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 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 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 2904. Protective Efficacy of Nucleic Acid Vaccines Against Transmission of Zika Virus During Pregnancy in Mice

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S84-S84
Author(s):  
Brett W Jagger ◽  
Kimberly A Dowd ◽  
Rita Chen ◽  
Pritesh Desai ◽  
Sunny Himansu ◽  
...  
Keyword(s):  
T Cell ◽  
Nucleic Acid ◽  
Plasmid Dna ◽  
Zika Virus ◽  
Vaccine Efficacy ◽  
Protective Efficacy ◽  
Cd8 T Cell ◽  
Antibody Responses ◽  
Cell Vaccine ◽  
Nucleic Acid Vaccines

Abstract Background Zika virus (ZIKV) caused an epidemic of microcephaly and congenital malformations in 2015–2016, prompting the development of ZIKV vaccines. Plasmid DNA and modified mRNA lipid nanoparticle-encapsulated (mRNA-LNP) vaccines were among the first to reach human clinical trials, where their evaluation is ongoing. Few studies have evaluated vaccine efficacy in the setting of infection during pregnancy, and there is an open question around antibody-dependent enhancement (ADE) of flaviviral disease due to cross-reactive fusion loop epitope (FLE) antibodies. Methods Female C57BL/6J mice and human STAT2 knock-in (hSTAT2-KI) mice were immunized with plasmid DNA (VRC5283) or mRNA-LNP (Moderna Inc.) vaccines encoding the ZIKV prM-E genes. Antibody responses were assayed, and immunized mice were mated and WT mice were transiently immunocompromised by administration of interferon blocking antibody, followed by ZIKV challenge. 1 week post-infection, ZIKV burden was measured via qRT-PCR. ZIKV-specific memory B cell (MBC), long-lived plasma cell (LLPC), and CD8+ T cell vaccine responses were also assayed. Results VRC5283 and mRNA-LNP vaccines were highly immunogenic, eliciting serum neutralizing EC50 responses >1:10,000, and markedly reduced placental ZIKV burden and fetal transmission. An improved mRNA-LNP construct with higher immunogenicity correlated with reduced placental viral burden. Significantly, an FLE-mutant mRNA-LNP vaccine yielded comparable EC50 responses without compromising vaccine efficacy; sera from these mice did not enhance dengue virus infection in vitro. Both VRC5283 and mRNA-LNP vaccines elicited MBC, LLPC, and CD8+ T cell responses, although MBC and LLPC responses were greater after mRNA-LNP immunization. Surprisingly, low-level ZIKV infection of the placenta and a minority of fetal heads were observed despite robust neutralizing antibody responses, which was not seen in the immunocompetent hSTAT2-KI model. Conclusion Nucleic acid vaccines were highly immunogenic and protective against vertical ZIKV transmission during pregnancy in mice. These data support and inform the ongoing clinical development of these vaccines in humans. Disclosures All Authors: No reported Disclosures.

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.

scholarly journals A DNA Vaccine for Venezuelan Equine Encephalitis Virus Delivered by Intramuscular Electroporation Elicits High Levels of Neutralizing Antibodies in Multiple Animal Models and Provides Protective Immunity to Mice and Nonhuman Primates

2011 ◽  
Vol 18 (5) ◽  
pp. 707-716 ◽  
Author(s):  
Lesley C. Dupuy ◽  
Michelle J. Richards ◽  
Barry Ellefsen ◽  
Lillian Chau ◽  
Alain Luxembourg ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Clinical Signs ◽  
Neutralizing Antibody ◽  
Venezuelan Equine Encephalitis Virus ◽  
Encephalitis Virus ◽  
Antibody Responses ◽  
Venezuelan Equine Encephalitis ◽  
Equine Encephalitis Virus

