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IntroductionIn this series of studies, immunoglobulin products (IgG) formulated for different routes of administration (IV, IM, SC) and prepared from geographically diverse plasma pools were tested for activity against common human coronaviruses (HCoV). IgG products from plasma obtained from Germany, Czech Republic, Slovak Republic, USA and Spain were tested for antibodies to four common HCoV: 229E, OC43, NL63 and HKU1. Since these products are manufactured from pooled plasma from thousands of donors, the antibodies therein are a representation of the HCoV exposure of the population at large.MethodsIgG products of different concentrations manufactured from geographically diverse plasma pools were tested for antibodies to four common HCoV by ELISA. In addition, neutralization assays were conducted using HCoV-229E expressed in MRC5 cells. Complete concentration-neutralization curves were obtained to calculate potencies.ResultsThe ELISA assays showed that when expressed as specific activity (anti-HCoV activity/mg IgG) similar activity against the four common HCoV was seen across the IgG products regardless of concentration or geographic origin. Highest anti-HCoV activity was seen against HCoV-229E, followed by HCoV-OC43 and then HCoV-NL63 and HCoV-HKU1. The neutralization assays showed similar potency for two preparations of IgG prepared by different processes.ConclusionsThese studies are the first demonstration of antibodies to common HCoV in IgG products. The level of activity was similar regardless of the geographic origin of the plasma pool. These antibodies demonstrated neutralization activity against HCoV-229E in MRC5 cells. These results may explain the cross-reactivity seen with pre-pandemic IgG products and SARS-CoV-2 and contribute to the variability in disease course in different patients.

BackgroundAntibodies raised against human seasonal coronaviruses (sCoVs), which are responsible for the common cold, are known to cross-react with SARS-CoV-2 antigens. This prompts questions about their protective role against SARS-CoV-2 infections and COVID-19 severity. However, the relationship between sCoV exposure and SARS-CoV-2 correlates of protection are not clearly identified.MethodsWe performed a cross-sectional analysis of cross-reactivity and cross-neutralization to SARS-CoV-2 antigens (S-RBD, S-trimer, N) using pre-pandemic serum from four different groups: pediatrics and adolescents, persons 21 to 70 years of age, older than 70 years of age, and persons living with HCV or HIV.FindingsAntibody 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 show a range of neutralizing activity (0-45%) in serum that interferes with SARS-CoV-2 spike attachment to ACE2. While the abundance of sCoV antibodies did not directly correlate with neutralization, we show that neutralizing activity is rather dependent on relative ratios of IgGs in sera directed to all four sCoV spike proteins. More specifically, we identified antibodies to NL63 and OC43 as being the most important predictors of neutralization.InterpretationOur data support that exposure to sCoVs triggers antibody responses that influence the efficiency of SARS-CoV-2 spike binding to ACE2, and may also impact COVID-19 disease severity through other latent variables.Research in ContextEvidence before this studyThere is a growing body of evidence showing that within the population there are varying levels of pre-existing immunity to SARS-CoV-2 infection and possibly COVID-19 disease severity. This immunity is believed to be attributable to prior infection by four prevalent seasonal coronaviruses (sCoVs) responsible for the common cold. Pre-existing immunity can be assessed in part by antibodies directed to sCoVs that also cross-react to SARS-CoV-2 antigens. The SARS-CoV-2 spike and, more specifically, the receptor binding domain are the primary targets for neutralizing antibodies. It is unclear if cross-reactive antibodies to SARS-CoV-2 are neutralizing and are also responsible for the broad spectrum of COVID-19 disease severity, from asymptomatic to critical, observed in the infected population.Added-value of this studyHere we carried out a detailed analysis of sCoV prevalence in samples acquired before the pandemic from individuals of various age groups and in people living with HIV and HCV. We then analyzed the frequency of all the different types of antibodies that cross-react to three SARS-CoV-2 antigens. We found a high level of people with cross-reactive antibodies, surprisingly we also detected that some people have antibodies that block the SARS-CoV-2 spike from binding to its human receptor, ACE2. By using machine learning, we were able to accurate predict which individuals can neutralize SARS-CoV-2 spike-ACE2 interactions based on their relative ratios of antibodies against the four sCoVs.Implications of all the available evidenceWe demonstrate that it not absolute levels of sCoVs antibodies that are predictive of neutralization but the relative ratios to all four sCoVs, with NL63 being the most weighted for this prediction. Machine learning also highlighted the existence of latent variables that contribute to the neutralization and that may be related to the type of cellular immune response triggered by the infection to certain sCoVs. This study is one of the first to identify a functional relationship between prior-exposure to sCoV and the establishment of a certain degree of immunity to SARS-CoV-2 by way of a cross-reactive antibody response.Graphical Abstract

