title: Meta-Analysis on Randomized Controlled Trials of Vaccines with QS-21 or ISCOMATRIX Adjuvant: Safety and Tolerability.
abstract: QS-21 shows in vitro hemolytic effect and causes side effects in vivo. New saponin adjuvant formulations with better toxicity profiles are needed. This study aims to evaluate the safety and tolerability of QS-21 and the improved saponin adjuvants (ISCOM, ISCOMATRIX and Matrix-M™) from vaccine trials.
  
  
  
  A systematic literature search was conducted from MEDLINE, EMBASE, Cochrane library and Clinicaltrials.gov. We selected for the meta-analysis randomized controlled trials (RCTs) of vaccines adjuvanted with QS-21, ISCOM, ISCOMATRIX or Matrix-M™, which included a placebo control group and reported safety outcomes. Pooled risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated using a random-effects model. Jadad scale was used to assess the study quality.
  
  
  
  Nine RCTs were eligible for the meta-analysis: six trials on QS-21-adjuvanted vaccines and three trials on ISCOMATRIX-adjuvanted, with 907 patients in total. There were no studies on ISCOM or Matrix-M™ adjuvanted vaccines matching the inclusion criteria. Meta-analysis identified an increased risk for diarrhea in patients receiving QS21-adjuvanted vaccines (RR 2.55, 95% CI 1.04-6.24). No increase in the incidence of the reported systemic AEs was observed for ISCOMATRIX-adjuvanted vaccines. QS-21- and ISCOMATRIX-adjuvanted vaccines caused a significantly higher incidence of injection site pain (RR 4.11, 95% CI 1.10-15.35 and RR 2.55, 95% CI 1.41-4.59, respectively). ISCOMATRIX-adjuvanted vaccines also increased the incidence of injection site swelling (RR 3.43, 95% CI 1.08-10.97).
  
  
  
  Our findings suggest that vaccines adjuvanted with either QS-21 or ISCOMATRIX posed no specific safety concern. Furthermore, our results indicate that the use of ISCOMATRIX enables a better systemic tolerability profile when compared to the use of QS-21. However, no better local tolerance was observed for ISCOMATRIX-adjuvanted vaccines in immunized non-healthy subjects. This meta-analysis is limited by the relatively small number of individuals recruited in the included trials, especially in the control groups.
authors.affiliation: Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: Emilia
authors.initials: E
authors.lastname: Bigaeva
authors.affiliation: Department of Pharmacy, Unit of PharmacoEpidemiology & PharmacoEconomics (PE2), University of Groningen, Groningen, The Netherlands.
authors.forename: Eva van
authors.initials: Ev
authors.lastname: Doorn
authors.affiliation: Department of Pharmacy, Unit of PharmacoEpidemiology & PharmacoEconomics (PE2), University of Groningen, Groningen, The Netherlands.
authors.forename: Heng
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, Unit of PharmacoEpidemiology & PharmacoEconomics (PE2), 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; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D012503:Saponins / Q000008:administration & dosage* / Q000009:adverse effects; D014612:Vaccines / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000276:Adjuvants, Immunologic; D012503:Saponins; D014612:Vaccines; C078785:saponin QA-21V1