ABSTRACT
Currently available mRNA vaccines are extremely safe and effective to prevent severe SARS-CoV-2 infections. However, the emergence of novel variants of concerns has highlighted the importance of high population-based vaccine rates to effectively suppress viral transmission and breakthrough infections. While initially left out from vaccine efforts, children have become one of the most affected age groups and are key targets to stop community and household spread. Antibodies are central for vaccine induced protection and emerging data points to the importance of additional Fc effector functions like opsononophagocytosis or cytotoxicity, particularly in the context of variants of concern that escape neutralizing antibodies. Here, we observed delayed induction and reduced magnitude of vaccine induced antibody titers in children 5-11 years receiving two doses of the age recommended 10 g dose of the Pfizer SARS-CoV-2 BNT162b2 vaccine compared to adolescents (12-15 years) or adults receiving the 30 g dose. Conversely, children mounted equivalent or more robust neutralization and opsonophagocytic functions at peak immunogenicity, pointing to a qualitatively more robust humoral functional response in children. Moreover, broad cross-variants of concern responses were observed across children, with enhanced IgM and parallel IgG cross-reactivity to variants of concern (VOCs) in children compared to adults. Collectively, these data argue that despite the lower magnitude of the BNT162b2 induced antibody response in children, vaccine induced immunity in children target VOCs broadly and exhibit enhanced functionality that may contribute to attenuation of disease.
Subject(s)
Breakthrough Pain , Severe Acute Respiratory Syndrome , Drug-Related Side Effects and Adverse ReactionsABSTRACT
COVID-19 convalescent plasma (CCP), a passive polyclonal antibody therapeutic, has exhibited mixed results in the treatment of COVID-19. Given that the therapeutic effect of CCP may extend beyond the ability of SARS-CoV-2-specific antibody binding and neutralization to influence the evolution of the endogenous antibody response, we took a systematic and comprehensive approach to analyze SARS-CoV-2 functional antibody profiles of participants in a randomized controlled trial of CCP treatment of individuals hospitalized with COVID-19 pneumonia where CCP was associated with both decreased mortality and improved clinical severity. Using systems serology, we found that the clinical benefit of CCP is related to a shift towards reduced inflammatory Spike (S) responses and enhanced Nucleocapsid (N) humoral responses. We found CCP had the greatest clinical benefit in participants with low pre-existing anti-SARS-CoV-2 antibody function, rather than S or N antibody levels or participant demographic features. Further, CCP induced immunomodulatory changes to recipient humoral profiles persisted for at least two months, marked by the selective evolution of anti-inflammatory Fc-glycan profiles and persistently expanded nucleocapsid-specific humoral immunity following CCP therapy. Together, our findings identify a novel mechanism of action of CCP, suggest optimal patient characteristics for CCP treatment, identify long-last immunomodulatory effects of CCP, and provide guidance for development of novel N-focused antibody therapeutics for severe COVID-19 hyperinflammation.
Subject(s)
COVID-19 , PneumoniaABSTRACT
Summary Background SARS-CoV-2 infection is associated with enhanced disease severity in pregnant women. Despite the potential of COVID-19 vaccines to reduce severe disease, vaccine uptake remained relatively low among pregnant women. Just as coordinated messaging from the CDC and leading obstetrics organizations began to increase vaccine confidence in this vulnerable group, the evolution of SARS-CoV-2 variants of concerns (VOC) including the Omicron VOC raised new concerns about vaccine efficacy, given their ability to escape vaccine-induced neutralizing antibodies. Early data point to a milder disease course following omicron VOC infection in vaccinated individuals. Thus, these data suggest that alternate vaccine induced immunity, beyond neutralization, may continue to attenuate omicron disease, such as antibody-Fc-mediated activity. However, whether vaccine induced antibodies raised in pregnancy continue to bind and leverage Fc-receptors remains unclear. Methods VOC including Omicron receptor binding domain (RBD) or full Spike specific antibody isotype binding titers and Fc{gamma}R binding were analyzed in pregnant women after the full dose regimen of either Pfizer/BioNtech BNT62b2 (n=10) or Moderna mRNA-1273 (n=10) vaccination using a multiplexing Luminex assay. Findings Comparable, albeit reduced, isotype recognition was observed to the Omicron Spike and receptor binding domain (RBD) following both vaccines. Yet, despite the near complete loss of Fc-receptor binding to the Omicron RBD, Fc-receptor binding was largely preserved to the Omicron Spike. Interpretation Reduced binding titer to the Omicron RBD aligns with observed loss of neutralizing activity. Despite the loss of neutralization, preserved Omicron Spike recognition and Fc-receptor binding potentially continues to attenuate disease severity in pregnant women. Funding NIH and the Bill and Melinda Gates Foundation
Subject(s)
COVID-19 , Migraine DisordersABSTRACT
Despite the dramatic spread of Omicron globally, even among highly vaccinated populations, death rates have not increased concomitantly. These data argue that alternative immune mechanisms, beyond neutralization, may continue to confer protection against severe disease. Beyond their ability to bind and block infection, antibodies contribute to control and clearance of multiple infections via their ability to direct antiviral immunity via Fc-effector mechanisms. Thus, here we probed the ability of vaccine induced antibodies, across three COVID-19 vaccines, to drive Fc-effector activity against Omicron. Despite the significant loss of IgM, IgA and IgG binding to the Omicron Receptor Binding Domain (RBD) across BNT162b2, mRNA-1273, and CoronaVac vaccines, stable isotype binding was observed across all of these vaccines to the Omicron Spike. Compromised RBD binding IgG was accompanied by a significant loss of cross RBD-specific antibody Fc{gamma}-receptor binding by the CoronaVac vaccine, but preservation of RBD-specific Fc{gamma}R2a and Fc{gamma}3a binding across the mRNA vaccines. Conversely, Spike-specific antibodies exhibited persistent binding to Fc{gamma}-receptors, across all three vaccines, albeit higher binding was observed with the mRNA vaccines, marked by a selective preservation of Fc{gamma}R2a and Fc{gamma}3a binding antibodies. Thus, despite the significant to near complete loss of Omicron neutralization across several vaccine platforms against Omicron, vaccine induced Spike-specific antibodies continue to recognize the virus and recruit Fc-receptors pointing to a persistent capacity for extra-neutralizing antibodies to contribute Omicron disease attenuation.
