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Editor's Note
May 28, 2021

Protection Because of Prior SARS-CoV-2 Infection

Author Affiliations
  • 1NYC Health and Hospitals, New York, New York
JAMA Intern Med. 2021;181(10):1409. doi:10.1001/jamainternmed.2021.2966

How much protection against future infections does prior infection with SARS-CoV-2 infection provide? This is an important question for advising individual patients, as well as for projecting future outbreaks of SARS-CoV-2.

In this issue of JAMA Internal Medicine, Vitale and colleagues1 use the results of diagnostic reverse-transcriptase–polymerase chain reaction tests in Lombardy, Italy, to compare the incidence of SARS-CoV-2 infection among persons with prior SARS-CoV-2 infection with persons who tested negative for the virus.

The differences were dramatic. The incidence density per 100 000 person days was 1.0 (95%, CI 0.5-1.5) for persons with a history of infection and 15.1 (95% CI, 14.5-15.7) for persons without a history of infection. These results complement those of Harvey and colleagues2 from the US, who found that patients with a positive diagnostic nucleic acid amplification test result for antibodies to SARS-CoV-2 were much less likely to develop SARS-CoV-2 infection at 90 days than persons without antibodies.

Before assuming that people with documented SARS-CoV-2 infections, whether by polymerase chain reaction diagnostic testing or by presence of antibodies, are protected against future infections, there are 2 caveats. First, we do not know how long natural immunity lasts. Second, we do not know if natural immunity to the wild-type virus is equally protective for SARS-CoV-2 variants (viruses with genetic variations). As has been indicated by Spellberg and colleagues,3 achieving herd immunity through natural infection is a long and painful process, and, historically, the only human disease to be eradicated, smallpox, was eradicated through vaccination, not natural infection.

Because it is likely that immunization plus history of natural infection is better protection than natural infection alone, all persons should be encouraged to get vaccinated even if they have been previously infected with SARS-CoV-2. Although unproven, it is possible that vaccination provides broader immunity to variants than natural infection. And because we do not know how long vaccine protection will last or whether there will be variants that escape protection from vaccination, we may need immunization boosters and or reformulated vaccinations in the future.

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Article Information

Published Online: May 28, 2021. doi:10.1001/jamainternmed.2021.2966

Corresponding Author: Mitchell H. Katz, MD, NYC Health and Hospitals, 125 Worth St, Room 514, New York, NY 10013 (

Conflict of Interest Disclosures: None reported.

Vitale  J, Mumoli  N, Clerici  P,  et al.  Assessment of SARS-CoV-2 reinfection 1 year after primary infection in a population in Lombardy, Italy.   JAMA Intern Med. Published online May 28, 2021. doi:10.1001/jamainternmed.2021.2959Google Scholar
Harvey  RA, Rassen  JA, Kabelac  CA,  et al.  Association of SARS-CoV-2 seropositive antibody test with risk of future infection.   JAMA Intern Med. 2021;181(5):672-679. doi:10.1001/jamainternmed.2021.0366PubMedGoogle ScholarCrossref
Spellberg  B, Nielsen  TB, Casadevall  A.  Antibodies, immunity, and COVID-19.   JAMA Intern Med. 2021;181(4):460-462. doi:10.1001/jamainternmed.2020.7986PubMedGoogle ScholarCrossref
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    2 Comments for this article
    Terminology regarding SARS-CoV-2 reinfection
    H. Robert Silverstein, MD | Preventive Medicine Center
    My recent comment in JAMA ( 5/24/21) in JAMA is relevant to your point:

    May 24, 2021


    "It might be just as accurate to refer to an asymptomatic (+) nasal swab in people fully vaccinated + 14 days, or in people after documented infection, as "colonized" rather than as actively infected. Such language presents a more benign and reasonable consideration. "
    Protection Because of Prior SARS-CoV-2 Infection: It Is (Long Past) Time for "Immunity Passport"
    Richard Paul Junghans, PhD, MD | Boston University School of Medicine; IT Bio, LLC
    Concerning persons recovered from Covid and caveats re their immunity as alluded to by Dr Katz, I respectfully submit that an alternate take on these data may be had with broad implications.

    Firstly, to say “We do not know how long natural immunity lasts” could equally be stated “There is as yet no evidence for a breakdown of natural immunity” after more than one year of observation. CDC reported ~6000 infections among 84 million fully vaccinated individuals in April 2021. By comparison, fewer than a dozen cases world-wide with re-infection have been documented per CDC criteria among more than
    150 million recovered. Accordingly, per the CDC website: “Cases of reinfection with COVID-19 have been reported but remain rare“.

    Re cited data of Vitale et al, one must caution that none of the 5 “re-infections” in 1579 recovered subjects met CDC criteria (WGS or viral culture), and the derived rate of 6% (re)infection vs control should be viewed as an upper limit. Persistent PCR re-positivity has been seen >90 days absent direct evidence of re-infection [1,2], and two negative tests are not assurance against later non-infectious RNA shedding [3]. Yet, even allowing the possibility that some or all of the 5 are true reinfections, these data imply ≥94% protection by natural infection, at least equal and likely superior to the best vaccines.

    Any expectation of superiority of vaccine would be against a consensus of experience [e.g., 4]. The vaccine employs one protein (spike or S) to induce immune response vs natural infection exposing 29 viral proteins, any of which presented in MHC can activate T cell responses. T cells are the main bulwark of immunity against infection, with B cells and Abs playing a secondary, dispensable role in COVID [5] or other viral immunity – whereon the abiding focus on Ab durability as surrogate for immunity is seen as misdirected. For elaboration, see [6].

    Re the caveat of susceptibility to variants, risk of selective escape from T cell recognition with single-protein vaccine is already low because features selecting for higher R value [7] have no direct bearing on mechanisms of immunity – a risk even more improbable with multi-protein peptide recognition in natural infection. (Comparisons with influenza are inapt due to genome differences.)

    Finally, to conclude “all persons should be encouraged to get vaccinated even if they have been previously infected” is of more than benign, belt-and-suspenders consequence. First, although rare, serious adverse events, including death, do occur, a risk without benefit for prior infectees. Second – and of consequence at the level of any world health decision in this generation – to include immune, previously infected people in vaccination under desperate worldwide vaccine shortages, delays access for those truly in need and directly predicts tens of thousands of unnecessary deaths.

    Between infection (estimated 90 million or 40% of U.S. adults by CDC) and vaccination, the COVID pandemic in the U.S. has slowed dramatically, approaching “herd immunity.” However, other countries in the throes of pandemic, grappling with deaths and vaccine shortages, may well consider granting “Immunity Passport” status to recovered individuals at little cost to their safety and to great benefit of the many who need timely vaccination. To maximize reallocation impact, investment in mass serology screening by fingerstick ELISAs at pennies per test could expand the confirmed recovered populations to be exempted, expand the vaccines redirected and multiply the lives saved [6].


    1. Chirathaworn, et al. PLoS One. 2020;15:e0236905.  2. Harvey, et al. JAMA Intern Med. 2021:e210366. 

    3. Kang. Disaster Med Public Health Prep. 2020;14:762-4.


    5. Sekine T, et al. Cell. 2020;183:158-68.


    7. Frampton et al. Lancet Infect Dis. 2021:S1473-3099(21)00170-5.