scholarly journals One-Health: a Safe, Efficient, Dual-Use Vaccine for Humans and Animals against Middle East Respiratory Syndrome Coronavirus and Rabies Virus

2016 ◽  
Vol 91 (2) ◽  
Author(s):  
Christoph Wirblich ◽  
Christopher M. Coleman ◽  
Drishya Kurup ◽  
Tara S. Abraham ◽  
John G. Bernbaum ◽  
...  
Keyword(s):  
Middle East ◽  
Infectious Diseases ◽  
Rabies Virus ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Middle East Respiratory Syndrome ◽  
Full Length ◽  
Mrna Levels ◽  
Vaccine Platform ◽  
S Protein

ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 and is a highly pathogenic respiratory virus. There are no treatment options against MERS-CoV for humans or animals, and there are no large-scale clinical trials for therapies against MERS-CoV. To address this need, we developed an inactivated rabies virus (RABV) that contains the MERS-CoV spike (S) protein expressed on its surface. Our initial recombinant vaccine, BNSP333-S, expresses a full-length wild-type MERS-CoV S protein; however, it showed significantly reduced viral titers compared to those of the parental RABV strain and only low-level incorporation of full-length MERS-CoV S into RABV particles. Therefore, we developed a RABV-MERS vector that contained the MERS-CoV S1 domain of the MERS-CoV S protein fused to the RABV G protein C terminus (BNSP333-S1). BNSP333-S1 grew to titers similar to those of the parental vaccine vector BNSP333, and the RABV G–MERS-CoV S1 fusion protein was efficiently expressed and incorporated into RABV particles. When we vaccinated mice, chemically inactivated BNSP333-S1 induced high-titer neutralizing antibodies. Next, we challenged both vaccinated mice and control mice with MERS-CoV after adenovirus transduction of the human dipeptidyl peptidase 4 (hDPP4) receptor and then analyzed the ability of mice to control MERS-CoV infection. Our results demonstrated that vaccinated mice were fully protected from the MERS-CoV challenge, as indicated by the significantly lower MERS-CoV titers and MERS-CoV and mRNA levels in challenged mice than those in unvaccinated controls. These data establish that an inactivated RABV-MERS S-based vaccine may be effective for use in animals and humans in areas where MERS-CoV is endemic. IMPORTANCE Rabies virus-based vectors have been proven to be efficient dual vaccines against rabies and emergent infectious diseases such as Ebola virus. Here we show that inactivated rabies virus particles containing the MERS-CoV S1 protein induce potent immune responses against MERS-CoV and RABV. This novel vaccine is easy to produce and may be useful to protect target animals, such as camels, as well as humans from deadly MERS-CoV and RABV infections. Our results indicate that this vaccine approach can prevent disease, and the RABV-based vaccine platform may be a valuable tool for timely vaccine development against emerging infectious diseases.

scholarly journals The deubiquitinating activity of Middle East respiratory syndrome coronavirus papain-like protease delays the innate immune response and enhances virulence in a mouse model

2019 ◽  
Author(s):  
Robert C. M. Knaap ◽  
Raúl Fernández-Delgado ◽  
Tim J. Dalebout ◽  
Nadia Oreshkova ◽  
Peter J. Bredenbeek ◽  
...  
Keyword(s):  
Immune Response ◽  
Middle East ◽  
Mouse Model ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Vaccine Development ◽  
Innate Immune ◽  
Middle East Respiratory Syndrome ◽  
Mrna Levels ◽  
Innate Immune Responses

