Correlates of protection from SARS-CoV-2 infection
Authors: Florian Krammer
Journal: The Lancet (2021)

Since the beginning of the COVID-19 pandemic, many scientists and public health officials assumed that infection with SARS-CoV-2 would protect from reinfection and that neutralising antibodies would correlate with protection or would be at least one of the protective immune mechanisms.1Krammer F Simon V Serology assays to manage COVID-19.Science. 2020; 368: 1060-1061Crossref PubMed Scopus (226) Google Scholar Early on, these assumptions were supported by non-human primate data showing protection from reinfection, a correlation between neutralising antibodies protection, and protection afforded by passive transfer of neutralising antibodies.2McMahan K Yu J Mercado NB et al.Correlates of protection against SARS-CoV-2 in rhesus macaques.Nature. 2021; 590: 630-634Crossref PubMed Scopus (736) Google Scholar, 3Yu J Tostanoski LH Peter L et al.DNA vaccine protection against SARS-CoV-2 in rhesus macaques.Science. 2020; 369: 806-811Crossref PubMed Scopus (758) Google Scholar, 4Deng W Bao L Liu J et al.Primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques.Science. 2020; 369: 818-823Crossref PubMed Scopus (335) Google Scholar However, reports of rare reinfections, the notion that antibody titres might wane within weeks (which is incorrect), and the fact that human coronaviruses that cause common colds do cause reinfections have cast doubt on these initial assumptions.5Tillett RL Sevinsky JR Hartley PD et al.Genomic evidence for reinfection with SARS-CoV-2: a case study.Lancet Infect Dis. 2021; 21: 52-58Summary Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 6Long Q-X Tang X-J Shi Q-L et al.Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections.Nat Med. 2020; 26: 1200-1204Crossref PubMed Scopus (2012) Google Scholar, 7Edridge 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 A study in the UK reported in The Lancet by Victoria Hall and colleagues,8Hall VJ Foulkes S Charlett A et al.SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: large, multicentre, prospective cohort study (SIREN).Lancet. 2021; (published online April 9.)https://doi.org/10.1016/S0140-6736(21)00675-9Summary Full Text Full Text PDF PubMed Scopus (424) Google Scholar called the SARS-CoV-2 Immunity and Reinfection Evaluation (SIREN) study, suggests that being seropositive to SARS-CoV-2 through natural infection protects robustly from asymptomatic and symptomatic reinfection. The study analysed data from 25 661 enrolled health-care workers between June 18, 2020, and Jan 11, 2021, including 8278 individuals with known previous SARS-CoV-2 infection, of whom the vast majority were antibody positive at enrolment and 17 383 individuals who were seronegative and had not previously been infected with SARS-CoV-2. 21 617 (84·2%) of 25 661 participants were women and 4010 (15·6%) were men, with a median age of 45·7 years. 87·3% of the participants were White, 6·9% were mixed race, 2·0% were Asian, 1·6% were Black, 1·3% were Chinese, 0·6% were from other ethnic groups, and 0·2% preferred not to specify. Individuals were followed up with questionnaires (every 2 weeks), PCR for SARS-CoV-2 (every 2 weeks), and serology (at enrolment and every 4 weeks). 1704 infections occurred in the naive cohort, while two probable (required supportive serological data or supportive viral genomic data) and 153 possible (two positive PCR results 90 days apart or an antibody-positive individual with new positive PCR test 4 weeks after the first antibody positive test) infections occurred in the SARS-CoV-2-experienced cohort. Additionally, 864 individuals in the naive group seroconverted over the study interval but were not counted towards SARS-CoV-2 infections. The authors report previous SARS-CoV-2 infection provided a 84% risk reduction for reinfection (adjusted incidence rate ratio [aIRR] 0·159, 95% CI 0·13–0·19) and 93% risk reduction for those with symptomatic infections (aIRR 0·074, 0·06–0·10). Importantly, a variant of concern known as B.1.1.7 did circulate during the final part of the observation period, causing about 50% of all infections, but did not seem to have an effect on reinfection rates. The findings of the authors suggest that infection and the development of an antibody response provides protection similar to or even better than currently used SARS-CoV-2 vaccines. Although antibodies induced by SARS-CoV-2 infection are more variable and often lower in titre than antibody responses induced after vaccination, this observation does make sense considering current SARS-CoV-2 vaccines induce systemic immune responses to spike proteins while natural infection also induces mucosal immune responses and immune responses against the many other open reading frames encoded by the approximately 29 900 nucleotides of SARS-CoV-2. The SIREN study adds to a growing number of studies, which demonstrate that infection does protect against reinfection, and probably in an antibody-dependent manner.9Pilz S Chakeri A Ioannidis JP et al.SARS-CoV-2 re-infection risk in Austria.Eur J Clin Invest. 