The Combined Expression of the Non-structural Protein NS1 and the N-Terminal Half of NS2 (NS2 1-180 ) by ChAdOx1 and MVA Confers Protection against Clinical Disease in Sheep upon Bluetongue Virus Challenge

Bluetongue, caused by bluetongue virus (BTV), is a widespread arthropod-borne disease of ruminants that entails a recurrent threat to the primary sector of developed and developing countries. In this work, we report MVA and ChAdOx1-vectored vaccines designed to simultaneously express the immunogenic NS1 protein and/or NS2-Nt, the N-terminal half of protein NS2 (NS2 1-180 ). A single dose of MVA or ChAdOx1 expressing NS1-NS2-Nt improved the protection conferred by NS1 alone in IFNAR(-/-) mice. Moreover, mice immunized with ChAdOx1/MVA-NS1, ChAdOx1/MVA-NS2-Nt or ChAdOx1/MVA-NS1-NS2-Nt developed strong cytotoxic CD8+ T-cell responses against NS1, NS2-Nt or both proteins and were fully protected against a lethal infection with BTV serotypes 1, 4 and 8. Furthermore, although a single immunization with ChAdOx1-NS1-NS2-Nt partially protected sheep against BTV-4, the administration of a booster dose of MVA-NS1-NS2-Nt promoted a faster viral clearance, reduction of the period and level of viremia and also protected from the pathology produced by BTV infection. Importance Current BTV vaccines are effective but they do not allow to distinguish between vaccinated and infected animals (DIVA strategy) and are serotype specific. In this work we have develop a DIVA multiserotype vaccination strategy based on adenoviral (ChAdOx1) and MVA vaccine vectors, the most widely used in current phase I and II clinical trials, and the conserved non-structural BTV proteins NS1 and NS2. This immunization strategy solves the major drawbacks of the current marketed vaccines.

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Enhanced T Cell Responses Induced by a Necrotic Dendritic Cell Vaccine, Expressing HCV NS3

Frontiers in Microbiology ◽

10.3389/fmicb.2020.559105 ◽

2020 ◽

Vol 11 ◽

Author(s):

Zelalem A. Mekonnen ◽

Makutiro G. Masavuli ◽

Wenbo Yu ◽

Jason Gummow ◽

Dawn M. Whelan ◽

...

Keyword(s):

T Cell ◽

Vaccination Strategy ◽

T Cell Responses ◽

Dendritic Cell Vaccine ◽

Effector Memory ◽

Cell Vaccine ◽

Cell Mediated Immunity ◽

Structural Protein ◽

Cell Responses ◽

Dc Vaccine

A vaccine that induces potent, broad and sustained cell-mediated immunity, resulting in effective memory has the potential to restrict hepatitis C (HCV) virus infection. Early, multi-functional CD4+ and CD8+ T cell responses against non-structural protein 3 (NS3) have been associated with HCV clearance. Necrotic cells generate strong immune responses and represent a major antigenic source used by dendritic cells (DC) for processing and presentation, but there is conflicting evidence as to their immunogenicity in vaccination. Immunization with DC loaded with viral antigens has been done in the past, but to date the immunogenicity of live vs. necrotic DC vaccines has not been investigated. We developed a DC2.4 cell line stably expressing HCV NS3, and compared the NS3-specific responses of live vs. necrotic NS3 DC. Vaccination of mice with necrotic NS3 DC increased the breadth of T-cell responses and enhanced the production of IL-2, TNF-α, and IFN-γ by effector memory CD4+ and CD8+T cells, compared to mice vaccinated with live NS3 DC. A single dose of necrotic NS3 DC vaccine induced a greater influx and activation of cross-presenting CD11c+ CD8α+ DC and necrosis-sensing Clec9A+ DC in the draining lymph nodes. Furthermore, using a hydrodynamic challenge model necrotic NS3 DC vaccination resulted in enhanced clearance of NS3-positive hepatocytes from the livers of vaccinated mice. Taken together, the data demonstrate that necrotic DC represent a novel and exciting vaccination strategy capable of inducing broad and multifunctional T cell memory.

