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Paul Chaplin - One of the best experts on this subject based on the ideXlab platform.
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Intratumoral virotherapy with 4-1BBL armed Modified Vaccinia Ankara eradicates solid tumors and promotes protective immune memory.
Journal for immunotherapy of cancer, 2021Co-Authors: Maria Hinterberger, Paul Chaplin, Mark Suter, Raphael Giessel, Giovanna Fiore, Fabienne Graebnitz, Barbara Bathke, Sonia T. Wennier, Ignacio Melero, Henning LauterbachAbstract:Background Human cancers are extraordinarily heterogeneous in terms of tumor antigen expression, immune infiltration and composition. A common feature, however, is the host's inability to mount potent immune responses that prevent tumor growth effectively. Often, naturally primed CD8+ T cells against solid tumors lack adequate stimulation and efficient tumor tissue penetration due to an immune hostile tumor microenvironment.Methods To address these shortcomings, we cloned tumor-associated antigens (TAA) and the immune-stimulatory ligand 4-1BBL into the genome of Modified Vaccinia Ankara (MVA) for intratumoral virotherapy.Results Local treatment with MVA-TAA-4-1BBL resulted in control of established tumors. Intratumoral injection of MVA localized mainly to the tumor with minimal leakage to the tumor-draining lymph node. In situ infection by MVA-TAA-4-1BBL triggered profound changes in the tumor microenvironment, including the induction of multiple proinflammatory molecules and immunogenic cell death. These changes led to the reactivation and expansion of antigen-experienced, tumor-specific cytotoxic CD8+ T cells that were essential for the therapeutic antitumor effect. Strikingly, we report the induction of a systemic antitumor immune response including tumor antigen spread by local MVA-TAA-4-1BBL treatment which controlled tumor growth at distant, untreated lesions and protected against local and systemic tumor rechallenge. In all cases, 4-1BBL adjuvanted MVA was superior to MVA.Conclusion Intratumoral 4-1BBL-armed MVA immunotherapy induced a profound reactivation and expansion of potent tumor-specific CD8+ T cells as well as favorable proinflammatory changes in the tumor microenvironment, leading to elimination of tumors and protective immunological memory.
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Cardiac safety of Modified Vaccinia Ankara for vaccination against smallpox in a young, healthy study population.
PloS one, 2015Co-Authors: Eva-maria Zitzmann-roth, Alfred Von Krempelhuber, Garth Virgin, Jens Vollmar, Frank Von Sonnenburg, Stephan De La Motte, Nathaly Arndtz-wiedemann, Nadine Uebler, Paul ChaplinAbstract:Background Conventional smallpox vaccines based on replicating Vaccinia virus (VV) strains (e.g. Lister Elstree, NYCBOH) are associated with a high incidence of myo-/pericarditis, a severe inflammatory cardiac complication. A new smallpox vaccine candidate based on a nonreplicating Modified Vaccinia Ankara (MVA) poxvirus has been assessed for cardiac safety in a large placebo-controlled clinical trial. Methods Cardiac safety of one and two doses of MVA compared to placebo was assessed in 745 healthy subjects. Vaccinia-naive subjects received either one dose of MVA and one dose of placebo, two doses of MVA, or two doses of placebo by subcutaneous injection four weeks apart;Vaccinia-experienced subjects received a single dose of MVA. Solicited and unsolicited adverse events (AE) and cardiac safety parameters (recorded as Adverse Events of Special Interest, AESI) were monitored after each injection. Results A total of 5 possibly related AESI (3 cases of palpitations, 2 of tachycardia) were reported during the study. No case of myo- or pericarditis occurred. One possibly related serious AE (SAE) was reported during the 6-month follow-up period (sarcoidosis). The most frequently observed AEs were injection site reactions. Conclusions Vaccination with MVA was safe and well tolerated and did not increase the risk for development of myo-/pericarditis.
