Arexvy
respiratory syncytial virus vaccine, adjuvanted (AS01E) · RSV preF3; TLR4 (AS01E adjuvant)Toxicity studies used AS01B adjuvant (double immunoenhancer dose) instead of the clinical AS01E formulation
Heplisav-B: what flexibility did regulators accept, and why?
hepatitis B vaccine (recombinant), adjuvanted · HBsAg; TLR9 (CpG 1018 adjuvant)
Flexibility accepted
OtherCriticised but acceptedBeyond the letter
Adjuvant-alone 8-week repeat-dose study designs not representative of the clinical dose regimen
Why: Acceptable when all safety data are taken into account · Weight of evidence
“According to EMA guidelines on adjuvants the study designs were not representative for the clinical dose regime of Heplisav B.”
“However, by taking all safety data into account (as discussed along this report) these deficiencies of the 8-week repeated dose toxicity studies were considered acceptable.”
Safety marginCriticised but acceptedBeyond the letter
No NOAEL in the mouse repeat-dose study of the adjuvanted vaccine; adjuvant dose did not match the clinical dose
Why: High dose 42-fold the clinical dose; numerous clinical studies at intended and greater doses provide a basis to evaluate safety · Human data
“While the adjuvant dose does not provide the direct toxicologic support (lack of NOAEL) intended by matching the clinical dose, on a mg/kg basis the highest adjuvant dose in the mouse toxicology study (2.5 mg/kg) was approximately 42-fold greater than the intended clinical dose of 0.06 mg/kg.”
“Numerous clinical studies at the current intended and greater doses have been conducted with possible autoimmune adverse events (Wegener’s granulomatous disease and thyroiditits) providing a basis to evaluate safety of this adjuvant.”
Same question, other vaccines
Cervarix
human papillomavirus bivalent (types 16, 18) vaccine, recombinant, AS04-adjuvanted · HPV 16/18 L1 VLPs; TLR4 (AS04 adjuvant)No genotoxicity or carcinogenicity studies with the vaccine (MPL adjuvant genotoxicity tested only)
Cyfendus
anthrax vaccine adsorbed, adjuvanted · B. anthracis PA; TLR9 (CpG 7909 adjuvant)Effectiveness established from animal post-exposure survival studies under the Animal Rule instead of human efficacy trials
Fendrix
hepatitis B vaccine (rDNA), AS04C-adjuvanted · HBsAg VLPs; TLR4 (AS04C adjuvant)No distribution or excretion data for the final vaccine or AS04C adjuvant
Flublok
influenza vaccine, recombinant hemagglutinin · Influenza HANo nonclinical toxicity or pharmacology studies with the quadrivalent vaccine; package bridged from trivalent RIV3
Gardasil
human papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant · HPV 6/11/16/18 L1 VLPsNo dedicated safety pharmacology studies; physical signs monitored within toxicity studies
Gardasil 9
human papillomavirus 9-valent vaccine, recombinant · HPV 9-valent L1 VLPsNo safety pharmacology study
HBVaxPro
hepatitis B vaccine (rDNA) · HBsAg VLPsNo dedicated nonclinical studies with HBVaxPro; data extrapolated from HEXAVAC, PROCOMVAX and the thiomersal-containing vaccine
Mosquirix
RTS,S/AS01 malaria vaccine · P. falciparum CSP-HBsAg (RTS,S) VLPs; TLR4 (AS01 adjuvant)No reproductive and developmental toxicity studies
Nuvaxovid
COVID-19 vaccine, recombinant spike protein nanoparticle, Matrix-M-adjuvanted · SARS-CoV-2 spike (nanoparticle)Rat DART used Matrix-M1 below the absolute human dose (maximum volume of clinical formulation)
PreHevbrio
hepatitis B vaccine (recombinant), 3-antigen · HBsAg S/pre-S1/pre-S2 VLPsPivotal repeat-dose toxicity study in rats not GLP-compliant
Shingrix
zoster vaccine recombinant, AS01B-adjuvanted · VZV glycoprotein E; TLR4 (AS01B adjuvant)Vaccine DART only in rats at 40% of the human dose; no full-human-dose rabbit study