AbstractMiddle East respiratory syndrome coronavirus (MERS-CoV) continues to cause zoonotic infections and serious disease, primarily in the Arabian Peninsula, due to repeated spill-over from dromedary camels and subsequent nosocomial transmission. Approved MERS vaccines for use in animals or humans are not currently available. MERS-CoV replication requires the virus-encoded papain-like protease (PLpro) to cleave multiple sites in the viral replicase polyproteins, thereby releasing functional non-structural proteins. Additionally, PLpro is a deubiquitinating enzyme (DUB) that can remove ubiquitin(-like) moieties from substrates, presumably to counteract host antiviral responses. In previous work, we determined the crystal structure of MERS-CoV PLpro in complex with ubiquitin, facilitating the design of PLpro mutations that impair DUB activity without affecting viral polyprotein cleavage. Here, we introduced these DUB-inactivating mutations into the viral genome and examined their impact on MERS-CoV infection both in cell culture and in a lethal mouse model. Although overall replication of DUB-negative and wild-type (wt) recombinant MERS-CoV was comparable in multiple cell lines, infection with DUB-negative virus markedly increased mRNA levels for interferon (IFN)-β and IFN-stimulated genes. Moreover, compared to a wt virus infection, the survival rate was significantly increased when DUB-negative MERS-CoV was used to infect transgenic mice expressing a human MERS-CoV receptor. Interestingly, DUB-negative and wt MERS-CoV replicated to the same titers in lungs of infected mice, but the DUB-negative virus was cleared faster, likely due to the observed accelerated and better-regulated innate immune responses, in contrast to delayed and subsequently excessive responses in wt virus-infected mice. This study provides the first direct evidence that the DUB activity of a coronaviral protease contributes to innate immune evasion and can profoundly enhance virulence in an animal model. Thus, reduction or removal of the innate immune-suppressive DUB activity of PLpros is a promising strategy for coronavirus attenuation in the context of rational vaccine development.Author SummaryAlthough zoonotic coronaviruses such as Middle East respiratory coronavirus (MERS-CoV) have pandemic potential, therapeutics and vaccines that counteract this public health threat are not currently available. Coronaviruses typically employ multiple strategies to evade the host’s innate immune response, which may enhance clinical disease and/or reduce the efficacy of modified live vaccines. The MERS-CoV-encoded papain-like protease (PLpro) is not only crucial for the expression of functional replicase proteins, but has also been postulated to antagonize ubiquitination-dependent steps during the activation of the innate immune response. Here, we report the generation of engineered MERS-CoVs mutants in which PLpro’s deubiquitinating (DUB) activity was specifically disrupted without affecting virus viability. In this manner, we could demonstrate that the DUB activity of PLpro suppresses the interferon response in MERS-CoV-infected cells. Strikingly, in the lungs of mice infected with DUB-negative MERS-CoV, innate immune responses were induced at an earlier stage of infection than in wt virus-infected mice. This group also showed a clearly increased survival, indicating that the DUB activity is an important MERS-CoV virulence factor. This proof-of-concept study establishes that the engineering of DUB-negative coronaviruses, which elicit a more effective immune response in the host, is a viable strategy for vaccine development.

scholarly journals A Highly Immunogenic and Protective Middle East Respiratory Syndrome Coronavirus Vaccine Based on a Recombinant Measles Virus Vaccine Platform

2015 ◽  
Vol 89 (22) ◽  
pp. 11654-11667 ◽  
Author(s):  
Anna H. Malczyk ◽  
Alexandra Kupke ◽  
Steffen Prüfer ◽  
Vivian A. Scheuplein ◽  
Stefan Hutzler ◽  
...  
Keyword(s):  
T Cell ◽  
Middle East ◽  
Neutralizing Antibodies ◽  
Measles Virus ◽  
Fluorescent Protein ◽  
Middle East Respiratory Syndrome ◽  
Type I ◽  
Emerging Infections ◽  
Protective Capacity ◽  
Vaccine Platform

