Immunology and evolvement of the adenovirus prime, MVA boost Ebola virus vaccine

Zhou, Yan; Sullivan, Nancy J.

doi:10.1016/j.coi.2015.06.006

Cited by 35 publications

(31 citation statements)

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“…2E). Cells that were positive only for interferon- γ and double-positive cells secreting interferon- γ and TNF- α (with the latter being associated with protection in macaques17) were the largest subgroups in the CD8+ T-cell response (Fig. 2E).…”

Section: Resultsmentioning

confidence: 99%

A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA

et al. 2016

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BACKGROUNDThe West African outbreak of Ebola virus disease that peaked in 2014 has caused more than 11,000 deaths. The development of an effective Ebola vaccine is a priority for control of a future outbreak. METHODSIn this phase 1 study, we administered a single dose of the chimpanzee adenovirus 3 (ChAd3) vaccine encoding the surface glycoprotein of Zaire ebolavirus (ZEBOV) to 60 healthy adult volunteers in Oxford, United Kingdom. The vaccine was administered in three dose levels -1×10 10 viral particles, 2.5×10 10 viral particles, and 5×10 10 viral particles -with 20 participants in each group. We then assessed the effect of adding a booster dose of a modified vaccinia Ankara (MVA) strain, encoding the same Ebola virus glycoprotein, in 30 of the 60 participants and evaluated a reduced prime-boost interval in another 16 participants. We also compared antibody responses to inactivated whole Ebola virus virions and neutralizing antibody activity with those observed in phase 1 studies of a recombinant vesicular stomatitis virus-based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV) to determine relative potency and assess durability. RESULTSNo safety concerns were identified at any of the dose levels studied. Four weeks after immunization with the ChAd3 vaccine, ZEBOV-specific antibody responses were similar to those induced by rVSV-ZEBOV vaccination, with a geometric mean titer of 752 and 921, respectively. ZEBOV neutralization activity was also similar with the two vaccines (geometric mean titer, 14.9 and 22.2, respectively). Boosting with the MVA vector increased virus-specific antibodies by a factor of 12 (geometric mean titer, 9007) and increased glycoprotein-specific CD8+ T cells by a factor of 5. Significant increases in neutralizing antibodies were seen after boosting in all 30 participants (geometric mean titer, 139; P<0.001). Virus-specific antibody responses in participants primed with ChAd3 remained positive 6 months after vaccination (geometric mean titer, 758) but were significantly higher in those who had received the MVA booster (geometric mean titer, 1750; P<0.001). CONCLUSIONSThe ChAd3 vaccine boosted with MVA elicited B-cell and T-cell immune responses to ZEBOV that were superior to those induced by the ChAd3 vaccine alone. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT02240875.)A BS TR AC T

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Section: Resultsmentioning

confidence: 99%

A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA

et al. 2016

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“…As the sole membrane protein encoded by the ebolavirus species, the GP plays a critical role in the entry and pathogenicity of EBOV and SUDV (50,51) and is a highly immunogenic protein containing both T-and B-cell epitopes able to activate T-and B-cell ebolavirusspecific immune responses that are associated with survival or asymptomatic infection (52,53). Moreover, other viral vector-based EBOV vaccines expressing GP have dem- onstrated effective protection against lethal challenge with EBOV in animal models (mice, guinea pigs, and NHPs), such as recombinant human adenovirus serotype 5-vector vaccines (rAd5-GP) (8,48,54), chimpanzee adenovirus serotype type 3-vector vaccines (ChAd3-EBO-Z) (23,37,44,46), recombinant vesicular stomatitis virus-vector vaccines (rVSV-GP) (27,(55)(56)(57), rabies virus-vector vaccines (RVΔG-GP) (43, 58), virus-like particles (59), and other vectors (4,60). On the other hand, the major matrix protein VP40 is responsible for the assembly, budding, and release of virion particles and triggers budding of filamentous particles that incorporate other proteins, such as GP, in a more native structure (10,11).…”

Section: Discussionmentioning

confidence: 99%

Distinct Immunogenicity and Efficacy of Poxvirus-Based Vaccine Candidates against Ebola Virus Expressing GP and VP40 Proteins

