SARS-CoV-2 mRNA vaccination elicits broad and potent Fc effector functions to VOCs in vulnerable populations

SARS-CoV-2 variants have continuously emerged even as highly effective vaccines have been widely deployed. Reduced neutralization observed against variants of concern (VOC) raises the question as to whether other antiviral antibody activities are similarly compromised, or if they might compensate for lost neutralization activity. In this study, the breadth and potency of antibody recognition and effector function was surveyed in both healthy individuals as well as immunologically vulnerable subjects following either natural infection or receipt of an mRNA vaccine. Considering pregnant women as a model cohort with higher risk of severe illness and death, we observed similar binding and functional breadth for healthy and immunologically vulnerable populations. In contrast, considerably greater functional antibody breadth and potency across VOC was associated with vaccination than prior infection. However, greater antibody functional activity targeting the endemic coronavirus OC43 was noted among convalescent individuals, illustrating a dichotomy in recognition between close and distant human coronavirus strains that was associated with exposure history. Probing the full-length spike and receptor binding domain (RBD) revealed that antibody-mediated Fc effector functions were better maintained against full-length spike as compared to RBD. This analysis of antibody functions in healthy and vulnerable populations across a panel of SARS-CoV-2 VOC and extending through endemic alphacoronavirus strains suggests the differential potential for antibody effector functions to contribute to protecting vaccinated and convalescent subjects as the pandemic progresses and novel variants continue to evolve. One Sentence SummaryAs compared to natural infection with SARS-CoV-2, vaccination drives superior functional antibody breadth raising hopes for candidate universal CoV vaccines.

Boosting of Cross-Reactive Antibodies to Endemic Coronaviruses by SARS-CoV-2 Infection but not Vaccination with Stabilized Spike

Pre-existing antibodies to endemic coronaviruses (CoV) that cross-react with SARS-CoV-2 have the potential to influence the antibody response to COVID-19 vaccination and infection for better or worse. In this observational study of mucosal and systemic humoral immunity in acutely infected, convalescent, and vaccinated subjects, we tested for cross reactivity against endemic CoV spike (S) protein at subdomain resolution. Elevated responses, particularly to the {beta}-CoV OC43, were observed in all natural infection cohorts tested and were correlated with the response to SARS-CoV-2. The kinetics of this response and isotypes involved suggest that infection boosts preexisting antibody lineages raised against prior endemic CoV exposure that cross react. While further research is needed to discern whether this recalled response is desirable or detrimental, the boosted antibodies principally targeted the better conserved S2 subdomain of the viral spike and were not associated with neutralization activity. In contrast, vaccination with a stabilized spike mRNA vaccine did not robustly boost cross-reactive antibodies, suggesting differing antigenicity and immunogenicity. In sum, this study provides evidence that antibodies targeting endemic CoV are robustly boosted in response to SARS-CoV-2 infection but not to vaccination with stabilized S, and that depending on conformation or other factors, the S2 subdomain of the spike protein triggers a rapidly recalled, IgG-dominated response that lacks neutralization activity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/21265574v1_figA1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@168d38aorg.highwire.dtl.DTLVardef@1183afcorg.highwire.dtl.DTLVardef@1c88b77org.highwire.dtl.DTLVardef@13c6e0a_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO Antibody responses to SARS-CoV-2 and endemic CoV spike proteins were measured in diverse cohorts. While antibodies to SARS-CoV-2 were induced across all isotypes, only IgA and IgG responses to endemic CoV were robustly boosted, and only among naturally-infected but not vaccinated individuals. These recalled, cross-reactive responses to endemic CoV primarily recognized the better conserved S2 domain and were non-neutralizing. While other antiviral activities of broadly cross-reactive S2-specifc antibodies are not known, the differing antigenicity of natural infection and vaccination with stabilized pre-fusion spike has potential implications for the breadth and level of protection afforded by each. C_FIG

Differentiation of SARS-CoV-2 naturally infected and vaccinated individuals in an inner-city emergency department

BackgroundEmergency Departments (EDs) can serve as surveillance sites for infectious diseases. Our purpose was to determine the burden of SARS-CoV-2 infection and prevalence of vaccination against COVID-19 among patients attending an urban ED in Baltimore City. MethodsUsing 1914 samples of known exposure status, we developed an algorithm to differentiate previously infected, vaccinated, and unexposed individuals using a combination of antibody assays. We applied this testing algorithm to 4360 samples ED patients obtained in the springs of 2020 and 2021. Using multinomial logistic regression, we determined factors associated with infection and vaccination. ResultsFor the algorithm, sensitivity and specificity for identifying vaccinated individuals was 100% and 99%, respectively, and 84% and 100% for naturally infected individuals. Among the ED subjects, seroprevalence to SARS-CoV-2 increased from 2% to 24% between April 2020 and March 2021. Vaccination prevalence rose to 11% by mid-March 2021. Marked differences in burden of disease and vaccination coverage were seen by sex, race, and ethnicity. Hispanic patients, though 7% of the study population, had the highest relative burden of disease (17% of total infections) but similar vaccination rates. Women and White individuals were more likely to be vaccinated than men or Black individuals (adjusted odds ratios [aOR] 1.35 [95% CI: 1.02, 1.80] and aOR 2.26 [95% CI: 1.67, 3.07], respectively). ConclusionsIndividuals previously infected with SARS-CoV-2 can be differentiated from vaccinated individuals using a serologic testing algorithm. SARS-CoV-2 exposure and vaccination uptake frequencies reflect gender, race and ethnic health disparities in this urban context. SummaryUsing an antibody testing algorithm, we distinguished between immune responses from SARS-CoV-2-infected and vaccinated individuals. When applied to blood samples from an emergency department in Baltimore, disparities in disease burden and vaccine uptake by sex, race, and ethnicity were identified.

A Third Dose of SARS-CoV-2 Vaccine Increases Neutralizing Antibodies Against Variants of Concern in Solid Organ Transplant Recipients

Vaccine-induced SARS-CoV-2 antibody responses are attenuated in solid organ transplant recipients (SOTRs) and breakthrough infections are more common. Additional SARS-CoV-2 vaccine doses increase anti-spike IgG in some SOTRs, but it is uncertain whether neutralization of variants of concern (VOCs) is enhanced. We tested 47 SOTRs for clinical and research anti-spike IgG, pseudoneutralization (ACE2 blocking), and live-virus neutralization (nAb) against VOCs before and after a third SARS-CoV-2 vaccine dose (70% mRNA, 30% Ad26.COV2.S) with comparison to 15 healthy controls after two mRNA vaccine doses. We used correlation analysis to compare anti-spike IgG assays and focused on thresholds associated with neutralizing activity. A third SARS-CoV-2 vaccine dose increased median anti-spike (1.6-fold) and receptor-binding domain (1.5-fold) IgG, as well as pseudoneutralization against VOCs (2.5-fold versus Delta). However, IgG and neutralization activity were significantly lower than healthy controls (p<0.001); 32% of SOTRs had zero detectable nAb against Delta after third vaccination. Correlation with nAb was seen at anti-spike IgG >4 AU on the clinical assay and >10^4 AU on the research assay. These findings highlight benefits of a third vaccine dose for some SOTRs and the need for alternative strategies to improve protection in a significant subset of this population.