NVX-CoV2373 vaccine protects cynomolgus macaque upper and lower airways against SARS-CoV-2 challenge

ABSTRACTThere is an urgent need for a safe and protective vaccine to control the global spread of SARS-CoV-2 and prevent COVID-19. Here, we report the immunogenicity and protective efficacy of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) produced from the full-length SARS-CoV-2 spike (S) glycoprotein stabilized in the prefusion conformation. Cynomolgus macaques (Macaca fascicularis) immunized with NVX-CoV2373 and the saponin-based Matrix-M adjuvant induced anti-S antibody that was neutralizing and blocked binding to the human angiotensin-converting enzyme 2 (hACE2) receptor. Following intranasal and intratracheal challenge with SARS-CoV-2, immunized macaques were protected against upper and lower infection and pulmonary disease. These results support ongoing phase 1/2 clinical studies of the safety and immunogenicity of NVX-CoV2327 vaccine (NCT04368988).HighlightsFull-length SARS-CoV-2 prefusion spike with Matrix-M1™ (NVX-CoV2373) vaccine.Induced hACE2 receptor blocking and neutralizing antibodies in macaques.Vaccine protected against SARS-CoV-2 replication in the nose and lungs.Absence of pulmonary pathology in NVX-CoV2373 vaccinated macaques.

Download Full-text

Protective efficacy of a SARS-CoV-2 DNA vaccine in wild-type and immunosuppressed Syrian hamsters

npj Vaccines ◽

10.1038/s41541-020-00279-z ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Rebecca L. Brocato ◽

Steven A. Kwilas ◽

Robert K. Kim ◽

Xiankun Zeng ◽

Lucia M. Principe ◽

...

Keyword(s):

Dna Vaccine ◽

Neutralizing Antibodies ◽

Protective Efficacy ◽

Phase 1 ◽

Severe Disease ◽

Disease Model ◽

Wild Type ◽

Jet Injection ◽

Syrian Hamsters ◽

Dna Targeting

AbstractA worldwide effort to counter the COVID-19 pandemic has resulted in hundreds of candidate vaccines moving through various stages of research and development, including several vaccines in phase 1, 2 and 3 clinical trials. A relatively small number of these vaccines have been evaluated in SARS-CoV-2 disease models, and fewer in a severe disease model. Here, a SARS-CoV-2 DNA targeting the spike protein and delivered by jet injection, nCoV-S(JET), elicited neutralizing antibodies in hamsters and was protective in both wild-type and transiently immunosuppressed hamster models. This study highlights the DNA vaccine, nCoV-S(JET), we developed has a great potential to move to next stage of preclinical studies, and it also demonstrates that the transiently-immunosuppressed Syrian hamsters, which recapitulate severe and prolonged COVID-19 disease, can be used for preclinical evaluation of the protective efficacy of spike-based COVID-19 vaccines.

Download Full-text

Recombinant Fc-fusion vaccine of RBD induced protection against SARS-CoV-2 in non-human primate and mice

10.1101/2020.11.29.402339 ◽

2020 ◽

Author(s):

Shihui Sun ◽

Lei He ◽

Zhongpeng Zhao ◽

Hongjing Gu ◽

Xin Fang ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Subunit Vaccine ◽

Macaca Fascicularis ◽

Protective Efficacy ◽

Phase 1 ◽

Pilot Scale ◽

Scale Production ◽

Human Igg1 ◽

Clinical Trails ◽

Human Primate

AbstractThe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to infect people globally. The increased COVID-19 cases and no licensed vaccines highlight the need to develop safe and effective vaccines against SARS-CoV-2 infection. Multiple vaccines candidates are under pre-clinical or clinical trails with different strengths and weaknesses. Here we developed a pilot scale production of a recombinant subunit vaccine (RBD-Fc Vacc) with the Receptor Binding Domain of SARS-CoV-2 S protein fused with the Fc domain of human IgG1. RBD-Fc Vacc induced SARS-CoV-2 specific neutralizing antibodies in non-human primates and human ACE2 transgenic mice. The antibodies induced in macaca fascicularis neutralized three divergent SARS-CoV2 strains, suggesting a broader neutralizing ability. Three times immunizations protected Macaca fascicularis (20ug or 40ug per dose) and mice (10ug or 20ug per dose) from SARS-CoV-2 infection respectively. These data support clinical development of SARS-CoV-2 vaccines for humans. RBD-Fc Vacc is currently being assessed in randomized controlled phase 1/II human clinical trails.SummaryThis study confirms protective efficacy of a SARS-CoV-2 RBD-Fc subunit vaccine.