ABSTRACTIn 2012, the first cases of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) were identified. Since then, more than 1,000 cases of MERS-CoV infection have been confirmed; infection is typically associated with considerable morbidity and, in approximately 30% of cases, mortality. Currently, there is no protective vaccine available. Replication-competent recombinant measles virus (MV) expressing foreign antigens constitutes a promising tool to induce protective immunity against corresponding pathogens. Therefore, we generated MVs expressing the spike glycoprotein of MERS-CoV in its full-length (MERS-S) or a truncated, soluble variant of MERS-S (MERS-solS). The genes encoding MERS-S and MERS-solS were cloned into the vaccine strain MVvac2genome, and the respective viruses were rescued (MVvac2-CoV-S and MVvac2-CoV-solS). These recombinant MVs were amplified and characterized at passages 3 and 10. The replication of MVvac2-CoV-S in Vero cells turned out to be comparable to that of the control virus MVvac2-GFP (encoding green fluorescent protein), while titers of MVvac2-CoV-solS were impaired approximately 3-fold. The genomic stability and expression of the inserted antigens were confirmed via sequencing of viral cDNA and immunoblot analysis.In vivo, immunization of type I interferon receptor-deficient (IFNAR−/−)-CD46Ge mice with 2 × 10550% tissue culture infective doses of MVvac2-CoV-S(H) or MVvac2-CoV-solS(H) in a prime-boost regimen induced robust levels of both MV- and MERS-CoV-neutralizing antibodies. Additionally, induction of specific T cells was demonstrated by T cell proliferation, antigen-specific T cell cytotoxicity, and gamma interferon secretion after stimulation of splenocytes with MERS-CoV-S presented by murine dendritic cells. MERS-CoV challenge experiments indicated the protective capacity of these immune responses in vaccinated mice.IMPORTANCEAlthough MERS-CoV has not yet acquired extensive distribution, being mainly confined to the Arabic and Korean peninsulas, it could adapt to spread more readily among humans and thereby become pandemic. Therefore, the development of a vaccine is mandatory. The integration of antigen-coding genes into recombinant MV resulting in coexpression of MV and foreign antigens can efficiently be achieved. Thus, in combination with the excellent safety profile of the MV vaccine, recombinant MV seems to constitute an ideal vaccine platform. The present study shows that a recombinant MV expressing MERS-S is genetically stable and induces strong humoral and cellular immunity against MERS-CoV in vaccinated mice. Subsequent challenge experiments indicated protection of vaccinated animals, illustrating the potential of MV as a vaccine platform with the potential to target emerging infections, such as MERS-CoV.

scholarly journals Rabies virus-based COVID-19 vaccine CORAVAX™ induces high levels of neutralizing antibodies against SARS-CoV-2

npj Vaccines ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Drishya Kurup ◽  
Christoph Wirblich ◽  
Holly Ramage ◽  
Matthias J. Schnell
Keyword(s):  
Global Health ◽  
Infectious Diseases ◽  
Rabies Virus ◽  
Causative Agent ◽  
Neutralizing Antibodies ◽  
Rapid Development ◽  
Emerging Infectious Diseases ◽  
Vaccine Platform ◽  
The World ◽  
Further Development

Abstract The recently emerged coronavirus SARS-CoV-2, the causative agent of COVID-19, is rapidly spreading in the world. The exponentially expanding threat of SARS-CoV-2 to global health highlights the urgent need for a vaccine. Herein we show the rapid development of a novel, highly efficient, and safe COVID-19 vaccine using a rabies virus-based vector that has proven to be an efficient vaccine against several emerging infectious diseases. This study reports that both a live and an inactivated rabies virus containing the SARS-CoV-2 spike S1 protein induces potent virus-neutralizing antibodies at much higher levels than seen in the sera of convalescent patients. In summary, the results provided here warrant further development of this safe and established vaccine platform against COVID-19.

scholarly journals A Highly Immunogenic, Protective, and Safe Adenovirus-Based Vaccine Expressing Middle East Respiratory Syndrome Coronavirus S1-CD40L Fusion Protein in a Transgenic Human Dipeptidyl Peptidase 4 Mouse Model

2019 ◽  
Vol 220 (10) ◽  
pp. 1558-1567 ◽  
Author(s):  
Anwar M Hashem ◽  
Abdullah Algaissi ◽  
Anurodh Shankar Agrawal ◽  
Sawsan S Al-amri ◽  
Rowa Y Alhabbab ◽  
...  
Keyword(s):  
Middle East ◽  
Fusion Protein ◽  
Neutralizing Antibodies ◽  
Recombinant Adenovirus ◽  
Dipeptidyl Peptidase ◽  
Middle East Respiratory Syndrome ◽  
Control Measures ◽  
Control Group ◽  
Vaccine Platform ◽  
Dipeptidyl Peptidase 4

