BNT162b2 induces robust cross-variant SARS-CoV-2 immunity in children

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.

A role for Nucleocapsid-specific antibody function in Covid-19 Convalescent plasma therapy

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.

Preserved recognition of Omicron Spike following COVID-19 mRNA vaccination in pregnancy

BackgroundSARS-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. MethodsVOC 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. FindingsComparable, 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. InterpretationReduced 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. FundingNIH and the Bill and Melinda Gates Foundation

Preserved Omicron Spike specific antibody binding and Fc-recognition across COVID-19 vaccine platforms

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.

Comprehensive antibody profiling of mRNA vaccination in children

While children have been largely spared from COVID-19 disease, the emergence of viral variants of concern (VOC) with increased transmissibility, combined with fluctuating mask mandates and school re-openings have led to increased infections and disease among children. Thus, there is an urgent need to roll out COVID-19 vaccines to children of all ages. However, whether children respond equivalently to adults to mRNA vaccines and whether dosing will elicit optimal immunity remains unclear. Given the recent announcement of incomplete immunity induced by the pediatric dose of the BNT162b2 vaccine in young children, here we aimed to deeply profile and compare the vaccine-induced humoral immune response in 6-11 year old children receiving the pediatric (50g) or adult (100g) dose of the mRNA-1273 vaccine compared to adults and naturally infected children or children that experienced multi inflammatory syndrome in children (MIS-C) for the first time. Children elicited an IgG dominant vaccine induced immune response, surpassing adults at a matched 100g dose, but more variable immunity at a 50g dose. Irrespective of titer, children generated antibodies with enhanced Fc-receptor binding capacity. Moreover, like adults, children generated cross-VOC humoral immunity, marked by a decline of omicron receptor binding domain-binding, but robustly preserved omicron Spike-receptor binding, with robustly preserved Fc-receptor binding capabilities, in a dose dependent manner. These data indicate that while both 50g and 100g of mRNA vaccination in children elicits robust cross-VOC antibody responses, 100ug of mRNA in children results in highly preserved omicron-specific functional humoral immunity. One-Sentence SummarymRNA vaccination elicits robust humoral immune responses to SARS-CoV-2 in children 6-11 years of age.

Early cross-coronavirus reactive signatures of protective humoral immunity against COVID-19

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.

Residual Risk of Transfusion-Transmitted Infection with Hepatitis C Virus since the Introduction of Nucleic Acid Testing in Korea / 대한수혈학회지

BACKGROUND: In 2005, the Korean Red cross introduced mini-pool nucleic acid testing (NAT) for human immunodeficiency virus (HIV) and hepatitis C virus (HCV), which upgraded to individual donation (ID) NAT including HBV in 2012. In this study, we analyzed the trend of HCV infection among blood donors after introduction of NAT by estimating the residual risk (RR) of transfusion transmitted infection (TTI) of HCV. METHODS: Donation data from 2003 to 2014 were analyzed using the Blood Information Management System (BIMS). Each donation was tested for antibodies and viral RNA for HCV. Prevalence and incidence rate (IR) among repeat donors were determined. RR was determined using the incidence rate/window period model. RESULTS: During the 12-year period, a total of 29,058,436 donations were screened with 34 HCV NAT yield donations. Calculated RR per million donations for HCV was significantly reduced from 13.41 in the pre-NAT period (2003~2004) to 0.52 in the post NAT period (2006~2007) (P<0.001). Most recently (2013~2014), RR for HCV with TTI was estimated by 0.16 per million donations (1:6,289,308). CONCLUSION: RR of TTI with HCV was remarkably decreased since introduction of NAT. However, the prevalence and IR of HCV RNA among first time donors was still high and yield cases were more frequent among repeat donors. Therefore, establishment of a sensitive and accurate screening system and measures for maintaining healthy donors should be considered in order to ensure blood safety.