ABSTRACTWe evaluated the immunogenicity and protective efficacy of a DNA vaccine expressing codon-optimized envelope glycoprotein genes of Venezuelan equine encephalitis virus (VEEV) when delivered by intramuscular electroporation. Mice vaccinated with the DNA vaccine developed robust VEEV-neutralizing antibody responses that were comparable to those observed after administration of the live-attenuated VEEV vaccine TC-83 and were completely protected from a lethal aerosol VEEV challenge. The DNA vaccine also elicited strong neutralizing antibody responses in rabbits that persisted at high levels for at least 6 months and could be boosted by a single additional electroporation administration of the DNA performed approximately 6 months after the initial vaccinations. Cynomolgus macaques that received the vaccine by intramuscular electroporation developed substantial neutralizing antibody responses and after an aerosol challenge had no detectable serum viremia and had reduced febrile reactions, lymphopenia, and clinical signs of disease compared to those of negative-control macaques. Taken together, our results demonstrate that this DNA vaccine provides a potent means of protecting against VEEV infections and represents an attractive candidate for further development.

scholarly journals Smallpox DNA Vaccine Protects Nonhuman Primates against Lethal Monkeypox

2004 ◽  
Vol 78 (9) ◽  
pp. 4433-4443 ◽  
Author(s):  
J. W. Hooper ◽  
E. Thompson ◽  
C. Wilhelmsen ◽  
M. Zimmerman ◽  
M. Ait Ichou ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Single Gene ◽  
Severe Disease ◽  
Vaccination Campaign ◽  
Health Concern ◽  
Lethal Challenge ◽  
Naturally Occurring

ABSTRACT Two decades after a worldwide vaccination campaign was used to successfully eradicate naturally occurring smallpox, the threat of bioterrorism has led to renewed vaccination programs. In addition, sporadic outbreaks of human monkeypox in Africa and a recent outbreak of human monkeypox in the U.S. have made it clear that naturally occurring zoonotic orthopoxvirus diseases remain a public health concern. Much of the threat posed by orthopoxviruses could be eliminated by vaccination; however, because the smallpox vaccine is a live orthopoxvirus vaccine (vaccinia virus) administered to the skin, the vaccine itself can pose a serious health risk. Here, we demonstrate that rhesus macaques vaccinated with a DNA vaccine consisting of four vaccinia virus genes (L1R, A27L, A33R, and B5R) were protected from severe disease after an otherwise lethal challenge with monkeypox virus. Animals vaccinated with a single gene (L1R) which encodes a target of neutralizing antibodies developed severe disease but survived. This is the first demonstration that a subunit vaccine approach to smallpox-monkeypox immunization is feasible.

scholarly journals Protein Vaccine Induces a Durable, More Broadly Neutralizing Antibody Response in Macaques than Natural Infection with SARS-CoV-2 P.1

2021 ◽  
Author(s):  
Albert To ◽  
Teri Ann S Wong ◽  
Michael M Lieberman ◽  
Karen S Thompson ◽  
Laurent Pessaint ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
Viral Vector ◽  
Protective Efficacy ◽  
Natural Infection ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Lung Pathology ◽  
Recombinant Subunit Vaccine ◽  
Broadly Neutralizing Antibody

FDA-approved and Emergency Use Authorized (EUA) vaccines using new mRNA and viral-vector technology are highly effective in preventing moderate to severe disease, however, information on their long-term efficacy and protective breadth against SARS-CoV-2 Variants of Concern (VOCs) is currently scarce. Here we describe the durability and broad-spectrum VOC immunity of a prefusion-stabilized spike (S) protein adjuvanted with liquid or lyophilized CoVaccine HTTM in cynomolgus macaques. This recombinant subunit vaccine is highly immunogenic and induces robust spike-specific and broadly neutralizing antibody responses effective against circulating VOCs (B.1.351 [Beta], P.1 [Gamma], B.1.617 [Delta]) for at least 3 months after the final boost. Protective efficacy and post-exposure immunity were evaluated using a heterologous P.1 challenge nearly 3 months after the last immunization. Our results indicate that while immunization with both high and low S doses shorten and reduce viral loads in the upper and lower respiratory tract, a higher antigen dose is required to provide durable protection against disease as vaccine immunity wanes. Histologically, P.1 infection causes similar COVID-19-like lung pathology as seen with early pandemic isolates. Post-challenge IgG concentrations were restored to peak immunity levels and vaccine-matched and cross-variant neutralizing antibodies were significantly elevated in immunized macaques indicating an efficient anamnestic response. Only low levels of P.1-specific neutralizing antibodies with limited breadth were observed in control (non-vaccinated but challenged) macaques suggesting that natural infection may not prevent reinfection by other VOCs. Overall, these results demonstrate that a properly dosed and adjuvanted recombinant subunit vaccine can provide long-lasting and protective immunity against circulating VOCs.

