Are higher antibody levels against seasonal human coronaviruses associated with a more robust humoral immune response after SARS-CoV-2 vaccination?

The SARS-CoV-2 belongs to the coronavirus family, which also includes common endemic coronaviruses (HCoVs). We hypothesized that immunity to HCoVs would be associated with stronger immunogenicity from SARS-CoV-2 vaccines. The study included samples from the COSRIP observational cohort study of adult paramedics in Canada. Participants provided blood samples, questionnaire data, and results of COVID-19 testing. Samples were tested for anti-spike IgG against SARS-CoV-2, HCoV-229E, HCoV-HKU1, HCoV-NL63, and HCoV-OC43 antigens. We first compared samples from vaccinated and unvaccinated participants, to determine which HCoV antibodies were affected by vaccination. We created scatter plots and performed correlation analysis to estimate the extent of the linear relationship between HCoVs and SARS-CoV-2 anti-spike antibodies. Further, using adjusted log-log multiple regression, we modeled the association between each strain of HCoV and SARS-CoV-2 antibodies. Of 1510 participants (mean age of 39 years), 94 (6.2%) had a history of COVID-19. There were significant differences between vaccinated and unvaccinated participant in anti-spike antibodies to HCoV-HKU1, and HCoV-OC43; however, levels for HCoV-229E and HCoV-NL63 were similar (suggesting that vaccination did not affect these baseline values). Among vaccinated individuals without prior COVID-19 infection, SARS-COV-2 anti-spike IgG demonstrated a weak positive relationship between both HCoV-229E (r = 0.11) and HCoV-NL63 (r = 0.12). From the adjusted log-log multiple regression model, higher HCoV-229E and HCoV-NL63 anti-spike IgG antibodies were associated with increased SARS-COV-2 anti-spike IgG antibodies. Vaccination appears to result in measurable increases in HCoV-HKU1, and HCoV-OC43 IgG levels. Anti-HCoV-229E and HCoV-NL63 antibodies were unaffected by vaccination, and higher levels were associated with significantly higher COVID-19 vaccine-induced SARS-COV-2 antibodies.

Organotypic human lung bud microarrays identify BMP-dependent SARS-CoV-2 infection in lung cells.

Although lung disease is the primary clinical outcome in COVID-19 patients, how SARS-CoV-2 induces lung pathology remains elusive. Here we describe a high-throughput platform to generate self-organizing and commensurate human lung buds derived from hESCs cultured on micropatterned substrates. Lung buds resemble human fetal lungs and display proximodistal patterning of alveolar and airway tissue directed by KGF. These lung buds are susceptible to infection by SARS-CoV-2 and endemic coronaviruses and can be used to track cell type-specific cytopathic effects in hundreds of lung buds in parallel. Transcriptomic comparisons of infected lung buds and postmortem tissue of COVID-19 patients identified an induction of BMP signaling pathway. BMP activity renders lung cells more susceptible to SARS-CoV-2 infection and its pharmacological inhibition impairs infection by this virus. These data highlight the rapid and scalable access to disease-relevant tissue using lung buds that recapitulate key features of human lung morphogenesis and viral infection biology.

Younger Children Develop Higher Effector Antibody Responses to SARS-CoV-2 Infection.

Background: The basis of the less severe clinical presentation of coronavirus disease 2019 (COVID-19) in children as compared with adults remains incompletely understood. Studies have suggested that a more potent boosting of immunity to endemic common cold coronaviruses (HCoVs) may protect children. Methods: To test this hypothesis, we conducted a detailed analysis of antibodies induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children aged 2 months to 14 years. Results: Younger children had higher titers of antibodies to SARS-CoV-2 receptor binding domain (RBD), S1 but not S2 domain, and total spike (S) protein, higher avidity RBD immunoglobulin G, and higher titers of neutralizing and complement-activating antibodies as compared with older children. In contrast, older children had higher titers of antibodies to HCoVs, which correlated with antibodies to the SARS-CoV-2 S2 domain but not with neutralizing or complement-activating antibodies. Conclusions: These results reveal a unique capacity of young children to develop effector antibody responses to SARS-CoV-2 infection independently of their immunity to HCoVs.

