Assessment of SARS-CoV-2 Reinfection 1 Year After Primary Infection in a Population in Lombardy, Italy | Infectious Diseases | JAMA Internal Medicine | JAMA Network
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Figure.  Cumulative Incidence of SARS-Cov-2 Infection
Cumulative Incidence of SARS-Cov-2 Infection

RT-PCR indicates reverse-transcriptase–polymerase chain reaction.

Table.  Population Characteristics
Population Characteristics
1.
Lumley  SF, O’Donnell  D, Stoesser  NE,  et al; Oxford University Hospitals Staff Testing Group.  Antibody status and Incidence of SARS-CoV-2 Infection in Health Care Workers.   N Engl J Med. 2021;384(6):533-540. doi:10.1056/NEJMoa2034545 PubMedGoogle ScholarCrossref
2.
Hall  VJ, Foulkes  S, Charlett  A,  et al; SIREN Study Group.  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(10283):1459-1469. doi:10.1016/S0140-6736(21)00675-9PubMedGoogle ScholarCrossref
3.
Hansen  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(10280):1204-1212. doi:10.1016/S0140-6736(21)00575-4PubMedGoogle ScholarCrossref
4.
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
5.
US Centers for Disease Control and Prevention. Investigative criteria for suspected cases of SARS-CoV-2 reinfection (ICR). Accessed March 1, 2021. https://www.cdc.gov/coronavirus/2019-ncov/php/invest-criteria.html
6.
Mumoli  N, Vitale  J, Mazzone  A.  Clinical immunity in discharged medical patients with COVID-19.   Int J Infect Dis. 2020;99:229-230. doi:10.1016/j.ijid.2020.07.065PubMedGoogle ScholarCrossref
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    2 Comments for this article
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    Persistent Cellular Immunity
    Peppino Peppino, MD ADJUNCT PROFESSOR | University of PALERMO post graduate medical school

    This paper is consistent with the growing body of literature that suggests that immunity elicited by SARS-CoV-2 infection lasts longer than it is thought (1). People, who were infected and get subsequent vaccination, have an enormous response with a massive quantity of antibodies, because they continue to develop their antibodies and probably immunity will be long lived (2). Reinfections by seasonal flu occur 6-12 months after the previous infection, indicating that protective immunity against these viruses may be short-lived. Similar early reports in convalescent SARS-CoV-2 patients documented rapidly declining antibody titers suggested that protective immunity may be
    also transient. Ali H Ellebedy, who led the study published recently in Nature on 24 May, found in the bone marrow of people, who were infected and later vaccinated, certain immune longer-lasting cells: memory B cells. These bone marrow plasma cells  may survive, hided away in bones, patrol the blood for reinfection and may create antibodies whenever needed for decades. Long-lived bone marrow plasma cells  are a persistent and essential source of protective antibodies. Ellebedy’s team had observed that a mRNA vaccine should trigger the production of the same cells (3). Hope, might be, as the memory B cells were also be able to neutralize some COVID-19 variants.

    1 ) Hansen 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(10280):1204-1212. doi:10.1016/S0140-6736(21)00575-4
    2 ) Turner, J.S., Kim, W., Kalaidina, E. et al. SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans. Nature (2021). https://doi.org/10.1038/s41586-021-03647-4
    3 ) Ellebedy, A. et al. Preprint at Research Square https://doi.org/10.21203/rs.3.rs-310773/v1 (2021).
    CONFLICT OF INTEREST: None Reported
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    We must stop ignoring natural immunity - it’s now long overdue
    Manish Joshi, MD | CAVHS
    This article by Vitale et al is another addition to a growing body of literature supporting the conclusion that natural immunity confers robust, durable, and high-level protection against COVID-19 (1-4). Yet some scientific journals, editorial commentary associated with this article, and public policy messaging continue to cast doubt. That doubt has real-world consequences for resource limited countries. We would like to review available data.

    Infection generates immunity. The “SIREN” study in the Lancet addressed the relationships between seropositivity in people with previous COVID-19 infection and subsequent risk of severe acute respiratory syndrome due to SARS-CoV-2 infection over the
    subsequent 7-12 months (1). Prior infection decreased risk of symptomatic re-infection by 93%. A large cohort study published in JAMA Internal Medicine looked at 3.2 million US patients and showed that the risk of infection was significantly lower (0.3%) in seropositive patients v/s those who are seronegative (3%) (2).

