Relative Ratios of Human Seasonal Coronavirus Antibodies Predict the Efficiency of Cross-Neutralization of SARS-CoV-2 Spike Binding to ACE2

Abstract

Antibodies raised against highly prevalent human seasonal coronaviruses (sCoVs), which are responsible for the common cold, are known to cross-react with SARS-CoV-2 antigens. This cross-reactivity prompts questions about their protective role against SARS-CoV-2 infections and COVID-19 disease severity. However, the relationship between sCoV exposure and SARS-CoV-2 correlates of protection have not been clearly identified. Here we performed a cross-sectional analysis of cross-reactivity and cross-neutralization to three SARS-CoV-2 antigens using pre-pandemic serum from four different groups: pediatrics and adolescents (<21 yrs of age), persons 21 to 70 yrs of age, persons older than 70 yrs of age, and persons living with HCV or HIV. We find that antibody cross-reactivity to SARS-CoV-2 antigens varied between 1.6% and 15.3% depending on the cohort and the isotype-antigen pair analyzed. We also demonstrate a broad range of neutralizing activity (0-45%) in pre-pandemic serum that interferes with SARS-CoV-2 spike attachment to ACE2. While the abundance of sCoV antibodies did not directly correlate with neutralization efficiency, by using machine learning methodologies, we show that neutralizing activity is rather dependent on the latent variables related to the pattern ratios of sCoVs antibodies presented by each person. These were independent of age or sex, and could be accurately predicted by comparing the relative ratios of IgGs in sera directed to NL63, 229E, HKU-1, and OC43 spike proteins. More specifically, we identified antibodies to NL63 and OC43 as being the two most important predictors of latent variables responsible for protection, and 229E as being the least weighted. Our data support that exposure to sCoVs triggers various cellular and immune responses that influence the efficiency of SARS-CoV-2 spike binding to ACE2, and may impact COVID-19 disease severity through various other latent variables.

A scalable serology solution for profiling humoral immune responses to SARS‐CoV‐2 infection and vaccination

“…Convalescent samples ranged from 0% to 100% inhibition, with a median value of 70%. The six negative samples ranged from 0% to 32% inhibition with a median of 26%, consistent with our previous observation that pre‐pandemic samples can achieve partial inhibition of the spike‐ACE2 interaction due to cross‐reactivity of antibodies targeting seasonal coronaviruses 20 . For DBS samples, four 3 mm punches eluted in 100 μL of PBS from a double‐vaccinated individual showed measurable neutralisation activity (Supplementary figure 15); however, we were unable to measure neutralisation in DBS samples from convalescent or singly vaccinated individuals (in contrast to serum).…”

A scalable serology solution for profiling humoral immune responses to SARS-CoV-2 infection and vaccination

“…Convalescent samples ranged from 0-100% inhibition, with a median value of 70%. The six negative samples ranged from 0-32% inhibition with a median of 26%, consistent with our previous observation that pre-pandemic samples can achieve partial inhibition of the spike-ACE2 interaction due to cross-reactivity of antibodies targeting seasonal coronaviruses 20 . For DBS samples, four 3 mm punches eluted in 100 μL of PBS from a double-vaccinated individual showed measurable neutralization activity (Supplementary figure 15); however, we were unable to measure neutralization in DBS samples from convalescent or singly vaccinated individuals (in contrast to serum).…”

Pre-Existing Cross-Reactive Antibody Responses Do Not Significantly Impact Inactivated COVID-19 Vaccine-Induced Neutralization

“…In previous studies of pre-pandemic cohorts, 4.2%-4.9% of serum samples displayed IgG reactivity against the SARS-CoV-2 S antigen, indicating cross-reactivity between SARS-CoV-2 and sCoVs (7,31). Immunity to sCoVs appears to last approximately 1 year, and re-infection with the same CoV frequently occurs beyond 12 months after infection (32).…”

“…Immunity to sCoVs appears to last approximately 1 year, and re-infection with the same CoV frequently occurs beyond 12 months after infection (32). Repeated infection leads to a high seroprevalence of sCoVs, with studies showing seroprevalence rates of 82.9% for OC43, 82.1% for 229E, 74.6% for NL63, and 59.2% for HKU-1 (31). Due to the high prevalence, a major hurdle in estimating the seroprevalence of IgG against sCoVs is the lack of a true negative reference population.…”

“…Some studies have shown that the pre-existing immune response to sCoVs mitigates the symptoms of SARS-CoV-2 infection and reduces the occurrence of severe COVID-19, with benefits including lower rates of intensive care unit (ICU) admission and death (33,34). Galipeau et al found a broad range of neutralizing activity (0-45%) in pre-pandemic serum samples, especially for NL63 and OC43 antibodies, which could interfere with the binding of SARS-CoV-2 to ACE2 receptors, so as to confer protection (31). In contrast, some studies have revealed that the highly cross-reactive OC43 S-IgG antibody titer, as a risk factor, is related to COVID-19 severity (16).…”