Antibodies targeting conserved non-canonical antigens and endemic coronaviruses associate with favorable outcomes in severe COVID-19.

While there have been extensive analyses characterizing cellular and humoral responses across the severity spectrum in COVID-19, outcome predictors within severe COVID-19 remain less comprehensively elucidated. Furthermore, properties of antibodies (Abs) directed against viral antigens beyond spike and their associations with disease outcomes remain poorly defined. We perform deep molecular profiling of Abs directed against a wide range of antigenic specificities in severe COVID-19 patients. The profiles included canonical (spike [S], receptor-binding domain [RBD], and nucleocapsid [N]) and non-canonical (orf3a, orf8, nsp3, nsp13, and membrane [M]) antigenic specificities. Notably, multivariate Ab profiles directed against canonical or non-canonical antigens are equally discriminative of survival in severe COVID-19. Intriguingly, pre-pandemic healthy controls have cross-reactive Abs directed against nsp13, a protein conserved across coronaviruses. Consistent with these findings, a model built on Ab profiles for endemic coronavirus antigens also predicts COVID-19 outcome. Our results suggest the importance of studying Abs targeting non-canonical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and endemic coronavirus antigens in COVID-19.

Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination.

During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination.

Comparable endemic coronavirus nucleoprotein-specific antibodies in mild and severe Covid-19 patients.

The severity of disease of Covid-19 is highly variable, ranging from asymptomatic to critical respiratory disease and death. Potential cross-reactive immune responses between SARS-CoV-2 and endemic coronavirus (eCoV) may hypothetically contribute to this variability. We herein studied if eCoV nucleoprotein (N)-specific antibodies in the sera of patients with mild or severe Covid-19 are associated with Covid-19 severity. There were comparable levels of eCoV N-specific antibodies early and during the first month of infection in Covid-19 patients with mild and severe symptoms, and healthy SARS-CoV-2-negative subjects. These results warrant further studies to investigate the potential role of eCoV-specific antibodies in immunity to SARS-CoV-2 infection.

Diverse Humoral Immune Responses in Younger and Older Adult COVID-19 Patients.

We sought to discover links between antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patient clinical variables, cytokine profiles, and antibodies to endemic coronaviruses. Serum samples from 30 patients of younger (26 to 39 years) and older (69 to 83 years) age groups and with varying clinical severities ranging from outpatient to mechanically ventilated were collected and used to probe a novel multi-coronavirus protein microarray. This microarray contained variable-length overlapping fragments of SARS-CoV-2 spike (S), envelope (E), membrane (M), nucleocapsid (N), and open reading frame (ORF) proteins created through in vitro transcription and translation (IVTT). The array also contained SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), human coronavirus OC43 (HCoV-OC43), and HCoV-NL63 proteins. IgG antibody responses to specific epitopes within the S1 protein region spanning amino acids (aa) 500 to 650 and within the N protein region spanning aa 201 to 300 were found to be significantly higher in older patients and further significantly elevated in those older patients who were ventilated. Additionally, there was a noticeable overlap between antigenic regions and known mutation locations in selected emerging SARS-CoV-2 variants of current clinical consequence (B.1.1.7, B1.351, P.1, CAL20.C, and B.1.526). Moreover, the older age group displayed more consistent correlations of antibody reactivity with systemic cytokine and chemokine responses than the younger adult group. A subset of patients, however, had little or no response to SARS-CoV-2 antigens and disproportionately severe clinical outcomes. Further characterization of these slow-low-responding individuals with cytokine analysis revealed significantly higher interleukin-10 (IL-10), IL-15, and interferon gamma-induced protein 10 (IP-10) levels and lower epidermal growth factor (EGF) and soluble CD40 ligand (sCD40L) levels than those of seroreactive patients in the cohort. IMPORTANCE As numerous viral variants continue to emerge in the coronavirus disease 2019 (COVID-19) pandemic, determining antibody reactivity to SARS-CoV-2 epitopes becomes essential in discerning changes in the immune response to infection over time. This study enabled us to identify specific areas of antigenicity within the SARS-CoV-2 proteome, allowing us to detect correlations of epitopes with clinical metadata and immunological signals to gain holistic insight into SARS-CoV-2 infection. This work also emphasized the risk of mutation accumulation in viral variants and the potential for evasion of the adaptive immune responses in the event of reinfection. We additionally highlighted the correlation of antigenicity between structural proteins of SARS-CoV-2 and endemic HCoVs, raising the possibility of cross-protection between homologous lineages. Finally, we identified a subset of patients with minimal antibody reactivity to SARS-CoV-2 infection, prompting discussion of the potential consequences of this alternative immune response.

