Protective Efficacy in Sheep of Adenovirus-Vectored Vaccines against Bluetongue Virus Is Associated with Specific T Cell Responses

ABSTRACTThe development of vaccines against bluetongue, a prevalent livestock disease, has been focused on surface antigens that induce strong neutralizing antibody responses. Because of their antigenic variability, these vaccines are usually serotype restricted. We now show that a single highly conserved nonstructural protein, NS1, expressed in a modified vaccinia Ankara virus (MVA) vector can provide multiserotype protection in IFNAR−/−129 mice against bluetongue virus (BTV) that is largely dependent on CD8 T cell responses. We found that the protective antigenic capacity of NS1 resides within the N terminus of the protein and is provided in the absence of neutralizing antibodies. The protective CD8 T cell response requires the presence of a specific peptide within the N terminus of NS1, since its deletion ablates the efficacy of the vaccine formulation. These data reveal the importance of the nonstructural protein NS1 in CD8 T cell-mediated protection against multiple BTV serotypes when vectorized as a recombinant MVA vaccine.IMPORTANCEConventional vaccines have controlled or limited BTV expansion in the past, but they cannot address the need for cross-protection among serotypes and do not allow distinguishing between infected and vaccinated animals (DIVA strategy). There is a need to develop universal vaccines that induce effective protection against multiple BTV serotypes. In this work we have shown the importance of the nonstructural protein NS1, conserved among all the BTV serotypes, in CD8 T cell-mediated protection against multiple BTV serotypes when vectorized as a recombinant MVA vaccine.

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Induction of Specific T-Cell Responses, Opsonizing Antibodies, and Protection against Plasmodium chabaudi adami Infection in Mice Vaccinated with Genomic Expression Libraries Expressed in Targeted and Secretory DNA Vectors

Infection and Immunity ◽

10.1128/iai.71.8.4506-4515.2003 ◽

2003 ◽

Vol 71 (8) ◽

pp. 4506-4515 ◽

Cited By ~ 18

Author(s):

A. Rainczuk ◽

T. Scorza ◽

P. M. Smooker ◽

T. W. Spithill

Keyword(s):

T Cell ◽

Immune Responses ◽

Genomic Library ◽

Protective Efficacy ◽

T Cell Responses ◽

Interleukin 4 ◽

Plasmodium Chabaudi ◽

Lethal Challenge ◽

Cell Responses ◽

Expression Libraries

ABSTRACT It has been proposed that a multivalent malaria vaccine is necessary to mimic the naturally acquired resistance to this disease observed in humans. A major experimental challenge is to identify the optimal components to be used in such a multivalent vaccine. Expression library immunization (ELI) is a method for screening genomes of a pathogen to identify novel combinations of vaccine sequences. Here we describe immune responses associated with, and the protective efficacy of, genomic Plasmodium chabaudi adami DS expression libraries constructed in VR1020 (secretory), monocyte chemotactic protein-3 (chemoattractant), and cytotoxic T lymphocyte antigen 4 (lymph node-targeting) DNA vaccine vectors. With splenocytes from vaccinated mice, specific T-cell responses, as well as gamma interferon and interleukin-4 production, were observed after stimulation with P. chabaudi adami-infected erythrocytes, demonstrating the specificity of genomic library vaccination for two of the three libraries constructed. Sera obtained from mice vaccinated with genomic libraries promoted the opsonization of P. chabaudi adami-infected erythrocytes by murine macrophages in vitro, further demonstrating the induction of malaria-specific immune responses following ELI. Over three vaccine trials using biolistic delivery of the three libraries, protection after lethal challenge with P. chabaudi adami DS ranged from 33 to 50%. These results show that protective epitopes or antigens are expressed within the libraries and that ELI induces responses specific to P. chabaudi adami malaria. This study further demonstrates that ELI is a suitable approach for screening the malaria genome to identify the components of multivalent vaccines.

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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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Experimental Infection of Human Volunteers with the Heat-Stable Enterotoxin-Producing Enterotoxigenic Escherichia coli Strain TW11681

Pathogens ◽

10.3390/pathogens8020084 ◽

2019 ◽

Vol 8 (2) ◽

pp. 84 ◽

Cited By ~ 2

Author(s):

Sunniva Todnem Sakkestad ◽

Hans Steinsland ◽

Steinar Skrede ◽

Elisabeth Kleppa ◽

Kristine Lillebø ◽

...