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Safety and immunogenicity of Modified Vaccinia Ankara as a smallpox vaccine in people with atopic dermatitis
Vaccine, 2014Co-Authors: Frank Von Sonnenburg, Alfred Von Krempelhuber, Jens Vollmar, Pamela Perona, Ulf Darsow, Johannes Ring, Siegfried Roesch, Nicole Baedeker, Herwig Kollaritsch, Paul ChaplinAbstract:Abstract Background Following vaccination with traditional smallpox vaccines or after exposure to vaccinated individuals, subjects with atopic dermatitis (AD) can develop eczema vaccinatum, a severe disease with disseminated eruption of pustular contagious lesions. Alternative smallpox vaccines with an improved safety profile would address this unmet medical need. Methods An open-label controlled Phase I clinical trial was conducted to investigate the safety and immunogenicity of Modified Vaccinia Ankara (MVA) in 15 healthy subjects compared to 45 subjects with either mild allergic rhinitis, a history of AD or presenting with mild active AD. MVA was given (Week 0 and 4) by a subcutaneous injection during a 28-week observation period. Results No serious adverse event was reported and vaccinations with MVA did not lead to any clinically relevant skin reactions in AD subjects. Unsolicited administration site reactions did not show any trends compared to the healthy subject group. The majority of adverse reactions were mild to moderate, and all reactions were transient and resolved without intervention. The majority of vaccinees had seroconverted by ELISA (80–93%) and PRNT (69–79%) already two weeks after the first vaccination, increasing to 100% after the second immunization, with peak GMT above 1000 and 145 for ELISA and PRNT, respectively. Conclusions MVA was equally well tolerated and immunogenic in all enrolled subjects with mild to moderate pain and redness at the injection site being the most frequent adverse reactions. There were no differences in the safety or immunogenicity profile of MVA in healthy subjects or those with AD or allergic rhinitis. The study has confirmed MVA as a promising smallpox vaccine candidate and demonstrated in a small study population that the vaccine has a similar safety and immunogenicity profile in healthy subjects and people with active AD. Clinical trials registration: NCT00189917 .
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Phase II Randomized, Double-Blinded Comparison of A Single High Dose (5×108 TCID50) of Modified Vaccinia Ankara Compared To A Standard Dose (1×108 TCID50) in Healthy Vaccinia-Naïve Individuals
Vaccine, 2014Co-Authors: Sharon E. Frey, Patricia L. Winokur, Heather Hill, Johannes B. Goll, Paul Chaplin, Robert B. BelsheAbstract:Introduction Reintroduction of Variola major as an agent of bioterrorism remains a concern. Time to seroconversion and plaque reduction neutralizing antibody titers (PRNT) of 1 or 2 standard doses (SD) were compared to a single high dose (HD) of Modified Vaccinia Ankara (MVA).
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Safety, Immunogenicity, and Surrogate Markers of Clinical Efficacy for Modified Vaccinia Ankara as a Smallpox Vaccine in HIV-Infected Subjects
The Journal of infectious diseases, 2012Co-Authors: Richard N. Greenberg, Alfred Von Krempelhuber, Edgar T Overton, Ian Frank, Garth Virgin, Jens Vollmar, David W. Haas, Mitchell Goldman, Nicole Bädeker, Paul ChaplinAbstract:Background. Human immunodeficiency virus (HIV)–infected persons are at higher risk for serious complications associated with traditional smallpox vaccines. Alternative smallpox vaccines with an improved safety profile would address this unmet medical need. Methods. The safety and immunogenicity of Modified Vaccinia Ankara (MVA) was assessed in 91 HIV-infected adult subjects (CD4 + T-cell counts, ≥350 cells/mm 3 ) and 60 uninfected volunteers. The primary objectives were to evaluate the safety of MVA and immunogenicity in HIV-infected and uninfected subjects. As a measure of the potential efficacy of MVA, the ability to boost the memory response in people previously vaccinated against smallpox was evaluated by the inclusion of Vaccinia-experienced HIV-infected and HIV-uninfected subjects. Results. MVA was well tolerated and immunogenic in all subjects. Antibody responses were comparable between uninfected and HIV-infected populations, with only 1 significantly lower total antibody titer at 2 weeks after the second vaccination, while no significant differences were observed for neutralizing antibodies. MVA rapidly boosted the antibody responses in Vaccinia-experienced subjects, supporting the efficacy of MVA against variola.
