Protective immunity after recovery from SARS-CoV-2 infection
Authors: Noah Kojima, Jeffrey D Klausner
Journal: The Lancet Infectious Diseases (2021)

The SARS-CoV-2 pandemic is now better controlled in settings with access to fast and reliable testing and highly effective vaccination rollouts. Several studies have found that people who recovered from COVID-19 and tested seropositive for anti-SARS-CoV-2 antibodies have low rates of SARS-CoV-2 reinfection. There are still looming questions surrounding the strength and duration of such protection compared with that from vaccination. We reviewed studies published in PubMed from inception to Sept 28, 2021, and found well conducted biological studies showing protective immunity after infection (panel). Furthermore, multiple epidemiological and clinical studies, including studies during the recent period of predominantly delta (B.1.617.2) variant transmission, found that the risk of repeat SARS-CoV-2 infection decreased by 80·5–100% among those who had had COVID-19 previously (panel). The reported studies were large and conducted throughout the world. Another laboratory-based study that analysed the test results of 9119 people with previous COVID-19 from Dec 1, 2019, to Nov 13, 2020, found that only 0·7% became reinfected.11Qureshi AI Baskett WI Huang W Lobanova I Naqvi SH Shyu CR Re-infection with SARS-CoV-2 in patients undergoing serial laboratory testing.Clin Infect Dis. 2021; (published online April 25.)https://doi.org/10.1093/cid/ciab345Crossref Scopus (46) Google Scholar In a study conducted at the Cleveland Clinic in Cleveland, OH, USA, those who had not previously been infected had a COVID-19 incidence rate of 4·3 per 100 people, whereas those who had previously been infected had a COVID-19 incidence rate of 0 per 100 people.6Shrestha NK Burke PC Nowacki AS Terpeluk P Gordon SM Necessity of COVID-19 vaccination in previously infected individuals.medRxiv. 2021; (published online June 19.) (preprint).https://doi.org/10.1101/2021.06.01.21258176Google Scholar Furthermore, a study conducted in Austria found that the frequency of hospitalisation due to a repeated infection was five per 14 840 (0·03%) people and the frequency of death due to a repeated infection was one per 14 840 (0·01%) people.4Pilz S Chakeri A Ioannidis JP et al.SARS-CoV-2 re-infection risk in Austria.Eur J Clin Invest. 2021; 51e13520Crossref Scopus (113) Google Scholar Due to the strong association and biological basis for protection,12Goel RR Apostolidis SA Painter MM et al.Distinct antibody and memory B cell responses in SARS-CoV-2 naïve and recovered individuals following mRNA vaccination.Sci Immunol. 2021; 6eabi6950Crossref PubMed Scopus (412) Google Scholar clinicians should consider counselling recovered patients on their risk for reinfection and document previous infection status in medical records.PanelBiological, epidemiological, and clinical evidence that previous COVID-19 infection reduces the risk for reinfectionBiological studies•Dan et al (2021):1Dan JM Mateus J Kato Y et al.Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.Science. 2021; 371eabf4063Crossref PubMed Scopus (1787) Google Scholar about 95% of participants tested retained immune memory at about 6 months after having COVID-19; more than 90% of participants had CD4+ T-cell memory at 1 month and 6–8 months after having COVID-19•Wang et al (2021):2Wang L Zhou T Zhang Y et al.Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants.Science. 2021; 373eabh1766Crossref Scopus (129) Google Scholar participants with a previous SARS-CoV-2 infection with an ancestral variant produce antibodies that cross-neutralise emerging variants of concern with high potencyEpidemiological studies•Hansen et al (2021):3Hansen 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 in a population-level observational study, people who had had COVID-19 previously were around 80·5% protected against reinfection•Pilz et al (2021):4Pilz S Chakeri A Ioannidis JP et al.SARS-CoV-2 re-infection risk in Austria.Eur J Clin Invest. 