Download Full-text

A single intranasal dose of chimpanzee adenovirus-vectored vaccine protects against SARS-CoV-2 infection in rhesus macaques

10.1101/2021.01.26.428251 ◽

2021 ◽

Author(s):

Ahmed O. Hassan ◽

Friederike Feldmann ◽

Haiyan Zhao ◽

David T. Curiel ◽

Atsushi Okumura ◽

...

Keyword(s):

Respiratory Tract ◽

Neutralizing Antibodies ◽

Lower Respiratory Tract ◽

Protective Efficacy ◽

Rhesus Macaques ◽

Angiotensin Converting Enzyme 2 ◽

Cell Responses ◽

Vectored Vaccine ◽

Dose Vaccine ◽

Intranasal Dose

SUMMARYThe deployment of a vaccine that limits transmission and disease likely will be required to end the Coronavirus Disease 2019 (COVID-19) pandemic. We recently described the protective activity of an intranasally-administered chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike (S) protein (ChAd-SARS-CoV-2-S) in the upper and lower respiratory tract of mice expressing the human angiotensin-converting enzyme 2 (ACE2) receptor. Here, we show the immunogenicity and protective efficacy of this vaccine in non-human primates. Rhesus macaques were immunized with ChAd-Control or ChAd-SARS-CoV-2-S and challenged one month later by combined intranasal and intrabronchial routes with SARS-CoV-2. A single intranasal dose of ChAd-SARS-CoV-2-S induced neutralizing antibodies and T cell responses and limited or prevented infection in the upper and lower respiratory tract after SARS-CoV-2 challenge. As this single intranasal dose vaccine confers protection against SARS-CoV-2 in non-human primates, it is a promising candidate for limiting SARS-CoV-2 infection and transmission in humans.

Download Full-text

A Novel SARS-CoV-2 Multitope Protein/Peptide Vaccine Candidate is Highly Immunogenic and Prevents Lung Infection in an Adeno Associated Virus Human Angiotensin-Converting Enzyme 2 (AAV hACE2) Mouse Model

10.1101/2020.11.30.399154 ◽

2020 ◽

Author(s):

Farshad Guirakhoo ◽

Lucy Kuo ◽

James Peng ◽

Juin Hua Huang ◽

Ben Kuo ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Candidate ◽

Phase 1 ◽

Peptide Vaccine ◽

Neutralizing Antibody ◽

Aluminum Phosphate ◽

Initial Development ◽

Angiotensin Converting Enzyme 2 ◽

Adjuvant System ◽

Favorable Safety

AbstractIn this report, we describe the initial development and proof-of-concept studies for UB-612, the first multitope protein-peptide vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen responsible for the Coronavirus Disease of 2019 (COVID-19). UB-612 consists of eight components rationally designed for induction of high neutralizing antibodies and broad T cell responses against SARS-CoV-2: the S1-RBD-sFc fusion protein, six synthetic peptides (one universal peptide and five SARS-CoV-2-derived peptides), a proprietary CpG TLR-9 agonist, and aluminum phosphate adjuvant. Through immunogenicity studies in guinea pigs and rats, we optimized the design of protein/peptide immunogens and selected an adjuvant system, yielding a vaccine that provided excellent S1-RBD binding and high neutralizing antibody responses, robust cellular responses, and a Th1-oriented response at low doses of the vaccine. Our candidate vaccine was then advanced into challenge studies, in which it reduced viral load and prevented development of disease in a mouse challenge model and in nonhuman primates (NHP, immunogenicity part is completed, challenge is ongoing). A GLP-compliant toxicity study has shown a favorable safety profile for the vaccine. With the Phase 1 trial ongoing in Taiwan and additional trials planned worldwide, UB-612 is a highly promising and differentiated vaccine candidate for prevention of SARS-CoV-2 transmission and COVID-19 disease.

Download Full-text

Vector Shedding and Blood Biodistribution in Patients with Severe Hemophilia a Following Administration of Valoctocogene Roxaparvovec

Blood ◽

10.1182/blood-2020-136459 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 21-21

Author(s):

Annie Clark ◽

Kevin Hammon ◽

Krystal Sandza ◽

Richard Torres ◽

Elli Koziol ◽

...