Richard Harrop - One of the best experts on this subject based on the ideXlab platform.
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Clinical and laboratory parameters associated with outcomes in patients with metastatic renal cell carcinoma treated with Modified Vaccinia Ankara delivering tumor antigen 5T4.
Journal of Clinical Oncology, 2010Co-Authors: Robert J. Amato, Richard Harrop, J. Podolnick, Stuart NaylorAbstract:e13132 Background: Two separate studies have been conducted to study the efficacy of Modified Vaccinia Ankara delivering tumor antigen 5T4 (TroVax) alone, in combination with either interleukin-2 or interferon-α totaling 53 patients (Clin Cancer Res 2008; 14[22], J Immunother 2009; 32[7]). We will review the overall survival of this patient population of 12 months and >24 months and provide correlation with their baseline clinical and laboratory parameters. Methods: We have reviewed baseline data of 53 patients. The entire baseline laboratory parameters were assessed. Clinical data such as pathology, diagnosed to initial therapy with TroVax, time of metastases development, the number of metastatic lesions and performance status. Both univariate and multivariate analyses were conducted. Results: Analysis of the data revealed the diagnosed time to start interval of therapy, metastasis to interval of receiving TroVax, the number of metastatic lesions, decreased leucocyte count, decreased platele...
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Vaccination of Renal Cell Cancer Patients With Modified Vaccinia Ankara Delivering the Tumor Antigen 5T4 (TroVax) Alone or Administered in Combination With Interferon-α (IFN-α): A Phase 2 Trial
Journal of immunotherapy (Hagerstown Md. : 1997), 2009Co-Authors: Robert J. Amato, William Shingler, Stuart Naylor, Madusha Goonewardena, Jackie De Belin, J. Jac, J. P. Willis, Somyata Saxena, Joan Hernandez-mcclain, Richard HarropAbstract:Attenuated Vaccinia virus, Modified Vaccinia Ankara (MVA) has been engineered to deliver the tumor antigen 5T4 (TroVax). MVA-5T4 has been evaluated in an open-label phase 2 trial in metastatic renal cell cancer patients in which the vaccine was administered alone or in combination with interferon-α-
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Vaccination of Patients With Metastatic Renal Cancer With Modified Vaccinia Ankara Encoding the Tumor Antigen 5T4 (TroVax) Given Alongside Interferon-α
Journal of immunotherapy (Hagerstown Md. : 1997), 2009Co-Authors: Robert E. Hawkins, C. Macdermott, Alaaeldin Shablak, Caroline Hamer, Fiona C. Thistlethwaite, N. Drury, P. Chikoti, William Shingler, Stuart Naylor, Richard HarropAbstract:Approximately 90% of renal cell tumors overexpress the tumor antigen 5T4. The attenuated strain of Vaccinia virus, Modified Vaccinia Ankara, has been engineered to express 5T4 (TroVax). We conducted an open-label phase 1/2 trial in which TroVax was administered alongside interferon-alpha (IFNalpha) to 11 patients with metastatic renal cell carcinoma. Antigen-specific cellular and humoral responses were monitored throughout the study, and clinical responses were assessed by measuring the changes in tumor burden by computed tomography scan (Response Evaluation Criteria In Solid Tumors). The primary objective was to assess the safety, immunogenicity, and efficacy of TroVax when given alongside IFNalpha. Treatment with TroVax plus IFNalpha was well tolerated with no serious adverse events attributed to TroVax. All 11 patients mounted 5T4-specific antibody responses and 5 (45%) mounted cellular responses. No objective tumor responses were seen, but the overall median time to progression (TTP) of 9 months (range: 2.1 to 26+ mo) was longer than expected for IFNalpha alone. For the 10 clear cell patients the TTP ranged from 3.9 to 26+ months, with a median TTP of 10.4 months. The high frequency of 5T4-specific immune responses and prolonged median TTP for clear cell patients compared with that expected for IFNalpha alone is encouraging and warrants further investigation.