Molecular biology of coronaviruses: an overview of virus-host interactions and pathogenesis.

Coronaviruses (CoV) are enveloped, plus-strand RNA viruses that have the largest known RNA genomes and infect birds and mammals, causing various diseases. Human coronaviruses (HCoVs) were first identified in the mid-1960s and have been known to cause enteric or respiratory infections. In the last two decades, three HCoVs have emerged, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which initiated the ongoing pandemic. SARS-CoV-2 causes a respiratory illness that presents as a mild upper respiratory disease but may result in acute respiratory distress syndrome, multi-organ failure and can be fatal, especially when underlying comorbidities are present. Children account for a low percentage of coronavirus disease 2019 (COVID-19) cases, with seemingly less severe disease. Most pediatric patients present mild or moderate symptoms or are asymptomatic. However, some cases may be severe. Therefore, SARS-CoV-2 infection and COVID-19 in pediatric patients must be studied in detail. This review describes general features of the molecular biology of CoVs and virus-host interactions that may be implicated in the pathogenesis of SARS-CoV-2.

Los coronavirus son virus envueltos de ARN de polaridad positiva, con los genomas más grandes que se conocen. Infectan aves y mamíferos, y causan una amplia variedad de enfermedades. Los coronavirus humanos se identificaron a mediados de la década de 1960 y se sabe que causan infecciones entéricas y respiratorias. En las últimas dos décadas han emergido tres coronavirus humanos pandémicos, incluido el coronavirus 2 del síndrome agudo respiratorio grave (SARS-CoV-2) que ha causado la pandemia actual. El SARS-CoV-2 produce enfermedad respiratoria que se presenta con padecimientos moderados de las vías respiratorias altas, pero puede resultar en síndrome respiratorio agudo, falla multiorgánica y muerte, en especial en casos con morbilidad subyacente. Los casos de COVID-19 en niños representan un porcentaje bajo y con síntomas menos graves de la enfermedad. La mayoría de los pacientes pediátricos son asintomáticos o presentan enfermedad leve o moderada; sin embargo, también en niños la enfermedad puede ser grave, por lo que la infección con SARS-CoV-2 y la COVID-19 en pacientes pediátricos deben estudiarse con detalle. En esta revisión se describen las características generales de la biología molecular de los coronavirus y de las interacciones virus-hospedero que se conocen para los coronavirus humanos identificados previamente, y que podrían estar implicados en la patogénesis del SARS-CoV-2.

Broad respiratory testing to identify SARS-CoV-2 viral co-circulation and inform diagnostic stewardship in the COVID-19 pandemic.