2021; 51e13520Crossref Scopus (113) Google Scholar in a retrospective observational study using national Austrian SARS-CoV-2 infection data, people who had had COVID-19 previously were around 91% protected against reinfection•Sheehan et al (2021):5Sheehan MM Reddy AJ Rothberg MB Reinfection rates among patients who previously tested positive for COVID-19: a retrospective cohort study.Clin Infect Dis. 2021; (published online March 15.)https://doi.org/10.1093/cid/ciab234PubMed Google Scholar in a retrospective cohort study in the USA, people who had had COVID-19 previously were 81·8% protected against reinfection•Shrestha et al (2021):6Shrestha NK Burke PC Nowacki AS Terpeluk P Gordon SM Necessity of COVID-19 vaccination in previously infected individuals.medRxiv. 2021; (published online June 19.) (preprint).https://doi.org/10.1101/2021.06.01.21258176Google Scholar in a retrospective cohort study in the USA, people who had had COVID-19 previously were 100% protected against reinfection•Gazit et al (2021):7Gazit S Shlezinger R Perez G et al.Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections.medRxiv. 2021; (published online Aug 25.) (preprint).https://doi.org/10.1101/2021.08.24.21262415PubMed Google Scholar in a retrospective observational study in Israel, SARS-CoV-2-naive vaccinees had a 13·06-times increased risk for breakthrough infection with the delta (B.1.617.2) variant compared with those who had had COVID-19 previously; evidence of waning natural immunity was also shown•Kojima et al (2021):8Kojima N Roshani A Brobeck M Baca A Klausner JD Incidence of severe acute respiratory syndrome coronavirus-2 infection among previously infected or vaccinated employees.medRxiv. 2021; (published online July 8.) (preprint).https://doi.org/10.1101/2021.07.03.21259976Google Scholar in a retrospective observational cohort of laboratory staff routinely screened for SARS-CoV-2, people who had had COVID-19 previously were 100% protected against reinfectionClinical studies•Hall et al (2021):9Hall VJ Foulkes S Charlett A et al.SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN).Lancet. 2021; 397: 1459-1469Summary Full Text Full Text PDF PubMed Scopus (424) Google Scholar in a large, multicentre, prospective cohort study, having had COVID-19 previously was associated with an 84% decreased risk of infection•Letizia et al (2021):10Letizia AG Ge Y Vangeti S et al.SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study.Lancet Respir Med. 2021; 9: 712-720Summary Full Text Full Text PDF PubMed Scopus (108) Google Scholar in a prospective cohort of US Marines, seropositive young adults were 82% protected against reinfection Biological studies •Dan et al (2021):1Dan JM Mateus J Kato Y et al.Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.Science. 2021; 371eabf4063Crossref PubMed Scopus (1787) Google Scholar about 95% of participants tested retained immune memory at about 6 months after having COVID-19; more than 90% of participants had CD4+ T-cell memory at 1 month and 6–8 months after having COVID-19•Wang et al (2021):2Wang L Zhou T Zhang Y et al.Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants.Science. 2021; 373eabh1766Crossref Scopus (129) Google Scholar participants with a previous SARS-CoV-2 infection with an ancestral variant produce antibodies that cross-neutralise emerging variants of concern with high potency Epidemiological studies •Hansen et al (2021):3Hansen 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 in a population-level observational study, people who had had COVID-19 previously were around 80·5% protected against reinfection•Pilz et al (2021):4Pilz S Chakeri A Ioannidis JP et al.SARS-CoV-2 re-infection risk in Austria.Eur J Clin Invest. 