Baltimore, MD—Pharmacists hear it all the time: "I don't need a COVID-19 vaccine because I already had it and have natural immunity." A new study suggests that might or might not be true, because only slightly more than half of those who believed they were infected with SARS-CoV-2 but were never tested actually had COVID-19.

A research letter published in JAMA reports on a cross-sectional study of unvaccinated U.S. adults. While antibodies were detected in 99% of individuals who reported a positive COVID-19 test result, that was the case in only 55% of those who believed they had COVID-19 but were never tested. Only 11% of those who believed they had never had COVID-19 infection showed antibodies.

Anti-receptor-binding domain (RBD) levels, which come from a humoral-type immune response following contact with SARS-CoV-2, were observed after a positive COVID-19 test result up to 20 months. That significantly extended previous 6-month durability data, according to the Johns Hopkins School of Medicine researchers.

"Previous COVID-19 infection is a possible surrogate for natural immunity, but 1 study suggested that 36% of COVID-recovered individuals are serologic nonresponders," the authors write to explain why they embarked on the study. "Even among individuals who develop antibodies, durability of this response beyond 6 months remains unknown. We characterized natural immunity and long-term durability among unvaccinated individuals using anti-spike antibodies, the first line of defense against SARS-CoV-2."

Researchers recruited healthy adults who reported no SARS-CoV-2 vaccination via a Twitter post and Facebook advertisement between September 11, 2021, and October 8, 2021. After participants completed an online questionnaire about demographics, COVID-19 status, and mask use, the study team created three equally sized sample groups among those who reported a test-confirmed COVID-19 infection ("COVID-confirmed"), believed they had COVID-19 but were never tested ("COVID-unconfirmed"), and did not believe they ever had COVID-19 and never tested positive ("no-COVID").

Antibody testing/qualitative detection of antibodies against the SARS-CoV-2 antinucleocapsid (N) protein (positive cutoff index >1.0) and semiquantitative detection of antibodies against the SARS-CoV-2 spike protein RBD (positive cutoff >0.8 U/mL)—of the group member occurred at LabCorp facilities nationwide.

Overall, 816 of 1,580 respondents who agreed to participate underwent serologic testing; they had a mean age of 48.0 years, 421 (52%) were women, and 669 (82%) were White. Of those, 14% reported routine mask use in public.

Results indicate that among 295 reported COVID-confirmed participants, 293 (99%) tested positive for anti-RBD antibodies (>250 U/mL, 44%; >500 U/mL, 27%; >1,000 U/mL, 15%). A median of 8.7 (IQR, 1.9-12.9; range, 0-20) months had passed since reported COVID-19 diagnosis. The median anti-RBD level among those who tested positive was 205 (IQR, 61-535) U/mL, although researchers advise that there was no evidence of an association between time after infection and antibody titer (0.8% increase [95% CI, –2.4% to 4.2%] per month, P = .62).

Among 275 reported COVID-unconfirmed participants, 152 (55%) tested positive for anti-RBD antibodies (>250 U/mL, 18%; >500 U/mL, 12%; >1,000 U/mL, 6%), with the median level among those who tested positive at 131 (IQR, 35-402) U/mL.

Among 246 reported no-COVID participants, 11% tested positive for anti-RBD antibodies (>250 U/mL, 2%; >500 U/mL, 2%; >1,000 U/mL, 2%). The median level among those who tested positive was 82 (IQR, 19-172) U/mL.

"Although evidence of natural immunity in unvaccinated healthy US adults up to 20 months after confirmed COVID-19 infection is encouraging, it is unclear how these antibody levels correlate with protection against future SARS-CoV-2 infections, particularly with emerging variants," the authors write. "The public health implications and long-term understanding of these findings merit further consideration."

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