Cellular Immune Responses to SARS-CoV-2 in Exposed Seronegative Individuals.

Some SARS-CoV-2-exposed individuals develop immunity without overt infection. We identified 11 individuals who were negative by nucleic acid testing during prolonged close contact and with no serological diagnosis of infection. As this could reflect natural immunity, cross-reactive immunity from previous coronavirus exposure, abortive infection due to de novo immune responses, or other factors, our objective was to characterize immunity against SARS-CoV-2 in these individuals. Blood was processed into plasma and peripheral blood mononuclear cells (PBMC) and screened for IgG, IgA, and IgM antibodies (Ab) against SARS-CoV-2 and common ß-coronaviruses OC43 and HKU1. Receptor blocking activity and interferon-alpha (IFN-α) in plasma were also measured. Circulating T cells against SARS-CoV-2 were enumerated and CD4+ and CD8+ T cell responses discriminated after in vitro stimulation. Exposed uninfected individuals were seronegative against SARS-CoV-2 spike (S) and selectively reactive against OC43 nucleocapsid protein (N), suggesting common ß-coronavirus exposure induced Ab cross-reactive against SARS-CoV-2 N. There was no evidence of protection from circulating angiotensin-converting enzyme (ACE2) or IFN-α. Six individuals had T cell responses against SARS-CoV-2, with four involving CD4+ and CD8+ T cells. We found no evidence of protection from SARS-CoV-2 through innate immunity or immunity induced by common ß-coronaviruses. Cellular immune responses against SARS-CoV-2 were associated with time since exposure, suggesting that rapid cellular responses may contain SARS-CoV-2 infection below the thresholds required for a humoral response.

Moderate to severe SARS-CoV-2 infection primes vaccine-induced immunity more effectively than asymptomatic or mild infection.

Hybrid immunity induced by vaccination following recovery from SARS-CoV-2 infection is more robust than immunity induced by either infection or vaccination alone. To investigate how infection severity influenced the strength and character of subsequent vaccine-induced humoral or cellular immune responses against SARS-CoV-2, we assessed humoral and cellular immune responses against SARS-CoV-2 following recovery from infection, vaccine dose 1 and vaccine dose 2 in 35 persons recovered from COVID-19. Persons with polymerase chain reaction or serologically confirmed SARS-CoV-2 infection were recruited into a study of immunity against SARS-CoV-2. Self-reported symptoms categorized them as experiencing asymptomatic, mild, moderate or severe infection based on duration, intensity and need for hospitalization. Whole blood was obtained before vaccination and after first and second doses. Humoral immunity was assessed by ELISA and cellular immunity by ELISpot and intracellular flow cytometry. Responses were compared between groups recovered from either asymptomatic/mild (n = 14) or moderate/severe (n = 21) infection. Most subjects experienced robust increases in humoral and cellular immunity against SARS-CoV-2 spike (S) protein following 1 vaccination. Quantitative responses to second vaccination were marginal when measured 2.5 months afterwards and moderate or severe infection maintained stronger responses. Polyfunctional CD8+ T cell responses were largely restricted to subjects recovered from moderate or severe infection. One vaccine dose triggered stronger immune responses than in a comparable group never infected with SARS-CoV-2, while the second dose produced only minor lasting increases in humoral or cellular responses. Infection history should be considered in planning COVID-19 vaccine administration.