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Vaccination of Renal Cell Cancer Patients with Modified Vaccinia Ankara Delivering Tumor Antigen 5T4 (TroVax) Administered with Interleukin 2: A Phase II Trial
Clinical cancer research : an official journal of the American Association for Cancer Research, 2008Co-Authors: Robert J. Amato, William Shingler, Stuart Naylor, J. Jac, J. P. Willis, Somyata Saxena, Joan Hernandez-mcclain, Richard HarropAbstract:Purpose: The attenuated Vaccinia virus Modified Vaccinia Ankara (MVA) has been engineered to deliver the tumor antigen 5T4 (TroVax). TroVax has been evaluated in an open-label phase II trial in metastatic renal cell cancer patients in which the vaccine was administered in combination with interleukin-2 (IL-2). The safety, immunologic, and clinical efficacy of TroVax in combination with IL-2 was determined. Experimental Design: Twenty-five patients with metastatic renal cell cancer were treated with TroVax plus IL-2. 5T4-specific cellular and humoral responses were monitored throughout the study. Clinical responses were assessed by measuring changes in tumor burden by computed tomography or magnetic resonance imaging scan. Results: TroVax was well tolerated with no serious adverse event attributed to vaccination. Of 25 intention-to-treat patients, 21 mounted 5T4-specific antibody responses. Two patients showed a complete response for >24 months and one a partial response for >12 months. Six patients had disease stabilization from 6 to >21 months. Median progression-free survival (PFS) and overall survival (OS) were >3.37 months (range, 1.50->24.76) and >12.87 months (range, 1.90->24.76), respectively. A statistically significant relationship was detected between the magnitude of 5T4-specific antibody responses and PFS and OS. Conclusion: TroVax in combination with IL-2 was safe and well tolerated in all patients. The high frequency of 5T4-specific immune responses and good clinical response rate are encouraging and warrant further investigation.
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Vaccination of renal cell cancer patients with TroVax (Modified Vaccinia Ankara delivering the tumor antigen 5T4) plus IFNα: A phase II trial
Journal of Clinical Oncology, 2008Co-Authors: Richard Harrop, C. Macdermott, Alaaeldin Shablak, Caroline Hamer, Fiona C. Thistlethwaite, N. Drury, P. Chikoti, William Shingler, Stuart Naylor, R. Hawkins ProfAbstract:3053 Background: The attenuated Vaccinia virus, Modified Vaccinia Ankara (MVA) has been engineered to express the tumor antigen 5T4 (TroVax [T]). Approximately 90% of renal cell tumors overexpress ...
Stephen R Walsh - One of the best experts on this subject based on the ideXlab platform.
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First-in-Human Randomized, Controlled Trial of Mosaic HIV-1 Immunogens Delivered via a Modified Vaccinia Ankara Vector.
The Journal of infectious diseases, 2018Co-Authors: Lindsey R. Baden, Stephen R Walsh, Michael S. Seaman, Jane A. Kleinjan, Yehuda Z. Cohen, Jennifer Johnson, J. Humberto Licona, Rachel D Filter, Jon A Gothing, Julia JenningsAbstract:Background Mosaic immunogens are bioinformatically engineered human immunodeficiency virus type 1 (HIV-1) sequences designed to elicit clade-independent coverage against globally circulating HIV-1 strains. Methods This phase 1, double-blinded, randomized, placebo-controlled trial enrolled healthy HIV-uninfected adults who received 2 doses of a Modified Vaccinia Ankara (MVA)-vectored HIV-1 bivalent mosaic immunogen vaccine or placebo on days 0 and 84. Two groups were enrolled: those who were HIV-1 vaccine naive (n = 15) and those who had received an HIV-1 vaccine (Ad26.ENVA.01) 4-6 years earlier (n = 10). We performed prespecified blinded cellular and humoral immunogenicity analyses at days 0, 14, 28, 84, 98, 112, 168, 270, and 365. Results All 50 planned vaccinations were administered. Vaccination was safe and generally well tolerated. No vaccine-related serious adverse events occurred. Both cellular and humoral cross-clade immune responses were elicited after 1 or 2 vaccinations in all participants in the HIV-1 vaccine-naive group. Env-specific responses were induced after a single immunization in nearly all subjects who had previously received the prototype Ad26.ENVA.01 vaccine. Conclusions No safety concerns were identified, and multiclade HIV-1-specific immune responses were elicited. Clinical Trials Registration NCT02218125.
