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

To the Editor:

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,^{1 , 2} 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.³ In a cohort of health care professionals (HCPs), vaccination in previously infected individuals was associated with lower risk of reinfection over time.⁴ Some have argued that HCPs with prior infection should be exempt from vaccine mandates indefinitely.⁵

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.⁶ 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 1.

Characteristics of SARS-CoV-2 Reinfections^a

Age/sex, state	Infection dates,b test method, locally predominant variant,c vaccination status,d symptom status, other test reasone			Days between 1st and 2nd infection	Days between 2nd and 3rd infection
26/F, Florida	3/26/2020	8/2/2021	1/21/2022	494	172
	PCR	PCR	PCR
	NA	≥85% Delta	≥85% Omicron
	Unvaccinated	Unvaccinated	Unvaccinated
	Symptomatic	Symptomatic	Asymptomatic
	Occupational exposure	Household exposure	Surveillance
23/F, Wisconsin	9/7/2020	12/19/2021	1/29/2022	468	41
	PCR	PCR	PCR
	NA	Mixed delta and omicron	≥85% Omicron
	Unvaccinated	Booster overdue	Booster Overdue
	Symptomatic	Symptomatic	Symptomatic
	Community exposure
32/F, Wisconsin	10/19/2020	10/16/2021	1/24/2022	362	100
	PCR	PCR	Antigen (Flowflex)
	NA	≥85% Delta	≥85% Omicron
	Unvaccinated	Booster overdue	Booster overdue
	Symptomatic	Symptomatic	Symptomatic
	Household exposure	Household exposure	Community exposure
25/F, Minnesota	10/25/2020	9/24/2021	1/19/2022	334	117
	PCR	PCR	PCR
	NA	≥85% Delta	≥85% Omicron
	Unvaccinated	Unvaccinated	Unvaccinated
	Symptomatic	Asymptomatic	Asymptomatic
		Community exposure	Surveillance
32/F, Minnesota	11/5/2020	10/4/2021	1/3/2022	333	91
	PCR	PCR	PCR
	NA	≥85% Delta	Mixed delta/omicron
	Unvaccinated	Booster overdue	Booster overdue
	Symptomatic	Asymptomatic	Symptomatic
		Household exposure
43/M, Minnesota	11/5/2020	6/30/2021	1/25/2022	237	209
	PCR	PCR	PCR
	NA	≥85% Alpha	≥85% Omicron
	Unvaccinated	Partially vaccinated	Booster overdue
	Symptomatic	Symptomatic	Asymptomatic
27/F, Minnesota	11/7/2020	10/21/2021	1/22/22	348	93
	PCR	Antigen (On/Go)	PCR
	NA	≥85% Delta	≥85% Omicron
	Unvaccinated	Unvaccinated	Unvaccinated
	Symptomatic	Symptomatic	Asymptomatic
		Household exposure	Surveillance
25/F, Wisconsin	11/28/2020	8/9/2021	1/16/2022	254	160
	PCR	PCR	PCR
	NA	≥85% Delta	≥85% Omicron
	Unvaccinated	Booster overdue	Up to date
	Symptomatic	Symptomatic	Symptomatic
		Posttravel	Household exposure
46/F, Minnesota	12/17/2020	4/5/2021	1/22/2022	109	292
	PCR	PCR	PCR
	NA	≥85% Alpha	≥85% Omicron
	Unvaccinated	Up to date	Up to date
	Symptomatic	Asymptomatic	Symptomatic
		Pretravel
56/F, Minnesota	1/30/2021	12/23/2021	1/22/2022	327	30
	PCR	PCR	PCR
	NA	Mixed delta and omicron	≥85% Omicron
	Unvaccinated	Unvaccinated	Unvaccinated
	Asymptomatic	Asymptomatic	Symptomatic
	Surveillance	Surveillance
22/F, Minnesota	3/2/2021	9/7/2021	1/27/2022	189	142
	PCR	PCR	PCR
	≥85% Alpha	≥85% Delta	≥85% Omicron
	Unvaccinated	Unvaccinated	Up to date
	Asymptomatic	Symptomatic	Asymptomatic
	Surveillance		Surveillance

^aF, female; M, male; mRNA, messenger RNA; NA, not applicable; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

^bInfection date is date of symptom onset or date of positive test result if asymptomatic.

^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.

^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.

^ePostexposure 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.

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.⁷ Although infection and vaccination appear to impart short-term protection of a similar magnitude,⁸ vaccination may still boost immunity or provide protection against new variants in individuals with one or more natural infections.