BACKGROUND: SARS-CoV-2 infection can present with a broad clinical differential that includes many other respiratory viruses; therefore, accurate tests are crucial to distinguish true COVID-19 cases from pathogens that do not require urgent public health interventions. Co-circulation of other respiratory viruses is largely unknown during the COVID-19 pandemic but would inform strategies to rapidly and accurately test patients with respiratory symptoms. METHODS: This study retrospectively examined 298,415 respiratory specimens collected from symptomatic patients for SARS-CoV-2 testing in the three months since COVID-19 was initially documented in the province of Alberta, Canada (March-May, 2020). By focusing on 52,285 specimens that were also tested with the Luminex Respiratory Pathogen Panel for 17 other pathogens, this study examines the prevalence of 18 potentially co-circulating pathogens and their relative rates in prior years versus since COVID-19 emerged, including four endemic coronaviruses. RESULTS: SARS-CoV-2 was identified in 2.2% of all specimens. Parallel broad multiplex testing detected additional pathogens in only 3.4% of these SARS-CoV-2-positive specimens: significantly less than in SARS-CoV-2-negative specimens (p < 0.0001), suggesting very low rates of SARS-CoV-2 co-infection. Furthermore, the overall co-infection rate was significantly lower among specimens with SARS-CoV-2 detected (p < 0.0001). Finally, less than 0.005% of all specimens tested positive for both SARS-CoV-2 and any of the four endemic coronaviruses tested, strongly suggesting neither co-infection nor cross-reactivity between these coronaviruses. CONCLUSIONS: Broad respiratory pathogen testing rarely detected additional pathogens in SARS-CoV-2-positive specimens. While helpful to understand co-circulation of respiratory viruses causing similar symptoms as COVID-19, ultimately these broad tests were resource-intensive and inflexible in a time when clinical laboratories face unprecedented demand for respiratory virus testing, with further increases expected during influenza season. A transition from broad, multiplex tests toward streamlined diagnostic algorithms targeting respiratory pathogens of public health concern could simultaneously reduce the overall burden on clinical laboratories while prioritizing testing of pathogens of public health importance. This is particularly valuable with ongoing strains on testing resources, exacerbated during influenza seasons.

Potential impact of individual exposure histories to endemic human coronaviruses on age-dependent severity of COVID-19.

BACKGROUND: Cross-reactivity to SARS-CoV-2 from exposure to endemic human coronaviruses (eHCoV) is gaining increasing attention as a possible driver of both protection against infection and COVID-19 severity. Here we explore the potential role of cross-reactivity induced by eHCoVs on age-specific COVID-19 severity in a mathematical model of eHCoV and SARS-CoV-2 transmission. METHODS: We use an individual-based model, calibrated to prior knowledge of eHCoV dynamics, to fully track individual histories of exposure to eHCoVs. We also model the emergent dynamics of SARS-CoV-2 and the risk of hospitalisation upon infection. RESULTS: We hypothesise that primary exposure with any eHCoV confers temporary cross-protection against severe SARS-CoV-2 infection, while life-long re-exposure to the same eHCoV diminishes cross-protection, and increases the potential for disease severity. We show numerically that our proposed mechanism can explain age patterns of COVID-19 hospitalisation in EU/EEA countries and the UK. We further show that some of the observed variation in health care capacity and testing efforts is compatible with country-specific differences in hospitalisation rates under this model. CONCLUSIONS: This study provides a "proof of possibility" for certain biological and epidemiological mechanisms that could potentially drive COVID-19-related variation across age groups. Our findings call for further research on the role of cross-reactivity to eHCoVs and highlight data interpretation challenges arising from health care capacity and SARS-CoV-2 testing.

Direct Observation of Repeated Infections With Endemic Coronaviruses.

BACKGROUND: Although the mechanisms of adaptive immunity to pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are still unknown, the immune response to the widespread endemic coronaviruses HKU1, 229E, NL63, and OC43 provide a useful reference for understanding repeat infection risk. METHODS: Here we used data from proactive sampling carried out in New York City from fall 2016 to spring 2018. We combined weekly nasal swab collection with self-reports of respiratory symptoms from 191 participants to investigate the profile of recurring infections with endemic coronaviruses. RESULTS: During the study, 12 individuals tested positive multiple times for the same coronavirus. We found no significant difference between the probability of testing positive at least once and the probability of a recurrence for the betacoronaviruses HKU1 and OC43 at 34 weeks after enrollment/first infection. We also found no significant association between repeat infections and symptom severity, but found strong association between symptom severity and belonging to the same family. CONCLUSIONS: This study provides evidence that reinfections with the same endemic coronavirus are not atypical in a time window shorter than 1 year and that the genetic basis of innate immune response may be a greater determinant of infection severity than immune memory acquired after a previous infection.