Multiple SARS-CoV-2 Reinfections: A Case Series of Thrice-Infected Individuals

More than 1 in 4 individuals in the United States have now experienced a COVID-19 (coronavirus disease 2019) infection. Symptomatic reinfection despite positive serology has been documented,1Gargouri S. Souissi A. Abid N. et al.Evidence of SARS-CoV-2 symptomatic reinfection in four healthcare professionals from the same hospital despite the presence of antibodies.Int J Infect Dis. 2022; 117: 146-154Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar,2Zhang J. Ding N. Ren L. et al.COVID-19 reinfection in the presence of neutralizing antibodies.Natl Sci Rev. 2021; 8nwab006Crossref Scopus (14) Google Scholar but little is known about the impact of reinfection on subsequent natural immunity. In a study conducted prior to the omicron variant’s prevalence, vaccination added no additional protection to natural immunity in the first year; however, booster impact was not ascertained.3León T.M. Dorabawila V. Nelson L. et al.COVID-19 cases and hospitalizations by COVID-19 vaccination status and previous COVID-19 diagnosis—California and New York, May-November 2021.MMWR Morb Mortal Wkly Rep. 2022; 71: 125-131Crossref PubMed Scopus (34) Google Scholar In a cohort of health care professionals (HCPs), vaccination in previously infected individuals was associated with lower risk of reinfection over time.4Shrestha N.K. Burke P.C. Nowacki A.S. Terpeluk P. Gordon S.M. Necessity of COVID-19 vaccination in persons who have already had COVID-19.https://doi.org/10.1093/cid/ciac022Google Scholar Some have argued that HCPs with prior infection should be exempt from vaccine mandates indefinitely.5McGonagle D.G. Health-care workers recovered from natural SARS-CoV-2 infection should be exempt from mandatory vaccination edicts.Lancet Rheumatol. 2022; 4e170Abstract Full Text Full Text PDF Scopus (2) Google Scholar We identified 11 HCPs with a distinct third infection (Table). Cases were captured via a robust program to identify and evaluate infected HCPs as previously described.6Breeher L. Boon A. Hainy C. Murad M.H. Wittich C. Swift M. A framework for sustainable contact tracing and exposure investigation for large health systems.Mayo Clin Proc. 2020; 95: 1432-1444Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar All HCPs were employed by a large health care institution with sites in 4 states employing over 73,000 HCPs. The study was deemed exempt by the Mayo Clinic Institutional Review Board (20-003887). Infections were classified as a repeat infection if occurring more than 90 days after a prior infection or if new COVID-19 symptoms began after complete resolution of prior symptoms. The 2 individuals reinfected within 90 days reported new anosmia. The median age was 27 years (range, 22 to 56 years), and 10 of the 11 HCPs were female. Of the first infections, 90.9% (10 of 11) occurred before the emergence of variants; 63.6% of second infections (7 of 11) occurred during delta variant predominance, and 90.9% of third infections (10 of 11) occurred during omicron prevalence. Vaccination status at the time of the 33 infections was unvaccinated in 20 (60.6%), booster overdue in 8 (24.2%), up to date in 4 (12.1%), or partially vaccinated in 1 (3.0%). Among the 11 HCPs, first, second, and third infections were asymptomatic in 2 (18.2%), 4 (36.4%), and 5 (45.4%), respectively. One second infection required hospitalization; no HCPs endorsed immunosuppression. The mean time to second infection was 314 days (95% CI, 238 to 390 days), while the mean interval between the second and third infection was 110 days (95% CI, 81 to 183 days) (P=.008 for difference in means).Table 1Characteristics of SARS-CoV-2 ReinfectionsaF, female; M, male; mRNA, messenger RNA; NA, not applicable; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.Age/sex, stateInfection dates,bInfection date is date of symptom onset or date of positive test result if asymptomatic. test method, locally predominant variant,cPredominant circulating strain at the time of the infection in the individual’s state per nextstrain.org. If a single variant accounted for ≥85% of sequenced infections, that variant is listed alone. If no variant accounted for 85% of infections, all circulating strains identified at that time in that state are listed. vaccination status,dVaccination status is “unvaccinated” when no doses have been received, “partially vaccinated” when one dose of mRNA vaccine has been received or a primary vaccination series was completed in the prior 14 days, “up to date” when a booster dose has been received or is not yet due (primary vaccination with mRNA vaccine was completed within the prior 5 months or Janssen vaccine within the prior 2 months), and “booster overdue” when primary vaccination with mRNA vaccine was completed more than 5 months earlier or Janssen vaccine more than 2 months earlier. symptom status, other test reasonePostexposure tests were performed within 14 days of prolonged close contact with a communicable source without recommended personal protective equipment. Surveillance testing programs were in place starting September 2, 2020, for workers in long-term care facilities and January 17, 2022, for unvaccinated staff.Days between 1st and 2nd infectionDays between 2nd and 3rd infection26/F, Florida3/26/20208/2/20211/21/2022494172PCRPCRPCRNA≥85% Delta≥85% OmicronUnvaccinatedUnvaccinatedUnvaccinatedSymptomaticSymptomaticAsymptomaticOccupational