Keyword(s):

Whole Blood ◽

Hemophilia A ◽

Phase 1 ◽

Full Length ◽

Severe Hemophilia ◽

Publicly Traded ◽

Male Subjects ◽

Vector Dna ◽

Ongoing Phase

Introduction: Long-term durable expression of hFVIII-SQ has been observed following BMN 270 (AAV5-hFVIII-SQ, valoctocogene roxaparvovec) single-dose administration in patients with severe hemophilia A. Although adeno-associated virus (AAV) vectors are replication incompetent and thus pose minimal risk for transmission or release into environment, a comprehensive assessment of vector shedding in secreta and excreta is required as part of the clinical development program. In addition, evaluation of vector biodistribution in blood is useful to characterize vector DNA processing and further understand the kinetics of vector DNA clearance. Vector shedding and biodistribution were evaluated from subjects from an ongoing Phase 1/2 study (Study 270-201, NCT02576795) and an ongoing Phase 3 study (Study 270-301, NCT03370913) following BMN 270 administration in patients with severe hemophilia A. Methods: In the Phase 1/2 study, 15 adult male subjects with severe hemophilia A received a single intravenous infusion of 6E12 vg/kg (n=1), 2E13 vg/kg (n=1), 4E13 vg/kg (n=6), or 6E13 vg/kg (n=7) BMN 270. In the Phase 3 study, 134 adult male subjects with severe hemophilia A received a single intravenous infusion of 6E13 vg/kg BMN 270. In both studies, measurement of vector DNA in blood, saliva, feces, semen, and urine was performed using a validated qPCR assay. Blood, saliva, urine, stool, and semen were collected until at least 3 consecutive negative results via qPCR were obtained. To further characterize vector DNA potentially capable of cell transduction, a novel immunocapture qPCR (iqPCR) assay was developed to measure the amount of intact AAV5 vector capsids in plasma and semen. Further assessments of the biodistribution of vector DNA in blood, including the evaluation of the contiguity and structural characteristics of BMN 270 vector genomes, were performed in blood, plasma, peripheral blood mononuclear cells (PBMC), and red blood cells using a drop-phase droplet-digital (dd)PCR assay. Results: Following BMN 270 administration at all dose levels, vector DNA was detected in all subjects in all biodistribution and shedding matrices evaluated (i.e., blood, saliva, urine, stool, and semen). Median peak vector DNA levels were greatest in blood followed by saliva, semen, stool, and urine. Peak vector DNA concentrations following BMN 270 administration were observed early. Following peak vector DNA concentrations, BMN 270 vector genomes were steadily cleared from the urine, semen, saliva, stool, and blood. In comparison to total vector DNA measured by qPCR, encapsidated vector DNA in plasma and semen was cleared more rapidly, as measured using iqPCR. Evaluation of total vector DNA in whole blood and blood fractions, indicate 3 phases of vector DNA clearance, which are associated with the expected lifespan of various transduced cell types. From approximately 24 weeks after BMN 270 administration and beyond, a slower rate of decline of vector DNA in whole blood is observed with the majority of transgene DNA present beyond 24 weeks in blood likely within the PBMC fraction. Further characterization of vector DNA in blood demonstrated that BMN 270 DNA transitioned from an initial truncated form into full-length transgenes over time. In addition, the fraction of DNA detected in whole blood that contains an inverted terminal repeat (ITR) fusion, indicating that the residual vector DNA may have formed circular episomes in the transduced cells, increased over time. By 52 weeks post-BMN 270 administration, the majority of vector DNA in whole blood was full-length and contained an ITR fusion. Conclusions: Vector shedding and distribution has been extensively evaluated in patients with severe hemophilia A treated with BMN 270. Both vector DNA and vector capsids were detected and steadily cleared in blood and shedding matrices. Based upon the replication incompetent nature of BMN 270 and the maximum potential exposure to the vector in secreta and excreta following BMN 270 administration, the risk of transmission to untreated individuals is considered extremely low. The biodistribution and characterization of vector DNA in blood cells demonstrates the formation of full-length transgenes with ITR fusions. Disclosures Clark: BioMarin Pharmaceutical In.: Current Employment. Hammon:BioMarin Pharmaceutical Inc.: Current Employment. Sandza:BioMarin Pharmaceutical Inc.: Current Employment. Torres:BioMarin Pharmaceutical Inc.: Current Employment. Koziol:BioMarin Pharmaceutical Inc.: Current Employment. Holcomb:BioMarin Pharmaceutical Inc.: Current Employment. Kim:BioMarin Pharmaceutical Inc.: Current Employment. Jayaram:BioMarin Pharmaceutical Inc.: Current Employment. Russell:BioMarin Pharmaceutical Inc.: Current Employment, Current equity holder in publicly-traded company; Amgen nc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Vettermann:BioMarin Pharmaceutical Inc.: Current Employment. Henshaw:BioMarin Pharmaceutical Inc.: Current Employment.

