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
Gardasil: what flexibility did regulators accept, and why?
human papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant · HPV 6/11/16/18 L1 VLPs
Flexibility accepted
Safety pharmacologyAccepted
No dedicated safety pharmacology studies; physical signs monitored within toxicity studies
Why: In accordance with the vaccine preclinical testing guidance (CPMP/SWP/465/95) · Within the guideline
“Safety pharmacology studies were not performed. However in the toxicological studies safety daily monitoring for physical signs did not reveal any notable respiratory problems. This approach is in accordance with Note for guidance on preclinical pharmacological and toxicological testing of vaccines (CPMP/SWP/465/95).”
OtherAccepted
Aluminium adjuvant not tested alone; already used in approved vaccines
Why: Adjuvant used in other vaccines approved in Europe; adjuvant guideline · Class precedent · Within the guideline
“The Merck Aluminium Adjuvant (aluminium hydroxyphosphate sulphate adjuvant) is used in other vaccines, which are approved in Europe, and it is agreed that no further studies on the adjuvant are required according Guideline on adjuvants in vaccines for human use (CHMP/VEG/134716/2004).”
SpeciesAcceptedBeyond the letter
Limited toxicology programme: repeat-dose toxicity in mouse only
Why: No toxicological concerns arising from the nonclinical studies · Weight of evidence
“A limited toxicological program has been performed with Gardasil. There are no toxicological concerns arising from the non-clinical studies with the vaccine.”
OtherVerdict not stated
Autoimmunity from cross-reactive antibodies not assessed in animals
Why: Not readily studied in animal models; can only be studied clinically · Human data
“Theoretically, the vaccine could give rise to antibodies, which cross-react to self-structures, resulting in autoimmune events. Such possibility is not readily studied in experimental animal models, but can only be studied in the clinical situation.”
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 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
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