ABSTRACT
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
Antibody transfer via breastmilk represents an evolutionary strategy to boost immunity in early life. Although SARS-CoV-2-specific antibodies have been observed in the breastmilk of mothers with COVID-19, the functional quality of these antibodies remains unclear. Here, we applied systems serology to characterize SARS-CoV-2-specific antibodies in maternal serum and breastmilk to define the mechanism of antibody transfer into breastmilk. Distinct SARS-CoV-2-specific antibody responses were observed in the serum and breastmilk of lactating individuals previously infected with SARS-CoV-2, with a dominant transfer of both IgA and IgM into breastmilk. A spike-specific functional IgG were present in breastmilk, breastmilk IgGs were functionally attenuated. Breastmilk antibodies were less inflammatory than maternal serum antibodies, pointing to a sieve offunctional antibodies to breastmilk. These data highlight the preferential breastmilk transfer of SARS-CoV-2-specific IgA and IgM to neonates, accompanied by selected subpopulations of IgG, positioned to create a non-pathologic, but highly protective barrier against COVID-19 disease.Funding Statement: This work was supported by by NHLBI (grants K08HL1469630-02 and K08HL146963-02S1, to KJG), the National Science Foundation Graduate Research Fellowship under Grant No. (#1745302, to KMP), the NIH (U19 AI142790, U19 AI135995, R37AI080289), the Massachusetts Consortium on Pathogen Readiness (MassCPR). Declaration of Interests: G.A. is the founder of Seromyx. K.J.G. has consulted for BillionToOne, Illumina, and Aetion. INCOMPLETE Ethics Approval Statement: This study was approved by the MGH-BWH Institutional Review Board and the BIDMC Institutional Review Board.
Subject(s)
COVID-19ABSTRACT
Recently approved vaccines have shown remarkable protection in limiting SARS-CoV-2 associated disease. However, immunologic mechanism(s) of protection, and how boosting alters immunity to wildtype and newly emerging strains, remains incompletely understood. Here we profiled the humoral immune response in a cohort of non-human primates immunized with a recombinant SARS-CoV-2 spike (S) glycoprotein (NVX-CoV2373) at two dose levels, administered as a one or two-dose regimen with a saponin-based adjuvant Matrix-M™. While antigen dose had minimal effects, boosting significantly altered the humoral response, driving unique vaccine-induced antibody fingerprints. Differences in antibody effector functions and neutralization were associated with protection in the upper and lower respiratory tract, pointing to compartment-specific determinants of protective immunity against infection. Moreover, NVX-CoV2373 elicited antibodies targeting emerging SARS-CoV-2 variants. Collectively, the data presented here suggest that a single dose may prevent disease, but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.Funding: This work was funded by Operation Warp Speed. We thank Colin Mann and Kathryn Hastie for production of Spike antigens. We thank Nancy Zimmerman, Mark and Lisa Schwartz, an anonymous donor (financial support), Terry and Susan Ragon, and the SAMANA Kay MGH Research Scholars award for their support. We acknowledge support from the Ragon Institute of MGH, MIT and Harvard, the Massachusetts Consortium on Pathogen Readiness (Mass CPR), the NIH (3R37AI080289-11S1, R01AI146785, U19AI42790-01, U19AI135995-02, U19AI42790-01, 1U01CA260476 – 01, CIVIC75N93019C00052), National Science Foundation Graduate Research Fellowship Grant No. #1745302, the Gates foundation Global Health Vaccine Accelerator Platform funding (OPP1146996 and INV-001650), and the Musk Foundation.Conflict of Interest: NP, MGX, JHT, BZ, SM, AMG, MJM, ADP, GG, GS, and LE are current or past employees of Novavax, Inc. and have stock options in the company. GA is the founder of Serom Yx Systems, Inc. AZ is a current employee of Moderna, Inc. but conducted this work before employment.Any opinion, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. YG, RC, MJG, CA, KMP, CL, DY, KB, MEM, JL, DM, CM, SS, FA, FK, EOS, DL, and MBF declare no competing interest.Ethical Approval: The work was conducted in accordance with a protocol approved by Texas Biomed’s Institutional Animal Care and Use Committee. All subjects signed informed consent and safety oversight was monitored by a data monitoring board.