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Vaccination With Recombinant Adenoviruses Expressing the Bluetongue Virus Subunits VP7 and VP2 Provides Protection Against Heterologous Virus Challenge

Frontiers in Veterinary Science ◽

10.3389/fvets.2021.645561 ◽

2021 ◽

Vol 8 ◽

Author(s):

José Manuel Rojas ◽

Diego Barba-Moreno ◽

Miguel Avia ◽

Noemí Sevilla ◽

Verónica Martín

Keyword(s):

T Cell ◽

Bluetongue Virus ◽

Neutralizing Antibodies ◽

Inner Core ◽

Core Protein ◽

T Cell Responses ◽

Outer Core ◽

Economic Losses ◽

Virus Challenge ◽

Cell Responses

Bluetongue virus (BTV) is the causative agent of a disease that affects domestic and wild ruminants and leads to critical economic losses. BTV is an arbovirus from the Reoviridae family that is typically transmitted by the bite of infected Culicoides midges. BTV possesses multiple serotypes (up to 28 have been described), and immunity to one serotype offers little cross-protection to other serotypes. The design of vaccines that provide protection across multiple serotypes is therefore highly desirable to control this disease. We previously reported that a recombinant replication-defective human adenovirus serotype 5 (Ad5) that expresses the VP7 inner core protein of BTV serotype 8 (Ad5VP7-8) induced T-cell responses and provided protection. In the present work, we evaluated as BTV vaccine the combination of Ad5VP7-8 with another recombinant Ad5 that expresses the outer core protein VP2 from BTV-1 (Ad5VP2-1). The combination of Ad5VP2-1 and Ad5VP7-8 protected against homologous BTV challenge (BTV-1 and BTV-8) and partially against heterologous BTV-4 in a murine model. Cross-reactive anti-BTV immunoglobulin G (IgG) were detected in immunized animals, but no significant titers of neutralizing antibodies were elicited. The Ad5VP7-8 immunization induced T-cell responses that recognized all three serotypes tested in this study and primed cytotoxic T lymphocytes specific for VP7. This study further confirms that targeting antigenic determinant shared by several BTV serotypes using cellular immunity could help develop multiserotype BTV vaccines.

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Expression of the Major Core Structural Protein (VP7) of Bluetongue Virus, by a Recombinant Capripox Virus, Provides Partial Protection of Sheep against a Virulent Heterotypic Bluetongue Virus Challenge

Virology ◽

10.1006/viro.1996.0306 ◽

1996 ◽

Vol 220 (1) ◽

pp. 227-231 ◽

Cited By ~ 66

Author(s):

A.M. WADE-EVANS ◽

C.H. ROMERO ◽

P. MELLOR ◽

H. TAKAMATSU ◽

J. ANDERSON ◽

...

Keyword(s):

Bluetongue Virus ◽

Structural Protein ◽

Partial Protection ◽

Virus Challenge

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Faculty Opinions recommendation of Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1157155.621340 ◽

2009 ◽

Author(s):

Sarah Rowland-Jones

Keyword(s):

T Cell ◽

Simian Immunodeficiency Virus ◽

Rhesus Monkeys ◽

T Cell Responses ◽

Effector Memory ◽

Virus Challenge ◽

Memory T Cell ◽

Cell Responses ◽

Immunodeficiency Virus ◽

Simian Immunodeficiency Virus Challenge

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Flavivirus NS1 and Its Potential in Vaccine Development

Vaccines ◽

10.3390/vaccines9060622 ◽

2021 ◽

Vol 9 (6) ◽

pp. 622

Author(s):

Kassandra L. Carpio ◽

Alan D. T. Barrett

Keyword(s):