    Perhaps even more important to the question of duration of immunity is a recent study that has demonstrated the presence of long-lived memory immune cells in those who have recovered from COVID-19 (3). This implies a prolonged (perhaps years) capacity to respond to new infection with new antibodies.

    In contrast to this collective data demonstrating both adequate and long-lasting protection in those who have recovered from COVID-19, the duration of vaccine-induced immunity is not fully known. To date >10,000 breakthrough infections (2 weeks after completion of vaccination) have been reported by CDC in the US, with a mortality of ~2% (5).

    How should we use the collective data to prioritize vaccination? These new data support simple and logical concepts. The goal of vaccination is to generate memory cells that can recognize SARS-CoV-2 and rapidly generate neutralizing antibodies that either prevent or mitigate both infection and transmission. Those who have survived COVID-19 must almost by definition have mounted an effective immune response; it is not surprising that the evolving literature shows that prior infection decreases vulnerability. In our view, the data suggest that people confirmed to have been infected with SARS-CoV-2 may not need vaccination, and  do not need vaccination in the short term. Given the number of persons who have been infected, this simple approach could free up vaccine (estimated ~200 million doses) for the more vulnerable population around the globe and could accelerate vaccine roll-out tremendously for those in need.(6) We should not be debating the implications of prior infection; we should be debating how to confirm prior infection.

    Manish Joshi, MD
    Thaddeus Bartter, MD
    Anita Joshi, BDS, MPH

    1. Hall 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
    2. Harvey RA, Rassen JA, Kabelac CA, et al. Association of SARS-CoV-2 Seropositive Antibody Test With Risk of Future Infection. JAMA Intern Med.
    3. Turner, J.S., Kim, W., Kalaidina, E. et al. SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans. Nature 2021
    4. Wang, Z., Yang, X., Zhong, J. et al. Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection. Nat Commun 12, 1724 (2021).
    5. https://www.cdc.gov/mmwr/volumes/70/wr/mm7021e3.htm
    6. Kuehn BM. High-Income Countries Have Secured the Bulk of COVID-19 Vaccines. JAMA. 2021;325(7):612
    CONFLICT OF INTEREST: None Reported
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    Research Letter
    May 28, 2021

    Assessment of SARS-CoV-2 Reinfection 1 Year After Primary Infection in a Population in Lombardy, Italy

    Author Affiliations
    • 1Magenta Hospital, ASST Ovest Milanese, Magenta, Italy
    • 2Legnano Hospital, ASST Ovest Milanese, Legnano, Italy
    JAMA Intern Med. 2021;181(10):1407-1408. doi:10.1001/jamainternmed.2021.2959

    Despite more than 150 million people becoming infected worldwide, SARS-CoV-2 reinfections are uncommon. The risk of a second infection in the population who has recovered from COVID-19 is crucial to improve quarantine management and optimize the ongoing vaccination campaign. The rate of reinfection among health care workers has been reported,1,2 but the rate of reinfection in the general population is less clear.3,4

    Methods

    We investigated the incidence of SARS-CoV-2 primary infection and reinfection among individuals who, during the first wave of the pandemic in Italy (February to July 2020), underwent diagnostic reverse-transcriptase–polymerase chain reaction (PCR; see eAppendix in the Supplement for the platform and specifics). Symptomatic and asymptomatic patients of any age, who were recruited in several screening and contact-tracing programs, were included. We obtained the approval of the local ethics committee, which, because of the observational characteristic of the study, granted a waiver of informed consent for participants. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.

    The study laboratory serves 4 hospitals (1400 beds) and one of the most severely affected sanitarian areas (560 Kmq; 470 000 inhabitants) in Lombardy, Italy, yielding 122 007 PCR test results. We defined cases (those with infection who were PCR-positive) and controls (those without infection who were PCR-negative) according to the World Health Organization guidelines; criteria are specified in eAppendix in the Supplement. The cohorts were considered to be at risk from the time of the first definition (date of positive test result for cases; date of second negative test result for controls) until the end of the observation (February 28, 2021) or a new positive PCR test result. Reinfections were defined by a second RT-PCR positivity beyond 90 days after complete resolution of the first infection and with at least 2 consecutive negative test results between episodes.5 The 90-day window was decided on the basis of reports of RNA virus persistence until 12 weeks.5 Statistical analyses were conducted using JMP, version 14.0 (SAS Institute), and Prism, version 9.0.2 (GraphPad). Statistical significance was set at P < .05.