scholarly journals Human convalescent plasma protects K18-hACE2 mice against severe respiratory disease

2021 ◽  
Vol 102 (5) ◽  
Author(s):  
Joseph W. Golden ◽  
Xiankun Zeng ◽  
Curtis R. Cline ◽  
Aura R. Garrison ◽  
Lauren E. White ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Severe Disease ◽  
Small Animal ◽  
Viral Receptor ◽  
Angiotensin Converting Enzyme 2 ◽  
Brain Infection ◽  
Keratin 18 ◽  
Human Infections

SARS-CoV-2 is the causative agent of COVID-19 and human infections have resulted in a global health emergency. Small animal models that reproduce key elements of SARS-CoV-2 human infections are needed to rigorously screen candidate drugs to mitigate severe disease and prevent the spread of SARS-CoV-2. We and others have reported that transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2) viral receptor under the control of the Keratin 18 (K18) promoter develop severe and lethal respiratory disease subsequent to SARS-CoV-2 intranasal challenge. Here we report that some infected mice that survive challenge have residual pulmonary damages and persistent brain infection on day 28 post-infection despite the presence of anti-SARS-COV-2 neutralizing antibodies. Because of the hypersensitivity of K18-hACE2 mice to SARS-CoV-2 and the propensity of virus to infect the brain, we sought to determine if anti-infective biologics could protect against disease in this model system. We demonstrate that anti-SARS-CoV-2 human convalescent plasma protects K18-hACE2 against severe disease. All control mice succumbed to disease by day 7; however, all treated mice survived infection without observable signs of disease. In marked contrast to control mice, viral antigen and lesions were reduced or absent from lungs and absent in brains of antibody-treated mice. Our findings support the use of K18-hACE2 mice for protective efficacy studies of anti-SARS-CoV-2 medical countermeasures (MCMs). They also support the use of this system to study SARS-CoV-2 persistence and host recovery.

scholarly journals Immune Serum Produced by DNA Vaccination Protects Hamsters against Lethal Respiratory Challenge with Andes Virus

2007 ◽  
Vol 82 (3) ◽  
pp. 1332-1338 ◽  
Author(s):  
Jay W. Hooper ◽  
Anthony M. Ferro ◽  
Victoria Wahl-Jensen
Keyword(s):  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
Lethal Dose ◽  
Case Fatality ◽  
Immune Serum ◽  
Human Infection ◽  
M Gene ◽  
Hamster Model ◽  
Highly Pathogenic ◽  
Andes Virus

ABSTRACT Hantavirus pulmonary syndrome (HPS) is a highly pathogenic disease (40% case fatality rate) carried by rodents chronically infected with certain viruses within the genus Hantavirus of the family Bunyaviridae. The primary mode of transmission to humans is thought to be inhalation of excreta from infected rodents; however, ingestion of contaminated material and rodent bites are also possible modes of transmission. Person-to-person transmission of HPS caused by one species of hantavirus, Andes virus (ANDV), has been reported. Previously, we reported that ANDV injected intramuscularly causes a disease in Syrian hamsters that closely resembles HPS in humans. Here we tested whether ANDV was lethal in hamsters when it was administered by routes that more accurately model the most common routes of human infection, i.e., the subcutaneous, intranasal, and intragastric routes. We discovered that ANDV was lethal by all three routes. Remarkably, even at very low doses, ANDV was highly pathogenic when it was introduced by the mucosal routes (50% lethal dose [LD50], ∼100 PFU). We performed passive transfer experiments to test the capacity of neutralizing antibodies to protect against lethal intranasal challenge. The neutralizing antibodies used in these experiments were produced in rabbits vaccinated by electroporation with a previously described ANDV M gene-based DNA vaccine, pWRG/AND-M. Hamsters that were administered immune serum on days −1 and +5 relative to challenge were protected against intranasal challenge (21 LD50). These findings demonstrate the utility of using the ANDV hamster model to study transmission across mucosal barriers and provide evidence that neutralizing antibodies produced by DNA vaccine technology can be used to protect against challenge by the respiratory route.

Sign in / Sign up

Export Citation Format

Share Document