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Background: Immunoassays for determining past SARS-CoV-2 infection have not been systematically evaluated in vaccinated persons in comparison with unvaccinated persons.Objective: To evaluate antinucleocapsid antibody (anti-N Ab) seropositivity in mRNA-1273 (Moderna) vaccinees with breakthrough SARS-CoV-2 infection.Design: Nested substudy of a phase 3 randomized, double-blind, placebo-controlled vaccine efficacy trial. (ClinicalTrials.gov: NCT04470427).Setting: 99 sites in the United States, July 2020 through March 2021.Participants: Participants were aged 18 years or older, had no known history of SARS-CoV-2 infection, and were at risk for SARS-CoV-2 infection or severe COVID-19. Substudy participants were diagnosed with SARS-CoV-2 infection during the trial's blinded phase.Intervention: 2 mRNA-1273 or placebo injections 28 days apart.Measurements: Nasopharyngeal swabs from days 1 and 29 (vaccination days) and from symptom-prompted illness visits were tested for SARS-CoV-2 via polymerase chain reaction (PCR). Serum samples from days 1, 29, and 57 and the participant decision visit (PDV, when participants were informed of treatment assignment; median day 149) were tested for anti-N Abs by the Elecsys immunoassay.Results: Among 812 participants with PCR-confirmed COVID-19 illness during the blinded phase of the trial (through March 2021), seroconversion to anti-N Abs (median of 53 days after diagnosis) occurred in 21 of 52 mRNA-1273 vaccinees (40% [95% CI, 27% to 54%]) versus 605 of 648 placebo recipients (93% [CI, 92% to 95%]). Each 1-log increase in SARS-CoV-2 viral copies at diagnosis was associated with 90% higher odds of anti-N Ab seroconversion (odds ratio, 1.90 [CI, 1.59 to 2.28]).Limitation: The scope was restricted to mRNA-1273 vaccinees and the Elecsys assay, the sample size was small, data on Delta and Omicron infections were lacking, and the analysis did not address a prespecified objective of the trial.Conclusion: Vaccination status should be considered when interpreting seroprevalence and seropositivity data based solely on anti-N Ab testing.Primary Funding Source: National Institute of Allergy and Infectious Diseases of the National Institutes of Health. [ABSTRACT FROM AUTHOR]