Subject(s)
Myotonic Dystrophy , Adenomatous Polyposis ColiABSTRACT
There is a persistent male bias in the prevalence and severity of COVID-19 disease. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of disease in adults, and play a key role in the placental anti-viral response. Moreover, the interferon response has been shown to alter Fc-receptor expression, and therefore may impact placental antibody transfer. Here we examined the intersection of viral-induced placental interferon responses, maternal-fetal antibody transfer, and fetal sex. Placental interferon stimulated genes (ISGs), Fc-receptor expression, and SARS-CoV-2 antibody transfer were interrogated in 68 pregnancies. Sexually dimorphic placental expression of ISGs, interleukin-10, and Fc receptors was observed following maternal SARS-CoV-2 infection, with upregulation in males. Reduced maternal SARS-CoV-2-specific antibody titers and impaired placental antibody transfer were noted in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.
Subject(s)
COVID-19ABSTRACT
In the absence of an effective vaccine or monoclonal therapeutic, transfer of convalescent plasma (CCP) was proposed early in the SARS-CoV-2 pandemic as an easily accessible therapy. However, despite the global excitement around this historically valuable therapeutic approach, results from CCP trials have been mixed and highly debated. Unlike other therapeutic interventions, CCP represents a heterogeneous drug. Each CCP unit is unique and collected from an individual recovered COVID-19 patient, making the interpretation of therapeutic benefit more complicated. While the prevailing view in the field would suggest that it is administration of neutralizing antibodies via CCP that centrally provides therapeutic benefit to newly infected COVID-19 patients, many hospitalized COVID-19 patients already possess neutralizing antibodies. Importantly, the therapeutic benefit of antibodies can extend far beyond their simple ability to bind and block infection, especially related to their ability to interact with the innate immune system. In our work we deeply profiled the SARS-CoV-2-specific Fc-response in CCP donors, along with the recipients prior to and after CCP transfer, revealing striking SARS-CoV-2 specific Fc-heterogeneity across CCP units and their recipients. However, CCP units possessed more functional antibodies than acute COVID-19 patients, that shaped the evolution of COVID-19 patient humoral profiles via distinct immunomodulatory effects that varied by pre-existing SARS-CoV-2 Spike (S)-specific IgG titers in the patients. Our analysis identified surprising influence of both S and Nucleocapsid (N) specific antibody functions not only in direct antiviral activity but also in anti-inflammatory effects. These findings offer insights for more comprehensive interpretation of correlates of immunity in ongoing large scale CCP trials and for the design of next generation therapeutic design.
Subject(s)
Severe Acute Respiratory Syndrome , Heart Block , COVID-19ABSTRACT
Recently approved vaccines have already shown remarkable protection in limiting SARS-CoV-2 associated disease. However, immunologic mechanism(s) of protection, as well as how boosting alters immunity to wildtype and newly emerging strains, remain incompletely understood. Here we deeply profiled the humoral immune response in a cohort of non-human primates immunized with a stable recombinant full-length SARS-CoV-2 spike (S) glycoprotein (NVX-CoV2373) at two dose levels, administered as a single or two-dose regimen with a saponin-based adjuvant Matrix-M™. While antigen dose had some effect on Fc-effector profiles, both antigen dose and boosting significantly altered overall titers, neutralization and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were strongly associated with distinct levels of protection in the upper and lower respiratory tract, pointing to the presence of combined, but distinct, compartment-specific neutralization and Fc-mechanisms as key determinants of protective immunity against infection. Moreover, NVX-CoV2373 elicited antibodies functionally target emerging SARS-CoV-2 variants, collectively pointing to the critical collaborative role for Fab and Fc in driving maximal protection against SARS-CoV-2. Collectively, the data presented here suggest that a single dose may prevent disease, but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.
ABSTRACT
Comorbid medical illnesses, such as obesity and diabetes, are associated with more severe COVID-19, hospitalization, and death. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multi-parameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins in a convalescent cohort of COVID-19 subjects who were either hospitalized (n=20) or not hospitalized (n=40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virus-specific CD4 T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4 T-cells and antibodies targeting the S1 domain of spike among subjects that were not hospitalized. These data reveal a functionally diverse and coordinated response between T cells and antibodies targeting SARS-CoV-2 which is reduced in the presence of comorbid illnesses that are known risk factors for severe COVID-19. Our data suggest that isolated measurements of the magnitudes of spike-specific immune responses are likely insufficient to anticipate vaccine efficacy in high-risk populations.