2021; 51e13520Crossref PubMed Scopus (113) Google Scholar, 10Lumley SF O'Donnell D Stoesser NE et al.Antibody status and incidence of SARS-CoV-2 infection in health care workers.N Engl J Med. 2021; 384: 533-540Crossref PubMed Scopus (629) Google Scholar, 11Letizia AG Ge Y Vangeti S et al.SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study.medRxiv. 2021; (published online Jan 29.) (preprint).https://doi.org/10.1101/2021.01.26.21250535Google Scholar, 12Sheehan MM Reddy AJ Rothberg MB Reinfection rates among patients who previously tested positive for COVID-19: a retrospective cohort study.medRxiv. 2021; (published online Feb 16.) (preprint).https://doi.org/10.1101/2021.02.14.21251715Google Scholar, 13Hansen 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; 397: 1204-1212Summary Full Text Full Text PDF PubMed Scopus (431) Google Scholar, 14Harvey RA Rassen JA Kabelac CA et al.Association of SARS-CoV-2 seropositive antibody test with risk of future infection.JAMA Intern Med. 2021; (published online Feb 24.)https://doi.org/10.1001/jamainternmed.2021.0366Crossref PubMed Scopus (166) Google Scholar, 15Addetia A Crawford KHD Dingens A et al.Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with high attack rate.J Clin Microbiol. 2020; 58: e02107-e02120Crossref PubMed Scopus (363) Google Scholar The SIREN study does have several limitations. Different serological assay platforms were used to determine seropositivity and not all of them have the same sensitivity over time or focus on the spike of SARS-CoV-2, which is the prime target of neutralising antibody responses. Additionally, although protection against B.1.1.7 was shown, the degree to which infection with so-called garden variety SARS-CoV-2 provides protection against reinfection with antigenically distinct variants of concern such as B.1.351 and P.1 remains unclear. Furthermore, the authors did not link quantitative antibody measurements to protection. This is an important piece of the puzzle since the protective titre for SARS-CoV-2 is still unknown, although non-human primate studies suggest that it is likely to be low.2McMahan K Yu J Mercado NB et al.Correlates of protection against SARS-CoV-2 in rhesus macaques.Nature. 2021; 590: 630-634Crossref PubMed Scopus (736) Google Scholar, 3Yu J Tostanoski LH Peter L et al.DNA vaccine protection against SARS-CoV-2 in rhesus macaques.Science. 2020; 369: 806-811Crossref PubMed Scopus (758) Google Scholar Establishment of antibody titres as a correlate of protection and defining a protective titre would be extremely important for public health considerations and for patient management. A correlate of protection and a protective threshold would also allow for the development of additional SARS-CoV-2 vaccines based on small immunogenicity-based phase 3 trials rather than large and costly field efficacy trials, which are becoming exceedingly difficult to perform. Determination of a protective titre should be a priority for future studies that investigate protection afforded by natural infection or vaccination. I report that the Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays and NDV-based SARS-CoV-2 vaccines on which I am named. I also report that I have previously published work on influenza virus vaccines with Sarah Gilbert, the lead investigator on the Oxford–AstraZeneca vaccine. I have consulted for CureVac, Merck, and Pfizer (before 2020); am currently consulting for Pfizer, Seqirus, and Avimex on SARS-CoV-2 and influenza virus vaccines; my laboratory is collaborating with Pfizer on animal models of SARS-CoV-2; my laboratory is collaborating with Norbert Pardi at the University of Pennsylvania on mRNA vaccines against SARS-CoV-2; my laboratory was previously working with GlaxoSmithKline on the development of influenza virus vaccines; and two of my mentees have recently joined Moderna. SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN)A previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals. Full-Text PDF