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safety and immunogenicity of Modified Vaccinia Ankara in hematopoietic stem cell transplant recipients a randomized controlled trial
The Journal of Infectious Diseases, 2013Co-Authors: Stephen R Walsh, David J Dominguez, Shringkhala Bajimaya, Lisa S Gagne, Elise Zablowsky, Marissa B Wilck, Kelly VerrillAbstract:Less than 200 years after the introduction of the smallpox vaccine, variola virus (VARV) was successfully eradicated by use of vaccines produced with Vaccinia virus (VACV) [1]. However, along with the dramatic success of the vaccination program, frequent and sometimes severe adverse reactions to VACV vaccine were encountered, particularly in subjects with immunologic defects or dermatopathologic conditions. Since eradication, VACV vaccine has been reserved for highly selected individuals at risk for orthopoxvirus infections, but there are ongoing concerns over the potential use of VARV as a biological weapon. The development of safer, yet effective vaccines for future use against smallpox therefore remains of considerable interest. Modified Vaccinia Ankara (MVA), an attenuated strain of VACV [2, 3], is much less reactogenic than widely used Vaccinia strains, such as Dryvax or Elstree [4–8]. MVA was administered to approximately 120 000 persons [9] but was never used in a VARV-endemic area, and its effectiveness at preventing clinical smallpox is unknown. MVA is severely host restricted, and it is either unable to replicate in mammalian cell lines or replicates at a very low level [3, 10, 11]. Approximately 15% of the MVA genome was deleted during in vitro passage, compared with the parental strain [10, 12], but the block in replication in nonpermissive mammalian cells occurs late in the viral life cycle. Thus, because MVA-infected cells express very high levels of virally encoded proteins [13–15], including those encoded by foreign transgenes, there is considerable interest in using MVA as a vector in vaccines to prevent human immunodeficiency virus (HIV) infection, malaria, and infectious diseases due to other pathogens [16–18]. There is also substantial interest in the use of MVA as a vector to deliver tumor-specific antigens to induce immune responses that may help control malignancies, and several of these therapeutic vaccines have advanced to clinical trials [18–20]. Because preliminary studies suggested MVA was safe in immunocompromised hosts [21–24], we hypothesized that MVA would be safe, well-tolerated, and immunogenic in an important, well-characterized immunocompromised population—recipients of a hematopoietic stem cell transplant (HSCT). Vaccination with either traditional calf lymph–derived VACV (such as Dryvax or Elstree) or modern tissue culture-grown strains (the recently approved ACAM2000) are contraindicated for HSCT recipients [25]. Thus, establishing safety and immunogenicity of MVA in this group has implications for pre-event smallpox vaccine contingency planning, as well as for potential therapeutic vaccines against malignancies. We therefore conducted a randomized, placebo-controlled, double-blind study of MVA-BN (IMVAMUNE; Bavarian Nordic A/S, Kvistgaard, Denmark) in 24 individuals who received a HSCT >2 years previously.
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Effect of Vaccination with Modified Vaccinia Ankara (ACAM3000) on Subsequent Challenge with Dryvax
The Journal of infectious diseases, 2010Co-Authors: Michael S. Seaman, Stephen R Walsh, Marissa B Wilck, Lindsey R. Baden, Lauren E. Grandpre, Colleen Devoy, Ayush Giri, Lizanne C. Noble, Jane A. Kleinjan, Kristen E. StevensonAbstract:Background Despite the success of smallpox vaccination, the immunological correlates of protection are not fully understood. To investigate this question, we examined the effect of immunization with Modified Vaccinia Ankara (MVA) upon challenge with replication competent Vaccinia (Dryvax).
