Gardasil
human papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant
Sources:EMA assessment report ↗
Species
RatMouseRabbit
Longest study
10 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse (repeat-dose), mouse and rat (single-dose), rat (DART), rabbit (local tolerance)
“A 10-week repeat-dose toxicity study was performed in BALB/c mice.”
Why that species
Rat chosen for DART after exploratory studies showed antibody responses to each vaccine HPV type
“In both exploratory studies, it was demonstrated that the vaccine was immunogenic in rats and that an anti-HPV antibody response was seen for each HPV type present in the vaccine. These results show that the rat is an appropriate animal model for investigating the potential toxic effects related to administration of Gardasil.”
Surrogate molecule
No surrogate; vaccine made by the same process as clinical GMP lots
“The monovalent L1 VLP and quadrivalent Gardasil vaccine formulations tested in these studies were made by the same manufacturing process as the GMP lots and are, therefore, similar to lots that were used in the clinic.”
Species: general tox
Mouse (BALB/c)
“A 10-week repeat-dose toxicity study was performed in BALB/c mice.”
Species: DART
Rat (female Sprague-Dawley; all phases of reproduction and development)
“The reproductive and developmental toxicity was assessed in a study in female Sprague-Dawley rats addressing all phases of reproduction and foetal development. An immune response to the vaccine was observed, and antibodies were shown to be transferred to the offspring during gestation and also lactation.”
Species: carcinogenicity
Not conducted
“No carcinogenicity studies were conducted, and this is in line with CPMP/SWP/465/95.”
Surrogate used in
Yes: published species-specific papillomavirus VLP vaccination models (CRPV, COPV) underpin the efficacy concept
“These studies with species-specific papillomaviruses have demonstrated the possibility to vaccinate against infection and development of tumour lesions using virus-like particles formed by recombinant viral capsid proteins (Breitburd et al 1995, Jansen et al 1995, Suzich et al 1995) and have been used as models for vaccine development.”
Study lengthopen answer page →
Longest pivotal study
10 (BALB/c mouse)
“A 10-week repeat-dose toxicity study was performed in BALB/c mice.”
Pivotal GLP studies
10-week IM repeat-dose study in BALB/c mice (1 or 3 doses); single-dose mouse and rat; rat DART; rabbit local tolerance
“A 10-week repeat-dose toxicity study was performed in BALB/c mice. Vaccine-treated mice received 1 or 3 doses of Gardasil at a concentration of 160/160/80/160 μg/ml of the HPV types 6/11/16/18 L1 VLPs.”
Route in tox
Intramuscular
“Local tolerance was assessed by intramuscular administration of the vaccine in rabbits.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (CPMP/SWP/465/95 vaccine guidance)
“No genotoxicity studies were conducted, and this is in line with CPMP/SWP/465/95.”
Carcinogenicity
Not conducted (CPMP/SWP/465/95 vaccine guidance)
“No carcinogenicity studies were conducted, and this is in line with CPMP/SWP/465/95.”
Reproductive & developmental
Female rat study covering all phases of reproduction and development; maternal antibodies transferred to offspring
“The reproductive and developmental toxicity was assessed in a study in female Sprague-Dawley rats addressing all phases of reproduction and foetal development. An immune response to the vaccine was observed, and antibodies were shown to be transferred to the offspring during gestation and also lactation.”
Safety pharmacology
Not performed; physical signs monitored in toxicity studies (vaccine guidance)
“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).”
Genotox: Ames
Not conducted (vaccine guidance)
“No genotoxicity studies were conducted, and this is in line with CPMP/SWP/465/95.”
Genotox: in vitro mammalian
Not conducted (vaccine guidance)
“No genotoxicity studies were conducted, and this is in line with CPMP/SWP/465/95.”
Genotox: in vivo
Not conducted (vaccine guidance)
“No genotoxicity studies were conducted, and this is in line with CPMP/SWP/465/95.”
Carcinogenicity model
Not conducted (CPMP/SWP/465/95 vaccine guidance)
“No carcinogenicity studies were conducted, and this is in line with CPMP/SWP/465/95.”
Carcinogenicity timing
Not required under vaccine guidance (CPMP/SWP/465/95)
“No carcinogenicity studies were conducted, and this is in line with CPMP/SWP/465/95.”
hERG / QT
Safety pharmacology not performed; no notable respiratory findings in toxicity studies
“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).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Gardasil don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology vaccines (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: No systemic toxicity; iliac lymph node enlargement/hyperplasia and injection-site inflammation in mice (EMA assessment report, p. 8)
NOAEL / key findings
No systemic toxicity; iliac lymph node enlargement/hyperplasia and injection-site inflammation in mice
“There was a treatment-related enlargement of the iliac lymph nodes. Treatment-related microscopic changes were noted in lymph nodes (hyperplasia) and in the muscle at the injection sites (inflammation).”
Risksopen answer page →
Immune & cytokine safety
Theoretical autoimmunity from cross-reactive antibodies, not readily studied in animals; left to clinical assessment
“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.”
