because the data in the system were person-identifiable, the authors were able to determine that 3·27% of those who were uninfected during the first surge had a positive test during the second surge, compared with 0·65% among those who had previously recorded a positive test. Thus, they determined from that, in general, past infection confers 80·5% protection against reinfection, which decreases to 47·1% in those aged 65 years and older. Hansen and colleagues acknowledge the many limitations of their analysis being restricted to only PCR data, including the possibility that people might change their behaviour after a positive PCR test. This confounder is addressed by noting that the findings are similar in a sensitivity analysis of nurses, doctors, social workers, and health-care assistants who were tested regularly due to their profession. Set against the more formal reinfection case reports that are based on differential virus sequence data and make reinfection appear an extremely rare event, many will find the data reported by Hansen and colleagues about protection through natural infection relatively alarming. Only 80·5% protection from reinfection in general, decreasing to 47·1% in people aged 65 years and older are more concerning figures than offered by previous studies. Until now, one of the largest datasets has come from Qatar during a period of high disease burden and reported an estimated reinfection risk of 0·2%.10Abu-Raddad LJ Chemaitelly H Malek JA et al.Assessment of the risk of SARS-CoV-2 reinfection in an intense re-exposure setting.Clin Infect Dis. 2020; (published online Dec 14.)https://doi.org/10.1101/2020.08.24.20179457Crossref PubMed Scopus (91) Google Scholar However, a key difference between the studies is that the Danish study is based on a universally accessible national testing programme for both symptomatic and non-symptomatic individuals, whereas the Qatar data are derived from a programme of PCR testing in the context of symptomatic disease. PCR-positive cases within the Danish dataset are thus likely to encompass a far higher proportion of asymptomatic cases presumed to elicit more marginal levels of protective immunity. The quality, quantity, and durability of protective immunity elicited by natural infection with SARS-CoV-2 are poor relative to the much higher levels of virus-neutralising antibodies and T cells induced by the vaccines currently being administered globally.11Walsh EE Frenck RW Falsey AR et al.Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates.N Engl J Med. 2020; 383: 2439-2450Crossref PubMed Scopus (1733) Google Scholar, 12Folegatti PM Ewer KJ Aley PK et al.Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.Lancet. 2020; 396: 467-478Summary Full Text Full Text PDF PubMed Scopus (1749) Google Scholar Emergence of variants of SARS-CoV-2 with variable escape from natural and vaccine-induced immunity complicates matters further. Precise correlates of protection against SARS-CoV-2 are not known, but emerging variants of concern might shift immunity below a protective margin, prompting the need for updated vaccines.13Altmann DM Boyton RJ Beale R Immunity to SARS-CoV-2 variants of concern.Science. 2021; 371: 1103-1104Crossref PubMed Scopus (127) Google Scholar Interestingly, vaccine responses even after single dose are substantially enhanced in individuals with a history of infection with SARS-CoV-2.14Manistry C Otter AD Treibel TA et al.Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals.Lancet. 2021; (published online Feb 25.)https://doi.org/10.1016/S0140-6736(21)00501-8Summary Full Text Full Text PDF Scopus (280) Google Scholar These data are all confirmation, if it were needed, that for SARS-CoV-2 the hope of protective immunity through natural infections might not be within our reach, and a global vaccination programme with high efficacy vaccines is the enduring solution. RJB and DMA are supported by UK Research and Innovation and Medical Research Council Newton (MR/S019553/1, MR/R02622X/1, and MR/V036939/1), National Institute for Health Research Imperial Biomedical Research Centre: Institute of Translational Medicine and Therapeutics, Cystic Fibrosis Trust Strategic Research Centre, and Horizon 2020 Marie Curie Actions. DMA and RJB have consulted as members of the Global T cell Expert Consortium, Oxford Immunotec, UK, outside of the area of work commented on here. Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational studyOur findings could inform decisions on which groups should be vaccinated and advocate for vaccination of previously infected individuals because natural protection, especially among older people, cannot be relied on. Full-Text PDF