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

npj Vaccines ◽  
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.

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

2020 ◽  
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 vaccine.

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

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.

A nucleic acid-based orthopoxvirus vaccine targeting the vaccinia virus L1, A27, B5 and A33 proteins protects rabbits against lethal rabbitpox virus aerosol challenge

2021 ◽  
Author(s):  
Eric M. Mucker ◽  
Joseph W. Golden ◽  
Christopher D. Hammerbeck ◽  
Jennifer M. Kishimori ◽  
Michael Royals ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Severe Disease ◽  
Aerosol Exposure ◽  
Nucleic Acid Vaccines ◽  
Rabbitpox Virus ◽  
Imported Cases ◽  
Route Of Exposure

In the age of COVID, nucleic acid vaccines have garnered much attention, at least in part, because of the simplicity of construction, production, and flexibility to adjust and adapt to an evolving outbreak. Orthopoxviruses remain a threat on multiple fronts, especially as emerging zoonosis. In response, we developed a DNA vaccine, termed 4pox, that protected nonhuman primates against monkeypox virus (MPXV) induced severe disease. Here, we examined the protective efficacy of the 4pox DNA vaccine delivered by intramuscular (i.m.) electroporation (EP) in rabbits challenged with aerosolized rabbitpox virus (RPXV), a model that recapitulates the respiratory route of exposure and low dose associated with natural smallpox exposure in humans. We found that 4pox vaccinated rabbits developed immunogen-specific antibodies, including neutralizing antibodies and did not develop any clinical disease, indicating protection against aerosolized RPXV. In contrast, unvaccinated animals developed significant signs of disease, including lesions, and were euthanized. These findings demonstrate that an unformulated, non-adjuvanted DNA vaccine delivered (i.m.) can protect against an aerosol exposure. Importance The eradication of smallpox and subsequent cessation of vaccination has left a majority of the population susceptible to variola virus or other emerging poxvirus. This is exemplified by human monkeypox, as evidenced by the increase in reported endemic and imported cases over the past decades. Therefore, a malleable vaccine technology that can be mass produced, and doesn’t require complex conditions for distribution and storage is sought. Herein, we show that a DNA vaccine, in the absence of a specialized formulation or adjuvant, can protect against a lethal aerosol insult of rabbitpox virus.

scholarly journals A Host-Restricted Self-Attenuated Influenza Virus Provides Broad Pan-Influenza A Protection in a Mouse Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Minjin Kim ◽  
Yucheol Cheong ◽  
Jinhee Lee ◽  
Jongkwan Lim ◽  
Sanguine Byun ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Protective Efficacy ◽  
Influenza Viruses ◽  
Cross Protection ◽  
Infection Model ◽  
Wild Type ◽  
Group 1

Influenza virus infections can cause a broad range of symptoms, form mild respiratory problems to severe and fatal complications. While influenza virus poses a global health threat, the frequent antigenic change often significantly compromises the protective efficacy of seasonal vaccines, further increasing the vulnerability to viral infection. Therefore, it is in great need to employ strategies for the development of universal influenza vaccines (UIVs) which can elicit broad protection against diverse influenza viruses. Using a mouse infection model, we examined the breadth of protection of the caspase-triggered live attenuated influenza vaccine (ctLAIV), which was self-attenuated by the host caspase-dependent cleavage of internal viral proteins. A single vaccination in mice induced a broad reactive antibody response against four different influenza viruses, H1 and rH5 (HA group 1) and H3 and rH7 subtypes (HA group 2). Notably, despite the lack of detectable neutralizing antibodies, the vaccination provided heterosubtypic protection against the lethal challenge with the viruses. Sterile protection was confirmed by the complete absence of viral titers in the lungs and nasal turbinates after the challenge. Antibody-dependent cellular cytotoxicity (ADCC) activities of non-neutralizing antibodies contributed to cross-protection. The cross-protection remained robust even after in vivo depletion of T cells or NK cells, reflecting the strength and breadth of the antibody-dependent effector function. The robust mucosal secretion of sIgA reflects an additional level of cross-protection. Our data show that the host-restricted designer vaccine serves an option for developing a UIV, providing pan-influenza A protection against both group 1 and 2 influenza viruses. The present results of potency and breadth of protection from wild type and reassortant viruses addressed in the mouse model by single immunization merits further confirmation and validation, preferably in clinically relevant ferret models with wild type challenges.