Download Full-text

Gamma-irradiated SARS-CoV-2 vaccine candidate, OZG-38.61.3, confers protection from SARS-CoV-2 challenge in human ACEII-transgenic mice

Scientific Reports ◽

10.1038/s41598-021-95086-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Raife Dilek Turan ◽

Cihan Tastan ◽

Derya Dilek Kancagi ◽

Bulut Yurtsever ◽

Gozde Sir Karakus ◽

...

Keyword(s):

Transgenic Mice ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Vaccine Candidate ◽

Protective Efficacy ◽

Phase 1 ◽

Challenge Test ◽

Viral Rna ◽

Viral Vaccine ◽

Gamma Irradiated

AbstractThe SARS-CoV-2 virus caused the most severe pandemic around the world, and vaccine development for urgent use became a crucial issue. Inactivated virus formulated vaccines such as Hepatitis A and smallpox proved to be reliable approaches for immunization for prolonged periods. In this study, a gamma-irradiated inactivated virus vaccine does not require an extra purification process, unlike the chemically inactivated vaccines. Hence, the novelty of our vaccine candidate (OZG-38.61.3) is that it is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. Efficiency and safety dose (either 1013 or 1014 viral RNA copy per dose) of OZG-38.61.3 was initially determined in BALB/c mice. This was followed by testing the immunogenicity and protective efficacy of the vaccine. Human ACE2-encoding transgenic mice were immunized and then infected with the SARS-CoV-2 virus for the challenge test. This study shows that vaccinated mice have lowered SARS-CoV-2 viral RNA copy numbers both in oropharyngeal specimens and in the histological analysis of the lung tissues along with humoral and cellular immune responses, including the neutralizing antibodies similar to those shown in BALB/c mice without substantial toxicity. Subsequently, plans are being made for the commencement of Phase 1 clinical trial of the OZG-38.61.3 vaccine for the COVID-19 pandemic.

Download Full-text

Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies

Cell Research ◽

10.1038/s41422-021-00487-9 ◽

2021 ◽

Author(s):

Renhong Yan ◽

Ruoke Wang ◽

Bin Ju ◽

Jinfang Yu ◽

Yuanyuan Zhang ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Clinical Intervention ◽

Structural Features ◽

Full Length ◽

Structural Basis ◽

Receptor Binding Domain ◽

S Protein ◽

Angiotensin Converting Enzyme 2 ◽

Neutralizing Activity ◽

Potent Neutralization

AbstractNeutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus disease 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2-infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). However, the structural basis for their potent neutralizing activity remains unclear. Here, we report cryo-EM structures of the ten most potent nAbs in their native full-length IgG-form or in both IgG-form and Fab-form bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBDs in the “up” conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of a large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides a structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and its correlation with more potent neutralization and the shedding of S1 subunit.

Download Full-text

A Monovalent and Trivalent MVA-Based Vaccine Completely Protects Mice Against Lethal Venezuelan, Western, and Eastern Equine Encephalitis Virus Aerosol Challenge

Frontiers in Immunology ◽

10.3389/fimmu.2020.598847 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lisa Henning ◽

