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1.
Nat Commun ; 13(1): 6309, 2022 Oct 23.
Article in English | MEDLINE | ID: covidwho-2087203

ABSTRACT

Coronavirus vaccines that are highly effective against current and anticipated SARS-CoV-2 variants are needed to control COVID-19. We previously reported a receptor-binding domain (RBD)-sortase A-conjugated ferritin nanoparticle (scNP) vaccine that induced neutralizing antibodies against SARS-CoV-2 and pre-emergent sarbecoviruses and protected non-human primates (NHPs) from SARS-CoV-2 WA-1 infection. Here, we find the RBD-scNP induced neutralizing antibodies in NHPs against pseudoviruses of SARS-CoV and SARS-CoV-2 variants including 614G, Beta, Delta, Omicron BA.1, BA.2, BA.2.12.1, and BA.4/BA.5, and a designed variant with escape mutations, PMS20. Adjuvant studies demonstrate variant neutralization titers are highest with 3M-052-aqueous formulation (AF). Immunization twice with RBD-scNPs protect NHPs from SARS-CoV-2 WA-1, Beta, and Delta variant challenge, and protect mice from challenges of SARS-CoV-2 Beta variant and two other heterologous sarbecoviruses. These results demonstrate the ability of RBD-scNPs to induce broad neutralization of SARS-CoV-2 variants and to protect animals from multiple different SARS-related viruses. Such a vaccine could provide broad immunity to SARS-CoV-2 variants.


Subject(s)
COVID-19 , Nanoparticles , SARS Virus , Viral Vaccines , Mice , Animals , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus , Antibodies, Viral , Mice, Inbred BALB C , COVID-19/prevention & control , Antibodies, Neutralizing/chemistry , Ferritins
2.
Nat Commun ; 13(1): 4617, 2022 08 08.
Article in English | MEDLINE | ID: covidwho-2036812

ABSTRACT

There is limited knowledge on durability of neutralization capacity and antibody affinity maturation generated following two versus three doses of SARS-CoV-2 mRNA vaccines in naïve versus convalescent individuals (hybrid immunity) against the highly transmissible Omicron BA.1, BA.2 and BA.3 subvariants. Virus neutralization titers against the vaccine-homologous strain (WA1) and Omicron sublineages are measured in a pseudovirus neutralization assay (PsVNA). In addition, antibody binding and antibody affinity against spike proteins from WA1, BA.1, and BA.2 is determined using surface plasmon resonance (SPR). The convalescent individuals who after SARS-CoV-2 infection got vaccinated develop hybrid immunity that shows broader neutralization activity and cross-reactive antibody affinity maturation against the Omicron BA.1 and BA.2 after either second or third vaccination compared with naïve individuals. Neutralization activity correlates with antibody affinity against Omicron subvariants BA.1 and BA.2 spikes. Importantly, at four months post-third vaccination the neutralization activity and antibody affinity against the Omicron subvariants is maintained and trended higher for the individuals with hybrid immunity compared with naïve adults. These findings about hybrid immunity resulting in superior immune kinetics, breadth, and durable high affinity antibodies support the need for booster vaccinations to provide effective protection from emerging SARS-CoV-2 variants like the rapidly spreading Omicron subvariants.


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Antibodies, Neutralizing , Antibodies, Viral , Antibody Affinity , COVID-19/prevention & control , Humans , Neutralization Tests , RNA, Messenger , SARS-CoV-2/genetics , Vaccination
3.
Clin Infect Dis ; 2022 Aug 04.
Article in English | MEDLINE | ID: covidwho-1973130

ABSTRACT

Our study demonstrates that neither 2020-convalescent plasma (CP) nor 2019/2020-immunoglobulin (IVIG) neutralize Omicron subvariants BA.1 to BA.5. In contrast, hyperimmune 2020-hCoV-2IG lots neutralized Omicron VOCs, similar to 2022-CP from BA.1 breakthrough infections. Therefore, high-titer hCoV-2IG and CP could be evaluated for treatment of high-risk individuals infected with circulating Omicron subvariants.

