Differential patterns of cross-reactive antibody response against SARS-CoV-2 spike protein detected for chronically ill and healthy COVID-19 naïve individuals

Abstract

Immunity to previously encountered viruses can alter response to unrelated pathogens. We reasoned that similar mechanism may also involve SARS-CoV-2 and thereby affect the specificity and the quality of the immune response against the virus. Here, we employed high-throughput next generation phage display method to explore the link between antibody immune response to previously encountered antigens and spike (S) glycoprotein. By profiling the antibody response in COVID-19 naïve individuals with a diverse clinical history (including cardiovascular, neurological, or oncological diseases), we identified 15 highly antigenic epitopes on spike protein that showed cross-reactivity with antigens of seasonal, persistent, latent or chronic infections from common human viruses. We observed varying degrees of cross-reactivity of different viral antigens with S in an epitope-specific manner. The data show that pre-existing SARS-CoV-2 S1 and S2 cross-reactive serum antibody is readily detectable in pre-pandemic cohort. In the severe COVID-19 cases, we found differential antibody response to the 15 defined antigenic and cross-reactive epitopes on spike. We also noted that despite the high mutation rates of Omicron (B.1.1.529) variants of SARS-CoV-2, some of the epitopes overlapped with the described mutations. Finally, we propose that the resolved epitopes on spike if targeted by re-called antibody response from SARS-CoV-2 infections or vaccinations can function in chronically ill COVID-19 naïve/unvaccinated individuals as immunogenic targets to boost antibodies augmenting the chronic conditions. Understanding the relationships between prior antigen exposure at the antibody epitope level and the immune response to subsequent infections with viruses from a different strain is paramount to guiding strategies to exit the COVID-19 pandemic.

Ethno‐demographic disparities in humoral responses to the COVID‐19 vaccine among healthcare workers

“…A recent study identified a total of 15 such SARS-CoV-2 spike protein epitopes that cross-react with antibodies generated against various acute and chronic viral antigens. 29 Several other studies have also reported the presence of cross-reactive antibodies in naïve or pre-COVID samples. [30][31][32][33] While several studies have assessed antibody variations in HCWs, few have investigated the association of sociodemographic factors.…”

“…This could potentially be explained by partial cross‐reactivity between preexisting antibodies from evolutionarily related viruses. A recent study identified a total of 15 such SARS‐CoV‐2 spike protein epitopes that cross‐react with antibodies generated against various acute and chronic viral antigens 29 . Several other studies have also reported the presence of cross‐reactive antibodies in naïve or pre‐COVID samples 30–33 …”

Molecular mimicry and autoimmunity in the time of COVID-19

“…One TCR distinguishes the viral/bacteria peptides, and the other is reactive to self-peptides”, and 3) “the TCR is a chimera having two β chains and one α chain, or two α chains and one β chain, which, in different mixtures, may result in recognition of self-antigens or foreign peptides inducing the development of autoimmunity” ( Fig. 1 ) [ 4 , 104 ].

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Unveiling the intricacies of COVID‐19: Autoimmunity, multi‐organ manifestations and the role of autoantibodies

“…In tandem with this discovery, samples seropositive for CMV and EBV manifested distinct antibody responses to specific SARS‐CoV‐2 epitopes. Furthermore, proteins associated with the neural and immune systems, as well as those linked to conditions like heart disease, Parkinson's disease, chronic pulmonary disease and inflammatory bowel diseases (IBD), also exhibited cross‐reactivity with specific S epitopes 108 . This cross‐reactivity underscores the potential interplay between prior immune responses and susceptibility to SARS‐CoV‐2.…”