Summary Background Among the most consequential unknowns of the devastating COVID-19 pandemic are the durability of immunity and time to likely reinfection. There are limited direct data on SARS-CoV-2 long-term immune responses and reinfection. The aim of this study is to use data on the durability of immunity among evolutionarily close coronavirus relatives of SARS-CoV-2 to estimate times to reinfection by a comparative evolutionary analysis of related viruses SARS-CoV, MERS-CoV, human coronavirus (HCoV)-229E, HCoV-OC43, and HCoV-NL63. Methods We conducted phylogenetic analyses of the S, M, and ORF1b genes to reconstruct a maximum-likelihood molecular phylogeny of human-infecting coronaviruses. This phylogeny enabled comparative analyses of peak-normalised nucleocapsid protein, spike protein, and whole-virus lysate IgG antibody optical density levels, in conjunction with reinfection data on endemic human-infecting coronaviruses. We performed ancestral and descendent states analyses to estimate the expected declines in antibody levels over time, the probabilities of reinfection based on antibody level, and the anticipated times to reinfection after recovery under conditions of endemic transmission for SARS-CoV-2, as well as the other human-infecting coronaviruses. Findings We obtained antibody optical density data for six human-infecting coronaviruses, extending from 128 days to 28 years after infection between 1984 and 2020. These data provided a means to estimate profiles of the typical antibody decline and probabilities of reinfection over time under endemic conditions. Reinfection by SARS-CoV-2 under endemic conditions would likely occur between 3 months and 5·1 years after peak antibody response, with a median of 16 months. This protection is less than half the duration revealed for the endemic coronaviruses circulating among humans (5–95% quantiles 15 months to 10 years for HCoV-OC43, 31 months to 12 years for HCoV-NL63, and 16 months to 12 years for HCoV-229E). For SARS-CoV, the 5–95% quantiles were 4 months to 6 years, whereas the 95% quantiles for MERS-CoV were inconsistent by dataset. Interpretation The timeframe for reinfection is fundamental to numerous aspects of public health decision making. As the COVID-19 pandemic continues, reinfection is likely to become increasingly common. Maintaining public health measures that curb transmission—including among individuals who were previously infected with SARS-CoV-2—coupled with persistent efforts to accelerate vaccination worldwide is critical to the prevention of COVID-19 morbidity and mortality. Funding US National Science Foundation.

Objectives The four seasonal coronaviruses 229E, NL63, OC43, and HKU1 are frequent causes of respiratory infections and show annual and seasonal variation. Increased understanding about these patterns could be informative about the epidemiology of SARS-CoV-2. Methods Results from PCR diagnostics for the seasonal coronaviruses, and other respiratory viruses, were obtained for 55,190 clinical samples analyzed at the Karolinska University Hospital, Stockholm, Sweden, between 14 September 2009 and 2 April 2020. Results Seasonal coronaviruses were detected in 2130 samples (3.9 %) and constituted 8.1 % of all virus detections. OC43 was most commonly detected (28.4 % of detections), followed by NL63 (24.0 %), HKU1 (17.6 %), and 229E (15.3 %). The overall fraction of positive samples was similar between seasons, but at species level there were distinct biennial alternating peak seasons for the Alphacoronaviruses, 229E and NL63, and the Betacoronaviruses, OC43 and HKU1, respectively. The Betacoronaviruses peaked earlier in the winter season (Dec-Jan) than the Alphacoronaviruses (Feb-Mar). Coronaviruses were detected across all ages, but diagnostics were more frequently requested for paediatric patients than adults and the elderly. OC43 and 229E incidence was relatively constant across age strata, while that of NL63 and HKU1 decreased with age. Conclusions Both the Alphacoronaviruses and Betacoronaviruses showed alternating biennial winter incidence peaks, which suggests some type of immune mediated interaction. Symptomatic reinfections in adults and the elderly appear relatively common. Both findings may be of relevance for the epidemiology of SARS-CoV-2.

HCoV-NL63 and HCoV-229E are two of the four human coronaviruses that circulate worldwide. These two viruses are unique in their relationship towards each other. Phylogenetically, the viruses are more closely related to each other than to any other human coronavirus, yet they only share 65% sequence identity. Moreover, the viruses use different receptors to enter their target cell. HCoV-NL63 is associated with croup in children, whereas all signs suggest that the virus probably causes the common cold in healthy adults. HCoV-229E is a proven common cold virus in healthy adults, so it is probable that both viruses induce comparable symptoms in adults, even though their mode of infection differs. Here, we present an overview of the current knowledge on both human coronaviruses, focusing on similarities and differences. [J Formos Med Assoc 2009; 108(4):270-279]