4.
PLoS Pathog ; 18(4): e1010468, 2022 04.
Article in English | MEDLINE | ID: covidwho-1779781

ABSTRACT

An overreactive inflammatory response and coagulopathy are observed in patients with severe form of COVID-19. Since increased levels of D-dimer (DD) are associated with coagulopathy in COVID-19, we explored whether DD contributes to the aberrant cytokine responses. Here we show that treatment of healthy human monocytes with DD induced a dose dependent increase in production of pyrogenic mediator, Prostaglandin E2 (PGE2) and inflammatory cytokines, IL-6 and IL-8. The DD-induced PGE2 and inflammatory cytokines were enhanced significantly by co-treatment with immune complexes (IC) of SARS CoV-2 recombinant S protein or of pseudovirus containing SARS CoV-2 S protein (PVCoV-2) coated with spike-specific chimeric monoclonal antibody (MAb) containing mouse variable and human Fc regions. The production of PGE2 and cytokines in monocytes activated with DD and ICs was sensitive to the inhibitors of ß2 integrin and FcγRIIa, and to the inhibitors of calcium signaling, Mitogen-Activated Protein Kinase (MAPK) pathway, and tyrosine-protein kinase. Importantly, strong increase in PGE2 and in IL-6/IL-8/IL-1ß cytokines was observed in monocytes activated with DD in the presence of IC of PVCoV-2 coated with plasma from hospitalized COVID-19 patients but not from healthy donors. The IC of PVCoV-2 with convalescent plasma induced much lower levels of PGE2 and cytokines compared with plasma from hospitalized COVID-19 patients. PGE2 and IL-6/IL-8 cytokines produced in monocytes activated with plasma-containing IC, correlated well with the levels of spike binding antibodies and not with neutralizing antibody titers. Our study suggests that a combination of high levels of DD and high titers of spike-binding antibodies that can form IC with SARS CoV-2 viral particles might accelerate the inflammatory status of lung infiltrating monocytes leading to increased lung pathology in patients with severe form of COVID-19.


Subject(s)
COVID-19 , Monocytes , Animals , Antigen-Antibody Complex , COVID-19/therapy , Cytokines/metabolism , Dinoprostone/metabolism , Fibrin Fibrinogen Degradation Products , Humans , Immunization, Passive , Immunologic Factors/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Mice , Spike Glycoprotein, Coronavirus/metabolism
6.
Vaccines (Basel) ; 10(3)2022 Mar 15.
Article in English | MEDLINE | ID: covidwho-1742768

ABSTRACT

In healthy adults, hybrid immunity induced by prior SARS-CoV-2 infection followed by two doses of mRNA vaccination provide protection against symptomatic SARS-CoV-2 infection. However, the role of hybrid immunity in autoimmune patients against Omicron is not well documented. Here, we report a young autoimmune patient with prior infection and two doses of mRNA-1273 vaccination who was exposed to Omicron and developed a symptomatic disease. Prior to Omicron infection, the patient had strong neutralizing antibody titers against the vaccine strain, but no neutralization of Omicron. Post Omicron infection, high neutralizing titers against Omicron were observed. Furthermore, enhanced neutralizing antibody titers against other variants of concern-Alpha, Beta, Gamma, and Delta-were observed, suggesting an expansion of cross-reactive memory B-cell response by the SARS-CoV-2 Omicron infection. Autoimmune patients may require careful monitoring of immune function over time to optimize booster vaccine administration.

7.
Clin Infect Dis ; 2021 Sep 23.
Article in English | MEDLINE | ID: covidwho-1700771

ABSTRACT

BACKGROUND: Following the failure of antibody therapies in treating COVID-19 hospitalized patients we investigated the impact of viral replication on the pharmacokinetics (PK) and efficacy of a hyperimmune SARS-CoV-2 Immune Globulin (CoVIG) product in treatment of SARS-CoV-2 infection using the adult Syrian hamster model. METHODS: The CoVIG was manufactured from plasma donors who had recovered from COVID-19. The dose used (400 mg/kg) was based on the dose given in clinical trials to hospitalized COVID-19 patients. Hamsters were given a single dose of CoVIG two days after challenge with the SARS-CoV-2 virus (isolate NY/PV08410/2020), followed by sampling of blood, nasal, tracheal and lung tissues at different time points. The blood samples were assayed for anti-SARS-CoV-2 spike binding and used to calculate PK parameters. Nasal washes, trachea, and lung samples were assayed for viral replication by PCR (sgRNA). RESULTS: CoVIG-treated hamsters showed a reduction in viral replication in the lower respiratory tract, but minimally in the upper respiratory tract, following challenge with SARS-CoV-2. Challenge with SARS-CoV-2 resulted in altered PK parameters proportionate to viral replication, resulting in decreased area under the curve (AUC), accelerated clearance and shorter half-life of CoVIG. CONCLUSIONS: These data indicate that in the presence of actively replicating SARS-CoV-2 virus, PK parameters are altered and should trigger an adjustment in dosing of CoVIG.

