title: Safety and tolerability evaluation of the use of Montanide ISA™51 as vaccine adjuvant: A systematic review.
abstract: Montanide ISA™51 (ISA 51) is a vaccine adjuvant which has been tested in therapeutic and prophylactic vaccine trials. The aim of this review is to present a comprehensive examination of the safety and tolerability of ISA 51 containing vaccines. A systematic literature search was conducted in PubMed, EMBASE and clinicaltrials.gov . Eligible studies were categorized into: (A) uncontrolled studies with non-healthy subjects, (B) controlled studies with non-healthy subjects, and (C) controlled studies with healthy subjects. Reported adverse events (AEs) were assessed. 91 studies were included in our review. Generally observed AEs included injection site reaction; injection site pain; myalgia; headache; gastro-intestinal disorders; fatigue and fever - regardless of the administration route and subject characteristic. Specific AEs, e.g. injection site reactions and rash, were more frequently reported from subjects receiving ISA 51-adjuvanted vaccines than from subjects receiving antigen or ISA 51 only. The reported AEs were mainly mild to moderate in intensity. Serious AEs (SAEs) were reported in 27% of the uncontrolled trials and 2 trials conducted with healthy subjects. Notably, 2 other trials conducted with healthy subjects were stopped due to unacceptable AEs. Some studies indicate that the mixing procedure of antigen and adjuvant might influence the occurrence of AEs. Reports on SAEs and premature termination of 2 trials advise caution when using ISA 51. Yet, AEs might be preventable by proper mixing of vaccine and adjuvant to a stable emulsion. Trials including an active control group are needed for a fair evaluation of adjuvant safety.
authors.affiliation: a Unit of PharmacoEpidemiology and PharmacoEconomics (PE2); Department of Pharmacy; University of Groningen ; Groningen , The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: van Doorn
authors.affiliation: a Unit of PharmacoEpidemiology and PharmacoEconomics (PE2); Department of Pharmacy; University of Groningen ; Groningen , The Netherlands.
authors.forename: Heng
authors.initials: H
authors.lastname: Liu
authors.affiliation: b Department of Medical Microbiology ; University of Groningen; University Medical Center of Groningen ; Groningen , The Netherlands.
authors.forename: Anke
authors.initials: A
authors.lastname: Huckriede
authors.affiliation: a Unit of PharmacoEpidemiology and PharmacoEconomics (PE2); Department of Pharmacy; University of Groningen ; Groningen , The Netherlands.
authors.forename: Eelko
authors.initials: E
authors.lastname: Hak
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology* / Q000473:pathology*; D005221:Fatigue / Q000139:chemically induced; D005334:Fever / Q000139:chemically induced; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008353:Mannitol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D009829:Oleic Acids / Q000008:administration & dosage* / Q000009:adverse effects*; D010146:Pain / Q000139:chemically induced; D012871:Skin Diseases / Q000139:chemically induced / Q000473:pathology; D014612:Vaccines / Q000008:administration & dosage
chemical_list: D000276:Adjuvants, Immunologic; D009829:Oleic Acids; D014612:Vaccines; C477385:montanide ISA 51; D008353:Mannitol
keywords: ISA 51; Montanide; adverse event; safety; systematic review; tolerability