2021; 51e13520Crossref Scopus (113) Google Scholar in a retrospective observational study using national Austrian SARS-CoV-2 infection data, people who had had COVID-19 previously were around 91% protected against reinfection•Sheehan et al (2021):5Sheehan MM Reddy AJ Rothberg MB Reinfection rates among patients who previously tested positive for COVID-19: a retrospective cohort study.Clin Infect Dis. 2021; (published online March 15.)https://doi.org/10.1093/cid/ciab234PubMed Google Scholar in a retrospective cohort study in the USA, people who had had COVID-19 previously were 81·8% protected against reinfection•Shrestha et al (2021):6Shrestha NK Burke PC Nowacki AS Terpeluk P Gordon SM Necessity of COVID-19 vaccination in previously infected individuals.medRxiv. 2021; (published online June 19.) (preprint).https://doi.org/10.1101/2021.06.01.21258176Google Scholar in a retrospective cohort study in the USA, people who had had COVID-19 previously were 100% protected against reinfection•Gazit et al (2021):7Gazit S Shlezinger R Perez G et al.Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections.medRxiv. 2021; (published online Aug 25.) (preprint).https://doi.org/10.1101/2021.08.24.21262415PubMed Google Scholar in a retrospective observational study in Israel, SARS-CoV-2-naive vaccinees had a 13·06-times increased risk for breakthrough infection with the delta (B.1.617.2) variant compared with those who had had COVID-19 previously; evidence of waning natural immunity was also shown•Kojima et al (2021):8Kojima N Roshani A Brobeck M Baca A Klausner JD Incidence of severe acute respiratory syndrome coronavirus-2 infection among previously infected or vaccinated employees.medRxiv. 2021; (published online July 8.) (preprint).https://doi.org/10.1101/2021.07.03.21259976Google Scholar in a retrospective observational cohort of laboratory staff routinely screened for SARS-CoV-2, people who had had COVID-19 previously were 100% protected against reinfection Clinical studies •Hall et al (2021):9Hall VJ Foulkes S Charlett A et al.SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN).Lancet. 2021; 397: 1459-1469Summary Full Text Full Text PDF PubMed Scopus (424) Google Scholar in a large, multicentre, prospective cohort study, having had COVID-19 previously was associated with an 84% decreased risk of infection•Letizia et al (2021):10Letizia AG Ge Y Vangeti S et al.SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study.Lancet Respir Med. 2021; 9: 712-720Summary Full Text Full Text PDF PubMed Scopus (108) Google Scholar in a prospective cohort of US Marines, seropositive young adults were 82% protected against reinfection Although those studies show that protection from reinfection is strong and persists for more than 10 months of follow-up,3Hansen 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 it is unknown how long protective immunity will truly last. Many systemic viral infections, such as measles, confer long-term, if not lifelong, immunity, whereas others, such as influenza, do not (due to changes in viral genetics).4Pilz S Chakeri A Ioannidis JP et al.SARS-CoV-2 re-infection risk in Austria.Eur J Clin Invest. 2021; 51e13520Crossref Scopus (113) Google Scholar We are limited by the length of current reported follow-up data to know with certainty the expected duration that previous infection will protect against COVID-19. Encouragingly, authors of a study conducted among recovered individuals who had experienced mild SARS-CoV-2 infection reported that mild infection induced a robust antigen-specific, long-lived humoral immune memory in humans.13Turner JS Kim W Kalaidina E et al.SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans.Nature. 2021; 595: 421-425Crossref PubMed Scopus (336) Google Scholar It important to note that antibodies are incomplete predictors of protection. After vaccination or infection, many mechanisms of immunity exist within an individual not only at the antibody level, but also at the level of cellular immunity.14Doshi P Covid-19: do many people have pre-existing immunity?.BMJ. 2020; 370m3563Google Scholar, 15Le Bert N Tan AT Kunasegaran K et al.SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls.Nature. 