9.
Clin Infect Dis ; 74(2): 327-334, 2022 01 29.
Article in English | MEDLINE | ID: covidwho-1662105

ABSTRACT

Convalescent plasma (CP) have been used for treatment of coronavirus disease 2019 (COVID-19), but their effectiveness varies significantly. Moreover, the impact of CP treatment on the composition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in COVID-19 patients and antibody markers that differentiate between those who survive and those who succumb to the COVID-19 disease are not well understood. Herein, we performed longitudinal analysis of antibody profile on 115 sequential plasma samples from 16 hospitalized COVID-19 patients treated with either CP or standard of care, only half of them survived. Differential antibody kinetics was observed for antibody binding, immunoglobulin M/immunoglobulin G/immunoglobulin A (IgM/IgG/IgA) distribution, and affinity maturation in "survived" versus "fatal" COVID-19 patients. Surprisingly, CP treatment did not predict survival. Strikingly, marked decline in neutralization titers was observed in the fatal patients prior to death, and convalescent plasma treatment did not reverse this trend. Furthermore, irrespective of CP treatment, higher antibody affinity to the SARS-CoV-2 prefusion spike was associated with survival outcome. Additionally, sustained elevated IgA response was associated with fatal outcome in these COVID-19 patients. These findings propose that treatment of COVID-19 patients with convalescent plasma should be carefully targeted, and effectiveness of treatment may depend on the clinical and immunological status of COVID-19 patients, as well as the quality of the antibodies in the convalescent plasma.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/therapy , Humans , Immunization, Passive
10.
EBioMedicine ; 74: 103748, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1568650

ABSTRACT

BACKGROUND: Limited knowledge exists regarding antibody affinity maturation following mRNA vaccination in naïve vs. COVID-19 recovered individuals and potential sex differences. METHODS: We elucidated post-vaccination antibody profiles of 69 naïve and 17 COVID-19 convalescent adults using pseudovirus neutralization assay (PsVNA) covering SARS-CoV-2 WA-1, variants of concern (VOCs) and variants of interest (VOIs). Surface Plasmon Resonance (SPR) was used to measure antibody affinity against prefusion spike and receptor binding domain (RBD) and RBD mutants. FINDINGS: Higher neutralizing antibodies were observed in convalescent vs. naïve adults against, WA-1, VOCs, and VOIs. Antibody binding to RBD and RBD mutants showed lower binding of post-vaccination sera from naïve compared with convalescent individuals. Moreover, we observed early antibody affinity maturation in convalescent individuals after one vaccine dose and higher antibody affinity after two doses compared with the naïve group. Among the naïve participants, antibody affinity against the SARS-CoV-2 prefusion spike was significantly higher for males than females even though there were no difference in neutralization titers between sexes. INTERPRETATION: This study demonstrates the impact of prior infection on vaccine-induced antibody affinity maturation and difference in antibody affinity between males and females. Further studies are needed to determine whether antibody affinity may contribute to correlates of protection against SARS-CoV-2 and its variants. FUNDING: The antibody characterization work described in this manuscript was supported by FDA's Medical Countermeasures Initiative (MCMi) grant #OCET 2021-1565 to S.K and intramural FDA-CBER COVID-19 supplemental funds. The SPARTA program was supported by the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH), Department of Health and Human Services contract 75N93019C00052, and the University of Georgia (US) grant UGA-001. T.M.R is also supported by the Georgia Research Alliance (US) grant GRA-001. The CTRU was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002378.