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

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.

scholarly journals Disruption of Adaptive Immunity Enhances Disease in SARS-CoV-2 Infected Syrian Hamsters

2020 ◽  
Author(s):  
Rebecca L. Brocato ◽  
Lucia M. Principe ◽  
Robert K. Kim ◽  
Xiankun Zeng ◽  
Janice A. Williams ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Animal Models ◽  
Adaptive Immunity ◽  
Protective Efficacy ◽  
Severe Disease ◽  
Clinical Signs ◽  
Spike Protein ◽  
Syrian Hamsters ◽  
Viral Loads ◽  
Neutralizing Monoclonal Antibody

AbstractAnimal models recapitulating human COVID-19 disease, especially with severe disease, are urgently needed to understand pathogenesis and evaluate candidate vaccines and therapeutics. Here, we develop novel severe disease animal models for COVID-19 involving disruption of adaptive immunity in Syrian hamsters. Cyclophosphamide (CyP) immunosuppressed or RAG2 knockout (KO) hamsters were exposed to SARS-CoV-2 by the respiratory route. Both the CyP-treated and RAG2 KO hamsters developed clinical signs of disease that were more severe than in immunocompetent hamsters, notably weight loss, viral loads, and fatality (RAG2 KO only). Disease was prolonged in transiently immunosuppressed hamsters and uniformly lethal in RAG2 KO hamsters. We evaluated the protective efficacy of a neutralizing monoclonal antibody and found that pretreatment, even in immunosuppressed animals, limited infection. Our results suggest that functional B and/or T cells are not only important for the clearance of SARS-CoV-2, but also play an early role in protection from acute disease.One Sentence SummaryAn antibody targeting the spike protein of SARS-CoV-2 limits infection in immunosuppressed Syrian hamster models.

scholarly journals A Spike protein-based subunit SARS-CoV-2 vaccine for pets: safety, immunogenicity, and protective efficacy in juvenile cats

2021 ◽  
Author(s):  
Kairat Tabynov ◽  
Madiana Orynbassar ◽  
Leila Yelchibayeva ◽  
Nurkeldi Turebekov ◽  
Toktassyn Yerubayev ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Neutralizing Antibodies ◽  
Large Scale ◽  
Protective Efficacy ◽  
Spike Protein ◽  
Wild Type Virus ◽  
Upper Respiratory Tract ◽  
Wild Type ◽  
Serum Samples ◽  
Virus Shedding

Abstract Whereas multiple vaccine types have been developed to curb the spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) among humans, there are very few vaccines being developed for animals including pets. To combat the threat of human-to-animal, animal-to-animal and animal-to-human transmission and the generation of new virus variants, we developed a subunit SARS-CoV-2 vaccine which is based on recombinant spike protein extracellular domain expressed in insect cells then formulated with appropriate adjuvants. Sixteen 8-12-week-old outbred female and male kittens (n=4/group) were randomly assigned into four treatment groups: Group 1, Antigen alone; Group 2, Sepivac SWE™ adjuvant; Group 3, aluminum hydroxide adjuvant; Group 4, PBS administered control animals. All animals were vaccinated twice at day 0 and 14, intramuscularly in a volume of 0.5 mL (Groups 1-3: 5 µg of Spike protein). On days 0 and 28 serum samples were collected to evaluate anti-spike IgG, inhibition of spike binding to angiotensin-converting enzyme 2 (ACE-2), neutralizing antibodies to Wuhan-01 SARS-CoV-2 D614G (wild-type) and Delta variant viruses, and whole blood for hematology studies. At day 28, all groups were challenged with SARS-CoV-2 wild-type virus 106 TCID50 intranasally. On day 31, tissue samples (lung, heart, and nasal turbinates) were collected for histology, viral RNA detection and virus titration. Parameters evaluated in this study included safety, immunogenicity, and protection from infection with wild-type SARS-CoV-2 virus. After two immunizations, both vaccines induced high titers of serum anti-spike IgG, ACE-2 binding inhibitory and neutralizing antibodies against both wild-type and Delta variant virus in the juvenile cats. Both subunit vaccines provided protection of juvenile cats against virus shedding from the upper respiratory tract, and against viral replication in the lower respiratory tract and hearts. These promising data warrant ongoing evaluation of the vaccine’s ability to protect cats against SARS-CoV-2 Delta variant and in particular to prevent transmission of the infection to naïve cats, before proceeding with large-scale field trials.

scholarly journals In contrast to TH2-biased approaches, TH1 COVID-19 vaccines protect Syrian hamsters from severe disease in the absence of dexamethasone-treatable vaccine-associated enhanced respiratory pathology

2021 ◽  
Author(s):  
Aileen Ebenig ◽  
Samada Muraleedharan ◽  
Julia Kazmierski ◽  
Daniel Todt ◽  
Arne Auste ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Viral Vectors ◽  
Severe Disease ◽  
Lymphoid Cells ◽  
Protein Vaccine ◽  
S Protein ◽  
Vaccine Candidates ◽  
Syrian Hamsters ◽  
Unvaccinated Control ◽  
Low Passage