Lázaro-Frías

Gómez‐Medina

Sánchez-Sampedro

et al. 2018

J Virol

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and species cause a severe disease in humans and nonhuman primates (NHPs) characterized by a high mortality rate. There are no licensed therapies or vaccines against Ebola virus disease (EVD), and the recent 2013 to 2016 outbreak in West Africa highlighted the need for EVD-specific medical countermeasures. Here, we generated and characterized head-to-head the immunogenicity and efficacy of five vaccine candidates against Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV) based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing either the virus glycoprotein (GP) or GP together with the virus protein 40 (VP40) forming virus-like particles (VLPs). In a human monocytic cell line, the different MVA vectors (termed MVA-EBOVs and MVA-SUDVs) triggered robust innate immune responses, with production of beta interferon (IFN-β), proinflammatory cytokines, and chemokines. Additionally, several innate immune cells, such as dendritic cells, neutrophils, and natural killer cells, were differentially recruited in the peritoneal cavity of mice inoculated with MVA-EBOVs. After immunization of mice with a homologous prime/boost protocol (MVA/MVA), total IgG antibodies against GP or VP40 from Zaire and Sudan ebolavirus were differentially induced by these vectors, which were mainly of the IgG1 and IgG3 isotypes. Remarkably, an MVA-EBOV construct coexpressing GP and VP40 protected chimeric mice challenged with EBOV to a greater extent than a vector expressing GP alone. These results support the consideration of MVA-EBOVs and MVA-SUDVs expressing GP and VP40 and producing VLPs as best-in-class potential vaccine candidates against EBOV and SUDV. EBOV and SUDV cause a severe hemorrhagic fever affecting humans and NHPs. Since their discovery in 1976, they have caused several sporadic epidemics, with the recent outbreak in West Africa from 2013 to 2016 being the largest and most severe, with more than 11,000 deaths being reported. Although some vaccines are in advanced clinical phases, less expensive, safer, and more effective licensed vaccines are desirable. We generated and characterized head-to-head the immunogenicity and efficacy of five novel vaccines against EBOV and SUDV based on the poxvirus MVA expressing GP or GP and VP40. The expression of GP and VP40 leads to the formation of VLPs. These MVA-EBOV and MVA-SUDV recombinants triggered robust innate and humoral immune responses in mice. Furthermore, MVA-EBOV recombinants expressing GP and VP40 induced high protection against EBOV in a mouse challenge model. Thus, MVA expressing GP and VP40 and producing VLPs is a promising vaccine candidate against EBOV and SUDV.

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“…A series of subsequent clinical trials of both DNA and recombinant adenovirus vectored vaccines proceeded over the ensuing 10 years and included optimization of vaccine components and refinement of the surface-glycoprotein-antigen design. Extensive studies of vaccine efficacy and correlates of immunity guided the development of these vaccines [54][55][56] . In parallel, there were substantial advances in understanding the structure, entry mechanisms, replication strategies and pathogenesis of Ebola virus that informed the design of vaccines and clinical trials.…”

Section: G G G a A A A A A A Aa A A A A A A A A A A A A A A A T T T Tmentioning

confidence: 99%

Emerging viral diseases from a vaccinology perspective: preparing for the next pandemic

2017

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Emerging infectious diseases will continue to threaten public health and are sustained by global commerce, travel and disruption of ecological systems. Most pandemic threats are caused by viruses from either zoonotic sources or vector-borne sources. Developing better ways to anticipate and manage the ongoing microbial challenge will be critical for achieving the United Nations Sustainable Development Goals and, conversely, each such goal will affect the ability to control infectious diseases. Here we discuss how technology can be applied effectively to better prepare for and respond to new viral diseases with a focus on new paradigms for vaccine development.

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Immunology and evolvement of the adenovirus prime, MVA boost Ebola virus vaccine

Cited by 35 publications

References 33 publications

A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA

A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA

Distinct Immunogenicity and Efficacy of Poxvirus-Based Vaccine Candidates against Ebola Virus Expressing GP and VP40 Proteins

Emerging viral diseases from a vaccinology perspective: preparing for the next pandemic

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