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
Mosquirix: what flexibility did regulators accept, and why?
RTS,S/AS01 malaria vaccine · P. falciparum CSP-HBsAg (RTS,S) VLPs; TLR4 (AS01 adjuvant)
Flexibility accepted
DARTVerdict not stated
No reproductive and developmental toxicity studies
Why: Vaccine not intended for administration to women of childbearing potential · Other reason
“and developmental toxicity studies were not included in this Application since the RTS,S/ AS01E candidate vaccine containing, AS01E, MPL, QS-21 is not intended for administration to women of childbearing potential.”
OtherAcceptedBeyond the letter
Toxicity studies used RTS,S/AS01B, with twice the antigen and adjuvant amounts of the marketed AS01E formulation
Why: Higher-content formulation well tolerated, supporting safe use of Mosquirix
“The tested RTS,S/AS01B formulation consists of 50 μg of RTS,S antigen combined with AS01B containing 50 μg of MPL and 50 μg of QS-21 in liposomes and therefore contains twice the amounts of these constituents than the RTS,S/AS01E (Mosquirix) candidate vaccine.”
“The results from the toxicity studies indicate that RTS,S/AS01B, AS01B, QS-21 and MPL are well tolerated by the animals and support the safe use of Mosquirix in human subjects.”
BiodistributionAccepted
No pharmacokinetic study of the vaccine antigen
Why: Pharmacokinetic studies are normally not required for a vaccine · Within the guideline
“Pharmacokinetic studies are normally not required for a vaccine. Pharmacokinetic study of the vaccine antigen was not studied which is considered acceptable by the CHMP.”
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
Heplisav-B
hepatitis B vaccine (recombinant), adjuvanted · HBsAg; TLR9 (CpG 1018 adjuvant)Adjuvant-alone 8-week repeat-dose study designs not representative of the clinical dose regimen
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