Humoral response in SARS-CoV, MERS-CoV and SARS-CoV-2

Analyses of patients infected with SARS-CoV has revealed seroconversion four days following disease onset in some individuals and the majority of patients seroconverted between two to three weeks of disease onset in patients infected with either SARS-CoV or Middle East Respiratory syndrome (MERS-CoV). Weak or delayed antibody responses were associated with poor outcomes. Analysis of SARS-CoV convalescent human plasma revealed that SARS-neutralizing antibodies peaked at four months' post recovery, but were undetectable in 16% of patients at 36 months. Evaluation of serum from MERS-CoV patients demonstrated that high antibody titers against MERS-CoV were only likely to be present in patients who had severe disease and those titers waned within six months following recovery. Mild or asymptomatic patients with MERS exhibited no serologic response. These observations demonstrate the importance of verifying high antibody titers in potential convalescent serum donors. Some cross-reactivity was observed in five patients with confirmed SARS-CoV-2 infection with SARS-CoV in vitro, but not with other coronaviruses, suggesting that convalescent plasma used to treat SARS-CoV-2 will ideally be obtained from COVID-19 survivors.

Emerging studies have begun to characterize the antibody response seen in patients with COVID-19. To et al. evaluated serum antibody responses in 23 SARS-CoV-2 patients in Hong Kong. The majority of patients were positive for anti-RBD IgG 10 days after symptom onset and 100% of patients were positive for anti-RBD IgG 14 days following symptom onset. Severe disease was associated with earlier production and higher titer of anti-RBD IgG. More recently, the kinetics of immune responses to SARS-CoV-2 infection were described in 285 patients with COVID-19. In this cohort, the median time required for the development of anti-viral IgG and IgM was 13 days after the start of symptoms, and all patients developed anti-viral IgG within 19 days. While there was over a four-fold log difference found in the anti-viral IgG levels among patients, there was no correlation between anti-viral IgG levels and clinical outcome measures (lymphocyte numbers, C reactive protein levels, or duration of hospitalization). As neutralization activity of the anti-viral antibodies was not tested, variability in antibody effectiveness may have contributed to the lack of correlation between anti-viral IgG and clinical outcomes. The use of seroconversion as a biomarker of acquired anti-viral immunity requires determination of the antibody levels indicative of prior infection. Serial antibody testing during the course of COVID-19 infection in 41 patients within this cohort revealed that 71% either seroconverted or demonstrated a four-fold increase in IgG-specific antibody titers, meeting the established criteria for serologic evidence of MERS-CoV infection. As it is infeasible to test all individuals throughout the course of COVID-19, further evaluation of immune responses in asymptomatic, mild, and severe SARS-CoV-2-infected patients will be needed to quantify the levels and persistence of antibody titers that confer anti-viral immunity.

Recently, Quniti and colleagues in Italy have reported their experience with COVID-19 infection in seven patients with primary immunodeficiency, two with X-linked agammaglobulinemia and five with common variable immune deficiency (CVID). All patients were maintained on IVIG. Interestingly, both agammaglobulinemia patients had mild disease of short duration. In contrast, all five CVID patient had more severe, prolonged COVID-19 infection with four patients requiring mechanical ventilation and one death. CVID patients were noted to have more comorbidities. Although the experience is quite limited, the milder course in the agammaglobulinemia patients suggests antibodies or B cells may aggravate COVID-19 infection. Alternatively, CVID is generally associated with more severe immune deficiency than X-linked agammaglobulinemia and variable B and T cell defects, suggesting a critical role for cellular immunity against COVID-19. As will be discussed below, the presence of anti-viral antibodies can be associated with exacerbation of disease.