Keyword(s):

Escherichia Coli ◽

T Cell ◽

Protective Efficacy ◽

T Cell Responses ◽

Enterotoxigenic Escherichia Coli ◽

Cd4 T Cell ◽

Infection Model ◽

Serological Response ◽

Cell Responses ◽

Heat Stable

Infection with enterotoxigenic Escherichia coli (ETEC) producing the heat-stable enterotoxin (ST) is one of the most important causes of childhood diarrhoea in low- and middle-income countries. Here, we undertook a controlled human infection model (CHIM) study to investigate whether ST-producing ETEC strain TW11681 would be suitable for testing the protective efficacy of new ST-based vaccine candidates in vaccine challenge models. In groups of three, nine volunteers ingested 1 × 106, 1 × 107, or 1 × 108 colony-forming units (CFU) of TW11681. Flow cytometry-based assays were used to measure CD4+ T cell responses and antibody levels targeting virulence factors expressed by the strain. We found that infection with TW11681 elicited few and mild symptoms, including mild diarrhoea in two volunteers, both of whom ingested 1 × 106 CFU. Averaged across all volunteers, the CD4+ T cell responses specific for E. coli YghJ mucinase peaked 10 days after infection (3.2-fold (p = 0.016)), while the CD4+ T cell responses specific for Colonization Factor Antigen I (CFA/I) major fimbrial subunit (CfaB) peaked after 28 days (3.6-fold (p = 0.063)). The serum CfaB-specific anti-IgA and anti-IgG/IgM levels were significantly increased and peaked 3 months after infection. Both remained elevated for the duration of the 12-month follow-up. The corresponding anti-YghJ serological response was strongest after 10 days, although a significant increase was seen only for IgA levels (3.2-fold (p = 0.008)). In conclusion, due to its low diarrhoea attack risk, TW11681 is probably not suitable for testing the efficacy of new vaccines in human challenge studies at doses 1 × 106 to 1 × 108. However, the strain may still be useful in CHIMs for studying ETEC host-pathogen interactions.

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Dysregulation of Toll-Like Receptor 7 Compromises Innate and Adaptive T Cell Responses and Host Resistance to an Attenuated West Nile Virus Infection in Old Mice

Journal of Virology ◽

10.1128/jvi.02488-15 ◽

2015 ◽

Vol 90 (3) ◽

pp. 1333-1344 ◽

Cited By ~ 16

Author(s):

Guorui Xie ◽

Huanle Luo ◽

Lan Pang ◽

Bi-hung Peng ◽

Evandro Winkelmann ◽

...

Keyword(s):

West Nile Virus ◽

T Cell ◽

Protective Efficacy ◽

T Cell Responses ◽

The Elderly ◽

Γδ T Cell ◽

West Nile ◽

Cell Responses ◽

Antigen Presenting ◽

Old Mice

ABSTRACTThe elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), a mosquito-borne flavivirus, has induced severe neurological symptoms, mostly in the elderly population. No vaccines are available for human use. Recent work showed that an attenuated WNV, a nonstructural (NS) 4B-P38G mutant, induced no lethality but strong immune responses in young (6- to 10-week-old) mice. While studying protective efficacy, we found unexpectedly that old (21- to 22-month) mice were susceptible to WNV NS4B-P38G mutant infection but were protected from subsequent lethal wild-type WNV challenge. Compared to responses in young mice, the NS4B-P38G mutant triggered higher inflammatory cytokine and interleukin-10 (IL-10) production, a delayed γδ T cell expansion, and lower antibody and WNV-specific T cell responses in old mice. Toll-like receptor 7 (TLR7) is expressed on multiple types of cells. Impaired TLR7 signaling in old mice led to dendritic cell (DC) antigen-presenting function compromise and a reduced γδ T cell and regulatory T cell (Treg) expansion during NS4B-P38G mutant infection. R848, a TLR7 agonist, decreased host vulnerability in NS4B-P38G-infected old mice by enhancing γδ T cell and Treg expansion and the antigen-presenting capacity of DCs, thereby promoting T cell responses. In summary, our results suggest that dysregulation of TLR7 partially contributes to impaired innate and adaptive T cell responses and an enhanced vulnerability in old mice during WNV NS4B-P38G mutant infection. R848 increases the safety and efficacy during immunization of old mice with the WNV NS4B-P38G mutant.IMPORTANCEThe elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), an emerging mosquito-borne flavivirus, has induced severe neurological symptoms more frequently in the elderly population. No vaccines are available for human use. Here, we used an aged mouse model to investigate the protective efficacy of an attenuated WNV, the nonstructural 4B-P38G mutant, which was previously shown to induce no lethality but strong immune responses in young adult mice. Studies that contribute to a mechanistic understanding of immune defects in the elderly will allow the development of strategies to improve responses to infectious diseases and to increase vaccine efficacy and safety in aging individuals.

