title: Live virus vaccines based on a vesicular stomatitis virus (VSV) backbone: Standardized template with key considerations for a risk/benefit assessment.
abstract: The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety of live, recombinant viral vaccines incorporating genes from heterologous viral and other microbial pathogens in their genome (so-called "chimeric virus vaccines"). Many such viral vector vaccines are now at various stages of clinical evaluation. Here, we introduce an attenuated form of recombinant vesicular stomatitis virus (rVSV) as a potential chimeric virus vaccine for HIV-1, with implications for use as a vaccine vector for other pathogens. The rVSV/HIV-1 vaccine vector was attenuated by combining two major genome modifications. These modifications acted synergistically to greatly enhance vector attenuation and the resulting rVSV vector demonstrated safety in sensitive mouse and non-human primate neurovirulence models. This vector expressing HIV-1 gag protein has completed evaluation in two Phase I clinical trials. In one trial the rVSV/HIV-1 vector was administered in a homologous two-dose regimen, and in a second trial with pDNA in a heterologous prime boost regimen. No serious adverse events were reported nor was vector detected in blood, urine or saliva post vaccination in either trial. Gag specific immune responses were induced in both trials with highest frequency T cell responses detected in the prime boost regimen. The rVSV/HIV-1 vector also demonstrated safety in an ongoing Phase I trial in HIV-1 positive participants. Additionally, clinical trial material has been produced with the rVSV vector expressing HIV-1 env, and Phase I clinical evaluation will initiate in the beginning of 2016. In this paper, we use a standardized template describing key characteristics of the novel rVSV vaccine vectors, in comparison to wild type VSV. The template facilitates scientific discourse among key stakeholders by increasing transparency and comparability of information. The Brighton Collaboration V3SWG template may also be useful as a guide to the evaluation of other recombinant viral vector vaccines.
authors.affiliation: Profectus BioSciences Inc., Tarrytown, NY 10591, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Clarke
authors.affiliation: Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP), Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA.
authors.forename: R Michael
authors.initials: RM
authors.lastname: Hendry
authors.affiliation: Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP), Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA. Electronic address: brightoncollaborationv3swg@gmail.com.
authors.forename: Vidisha
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Rose
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Seligman
authors.affiliation: Paul-Ehrlich-Institut, 63225 Langen, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Klug
authors.affiliation: Global Healthcare Consulting, New Delhi, India.
authors.forename: Sonali
authors.initials: S
authors.lastname: Kochhar
authors.affiliation: Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP), Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA.
authors.forename: Lisa Marie
authors.initials: LM
authors.lastname: Mac
authors.affiliation: Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP), Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA.
authors.forename: Baevin
authors.initials: B
authors.lastname: Carbery
authors.affiliation: Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP), Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Chen
mesh_terms: D016915:AIDS Vaccines / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017321:Clinical Trials, Phase I as Topic; D004337:Drug Carriers; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005822:Genetic Vectors; D006801:Humans; D011323:Primates; D018570:Risk Assessment; D013601:T-Lymphocytes / Q000276:immunology; D014613:Vaccines, Attenuated / Q000009:adverse effects / Q000235:genetics; D014614:Vaccines, Synthetic / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D018116:Vesiculovirus / Q000235:genetics*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D004337:Drug Carriers; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; D054299:env Gene Products, Human Immunodeficiency Virus; D054301:gag Gene Products, Human Immunodeficiency Virus
keywords: Brighton collaboration; Risk/benefit assessment; Vaccine safety; Vaccines; Vesicular stomatitis virus vector; Viral vector