Subject(s)
COVID-19 , Heart Block , DeathABSTRACT
With the emergence of SARS-CoV-2 variants, fluctuating mask mandates, and school re-openings, increased infections and disease surged among children recently. Thus, there is an urgent need for COVID-19 vaccines for children of all ages. However, whether young children will respond appropriately to mRNA vaccines remains unclear. Here, we deeply profiled the vaccine-induced humoral immune response in 7-11 year old children receiving the mRNA-1273 vaccine. Vaccinated children induced significantly higher antibody titers and functions compared to naturally infected children. Moreover, we observed comparable SARS-CoV-2 titers and neutralizing activity across variants of concern and superior Fc{gamma}-receptor binding and phagocytic antibodies in children compared to vaccinated adults. Our data indicate that mRNA vaccination elicits robust antibody responses and drives superior antibody functionality in children. One-Sentence SummarymRNA vaccination elicits robust humoral immune responses to SARS-CoV-2 in children 7-11 years of age.
Subject(s)
COVID-19ABSTRACT
The introduction of vaccines has inspired new hope in the battle against SARS-CoV-2. However, the emergence of viral variants, in the absence of potent antivirals, has left the world struggling with the uncertain nature of this disease. Antibodies currently represent the strongest correlate of immunity against COVID-19, thus we profiled the earliest humoral signatures in a large cohort of severe and asymptomatic COVID-19 individuals. While a SARS-CoV-2-specific immune response evolved rapidly in survivors of COVID-19, non-survivors exhibited blunted and delayed humoral immune evolution, particularly with respect to S2-specific antibody evolution. Given the conservation of S2 across {beta}-coronaviruses, we found the early development of SARS-CoV-2-specific immunity occurred in tandem with pre-existing common {beta}-coronavirus OC43 humoral immunity in survivors, which was selectively also expanded in individuals that develop paucisymptomatic infection. These data point to the importance of cross-coronavirus immunity as a correlate of protection against COVID-19.
Subject(s)
COVID-19ABSTRACT
The robust protection conferred by SARS-CoV-2 mRNA vaccines represents a critical milestone in the COVID-19 vaccine development. However, the emergence of variants has inspired renewed concern related to the protective efficacy of currently approved vaccines, which lose neutralizing potency against some variants. However, emerging data suggest that antibody functions, beyond neutralization, may contribute to protection from disease. Thus, here we profiled the binding and functional capacity of convalescent antibodies and Moderna mRNA-1273 COVID-19 vaccine-induced antibodies across SARS-CoV-2 variants of concern (VOC). While neutralizing antibody responses are affected by VOCs, antibodies generated after infection exhibited robust binding to VOCs but compromised interactions with Fc-receptors. Conversely, vaccine-induced antibodies bound robustly to VOCs and continued interacting with Fc-receptors and mediated antibody effector functions. These data point to a previously unappreciated resilience in the mRNA vaccine-induced humoral immune response that may continue to provide protection from SARS-CoV-2 VOCs independent of neutralization.Trial Registration: This work used samples from the phase 1, dose-escalation, open-labelclinical trial designed to determine the safety, reactogenicity, and immunogenicity of mRNA-1273 (mRNA-1273 ClinicalTrials.gov number, NCT04283461 mRNA-1273 study; DOI: 10.1056/NEJMoa2022483).Funding: We acknowledge support from the Ragon Institute of MGH, MIT, and Harvard, the Massachusetts Consortium on Pathogen Readiness (MassCPR), the NIH (3R37AI080289-11S1, R01AI146785, U19AI42790-01, U19AI135995-02, U19AI42790-01, 1U01CA260476 – 01, CIVIC75N93019C00052), the Gates Foundation Global Health Vaccine Accelerator Platform funding (OPP1146996 and INV-001650), Translational Research Institute for Space Health through NASA Cooperative Agreement (NNX16AO69A), and the Musk Foundation. This work used samples from the phase 1 mRNA-1273 study (NCT04283461; DOI: 10.1056/NEJMoa2022483). The mRNA-1273 phase 1 study was sponsored and primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD. This trial has been funded in part with federal funds from the NIAID under grant awards UM1AI148373, to Kaiser Washington; UM1AI148576, UM1AI148684, and NIH P51 OD011132, to Emory University; NIH AID AI149644, and contract award HHSN272201500002C, to Emmes. Funding for the manufacture of mRNA-1273 phase 1 material was provided by the Coalition for Epidemic Preparedness Innovation.Declaration of Interest: G.A. is a founder of Seromyx Systems Inc. A.C. is employee of Moderna Inc. D.D., P.M., A.S.M, and E.R.M. are employees of Space Exploration Technologies Corp. All other authors have declared that no conflict of interest exists.Ethical Approval: The MGH IRB reviewed the ethics protocol for secondary use under record 2020P004042 and the project was deemed Not Human Research.