AbstractBackgroundInfection control measures have played a major role in limiting human/camel-to-human transmission of Middle East respiratory syndrome coronavirus (MERS-CoV); however, development of effective and safe human or camel vaccines is warranted.MethodsWe extended and optimized our previous recombinant adenovirus 5 (rAd5)–based vaccine platform characterized by in vivo amplified and CD40-mediated specific responses to generate MERS-CoV S1 subunit-based vaccine. We generated rAd5 constructs expressing CD40-targeted S1 fusion protein (rAd5-S1/F/CD40L), untargeted S1 (rAd5-S1), and Green Fluorescent Protein (rAd5-GFP), and evaluated their efficacy and safety in human dipeptidyl peptidase 4 transgenic (hDPP4 Tg+) mice.ResultsImmunization of hDPP4 Tg+ mice with a single dose of rAd5-S1/F/CD40L elicited as robust and significant specific immunoglobulin G and neutralizing antibodies as those induced with 2 doses of rAd5-S1. After MERS-CoV challenge, both vaccines conferred complete protection against morbidity and mortality, as evidenced by significantly undetectable/reduced pulmonary viral loads compared to the control group. However, rAd5-S1– but not rAd5-S1/F/CD40L–immunized mice exhibited marked pulmonary perivascular hemorrhage post–MERS-CoV challenge despite the observed protection.ConclusionsIncorporation of CD40L into rAd5-based MERS-CoV S1 vaccine targeting molecule and molecular adjuvants not only enhances immunogenicity and efficacy but also prevents inadvertent pulmonary pathology after viral challenge, thereby offering a promising strategy to enhance safety and potency of vaccines.

scholarly journals Immunogenicity of Different Forms of Middle East Respiratory Syndrome S Glycoprotein

Acta Naturae ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 38-47 ◽  
Author(s):  
T. A. Ozharovskaia ◽  
O. V. Zubkova ◽  
I. V. Dolzhikova ◽  
A. S. Gromova ◽  
D. M. Grousova ◽  
...  
Keyword(s):  
Immune Response ◽  
Middle East ◽  
Neutralizing Antibodies ◽  
Transmembrane Domain ◽  
Middle East Respiratory Syndrome ◽  
Full Length ◽  
Acute Lower Respiratory Infection ◽  
Th2 Response ◽  
Humoral Immune ◽  
Immunodominant Antigen

The Middle East respiratory syndrome coronavirus (MERS-CoV) was identified in 2012 during the first Middle East respiratory syndrome (MERS) outbreaks. MERS-CoV causes an acute lower-respiratory infection in humans, with a fatality rate of ~35.5%. Currently, there are no registered vaccines or means of therapeutic protection against MERS in the world. The MERS-CoV S glycoprotein plays the most important role in the viral life cycle (virus internalization). The S protein is an immunodominant antigen and the main target for neutralizing antibodies. In the present study, the immunogenicities of five different forms of the MERS-CoV S glycoprotein were compared: the full-length S glycoprotein, the full-length S glycoprotein with the transmembrane domain of the G glycoprotein of VSV (S-G), the receptor-binding domain (RBD) of the S glycoprotein, the membrane-fused RBD (the RBD fused with the transmembrane domain of the VSV G glycoprotein (RBD-G)), and the RBD fused with Fc of human IgG1 (RBD-Fc). Recombinant vectors based on human adenoviruses type 5 (rAd5) were used as delivery vehicles. Vaccination with all of the developed rAd5 vectors elicited a balanced Th1/Th2 response in mice. The most robust humoral immune response was induced after the animal had been vaccinated with the membrane-fused RBD (rAd5-RBD-G). Only immunization with membrane forms of the glycoprotein (rAd5-S, rAd5-S-G, and rAd5-RBD-G) elicited neutralizing antibodies among all vaccinated animals. The most significant cellular immune response was induced after vaccination of the animals with the full-length S (rAd5-S). These investigations suggest that the full-length S and the membrane form of the RBD (RBD-G) are the most promising vaccine candidates among all the studied forms of S glycoprotein.