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Safety and Immunogenicity of Modified Vaccinia Ankara (ACAM3000): Effect of Dose and Route of Administration
The Journal of infectious diseases, 2010Co-Authors: Marissa B Wilck, Stephen R Walsh, Michael S. Seaman, Lindsey R. Baden, Lauren E. Grandpre, Colleen Devoy, Ayush Giri, Lizanne C. Noble, Jane A. Kleinjan, Kristen E. StevensonAbstract:Background We conducted a clinical trial of the safety and immunogenicity of Modified Vaccinia Ankara (ACAM3000 MVA) to examine the effects of dose and route of administration.
Peter P. C. Mertens - One of the best experts on this subject based on the ideXlab platform.
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vaccination of horses with a recombinant Modified Vaccinia Ankara virus mva expressing african horse sickness ahs virus major capsid protein vp2 provides complete clinical protection against challenge
Vaccine, 2014Co-Authors: Berta Alberca, Peter P. C. Mertens, Katarzyna Bachanekbankowska, Marta Cabana, Eva Calvopinilla, Elisenda Viaplana, Lorraine Frost, Simon Gubbins, Alicia Urniza, Javier CastilloolivaresAbstract:African horse sickness virus (AHSV) is an arthropod-borne pathogen that infects all species of equidae and causes high mortality in horses. Previously, a recombinant Modified Vaccinia Ankara (MVA) virus expressing the protein VP2 of AHSV serotype 4 was shown to induce virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR −/−) against virulent AHSV challenge. This study builds on the previous work, examining the protective efficacy of MVA-VP2 vaccination in the natural host of AHSV infection. A study group of 4 horses was vaccinated twice with a recombinant MVA virus expressing the major capsid protein (VP2) of AHSV serotype 9. Vaccinated animals and a control group of unvaccinated horses were then challenged with a virulent strain of AHSV-9. The vaccinated animals were completely protected against clinical disease and also against viraemia as measured by standard end-point dilution assays. In contrast, all control horses presented viraemia after challenge and succumbed to the infection. These results demonstrate the potential of recombinant MVA viruses expressing the outer capsid VP2 of AHSV as a protective vaccine against AHSV infection in the field.
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vaccination of mice with a Modified Vaccinia Ankara mva virus expressing the african horse sickness virus ahsv capsid protein vp2 induces virus neutralising antibodies that confer protection against ahsv upon passive immunisation
Virus Research, 2014Co-Authors: Eva Calvopinilla, Peter P. C. Mertens, Simon Gubbins, Francisco De La Poza, Javier Ortego, Javier CastilloolivaresAbstract:Abstract In previous studies we showed that a recombinant Modified Vaccinia Ankara (MVA) virus expressing the protein VP2 of AHSV serotype 4 (MVA-VP2) induced virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR−/−) against challenge. We continued these studies and determined, in the IFNAR−/− mouse model, whether the antibody responses induced by MVA-VP2 vaccination play a key role in protection against AHSV. Thus, groups of mice were vaccinated with wild type MVA (MVA-wt) or MVA-VP2 and the antisera from these mice were used in a passive immunisation experiment. Donor antisera from (a) MVA-wt; (b) MVA-VP2 vaccinated; or (c) MVA-VP2 vaccinated and AHSV infected mice, were transferred to AHSV non-immune recipient mice. The recipients were challenged with virulent AHSV together with MVA-VP2 vaccinated and MVA-wt vaccinated control animals and the levels of protection against AHSV-4 were compared between all these groups. The results showed that following AHSV challenge, mice that were passively immunised with MVA-VP2 vaccinated antisera were highly protected against AHSV disease and had lower levels of viraemia than recipients of MVA-wt antisera. Our study indicates that MVA-VP2 vaccination induces a highly protective humoral immune response against AHSV.