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Secretion of Functional Monocyte Chemotactic Protein 3 by Recombinant Mycobacterium bovis BCG Attenuates Vaccine Virulence and Maintains Protective Efficacy against M. tuberculosis Infection

Infection and Immunity ◽

10.1128/iai.00897-06 ◽

2006 ◽

Vol 75 (1) ◽

pp. 523-526 ◽

Cited By ~ 11

Author(s):

Anthony A. Ryan ◽

Joanne M. Spratt ◽

Warwick J. Britton ◽

James A. Triccas

Keyword(s):

T Cell ◽

Mycobacterium Bovis ◽

Protective Efficacy ◽

T Cell Responses ◽

Lymphocyte Migration ◽

Immunodeficient Mice ◽

Cell Responses ◽

Monocyte Chemotactic Protein ◽

Chemotactic Protein

ABSTRACT A strain of Mycobacterium bovis BCG that secretes high levels of functional murine monocyte chemotactic protein 3 (BCGMCP-3) was developed. Mice vaccinated with BCGMCP-3 displayed increased lymphocyte migration in vivo and augmented antigen-specific T-cell responses compared to mice vaccinated with BCG alone. The level of protection afforded by BCGMCP-3 was equivalent to that with control BCG; however, immunodeficient mice infected with BCGMCP-3 survived significantly longer than mice infected with the control BCG strain. Therefore, BCGMCP-3 may be a safer alternative than conventional BCG for vaccination of immunocompromised individuals.

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Recall T cell responses to bluetongue virus produce a narrowing of the T cell repertoire

Veterinary Research ◽

10.1186/s13567-017-0444-3 ◽

2017 ◽

Vol 48 (1) ◽

Cited By ~ 8

Author(s):

José-Manuel Rojas ◽

Teresa Rodríguez-Calvo ◽

Noemí Sevilla

Keyword(s):

T Cell ◽

Bluetongue Virus ◽

T Cell Responses ◽

T Cell Repertoire ◽

Cell Repertoire ◽

Cell Responses ◽

Virus Produce

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T cell responses to bluetongue virus are directed against multiple and identical CD4+ and CD8+ T cell epitopes from the VP7 core protein in mouse and sheep

Vaccine ◽

10.1016/j.vaccine.2011.07.061 ◽

2011 ◽

Vol 29 (40) ◽

pp. 6848-6857 ◽

Cited By ~ 26

Author(s):

José-Manuel Rojas ◽

Teresa Rodríguez-Calvo ◽

Lourdes Peña ◽

Noemí Sevilla

Keyword(s):

T Cell ◽

Bluetongue Virus ◽

Core Protein ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Epitopes ◽

Cell Responses

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Early life T cell responses to pneumococcal conjugates increase with age and determine the polysaccharide-specific antibody response and protective efficacy

European Journal of Immunology ◽

10.1002/eji.200535102 ◽

2006 ◽

Vol 36 (2) ◽

pp. 287-295 ◽

Cited By ~ 23

Author(s):

Håvard Jakobsen ◽

Solveig Hannesdottir ◽

Stefania P. Bjarnarson ◽

Dominique Schulz ◽

Emanuelle Trannoy ◽

...

Keyword(s):

T Cell ◽

Antibody Response ◽

Specific Antibody ◽

Early Life ◽

Protective Efficacy ◽

T Cell Responses ◽

Specific Antibody Response ◽

Cell Responses

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Enhanced Immunogenicity of CD4+ T-Cell Responses and Protective Efficacy of a DNA-Modified Vaccinia Virus Ankara Prime-Boost Vaccination Regimen for Murine Tuberculosis

Infection and Immunity ◽

10.1128/iai.69.2.681-686.2001 ◽

2001 ◽

Vol 69 (2) ◽

pp. 681-686 ◽

Cited By ~ 169

Author(s):

Helen McShane ◽

Roger Brookes ◽

Sarah C. Gilbert ◽

Adrian V. S. Hill

Keyword(s):

T Cell ◽

Vaccinia Virus ◽

Dna Vaccines ◽

Protective Efficacy ◽

T Cell Responses ◽

Cell Responses ◽

Modified Vaccinia Virus Ankara ◽

Challenge Study ◽

Ifn Γ ◽

Mycobacterial Protein

ABSTRACT DNA vaccines whose DNA encodes a variety of antigens fromMycobacterium tuberculosis have been evaluated for immunogenicity and protective efficacy. CD8+ T-cell responses and protection achieved in other infectious disease models have been optimized by using a DNA immunization to prime the immune system and a recombinant virus encoding the same antigen(s) to boost the response. A DNA vaccine (D) and recombinant modified vaccinia virus Ankara (M) in which the DNA encodes early secreted antigenic target 6 and mycobacterial protein tuberculosis 63 synthesized, and each was found to generate specific gamma interferon (IFN-γ)-secreting CD4+ T cells. Enhanced CD4+ IFN-γ T-cell responses were produced by both D-M and M-D immunization regimens. Significantly higher levels of IFN-γ were seen with a D-D-D-M immunization regimen. The most immunogenic regimens were assessed in a challenge study and found to produce protection equivalent to that produced by Mycobacterium bovis BCG. Thus, heterologous prime-boost regimens boost CD4+ as well as CD8+T-cell responses, and the use of heterologous constructs encoding the same antigen(s) may improve the immunogenicity and protective efficacy of DNA vaccines against tuberculosis and other diseases.

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