Biodistribution & persistence
ADME studies not performed (vaccine guidance)
“Experimental studies to demonstrate absorption, distribution, metabolism, and excretion of the active ingredients in Gardasil have not been performed for any of the component viruses. This is in line with Note for guidance on preclinical pharmacological and toxicological testing of vaccines (CPMP/SWP/465/95).”
Modality-specific risk
Injection-site reactogenicity: minimal irritation in rabbits, similar to aluminium adjuvant placebo
“Intramuscular administration of Gardasil caused minimal irritation at injection site and the changes observed were similar in severity to those produced by the injection of the Merck aluminium adjuvant as placebo control.”
Anti-drug antibodies: animals
All rats mounted antibody responses to all 4 HPV VLP types, confirming exposure
“There were no deaths or treatment-related physical signs during the study. All animals mounted specific antibody responses to all 4 HPV VLPs.”
Anti-drug antibodies: patients
Monovalent precursor vaccine: 90-100% of subjects reached the pre-specified cRIA level 4 weeks post dose 3
“The vaccine proved immunogenic with 90-100% of subjects reaching the pre-specified cRIA level of >200 mMU/ml 4 weeks postdose 3.”
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Gardasil don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology vaccines (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: No systemic toxicity; iliac lymph node enlargement/hyperplasia and injection-site inflammation in mice (EMA assessment report, p. 8)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
10-week IM BALB/c mouse study (1 or 3 doses); recovery phase not stated
“A 10-week repeat-dose toxicity study was performed in BALB/c mice. Vaccine-treated mice received 1 or 3 doses of Gardasil at a concentration of 160/160/80/160 μg/ml of the HPV types 6/11/16/18 L1 VLPs.”
Pivotal GLP studies
10-week IM repeat-dose study in BALB/c mice (1 or 3 doses); single-dose mouse and rat; rat DART; rabbit local tolerance
“A 10-week repeat-dose toxicity study was performed in BALB/c mice. Vaccine-treated mice received 1 or 3 doses of Gardasil at a concentration of 160/160/80/160 μg/ml of the HPV types 6/11/16/18 L1 VLPs.”
DART package
Species: DART
Rat (female Sprague-Dawley; all phases of reproduction and development)
“The reproductive and developmental toxicity was assessed in a study in female Sprague-Dawley rats addressing all phases of reproduction and foetal development. An immune response to the vaccine was observed, and antibodies were shown to be transferred to the offspring during gestation and also lactation.”
Reproductive & developmental
Female rat study covering all phases of reproduction and development; maternal antibodies transferred to offspring
“The reproductive and developmental toxicity was assessed in a study in female Sprague-Dawley rats addressing all phases of reproduction and foetal development. An immune response to the vaccine was observed, and antibodies were shown to be transferred to the offspring during gestation and also lactation.”
PPND / ePPND: when
Rat reproductive and developmental study covering all phases (including lactation) completed before the marketing application
“The reproductive and developmental toxicity was assessed in a study in female Sprague-Dawley rats addressing all phases of reproduction and foetal development. An immune response to the vaccine was observed, and antibodies were shown to be transferred to the offspring during gestation and also lactation.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity studies were conducted, and this is in line with CPMP/SWP/465/95.”
Carcinogenicity model
Not conducted (CPMP/SWP/465/95 vaccine guidance)
“No carcinogenicity studies were conducted, and this is in line with CPMP/SWP/465/95.”
Carcinogenicity timing
Not required under vaccine guidance (CPMP/SWP/465/95)
“No carcinogenicity studies were conducted, and this is in line with CPMP/SWP/465/95.”
Safety marginopen answer page →
Safety margin at NOAEL
Mouse repeat-dose: ~1450-fold the projected human dose on a body weight basis
“On a body weight basis, the dose of the vaccine administered to mice was approximately 1450-fold the projected human dose.”
NOAEL / key findings
No systemic toxicity; iliac lymph node enlargement/hyperplasia and injection-site inflammation in mice
“There was a treatment-related enlargement of the iliac lymph nodes. Treatment-related microscopic changes were noted in lymph nodes (hyperplasia) and in the muscle at the injection sites (inflammation).”
Efficacy evidenceopen answer page →
Efficacy evidence
Immunogenicity in rhesus macaques, chimpanzees and African green monkeys; neutralising antibodies; no HPV challenge model
“In each of the 3 non-human primate species tested, the intramuscular administration of Gardasil, or it’s monovalent components, was found to elicit immune responses resulting in production of antibodies against the HPV VLP types present in the vaccine.”
Why that model
No animal model of human papillomavirus infection; species-specific papillomaviruses used instead
“There is no animal model for human papillomavirus infection, however there are other species-specific papillomaviruses that have been studied in animal models.”
Reviewer's view of the efficacy data
Species-specific models support vaccination; serum transfer of protection suggests humoral-mediated efficacy
“Studies in animal models with species-specific papillomaviruses have demonstrated the possibility to vaccinate against infection and development of tumour lesions using virus-like particles formed by recombinant viral capsid proteins. Protection could be transferred with serum, suggesting that the efficacy of Gardasil is mediated by development of humoral immune response.”
Flexibilityopen answer page →
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.”
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