Comparative Analysis of Antimicrobial Antibodies between Mild and Severe COVID-19

Abstract

Patients with 2019 coronavirus disease (COVID-19) exhibit a broad spectrum of clinical presentations. A person's antimicrobial antibody profile, as partially shaped by past infection or vaccination, can reflect the immune system health that is critical to control and resolve the infection. We performed an explorative immunoproteomics study using microbial protein arrays displaying 318 full-length antigens from 77 viruses and 3 bacteria. We compared antimicrobial antibody profiles between 135 patients with mild COVID-19 disease and 215 patients with severe disease in 3 independent cohorts from Mexico and Italy. Severe disease patients were older with higher prevalence of comorbidities. We confirmed that severe disease patients elicited a stronger anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) response. We showed that antibodies against HCoV-229E and HcoV-NL63 but not against HcoV-HKU1 and HcoV-OC43 were also higher in those who had severe disease. We revealed that for a set of IgG and IgA antibodies targeting coronaviruses, herpesviruses, and other respiratory viruses, a subgroup of patients with the highest reactivity levels had a greater incidence of severe disease compared to those with mild disease across all three cohorts. On the contrary, fewer antibodies showed consistent greater prevalence in mild disease in all 3 cohorts. IMPORTANCE The clinical presentations of COVID-19 range from asymptomatic to critical illness that may lead to intensive care or even death. The health of the immune system, as partially shaped by past infections or vaccinations, is critical to control and resolve the infection. Using an innovative protein array platform, we surveyed antibodies against hundreds of full-length microbial antigens from 80 different viruses and bacteria in COVID-19 patients from different geographic regions with mild or severe disease. We not only confirmed the association of severe COVID-19 disease with higher reactivity of antibody responses to SARS-CoV-2 but also uncovered known and novel associations with antibody responses against herpesviruses and other respiratory viruses. Our study represents a significant step forward in understanding the factors contributing to COVID-19 disease severity. We also demonstrate the power of comprehensive antimicrobial antibody profiling in deciphering risk factors for severe COVID-19. We anticipate that our approach will have broad applications in infectious diseases.

Keywords: COVID-19; SARS-CoV-2; antibody profiling; herpesvirus; human coronavirus; protein arrays; respiratory virus; virus antibody.

FIG 1

IgG (A) and IgA (B) antibodies against SARS-CoV-2 nucleocapsid protein (NC) were higher in severe COVID-19 disease than in mild disease. Each gray dot represents one COVID-19 patient. The lines indicate medians and upper and lower 25th percentiles. MNI, median normalized intensity. **, P < 0.01 (t test).

FIG 2

Comparison of IgG antibodies against nucleocapsid (NC) proteins from 7 human coronaviruses displayed on the microbial protein arrays in mild and severe COVID-19 disease. Abbreviations: HCoV-229, human coronavirus 229E; HCoV-HKU1, human coronavirus HKU1; HCoV-NL63, human coronavirus NL63; HCoV-OC43, human coronavirus OC43; MERS-CoV, Middle East respiratory syndrome-associated coronavirus; SARS-CoV, severe acute respiratory syndrome-associated coronavirus; SARS-CoV-2, severe acute respiratory syndrome-associated coronavirus 2. The lines indicate medians and upper and lower 25th percentiles. MNI, median normalized intensity. ***, P < 0.001; **, P < 0.01; ns, not significant (t test).

FIG 3

Selected IgG and IgA antibodies showing recurrent higher reactivity in severe COVID-19 disease. (A) The 7 most reactive IgG antibodies with higher reactivity in severe disease. These antibodies were selected from the 23 antibodies in Table 3. (B) The 5 IgA antibodies with high reactivity in severe disease. The x axis is labeled with the source virus name followed by the uniport ID of the target antigen. x-axis labels are colored based on microbial species. Abbreviations: HHV5, human herpesvirus 5 (cytomegalovirus); HHV1, human herpesvirus 1; HHV3, human herpesvirus 3 (varicella-zoster virus); MeV, measles morbillivirus; redundant hRSV, human respiratory syncytial virus (human orthopneumovirus); hRVC, human group C rotavirus; hCoV-229E, human coronavirus 229E; SARS-CoV, severe acute respiratory syndrome-associated coronavirus; SARS-CoV-2, severe acute respiratory syndrome-associated coronavirus 2. The lines indicate medians and upper and lower 25th percentiles. MNI, median normalized intensity. ***, P < 0.001; **, P < 0.01; *, P < 0.05; ns, not significant (t test).

FIG 4

Correlations among clinical parameters and IgG and IgA antibodies with confirmed differential reactivity between mild and severe COVID-19 disease. Clinical parameters available for more than 10% of the COVID-19 patients were included in the analysis. Red indicates a positive correlation and green indicates a negative correlation.