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
Shingrix: what flexibility did regulators accept, and why?
zoster vaccine recombinant, AS01B-adjuvanted · VZV glycoprotein E; TLR4 (AS01B adjuvant)
Flexibility accepted
DARTCriticised but acceptedBeyond the letter
Vaccine DART only in rats at 40% of the human dose; no full-human-dose rabbit study
Why: Rabbit full-dose study only considered warranted if recommended for females of child bearing age · Other reason
“Treatment of female CD rats with the candidate vaccine at 40% of the full human dose per occasion was well tolerated, did not lead to maternal toxicity, and did not adversely affect embryo-fetal or pre- and post-natal survival, growth or development of the offspring.”
“Since Shingrix has been shown to induce significant systemic reactogenicity not only in rabbits (CRP increase, maternal toxicity) but also in humans (fatigue, headache, myalgia and shivering) which could adversely affect pregnancy outcomes, it might be warranted to evaluate a full human dose of the vaccine in a reproductive-developmental toxicity study in rabbits if this vaccine is recommended for females of child bearing age.”
SpeciesAccepted
Vaccine repeat-dose toxicity in one relevant species (rabbit)
Why: Conducted per WHO and EMA guidelines: full human dose, more doses than clinical, clinical route · Within the guideline
“Repeated dose toxicity has thus been evaluated in one relevant animal species (rabbits) and the studies have been conducted according to the relevant WHO and EMA guidelines, including recommendations on dose (full human dose), number of doses (exceeding proposed number in the clinic) and of route of administration (IM is proposed route of administration for licensure).”
Safety pharmacologyAccepted
Vaccine cardiovascular safety pharmacology in rat, not an appropriate QT species per ICH S7B
Why: Justification no longer needed given the pivotal conscious dog study · Within the guideline · Weight of evidence
“Previous CHMP scientific advice pointed out that a justification for the choice of the rat should be provided as according to ICH S7B the rat is not considered being an appropriate species for investigation for the potential to prolong the QT interval (the ionic mechanisms of repolarization in adult rats and mice differ from larger species). This is no longer needed in view of the pivotal dog study.”
OtherAccepted
No toxicokinetic data
Why: Circulating antigen levels not required for vaccines (WHO adjuvant guideline) · Within the guideline
“Toxicokinetic data were not generated since the determination of circulating levels of antigens is not required for vaccines. This is in line with the Guideline on the nonclinical evaluation of vaccine adjuvants and adjuvanted vaccines (WHO, 2013). The absence of toxicokinetic data is considered acceptable.”
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
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