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A Modified Vaccinia Ankara Virus (MVA) Vaccine Expressing African Horse Sickness Virus (AHSV) VP2 Protects Against AHSV Challenge in an IFNAR −/− Mouse Model
PloS one, 2011Co-Authors: Javier Castillo-olivares, Javier Ortego, Eva Calvo-pinilla, Isabel Casanova, Katarzyna Bachanek-bankowska, Rachael Chiam, Sushila Maan, Jose Maria Nieto, Peter P. C. MertensAbstract:African horse sickness (AHS) is a lethal viral disease of equids, which is transmitted by Culicoides midges that become infected after biting a viraemic host. The use of live attenuated vaccines has been vital for the control of this disease in endemic regions. However, there are safety concerns over their use in non-endemic countries. Research efforts over the last two decades have therefore focused on developing alternative vaccines based on recombinant baculovirus or live viral vectors expressing structural components of the AHS virion. However, ethical and financial considerations, relating to the use of infected horses in high biosecurity installations, have made progress very slow. We have therefore assessed the potential of an experimental mouse-model for AHSV infection for vaccine and immunology research. We initially characterised AHSV infection in this model, then tested the protective efficacy of a recombinant vaccine based on Modified Vaccinia Ankara expressing AHS-4 VP2 (MVA-VP2).
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Induction of Antibody Responses to African Horse Sickness Virus (AHSV) in Ponies after Vaccination with Recombinant Modified Vaccinia Ankara (MVA)
PloS one, 2009Co-Authors: Rachael Chiam, Peter P. C. Mertens, Sushila Maan, Emma Sharp, Shujing Rao, Barbara Blacklaws, Nicholas Davis-poynter, James Wood, Javier Castillo-olivaresAbstract:Background: African horse sickness virus (AHSV) causes a non-contagious, infectious disease in equids, with mortality rates that can exceed 90% in susceptible horse populations. AHSV vaccines play a crucial role in the control of the disease; however, there are concerns over the use of polyvalent live attenuated vaccines particularly in areas where AHSV is not endemic. Therefore, it is important to consider alternative approaches for AHSV vaccine development. We have carried out a pilot study to investigate the ability of recombinant Modified Vaccinia Ankara (MVA) vaccines expressing VP2, VP7 or NS3 genes of AHSV to stimulate immune responses against AHSV antigens in the horse. Methodology/Principal Findings: VP2, VP7 and NS3 genes from AHSV-4/Madrid87 were cloned into the Vaccinia transfer vector pSC11 and recombinant MVA viruses generated. Antigen expression or transcription of the AHSV genes from cells infected with the recombinant viruses was confirmed. Pairs of ponies were vaccinated with MVAVP2, MVAVP7 or MVANS3 and both MVA vector and AHSV antigen-specific antibody responses were analysed. Vaccination with MVAVP2 induced a strong AHSV neutralising antibody response (VN titre up to a value of 2). MVAVP7 also induced AHSV antigen–specific responses, detected by western blotting. NS3 specific antibody responses were not detected. Conclusions: This pilot study demonstrates the immunogenicity of recombinant MVA vectored AHSV vaccines, in particular MVAVP2, and indicates that further work to investigate whether these vaccines would confer protection from lethal AHSV challenge in the horse is justifiable. Copyright: © 2009 Chiam et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Lindsey R. Baden - One of the best experts on this subject based on the ideXlab platform.
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First-in-Human Randomized, Controlled Trial of Mosaic HIV-1 Immunogens Delivered via a Modified Vaccinia Ankara Vector.