Since December 2019, the novel human coronavirus SARS-CoV-2 has spread globally, causing millions of deaths. Unprecedented efforts have enabled development and authorization of a range of vaccines, which reduce transmission rates and confer protection against the associated disease COVID-19. These vaccines are conceptually diverse, including e.g. classical adjuvanted whole-inactivated virus, viral vectors, and mRNA vaccines. We have analysed two prototypic model vaccines, the strongly TH1-biased measles vaccine-derived candidate MeVvac2-SARS2-S(H) and a TH2-biased Alum-adjuvanted, non-stabilized Spike (S) protein side-by-side, for their ability to protect Syrian hamsters upon challenge with a low-passage SARS-CoV-2 patient isolate. As expected, the MeVvac2-SARS2-S(H) vaccine protected the hamsters safely from severe disease. In contrast, the protein vaccine induced vaccine-associated enhanced respiratory disease (VAERD) with massive infiltration of eosinophils into the lungs. Global RNA-Seq analysis of hamster lungs revealed reduced viral RNA and less host dysregulation in MeVvac2-SARS2-S(H) vaccinated animals, while S protein vaccination triggered enhanced host gene dysregulation compared to unvaccinated control animals. Of note, mRNAs encoding the major eosinophil attractant CCL-11, the TH2 response-driving cytokine IL-19, as well as TH2-cytokines IL-4, IL-5, and IL-13 were exclusively up-regulated in the lungs of S protein vaccinated animals, consistent with previously described VAERD induced by RSV vaccine candidates. IL-4, IL-5, and IL-13 were also up-regulated in S-specific splenocytes after protein vaccination. Using scRNA-Seq, T cells and innate lymphoid cells were identified as the source of these cytokines, while Ccl11 and Il19 mRNAs were expressed in lung macrophages displaying an activated phenotype. Interestingly, the amount of viral reads in this macrophage population correlated with the abundance of Fc-receptor reads. These findings suggest that VAERD is triggered by induction of TH2-type helper cells secreting IL-4, IL-5, and IL-13, together with stimulation of macrophage subsets dependent on non-neutralizing antibodies. Via this mechanism, uncontrolled eosinophil recruitment to the infected tissue occurs, a hallmark of VAERD immunopathogenesis. These effects could effectively be treated using dexamethasone and were not observed in animals vaccinated with MeVvac2-SARS2-S(H). Taken together, our data validate the potential of TH2-biased COVID-19 vaccines and identify the transcriptional mediators that underlie VAERD, but confirm safety of TH1-biased vaccine concepts such as vector-based or mRNA vaccines. Dexamethasone, which is already in use for treatment of severe COVID-19, may alleviate such VAERD, but in-depth scrutiny of any next-generation protein-based vaccine candidates is required, prior and after their regulatory approval.

scholarly journals Immunogenicity and Protective Efficacy of a Polyvalent DNA Vaccine against Human Orthopoxvirus Infections Based on Smallpox Virus Genes

2013 ◽  
Vol 2013 ◽  
pp. 1-8
Author(s):  
Rinat A. Maksyutov ◽  
Elena V. Gavrilova ◽  
Galina V. Kochneva ◽  
Sergei N. Shchelkunov
Keyword(s):  
Vaccinia Virus ◽  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
Dna Vaccines ◽  
Protective Efficacy ◽  
Surface Membrane ◽  
Virus Envelope ◽  
Extracellular Virus ◽  
Rous Sarcoma ◽  
Sarcoma Virus

DNA vaccines combining plasmids carrying the variola virus genes M1R, A30L, and F8L of intracellular virion surface membrane proteins as well as A36R and B7R of the extracellular virus envelope proteins under control of Rous sarcoma virus or cytomegalovirus promoters have been constructed. These DNA vaccines induced production of a high titers of vaccinia virus-neutralizing antibodies in mice similar to those elicited by the live vaccinia virus immunization. Mice vaccinated by created DNA vaccine were completely protected against a lethal (10 LD50) challenge with highly pathogenic ectromelia virus. These results suggest that such vaccine should be efficient in immunization of humans against smallpox.

scholarly journals Construction and Nonclinical Testing of a Puumala Virus Synthetic M Gene-Based DNA Vaccine

2012 ◽  
Vol 20 (2) ◽  
pp. 218-226 ◽  
Author(s):  
R. L. Brocato ◽  
M. J. Josleyn ◽  
V. Wahl-Jensen ◽  
C. S. Schmaljohn ◽  
J. W. Hooper
Keyword(s):  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
High Titer ◽  
Disease Model ◽  
Case Fatality ◽  
Hemorrhagic Fever ◽  
Puumala Virus ◽  
M Gene ◽  
Reading Frame ◽  
Andes Virus

ABSTRACTPuumala virus (PUUV) is a causative agent of hemorrhagic fever with renal syndrome (HFRS). Although PUUV-associated HFRS does not result in high case-fatality rates, the social and economic impact is considerable. There is no licensed vaccine or specific therapeutic to prevent or treat HFRS. Here we report the synthesis of a codon-optimized, full-length M segment open reading frame and its cloning into a DNA vaccine vector to produce the plasmid pWRG/PUU-M(s2). pWRG/PUU-M(s2) delivered by gene gun produced high-titer neutralizing antibodies in hamsters and nonhuman primates. Vaccination with pWRG/PUU-M(s2) protected hamsters against infection with PUUV but not against infection by related HFRS-associated hantaviruses. Unexpectedly, vaccination protected hamsters in a lethal disease model of Andes virus (ANDV) in the absence of ANDV cross-neutralizing antibodies. This is the first evidence that an experimental DNA vaccine for HFRS can provide protection in a hantavirus lethal disease model.

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