Subject(s)
/immunology , Antibodies, Neutralizing/blood , Antibody Affinity/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Viral/blood , COVID-19/immunology , Cell Line , Female , Humans , Male , Neutralization Tests , Protein Domains/immunology , Surface Plasmon Resonance , Vaccination , /immunology
11.
Sci Adv ; 7(42): eabi6533, 2021 Oct 15.
Article in English | MEDLINE | ID: covidwho-1467653

ABSTRACT

Mucosal immunity plays a key role in prevention of SARS-CoV-2 virus spread to the lungs. In this study, we evaluated systemic and mucosal immune signatures in asymptomatic SARS-CoV-2­infected versus symptomatic COVID-19 adults compared with RSV-infected adults. Matched serum and nasal wash pairs were subjected to cytokine/chemokine analyses and comprehensive antibody profiling including epitope repertoire analyses, antibody kinetics to SARS-CoV-2 prefusion spike and spike RBD mutants, and neutralization of SARS-CoV-2 variants of concern. The data suggest independent evolution of antibody responses in the mucosal sites as reflected in differential IgM/IgG/IgA epitope repertoire compared with serum. Antibody affinity against SARS-CoV-2 prefusion spike for both serum and nasal washes was significantly higher in asymptomatic adults compared with symptomatic COVID-19 patients. Last, the cytokine/chemokine responses in the nasal washes were more robust than in serum. These data underscore the importance of evaluating mucosal immune responses for better therapeutics and vaccines against SARS-CoV-2.

12.
iScience ; 24(9): 103006, 2021 Sep 24.
Article in English | MEDLINE | ID: covidwho-1364140

ABSTRACT

Hyperimmune immunoglobulin (hCoV-2IG) generated from SARS-CoV-2 convalescent plasma (CP) are under evaluation in clinical trials. Here we explored the antibody epitope repertoire, and virus neutralizing capacity of six hCoV-2IG batches as well as nine CP against SARS-CoV-2 and emerging variants of concern (VOCs). Epitope-mapping by gene-fragment phage display library spanning the SARS-CoV-2 spike demonstrated broad recognition of multiple antigenic sites spanning the entire spike that was higher for hCoV-2IG than CP, with predominant binding to the fusion peptide. In the pseudovirus neutralization assay and in the wild-type SARS-CoV-2 PRNT assay, hCoV-2IG lots showed higher titers against the WA-1 strain compared with CP. Neutralization of VOCs were reduced to different extent by hCoV-2IG lots but were higher than CP. Significant reduction of hCoV-2IG binding was observed to RBD-E484K followed by RBD-N501Y (but not RBD-K417N). This study suggests that post-exposure treatment with hCoV-2IG could be preferable to CP.

13.
Vaccine ; 39(37): 5233-5239, 2021 08 31.
Article in English | MEDLINE | ID: covidwho-1347849

ABSTRACT

Modern vaccinology has experienced major conceptual and technological advances over the past 30 years. These include atomic-level structures driving immunogen design, new vaccine delivery methods, powerful adjuvants, and novel animal models. In addition, utilizing advanced assays to learn how the immune system senses a pathogen and orchestrates protective immunity has been critical in the design of effective vaccines and therapeutics. The National Institute of Allergy and Infectious Diseases of the National Institutes of Health convened a workshop in September 2020 focused on next generation assays for vaccine development (Table 1). The workshop focused on four critical pathogens: severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and human immunodeficiency virus (HIV)-which have no licensed vaccines-and tuberculosis (TB) and influenza-both of which are in critical need of improved vaccines. The goal was to share progress and lessons learned, and to identify any commonalities that can be leveraged to design vaccines and therapeutics.


Subject(s)
COVID-19 , Tuberculosis , Animals , Humans , Laboratories , SARS-CoV-2 , Tuberculosis/prevention & control , United States , Vaccinology
15.
Nature ; 594(7864): 553-559, 2021 06.
Article in English | MEDLINE | ID: covidwho-1221200

ABSTRACT

Betacoronaviruses caused the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, as well as the current pandemic of SARS coronavirus 2 (SARS-CoV-2)1-4. Vaccines that elicit protective immunity against SARS-CoV-2 and betacoronaviruses that circulate in animals have the potential to prevent future pandemics. Here we show that the immunization of macaques with nanoparticles conjugated with the receptor-binding domain of SARS-CoV-2, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV and SARS-CoV-2 (including the B.1.1.7, P.1 and B.1.351 variants). Vaccination of macaques with these nanoparticles resulted in a 50% inhibitory reciprocal serum dilution (ID50) neutralization titre of 47,216 (geometric mean) for SARS-CoV-2, as well as in protection against SARS-CoV-2 in the upper and lower respiratory tracts. Nucleoside-modified mRNAs that encode a stabilized transmembrane spike or monomeric receptor-binding domain also induced cross-neutralizing antibody responses against SARS-CoV and bat coronaviruses, albeit at lower titres than achieved with the nanoparticles. These results demonstrate that current mRNA-based vaccines may provide some protection from future outbreaks of zoonotic betacoronaviruses, and provide a multimeric protein platform for the further development of vaccines against multiple (or all) betacoronaviruses.