Kathrin Endt ◽

Robin Steigerwald ◽

Michael Anderson ◽

Ariane Volkmann

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

Viral Vector ◽

Protective Efficacy ◽

Phase 1 ◽

Severe Disease ◽

Clinical Signs ◽

T Cell Responses ◽

Vaccine Platform ◽

Cell Responses

Venezuelan, eastern and western equine encephalitis viruses (EEV) can cause severe disease of the central nervous system in humans, potentially leading to permanent damage or death. Yet, no licensed vaccine for human use is available to protect against these mosquito-borne pathogens, which can be aerosolized and therefore pose a bioterror threat in addition to the risk of natural outbreaks. Using the mouse aerosol challenge model, we evaluated the immunogenicity and efficacy of EEV vaccines that are based on the modified vaccinia Ankara-Bavarian Nordic (MVA-BN®) vaccine platform: three monovalent vaccines expressing the envelope polyproteins E3-E2-6K-E1 of the respective EEV virus, a mixture of these three monovalent EEV vaccines (Triple-Mix) as a first approach to generate a multivalent vaccine, and a true multivalent alphavirus vaccine (MVA-WEV, Trivalent) encoding the polyproteins of all three EEVs in a single non-replicating MVA viral vector. BALB/c mice were vaccinated twice in a four-week interval and samples were assessed for humoral and cellular immunogenicity. Two weeks after the second immunization, animals were exposed to aerosolized EEV. The majority of vaccinated animals exhibited VEEV, WEEV, and EEEV neutralizing antibodies two weeks post-second administration, whereby the average VEEV neutralizing antibodies induced by the monovalent and Trivalent vaccine were significantly higher compared to the Triple-Mix vaccine. The same statistical difference was observed for VEEV E1 specific T cell responses. However, all vaccinated mice developed comparable interferon gamma T cell responses to the VEEV E2 peptide pools. Complete protective efficacy as evaluated by the prevention of mortality and morbidity, lack of clinical signs and viremia, was demonstrated for the respective monovalent MVA-EEV vaccines, the Triple-Mix and the Trivalent single vector vaccine not only in the homologous VEEV Trinidad Donkey challenge model, but also against heterologous VEEV INH-9813, WEEV Fleming, and EEEV V105-00210 inhalational exposures. These EEV vaccines, based on the safe MVA vector platform, therefore represent promising human vaccine candidates. The trivalent MVA-WEV construct, which encodes antigens of all three EEVs in a single vector and can potentially protect against all three encephalitic viruses, is currently being evaluated in a human Phase 1 trial.

Download Full-text

SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 elicits immunogenicity in baboons and protection in mice

10.1101/2020.06.29.178509 ◽

2020 ◽

Cited By ~ 14

Author(s):

Jing-Hui Tian ◽

Nita Patel ◽

Robert Haupt ◽

Haixia Zhou ◽

Stuart Weston ◽

...

Keyword(s):

T Cells ◽

Low Dose ◽

Vaccine Candidate ◽

High Titer ◽

Phase 1 ◽

Herd Immunity ◽

Helper T Cells ◽

Angiotensin Converting Enzyme 2 ◽

Follicular Helper ◽

Ongoing Phase

AbstractThe COVID-19 pandemic continues to spread throughout the world with an urgent need for a safe and protective vaccine to effectuate herd immunity to control the spread of SARS-CoV-2. Here, we report the development of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) produced from the full-length spike (S) protein, stabilized in the prefusion conformation. Purified NVX-CoV2373 S form 27.2nm nanoparticles that are thermostable and bind with high affinity to the human angiotensin-converting enzyme 2 (hACE2) receptor. In mice and baboons, low-dose NVX-CoV2373 with saponin-based Matrix-M adjuvant elicits high titer anti-S IgG that is associated with blockade of hACE2 receptor binding, virus neutralization, and protection against SARS-CoV-2 challenge in mice with no evidence of vaccine-associated enhanced respiratory disease (VAERD). NVX-CoV2373 vaccine also elicits multifunctional CD4+ and CD8+ T cells, CD4+ T follicular helper T cells (Tfh), and the generation of antigen-specific germinal center (GC) B cells in the spleen. These results support the ongoing phase 1/2 clinical evaluation of the safety and immunogenicity of NVX-CoV2327 with Matrix-M (NCT04368988).

Download Full-text

Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies

10.1101/2020.10.13.336800 ◽

2020 ◽

Author(s):

Renhong Yan ◽

Ruoke Wang ◽

Bin Ju ◽

Jinfang Yu ◽

Yuanyuan Zhang ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Clinical Intervention ◽

Structural Features ◽

Full Length ◽

Structural Basis ◽

Virus Infections ◽

Virus Diseases ◽

S Protein ◽

Angiotensin Converting Enzyme 2 ◽

Potent Neutralization

AbstractNeutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus virus diseases 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2 infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). In order to understand the mechanism of these nAbs on neutralizing SARS-CoV-2 virus infections, we have performed cryo-EM analysis and here report cryo-EM structures of the ten most potent nAbs in their native full-length IgG or Fab forms bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBD in the “up” conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and their correlation with more potent neutralization and the shedding of S1 subunit.

Download Full-text