2020; 584: 457-462Crossref PubMed Scopus (1350) Google Scholar, 16Shrotri M van Schalkwyk MCI Post N et al.T cell response to SARS-CoV-2 infection in humans: a systematic review.PLoS One. 2021; 16e0245532Crossref PubMed Scopus (97) Google Scholar It is known that SARS-CoV-2 infection induces specific and durable T-cell immunity, which has multiple SARS-CoV-2 spike protein targets (or epitopes) as well as other SARS-CoV-2 protein targets. The broad diversity of T-cell viral recognition serves to enhance protection to SARS-CoV-2 variants,15Le Bert N Tan AT Kunasegaran K et al.SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls.Nature. 2020; 584: 457-462Crossref PubMed Scopus (1350) Google Scholar with recognition of at least the alpha (B.1.1.7), beta (B.1.351), and gamma (P.1) variants of SARS-CoV-2.17Redd AD Nardin A Kared H et al.CD8+ T-cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants.Open Forum Infect Dis. 2021; 8ofab143Crossref Scopus (46) Google Scholar Researchers have also found that people who recovered from SARS-CoV infection in 2002–03 continue to have memory T cells that are reactive to SARS-CoV proteins 17 years after that outbreak.15Le Bert N Tan AT Kunasegaran K et al.SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls.Nature. 2020; 584: 457-462Crossref PubMed Scopus (1350) Google Scholar Additionally, a memory B-cell response to SARS-CoV-2 evolves between 1·3 and 6·2 months after infection, which is consistent with longer-term protection.18Gaebler C Wang Z Lorenzi JCC et al.Evolution of antibody immunity to SARS-CoV-2.Nature. 2021; 591: 639-644Crossref PubMed Scopus (1054) Google Scholar Some people who have recovered from COVID-19 might not benefit from COVID-19 vaccination.6Shrestha NK Burke PC Nowacki AS Terpeluk P Gordon SM Necessity of COVID-19 vaccination in previously infected individuals.medRxiv. 2021; (published online June 19.) (preprint).https://doi.org/10.1101/2021.06.01.21258176Google Scholar, 19Goldberg Y Mandel M Woodbridge Y et al.Protection of previous SARS-CoV-2 infection is similar to that of BNT162b2 vaccine protection: a three-month nationwide experience from Israel.medRxiv. 2021; (published online April 24.) (preprint).https://doi.org/10.1101/2021.04.20.21255670Google Scholar In fact, one study found that previous COVID-19 was associated with increased adverse events following vaccination with the Comirnaty BNT162b2 mRNA vaccine (Pfizer–BioNTech).20Raw RK Kelly CA Rees J Wroe C Chadwick DR Previous COVID-19 infection, but not long-COVID, is associated with increased adverse events following BNT162b2/Pfizer vaccination.J Infect. 2021; 83: 381-412Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar In addition, there are rare reports of serious adverse events following COVID-19 vaccination.21Centers for Disease Control and PreventionSelected adverse events reported after COVID-19 vaccination.https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/adverse-events.htmlDate: Oct 26, 2021Date accessed: November 2, 2021Google Scholar In Switzerland, residents who can prove they have recovered from a SARS-CoV-2 infection through a positive PCR or other test in the past 12 months are considered equally protected as those who have been fully vaccinated.22Schengen Visa InfoSwitzerland plans to extend COVID certificate requirement until mid-November.https://www.schengenvisainfo.com/news/switzerland-plans-to-extend-covid-certificate-requirement-until-mid-november/Date: Oct 22, 2021Date accessed: November 2, 2021Google Scholar Although longer follow-up studies are needed, clinicians should remain optimistic regarding the protective effect of recovery from previous infection. Community immunity to control the SARS-CoV-2 epidemic can be reached with the acquired immunity due to either previous infection or vaccination. Acquired immunity from vaccination is certainly much safer and preferred. Given the evidence of immunity from previous SARS-CoV-2 infection, however, policy makers should consider recovery from previous SARS-CoV-2 infection equal to immunity from vaccination for purposes related to entry to public events, businesses, and the workplace, or travel requirements. NK has received consulting fees from Curative. JDK serves as an independent medical director of Curative.