title: Live virus vaccines based on a yellow fever vaccine 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 viruses inserted into the backbone of another virus (so-called "chimeric virus vaccines"). Many viral vector vaccines are in advanced clinical trials. The first such vaccine to be approved for marketing (to date in Australia, Thailand, Malaysia, and the Philippines) is a vaccine against the flavivirus, Japanese encephalitis (JE), which employs a licensed vaccine (yellow fever 17D) as a vector. In this vaccine, two envelope proteins (prM-E) of YF 17D virus were exchanged for the corresponding genes of JE virus, with additional attenuating mutations incorporated into the JE gene inserts. Similar vaccines have been constructed by inserting prM-E genes of dengue and West Nile into YF 17D virus and are in late stage clinical studies. The dengue vaccine is, however, more complex in that it requires a mixture of four live vectors each expressing one of the four dengue serotypes. This vaccine has been evaluated in multiple clinical trials. No significant safety concerns have been found. The Phase 3 trials met their endpoints in terms of overall reduction of confirmed dengue fever, and, most importantly a significant reduction in severe dengue and hospitalization due to dengue. However, based on results that have been published so far, efficacy in preventing serotype 2 infection is less than that for the other three serotypes. In the development of these chimeric vaccines, an important series of comparative studies of safety and efficacy were made using the parental YF 17D vaccine virus as a benchmark. In this paper, we use a standardized template describing the key characteristics of the novel flavivirus vaccine vectors, in comparison to the parental YF 17D vaccine. The template facilitates scientific discourse among key stakeholders by increasing the 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: Kleiner Perkins Caufield & Byers, Menlo Park, CA 94025, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Monath
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA. Electronic address: stephen_seligman@nymc.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Seligman
authors.affiliation: National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, UK.
authors.forename: James S
authors.initials: JS
authors.lastname: Robertson
authors.affiliation: Discovery Department, Sanofi Pasteur, 69280 Marcy l'Etoile, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Guy
authors.affiliation: Barcelona Centre for International Health Research (CRESIB), 08036 Barcelona, Spain.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Hayes
authors.affiliation: Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Condit
authors.affiliation: International AIDS Vaccine Initiative (IAVI), New York, NY 10004, USA; U.S. Military HIV Research Program (MHRP), Bethesda, MD 20817, USA.
authors.forename: Jean Louis
authors.initials: JL
authors.lastname: Excler
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: D004337:Drug Carriers; D005822:Genetic Vectors; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D014613:Vaccines, Attenuated / Q000009:adverse effects / Q000235:genetics; D014614:Vaccines, Synthetic / Q000009:adverse effects / Q000235:genetics; D014765:Viral Vaccines / Q000009:adverse effects* / Q000235:genetics*; D015005:Yellow fever virus / Q000235:genetics*
chemical_list: D004337:Drug Carriers; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; D014765:Viral Vaccines
keywords: Brighton Collaboration; Risk/benefit assessment; Vaccine safety; Vaccines; Viral vector; Yellow fever vaccine