    Results

    The baseline demographic characteristics are shown in the Table. The median (interquartile range) age of the patients was 59 (40-78) years, but positive cases were older and geographically distributed more in the industrial area of Legnano.

    During the follow-up (mean [SD], 280 [41] days) 5 reinfections (0.31%; 95% CI, 0.03%-0.58%) were confirmed in the cohort of 1579 positive patients. Most of these patients were evaluated, treated, and followed in hospitals or dedicated COVID-19 ambulatories.6 Only 1 was hospitalized, and 4 patients had a close relationship (2 patients work in hospitals, 1 patient underwent transfusions every week, and 1 patient retired in a nursing home) with health facilities. The mean (SD) interval between primary infection and reinfection was longer than 230 (90) days.

    Of 13 496 persons who initially were not infected with SARS-CoV-2, 528 (3.9%; 95% CI, 3.5%-4.2%) subsequently developed a primary infection. The incidence density per 100 000 person days was 1.0 (95% CI, 0.5-1.5) for reinfections compared with 15.1 (95% CI, 14.5-15.7) for new infections, while the incidence rate ratio adjusted for age, sex, ethnicity, and the sanitarian area was 0.07 (95% CI, 0.06-0.08). After analyzing the cumulative incidence during follow-up, we confirmed that the 2 cohorts were significantly different (hazard ratio, 0.06; 95% CI, 0.05-0.08; log-rank test P < .001) (Figure).

    Discussion

    The study results suggest that reinfections are rare events and patients who have recovered from COVID-19 have a lower risk of reinfection. Natural immunity to SARS-CoV-2 appears to confer a protective effect for at least a year, which is similar to the protection reported in recent vaccine studies. However, the observation ended before SARS-CoV-2 variants began to spread, and it is unknown how well natural immunity to the wild-type virus will protect against variants.

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    Article Information

    Accepted for Publication: May 3, 2021.

    Published Online: May 28, 2021. doi:10.1001/jamainternmed.2021.2959

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Vitale J et al. JAMA Internal Medicine.

    Corresponding Author: Nicola Mumoli, MD, Department of Internal Medicine, Ospedale Fornaroli; via al Donatore di Sangue 50, 20013 Magenta (MI), Italy (nimumoli@tiscali.it).

    Author Contributions: Dr Mumoli had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Vitale and Mumoli contributed equally to this letter.

    Concept and design: Vitale, Mumoli, Clerici, Mazzone.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Vitale, Mumoli, Clerici.

    Critical revision of the manuscript for important intellectual content: Vitale, Mumoli, De Paschale, Evangelista, Cei, Mazzone.

    Statistical analysis: Vitale, Mumoli.

    Obtained funding: Clerici.

    Administrative, technical, or material support: Mumoli, Clerici, De Paschale.

    Supervision: Mumoli, Clerici, Evangelista, Mazzone.

    Conflict of Interest Disclosures: None reported.

    References
    1.
    Lumley  SF, O’Donnell  D, Stoesser  NE,  et al; Oxford University Hospitals Staff Testing Group.  Antibody status and Incidence of SARS-CoV-2 Infection in Health Care Workers.   N Engl J Med. 2021;384(6):533-540. doi:10.1056/NEJMoa2034545 PubMedGoogle ScholarCrossref
    2.
    Hall  VJ, Foulkes  S, Charlett  A,  et al; SIREN Study Group.  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(10283):1459-1469. doi:10.1016/S0140-6736(21)00675-9PubMedGoogle ScholarCrossref
    3.
    Hansen  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(10280):1204-1212. doi:10.1016/S0140-6736(21)00575-4PubMedGoogle ScholarCrossref
    4.
    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
    5.
    US Centers for Disease Control and Prevention. Investigative criteria for suspected cases of SARS-CoV-2 reinfection (ICR). Accessed March 1, 2021. https://www.cdc.gov/coronavirus/2019-ncov/php/invest-criteria.html
    6.
    Mumoli  N, Vitale  J, Mazzone  A.  Clinical immunity in discharged medical patients with COVID-19.   Int J Infect Dis. 2020;99:229-230. doi:10.1016/j.ijid.2020.07.065PubMedGoogle ScholarCrossref
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