The Journal of infectious diseases, 2018Co-Authors: Lindsey R. Baden, Stephen R Walsh, Michael S. Seaman, Jane A. Kleinjan, Yehuda Z. Cohen, Jennifer Johnson, J. Humberto Licona, Rachel D Filter, Jon A Gothing, Julia JenningsAbstract:Background Mosaic immunogens are bioinformatically engineered human immunodeficiency virus type 1 (HIV-1) sequences designed to elicit clade-independent coverage against globally circulating HIV-1 strains. Methods This phase 1, double-blinded, randomized, placebo-controlled trial enrolled healthy HIV-uninfected adults who received 2 doses of a Modified Vaccinia Ankara (MVA)-vectored HIV-1 bivalent mosaic immunogen vaccine or placebo on days 0 and 84. Two groups were enrolled: those who were HIV-1 vaccine naive (n = 15) and those who had received an HIV-1 vaccine (Ad26.ENVA.01) 4-6 years earlier (n = 10). We performed prespecified blinded cellular and humoral immunogenicity analyses at days 0, 14, 28, 84, 98, 112, 168, 270, and 365. Results All 50 planned vaccinations were administered. Vaccination was safe and generally well tolerated. No vaccine-related serious adverse events occurred. Both cellular and humoral cross-clade immune responses were elicited after 1 or 2 vaccinations in all participants in the HIV-1 vaccine-naive group. Env-specific responses were induced after a single immunization in nearly all subjects who had previously received the prototype Ad26.ENVA.01 vaccine. Conclusions No safety concerns were identified, and multiclade HIV-1-specific immune responses were elicited. Clinical Trials Registration NCT02218125.
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Effect of Vaccination with Modified Vaccinia Ankara (ACAM3000) on Subsequent Challenge with Dryvax
The Journal of infectious diseases, 2010Co-Authors: Michael S. Seaman, Stephen R Walsh, Marissa B Wilck, Lindsey R. Baden, Lauren E. Grandpre, Colleen Devoy, Ayush Giri, Lizanne C. Noble, Jane A. Kleinjan, Kristen E. StevensonAbstract:Background Despite the success of smallpox vaccination, the immunological correlates of protection are not fully understood. To investigate this question, we examined the effect of immunization with Modified Vaccinia Ankara (MVA) upon challenge with replication competent Vaccinia (Dryvax).
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Safety and Immunogenicity of Modified Vaccinia Ankara (ACAM3000): Effect of Dose and Route of Administration
The Journal of infectious diseases, 2010Co-Authors: Marissa B Wilck, Stephen R Walsh, Michael S. Seaman, Lindsey R. Baden, Lauren E. Grandpre, Colleen Devoy, Ayush Giri, Lizanne C. Noble, Jane A. Kleinjan, Kristen E. StevensonAbstract:Background We conducted a clinical trial of the safety and immunogenicity of Modified Vaccinia Ankara (ACAM3000 MVA) to examine the effects of dose and route of administration.
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Immunogenicity of recombinant Modified Vaccinia Ankara following a single or multi-dose vaccine regimen in rhesus monkeys.
Vaccine, 2009Co-Authors: Lauren E. Grandpre, Lindsey R. Baden, Colleen Devoy, Dan H. Barouch, Jonathan S. Duke-cohan, Bonnie A. Ewald, Norman L. Letvin, Ellis L. Reinherz, Raphael Dolin, Michael S. SeamanAbstract:Modified Vaccinia Ankara (MVA) is a replication-defective strain of Vaccinia virus (VV) that is being investigated in humans as an alternative vaccine against smallpox. Understanding the parameters of a MVA vaccine regimen that can effectively enhance protective immunity will be important for clinical development. The present studies utilize cohorts of rhesus monkeys immunized with recombinant MVA (rMVA) or recombinant VV (rVV) vaccine vectors to investigate the magnitude, breadth, and durability of anti-VV immunity elicited by a single or multi-dose vaccine regimen. These data demonstrate that a single immunization with rMVA elicits weaker cellular and humoral immunity compared to a single inoculation with rVV. However, vaccine-elicited antibody responses, but not T cell responses, are significantly enhanced with repeated immunizations of rMVA. Importantly, only monkeys receiving up to four inoculations with rMVA generated neutralizing antibody (NAb) responses that were comparable in magnitude and durability to those elicited in monkeys receiving two inoculations with rVV. These data also show that the breadth of antibody responses against protein antigens associated with two antigenically distinct forms of infectious VV are similar in rMVA- and rVV-immunized monkeys. Together, these studies suggest that a multi-dose vaccine regimen utilizing up to four inoculations of MVA generates robust and durable antibody-mediated immunity comparable to that elicited by replication-competent VV.