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 9: what flexibility did regulators accept, and why?
human papillomavirus 9-valent vaccine, recombinant · HPV 9-valent L1 VLPs
Flexibility accepted
Safety pharmacologyAccepted
No safety pharmacology study
Why: WHO vaccine guidance; no CNS, respiratory, cardiovascular or renal signs in nonclinical or clinical studies · Within the guideline · Human data
“Therefore, given that there were no signs of CNS, respiratory, cardiovascular and renal effects for the 9vHPV vaccine, a nonclinical safety pharmacology study was deemed to be not necessary for the 9vHPV vaccine. This was found acceptable by the CHMP under the current requirements.”
“This is in accordance with the WHO Guidelines on the Nonclinical Evaluation of Vaccines, which suggests that safety pharmacology tests for vaccines should be performed only if data from nonclinical and/or human clinical studies suggest that the vaccine may affect physiological functions (central nervous system (CNS), respiratory, cardiovascular, and renal functions) other than the immune system.”
OtherVerdict not stated
AAHS adjuvant not tested alone
Why: Adjuvant used in several other Merck vaccines with an established safety profile · Class precedent
“Toxicology studies of AAHS alone were not performed because this adjuvant has been used before in several other Merck vaccines and has an established safety profile.”
RecoveryCriticised but acceptedBeyond the letter
21-day recovery too short to show recovery of injection-site inflammation and lymph node hyperplasia at the higher alum content
Why: No myofibre degeneration and reduced inflammation at end of recovery suggest ongoing resolution · Weight of evidence
“Given a total amount of 500 µg Alum within the 9vHPV vaccine formulation (instead of 225 µg in GARDASIL), a 21-day recovery period appears not sufficiently long to allow detection of fully or partial recovery of the effect when evaluated by muscle inflammation and lymph node hyperplasia.”
“Nonetheless, absence of myofiber degeneration and reduced severity of inflammation at the end of recovery suggest ongoing resolution of the skeletal muscle changes.”
SpeciesAcceptedBeyond the letter
All toxicology studies in one species (rat); safety assessment leans on the 4-valent Gardasil database
Why: Large safety database for the 4-valent vaccine; no important difference in safety anticipated · Class precedent · Human data
“Non-clinical toxicological testing of the 9vHPV vaccine includes 3 GLP-compliant studies in Sprague-Dawley rats, consisting of a repeat-dose toxicity study (complete toxicity with local tolerance and non-GLP immunogenicity assessments), a female fertility and embryo-foetal developmental toxicity study, and a postnatal developmental toxicity study.”
“Of much more importance for the safety assessment is the large safety database available for the 4-valent vaccine (Gardasil). Based on the similarities between the vaccines, no important difference in safety is anticipated.”
OtherVerdict not stated
Autoimmunity risk from lymphoid stimulation not characterisable in animals; deferred to post-marketing in humans
Why: Can only be characterised in the post-marketing setting in humans · Human data
“Theoretically, lymphoid stimulatory effect seen in repeat-dose toxicity study might cause/exacerbate autoimmune diseases, but such a risk can only be characterized in post-marketing setting in humans.”
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
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