Vaccine Development ◽

Virus Assembly ◽

Ns1 Protein ◽

Human Pathogens ◽

Unusual Structure ◽

Replication Complex ◽

Virus Challenge ◽

Humoral Immune ◽

Tick Borne Encephalitis ◽

Flavivirus Infection

The Flavivirus genus contains many important human pathogens, including dengue, Japanese encephalitis (JE), tick-borne encephalitis (TBE), West Nile (WN), yellow fever (YF) and Zika (ZIK) viruses. While there are effective vaccines for a few flavivirus diseases (JE, TBE and YF), the majority do not have vaccines, including WN and ZIK. The flavivirus nonstructural 1 (NS1) protein has an unusual structure–function because it is glycosylated and forms different structures to facilitate different roles intracellularly and extracellularly, including roles in the replication complex, assisting in virus assembly, and complement antagonism. It also plays a role in protective immunity through antibody-mediated cellular cytotoxicity, and anti-NS1 antibodies elicit passive protection in animal models against a virus challenge. Historically, NS1 has been used as a diagnostic marker for the flavivirus infection due to its complement fixing properties and specificity. Its role in disease pathogenesis, and the strong humoral immune response resulting from infection, makes NS1 an excellent target for inclusion in candidate flavivirus vaccines.

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Development of Bacteriophage Virus-Like Particle Vaccines Displaying Conserved Epitopes of Dengue Virus Non-Structural Protein 1

Vaccines ◽

10.3390/vaccines9070726 ◽

2021 ◽

Vol 9 (7) ◽

pp. 726

Author(s):

Nikole L. Warner ◽

Kathryn M. Frietze

Keyword(s):

Dengue Virus ◽

Population Based ◽

Ns1 Protein ◽

Structural Protein ◽

Denv Serotypes ◽

Conserved Regions ◽

Virus Like Particle ◽

Dependent Cell ◽

Infected Cells ◽

Plasma Leakage

Dengue virus (DENV) is a major global health problem, with over half of the world’s population at risk of infection. Despite over 60 years of efforts, no licensed vaccine suitable for population-based immunization against DENV is available. Here, we describe efforts to engineer epitope-based vaccines against DENV non-structural protein 1 (NS1). NS1 is present in DENV-infected cells as well as secreted into the blood of infected individuals. NS1 causes disruption of endothelial cell barriers, resulting in plasma leakage and hemorrhage. Immunizing against NS1 could elicit antibodies that block NS1 function and also target NS1-infected cells for antibody-dependent cell cytotoxicity. We identified highly conserved regions of NS1 from all four DENV serotypes. We generated synthetic peptides to these regions and chemically conjugated them to bacteriophage Qβ virus-like particles (VLPs). Mice were immunized two times with the candidate vaccines and sera were tested for the presence of antibodies that bound to the cognate peptide, recombinant NS1 from all four DENV serotypes, and DENV-2-infected cells. We found that two of the candidate vaccines elicited antibodies that bound to recombinant NS1, and one candidate vaccine elicited antibodies that bound to DENV-infected cells. These results show that an epitope-specific vaccine against conserved regions of NS1 could be a promising approach for DENV vaccines or therapeutics to bind circulating NS1 protein.

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HIV mRNA Vaccines—Progress and Future Paths

Vaccines ◽

10.3390/vaccines9020134 ◽

2021 ◽

Vol 9 (2) ◽

pp. 134

Author(s):

Zekun Mu ◽

Barton F. Haynes ◽

Derek W. Cain

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

Vaccination Strategy ◽

T Cell Responses ◽

Neutralizing Antibody ◽

Cytotoxic T Cell ◽

Therapeutic Vaccines ◽

Cell Responses ◽

Broadly Neutralizing Antibody ◽

Cytotoxic T Cell Responses

The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host’s cells to manufacture protein immunogens which, in turn, are targets for antibody and cytotoxic T cell responses. mRNA-based vaccines have been the subject of research for over three decades as a platform to protect against or treat a variety of cancers, amyloidosis and infectious diseases. In this review, we discuss mRNA-based approaches for the generation of prophylactic and therapeutic vaccines to HIV. We examine the special immunological hurdles for a vaccine to elicit broadly neutralizing antibodies and effective T cell responses to HIV. Lastly, we outline an mRNA-based HIV vaccination strategy based on the immunobiology of broadly neutralizing antibody development.

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