exposureHousehold exposureSurveillance23/F, Wisconsin9/7/202012/19/20211/29/202246841PCRPCRPCRNAMixed delta and omicron≥85% OmicronUnvaccinatedBooster overdueBooster OverdueSymptomaticSymptomaticSymptomaticCommunity exposure32/F, Wisconsin10/19/202010/16/20211/24/2022362100PCRPCRAntigen (Flowflex)NA≥85% Delta≥85% OmicronUnvaccinatedBooster overdueBooster overdueSymptomaticSymptomaticSymptomaticHousehold exposureHousehold exposureCommunity exposure25/F, Minnesota10/25/20209/24/20211/19/2022334117PCRPCRPCRNA≥85% Delta≥85% OmicronUnvaccinatedUnvaccinatedUnvaccinatedSymptomaticAsymptomaticAsymptomaticCommunity exposureSurveillance32/F, Minnesota11/5/202010/4/20211/3/202233391PCRPCRPCRNA≥85% DeltaMixed delta/omicronUnvaccinatedBooster overdueBooster overdueSymptomaticAsymptomaticSymptomaticHousehold exposure43/M, Minnesota11/5/20206/30/20211/25/2022237209PCRPCRPCRNA≥85% Alpha≥85% OmicronUnvaccinatedPartially vaccinatedBooster overdueSymptomaticSymptomaticAsymptomatic27/F, Minnesota11/7/202010/21/20211/22/2234893PCRAntigen (On/Go)PCRNA≥85% Delta≥85% OmicronUnvaccinatedUnvaccinatedUnvaccinatedSymptomaticSymptomaticAsymptomaticHousehold exposureSurveillance25/F, Wisconsin11/28/20208/9/20211/16/2022254160PCRPCRPCRNA≥85% Delta≥85% OmicronUnvaccinatedBooster overdueUp to dateSymptomaticSymptomaticSymptomaticPosttravelHousehold exposure46/F, Minnesota12/17/20204/5/20211/22/2022109292PCRPCRPCRNA≥85% Alpha≥85% OmicronUnvaccinatedUp to dateUp to dateSymptomaticAsymptomaticSymptomaticPretravel56/F, Minnesota1/30/202112/23/20211/22/202232730PCRPCRPCRNAMixed delta and omicron≥85% OmicronUnvaccinatedUnvaccinatedUnvaccinatedAsymptomaticAsymptomaticSymptomaticSurveillanceSurveillance22/F, Minnesota3/2/20219/7/20211/27/2022189142PCRPCRPCR≥85% Alpha≥85% Delta≥85% OmicronUnvaccinatedUnvaccinatedUp to dateAsymptomaticSymptomaticAsymptomaticSurveillanceSurveillancea F, female; M, male; mRNA, messenger RNA; NA, not applicable; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.b Infection date is date of symptom onset or date of positive test result if asymptomatic.c Predominant circulating strain at the time of the infection in the individual’s state per nextstrain.org. If a single variant accounted for ≥85% of sequenced infections, that variant is listed alone. If no variant accounted for 85% of infections, all circulating strains identified at that time in that state are listed.d Vaccination status is “unvaccinated” when no doses have been received, “partially vaccinated” when one dose of mRNA vaccine has been received or a primary vaccination series was completed in the prior 14 days, “up to date” when a booster dose has been received or is not yet due (primary vaccination with mRNA vaccine was completed within the prior 5 months or Janssen vaccine within the prior 2 months), and “booster overdue” when primary vaccination with mRNA vaccine was completed more than 5 months earlier or Janssen vaccine more than 2 months earlier.e Postexposure tests were performed within 14 days of prolonged close contact with a communicable source without recommended personal protective equipment. Surveillance testing programs were in place starting September 2, 2020, for workers in long-term care facilities and January 17, 2022, for unvaccinated staff. Open table in a new tab This case series is subject to limitations. Following current public health guidance, postinfection testing to document polymerase chain reaction clearance was not routinely performed. However, persistence of polymerase chain reaction positivity longer than 90 days in immunocompetent individuals is unusual. Second, most third infections occurred during the omicron surge, and other variants may not display the same immune evasion to natural immunity. Third, the number of infections is too small to draw conclusions about the protective effect of prior infection or vaccination. Finally, samples were not available for genetic sequencing to confirm the variant(s) causing infection. This case series provides new evidence of the potential for multiple reinfections in immunocompetent individuals. We noted a shorter interval between the second and third infections compared with the interval between the first and second infections, recognizing that almost all third infections occurred while the omicron variant was the predominant circulating strain. Omicron is known to partially evade vaccine-mediated and natural immunity.7Altarawneh HN, Chemaitelly H, Hasan MR, et al. Protection against the omicron variant from previous SARS-CoV-2 infection [published online ahead of print February 9, 2022]. N Engl J Med. doi: 10.1056/NEJMc2200133Google Scholar Although infection and vaccination appear to impart short-term protection of a similar magnitude,8Kojima N. Shrestha N.K. Klausner J.D. A systematic review of the protective effect of prior SARS-CoV-2 infection on repeat infection.Eval Health Prof. 2021; 44: 327-332Crossref PubMed Scopus (17) Google Scholar vaccination may still boost immunity or provide protection against new variants in individuals with one or more natural infections. Author contributions: Dr Swift—conceptualization, formal analysis, investigation, data curation, writing/original draft, visualization, and supervision; Dr Hainy—investigation, data curation, and writing/reviewing and editing; Dr Sampathkumar—validation, writing/reviewing and editing; Dr Breeher—conceptualization, validation, and writing/reviewing and editing.