scholarly journals Middle East Respiratory Syndrome Coronavirus (MERS-CoV): Infection, Immunological Response, and Vaccine Development

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Ayman Mubarak ◽  
Wael Alturaiki ◽  
Maged Gomaa Hemida
Keyword(s):  
Middle East ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Current Knowledge ◽  
Immunological Response ◽  
Middle East Respiratory Syndrome ◽  
World Health ◽  
Dipeptidyl Peptidase 4 ◽  
Health Organization

Middle East respiratory syndrome coronavirus (MERS-CoV) first emerged in late 2012. Since its emergence, a total of 2279 patients from 27 countries have been infected across the globe according to a World Health Organization (WHO) report (Feb. 12th, 2019). Approximately 806 patients have died. The virus uses its spike proteins as adhesive factors that are proinflammatory for host entry through a specific receptor called dipeptidyl peptidase-4 (DPP4). This receptor is considered a key factor in the signaling and activation of the acquired and innate immune responses in infected patients. Using potent antigens in combination with strong adjuvants may effectively trigger the activation of specific MERS-CoV cellular responses as well as the production of neutralizing antibodies. Unfortunately, to date, there is no effective approved treatment or vaccine for MERS-CoV. Thus, there are urgent needs for the development of novel MERS-CoV therapies as well as vaccines to help minimize the spread of the virus from infected patients, thereby mitigating the risk of any potential pandemics. Our main goals are to highlight and describe the current knowledge of both the innate and adaptive immune responses to MERS-CoV and the current state of MERS-CoV vaccine development. We believe this study will increase our understanding of the mechanisms that enhance the MERS-CoV immune response and subsequently contribute to the control of MERS-CoV infections.

scholarly journals Middle East respiratory syndrome: obstacles and prospects for vaccine development

2015 ◽  
Vol 14 (7) ◽  
pp. 949-962 ◽  
Author(s):  
Amy B Papaneri ◽  
Reed F Johnson ◽  
Jiro Wada ◽  
Laura Bollinger ◽  
Peter B Jahrling ◽  
...  
Keyword(s):  
Middle East ◽  
Vaccine Development ◽  
Middle East Respiratory Syndrome

scholarly journals Overview of Plant-Derived Vaccine Antigens: Dengue Virus

2011 ◽  
Vol 14 (3) ◽  
pp. 400 ◽  
Author(s):  
Ravindra B Malabadi ◽  
Advaita Ganguly ◽  
Jaime A Teixeira da Silva ◽  
Archana Parashar ◽  
Mavanur R Suresh ◽  
...  
Keyword(s):  
Infectious Diseases ◽  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Low Cost ◽  
Current Status ◽  
Human Immune Deficiency Virus ◽  
Dengue Vaccine ◽  
New Methods ◽  
Vaccine Antigens

ABSTRACT - This review highlights the advantages and current status of plant-derived vaccine development with special reference to the dengue virus. There are numerous problems involved in dengue vaccine development, and there is no vaccine against all four dengue serotypes. Dengue vaccine development using traditional approaches has not been satisfactory in terms of inducing neutralizing antibodies. Recently, these issues were addressed by showing a very good response to inducing neutralizing antibodies by plant-derived dengue vaccine antigens. This indicates the feasibility of using plant-derived vaccine antigens as a low-cost method to combat dengue and other infectious diseases. The application of new methods and strategies such as dendritic cell targeting in cancer therapy, severe acute respiratory syndrome, tuberculosis, human immune deficiency virus, and malaria might play an important role. These new methods are more efficient than traditional protocols. It is expected that in the near future, plant-derived vaccine antigens or antibodies will play an important role in the control of human infectious diseases. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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