Subject(s)
Antibodies, Neutralizing/immunology , Betacoronavirus/immunology , COVID-19/immunology , COVID-19/prevention & control , Common Cold/prevention & control , Cross Reactions/immunology , Pandemics , Viral Vaccines/immunology , Adjuvants, Immunologic , Administration, Intranasal , Animals , COVID-19/epidemiology , COVID-19 Vaccines/immunology , Common Cold/immunology , Common Cold/virology , Disease Models, Animal , Female , Humans , Macaca/immunology , Male , Models, Molecular , Nanoparticles/chemistry , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Trachea , Vaccination
16.
Nat Commun ; 12(1): 1221, 2021 02 22.
Article in English | MEDLINE | ID: covidwho-1096322

ABSTRACT

Hospitalized COVID-19 patients often present with a large spectrum of clinical symptoms. There is a critical need to better understand the immune responses to SARS-CoV-2 that lead to either resolution or exacerbation of the clinical disease. Here, we examine longitudinal plasma samples from hospitalized COVID-19 patients with differential clinical outcome. We perform immune-repertoire analysis including cytokine, hACE2-receptor inhibition, neutralization titers, antibody epitope repertoire, antibody kinetics, antibody isotype and antibody affinity maturation against the SARS-CoV-2 prefusion spike protein. Fatal cases demonstrate high plasma levels of IL-6, IL-8, TNFα, and MCP-1, and sustained high percentage of IgA-binding antibodies to prefusion spike compared with non-ICU survivors. Disease resolution in non-ICU and ICU patients associates with antibody binding to the receptor binding motif and fusion peptide, and antibody affinity maturation to SARS-CoV-2 prefusion spike protein. Here, we provide insight into the immune parameters associated with clinical disease severity and disease-resolution outcome in hospitalized patients that could inform development of vaccine/therapeutics against COVID-19.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Affinity/immunology , COVID-19/immunology , Immunoglobulin A/immunology , SARS-CoV-2/immunology , Adult , Aged , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/blood , COVID-19/virology , Cohort Studies , Cytokines/blood , Cytokines/immunology , Cytokines/metabolism , Epitopes/immunology , Female , Hospitalization/statistics & numerical data , Humans , Immunoglobulin A/blood , Male , Middle Aged , Neutralization Tests , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/immunology , Surface Plasmon Resonance
17.
Sci Transl Med ; 12(550)2020 07 01.
Article in English | MEDLINE | ID: covidwho-591374

ABSTRACT

Multiple vaccine candidates against SARS-CoV-2 based on viral spike protein are under development. However, there is limited information on the quality of antibody responses generated with these vaccine modalities. To better understand antibody responses induced by spike protein-based vaccines, we performed a qualitative study by immunizing rabbits with various SARS-CoV-2 spike protein antigens: S ectodomain (S1+S2; amino acids 16 to 1213), which lacks the cytoplasmic and transmembrane domains (CT-TM), the S1 domain (amino acids 16 to 685), the receptor binding domain (RBD) (amino acids 319 to 541), and the S2 domain (amino acids 686 to 1213, lacking the RBD, as control). Resulting antibody quality and function were analyzed by enzyme-linked immunosorbent assay (ELISA), RBD competition assay, surface plasmon resonance (SPR) against different spike proteins in native conformation, and neutralization assays. All three antigens (S1+S2 ectodomain, S1 domain, and RBD), but not S2, generated strong neutralizing antibodies against SARS-CoV-2. Vaccination-induced antibody repertoire was analyzed by SARS-CoV-2 spike genome fragment phage display libraries (SARS-CoV-2 GFPDL), which identified immunodominant epitopes in the S1, S1-RBD, and S2 domains. Furthermore, these analyses demonstrated that the RBD immunogen elicited a higher antibody titer with five-fold higher affinity antibodies to native spike antigens compared with other spike antigens, and antibody affinity correlated strongly with neutralization titers. These findings may help guide rational vaccine design and facilitate development and evaluation of effective therapeutics and vaccines against COVID-19 disease.


Subject(s)
Antibodies, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Neutralizing/immunology , Antibody Formation/immunology , Antigens, Viral/immunology , Epitopes/immunology , Female , Immunization , Neutralization Tests , Rabbits
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