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Lasting immunity will be critical for overcoming COVID-19. However, the factors associated with the development of high titers of anti–SARS-CoV-2 Abs and how long those Abs persist remain incompletely defined. In particular, an understanding of the relationship between COVID-19 symptoms and anti–SARS-CoV-2 Abs is limited. To address these unknowns, we quantified serum anti–SARS- CoV-2 Abs in clinically diverse COVID-19 convalescent human subjects 5 wk (n = 113) and 3 mo (n = 79) after symptom resolution with three methods: a novel multiplex assay to quantify IgG against four SARS-CoV-2 Ags, a new SARS-CoV-2 receptor binding domain-angiotensin converting enzyme 2 inhibition assay, and a SARS-CoV-2 neutralizing assay. We then identified clinical and demographic factors, including never-before-assessed COVID-19 symptoms, that consistently correlate with high anti–SARS-CoV-2 Ab levels. We detected anti–SARS-CoV-2 Abs in 98% of COVID-19 convalescent subjects 5 wk after symptom resolution, and Ab levels did not decline at 3 mo. Greater disease severity, older age, male sex, higher body mass index, and higher Charlson Comorbidity Index score correlated with increased anti–SARS-CoV-2 Ab levels. Moreover, we report for the first time (to our knowledge) that COVID-19 symptoms, most consistently fever, body aches, and low appetite, correlate with higher anti–SARS-CoV-2 Ab levels. Our results provide robust and new insights into the development and persistence of anti–SARS-CoV-2 Abs.

The consequences of past COVID-19 infection for personal health and long-term population immunity are only starting to be revealed. Unfortunately, detecting past infection is currently a challenge, limiting clinical and research endeavors. Widely available anti-SARS-CoV-2 antibody tests cannot differentiate between past infection and vaccination given vaccine-induced anti-spike antibodies and the rapid loss of infection-induced anti-nucleocapsid antibodies. Anti-membrane antibodies develop after COVID-19, but their long-term persistence is unknown. Here, we demonstrate that anti-membrane IgG is a sensitive and specific marker of past COVID-19 infection and persists at least one year. We also confirm that anti-receptor binding domain (RBD) Ig is a long-lasting, sensitive, and specific marker of past infection and vaccination, while anti-nucleocapsid IgG lacks specificity and quickly declines after COVID-19. Thus, a combination of anti-membrane and anti-RBD antibodies can accurately differentiate between distant COVID-19 infection, vaccination, and naïve states to advance public health, individual healthcare, and research goals.

Lasting immunity will be critical for overcoming COVID-19. However, the factors associated with the development of high titers of anti-SARS-CoV-2 antibodies and how long those antibodies persist remain incompletely defined. In particular, an understanding of the relationship between COVID-19 symptoms and anti-SARS-CoV-2 antibodies is limited. To address these unknowns, we quantified serum anti-SARS-CoV-2 antibodies in clinically diverse COVID-19 convalescent human subjects five weeks (n=113) and three months (n=79) after symptom resolution with three methods: a novel multiplex assay to quantify IgG against four SARS-CoV-2 antigens, a new SARS-CoV-2 receptor binding domain-angiotensin converting enzyme 2 inhibition assay, and a SARS-CoV-2 neutralizing assay. We then identified clinical and demographic factors, including never before assessed COVID-19 symptoms, that consistently correlate with high anti-SARS-CoV-2 antibody levels. We detected anti-SARS-CoV-2 antibodies in 98% of COVID-19 convalescent subjects five weeks after symptom resolution and antibody levels did not decline at three months. Greater disease severity, older age, male sex, higher body mass index, and higher Charlson Comorbidity Index score correlated with increased anti-SARS-CoV-2 antibody levels. Moreover, we report for the first time that COVID-19 symptoms, most consistently fever, body aches, and low appetite, correlate with higher anti-SARS-CoV-2 antibody levels. Our results provide robust and new insights into the development and persistence of anti-SARS-CoV-2 antibodies.