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
Cervarix: what flexibility did regulators accept, and why?
human papillomavirus bivalent (types 16, 18) vaccine, recombinant, AS04-adjuvanted · HPV 16/18 L1 VLPs; TLR4 (AS04 adjuvant)
Flexibility accepted
CarcinogenicityAccepted
No genotoxicity or carcinogenicity studies with the vaccine (MPL adjuvant genotoxicity tested only)
Why: L1 protein vaccine without HPV oncoproteins; not usually required for recombinant protein vaccines (WHO) · Within the guideline · Low-risk modality
“The mutagenic and carcinogenic potential of the Cervarix vaccine was not further evaluated, which is accepted since the vaccine is based on L1 protein and HPV oncoproteins are absent.”
“The genotoxic and oncogenic potential of Cervarix were not evaluated. Such studies are not usually required for recombinant protein vaccines, consistent with WHO guidelines on vaccine nonclinical safety evaluation.”
OtherCriticised but acceptedBeyond the letter
MPL-alone repeat-dose toxicity only from short intravenous studies done before Cervarix development, not by the intramuscular clinical route
Why: MPL adsorbed to aluminium has an acceptable safety margin at the proposed dose, route and regimen · Pharmacology or kinetics
“While the repeat-dose toxicity studies of MPL were performed following intravenous administrations of MPL, they can be viewed as providing limited supportive toxicity information for administration of MPL via the intramuscular (IM) route of administration intended for Cervarix.”
“Overall, these data indicate that MPL adsorbed to aluminum hydroxide, as it exists in Cervarix, the product described in Biologics License Application (BLA) STN 125259, is suitable as a human vaccine adjuvant at the proposed dosage and formulation, as it appears to have an acceptable safety margin, especially when administered by the proposed route of administration and dosing regimen.”
DARTVerdict not stated
Ventricular septal defects in rat vaccine/AS04 DART and rabbit MPL studies above historical controls; treatment relation unclear
Why: Sponsor attributes defects to spontaneous delay in normal development
“However, concerning is that the incidence of ventricular septal defect in both studies is higher than in the historical control and did not occur in concurrent control groups.”
“Sponsor concludes that the incidence of IVSD in rats and rabbits in studies -b(4)-249 and --b(4)-- 1729/8 is of spontaneous nature. Sponsor attributes the occurrence of membranous intraventricular septal defects to a delay in normal development that will close with further normal development.”
Same question, other vaccines
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
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