Gardasil 9
human papillomavirus 9-valent vaccine, recombinant
Species
Rat
Longest study
13 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
Rat only (repeat-dose, fertility/embryo-foetal and postnatal studies)
“Toxicology studies supporting the safety of the 9vHPV vaccine included 3 GLP-compliant studies in rats consisting of: i) a repeat-dose toxicity study (with local tolerance and non-GLP immunogenicity assessments), ii) an intramuscular developmental toxicity and immunogenicity study with female fertility and embryo-foetal evaluation and iii) an intramuscular developmental toxicity and immunogenicity study with postnatal evaluation.”
Why that species
Rat immunogenic: humoral responses to all 9 HPV types at all dose levels in the toxicity study
“the 9vHPV vaccine induced humoral immune responses against all 9 HPV serotypes (HPV Type 6, -11, -16, -18, -33, -31, -45, -52, and -58) following one or four intramuscular injections to rats at all dose levels, as a pharmacological effect.”
Surrogate molecule
No surrogate; Gardasil 9 itself tested in all three GLP studies
“The nonclinical toxicology of Gardasil 9 was evaluated in 3 studies, all carried out under GLP-compliant conditions.”
Species: general tox
Rat
“Toxicology studies supporting the safety of the 9vHPV vaccine included 3 GLP-compliant studies in rats consisting of: i) a repeat-dose toxicity study (with local tolerance and non-GLP immunogenicity assessments), ii) an intramuscular developmental toxicity and immunogenicity study with female fertility and embryo-foetal evaluation and iii) an intramuscular developmental toxicity and immunogenicity study with postnatal evaluation.”
Species: DART
Rat (female fertility/embryo-foetal and postnatal development)
“The reproductive and developmental toxicity of the 9vHPV vaccine was assessed in two GLP-compliant studies using female rats.”
Species: carcinogenicity
Not conducted
“The oncogenic/carcinogenic potential of the 9vHPV vaccine in long and short-term studies was not evaluated. According to current requirements as mentioned above, carcinogenicity studies are generally not required for vaccines and this is acceptable also for Gardasil 9.”
Surrogate used in
No surrogate used; Gardasil 9 tested directly
“The nonclinical toxicology of Gardasil 9 was evaluated in 3 studies, all carried out under GLP-compliant conditions.”
Study lengthopen answer page →
Longest pivotal study
13 (rat, IM, 4 doses every 21 days)
“A recovery group consisting of 10 males and 10 females rats per group were sacrificed 21 days after the interim necropsy (day 67). Study duration was 13 weeks.”
Pivotal GLP studies
13-week IM rat repeat-dose (with local tolerance); rat fertility/embryo-foetal study; rat postnatal developmental study
“Toxicology studies supporting the safety of the 9vHPV vaccine included 3 GLP-compliant studies in rats consisting of: i) a repeat-dose toxicity study (with local tolerance and non-GLP immunogenicity assessments), ii) an intramuscular developmental toxicity and immunogenicity study with female fertility and embryo-foetal evaluation and iii) an intramuscular developmental toxicity and immunogenicity study with postnatal evaluation.”
Route in tox
Intramuscular (quadriceps)
“Route and site of administration: Intramuscular (into each quadriceps) administration.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (vaccine guidance; CHMP agreed)
“The in vitro and in vivo genetic toxicity/mutagenic potential of the 9vHPV vaccine were not evaluated.”
Carcinogenicity
Not conducted (not required for vaccines)
“The oncogenic/carcinogenic potential of the 9vHPV vaccine in long and short-term studies was not evaluated. According to current requirements as mentioned above, carcinogenicity studies are generally not required for vaccines and this is acceptable also for Gardasil 9.”
Reproductive & developmental
Two GLP rat studies (fertility/EFD and postnatal); no adverse effects; up to 240 and 160 times human dose (mg/kg)
“Reproduction studies have been performed in rats at doses up to 240 and 160 times the human dose on mg/kg basis and revealed no evidence of impaired fertility or harm to the fetus due to V503 vaccine.”
Safety pharmacology
Not conducted; no CNS, respiratory, cardiovascular or renal signs in toxicity or clinical studies (CHMP accepted)
“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.”
Genotox: Ames
Not conducted (vaccine)
“No studies have been performed in animals to evaluate the carcinogenic potential and the genotoxic risk of V503 vaccine.”
Genotox: in vitro mammalian
Not conducted (vaccine)
“No studies have been performed in animals to evaluate the carcinogenic potential and the genotoxic risk of V503 vaccine.”
Genotox: in vivo
Not conducted (vaccine)
“No studies have been performed in animals to evaluate the carcinogenic potential and the genotoxic risk of V503 vaccine.”
Carcinogenicity model
Not conducted (not required for vaccines)
“The oncogenic/carcinogenic potential of the 9vHPV vaccine in long and short-term studies was not evaluated. According to current requirements as mentioned above, carcinogenicity studies are generally not required for vaccines and this is acceptable also for Gardasil 9.”
Carcinogenicity timing
Not required for vaccines
“The oncogenic/carcinogenic potential of the 9vHPV vaccine in long and short-term studies was not evaluated. According to current requirements as mentioned above, carcinogenicity studies are generally not required for vaccines and this is acceptable also for Gardasil 9.”
hERG / QT
Safety pharmacology not conducted
“Safety pharmacology studies were not performed for the 9vHPV vaccine.”
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 9 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 NOAEL stated; only immune-response and injection-site effects in rats (EMA assessment report, p. 24)
NOAEL / key findings
No NOAEL stated; only immune-response and injection-site effects in rats
“The only treatment-related effects were indicative of the immune response and injection site reactions.”
Risksopen answer page →
Immune & cytokine safety
Transient spleen weight increase from immune stimulation; theoretical autoimmunity risk left to post-marketing
“The increase in splenic weights was considered an expected secondary effect to the stimulation of the immune system by vaccination and was converted to normal range following a 21-day recovery. Theoretically, immune stimulation holds a risk of causing/exacerbating autoimmune diseases, but such a risk can only be characterized in post-marketing settings.”
Biodistribution & persistence
No ADME studies (vaccine guidance; acceptable)
“No studies on absorption, distribution, metabolism or excretion were performed. This is in line with the CHMP Note for Guidance on Preclinical Pharmacological and Toxicological Testing of Vaccines and is therefore acceptable.”
Modality-specific risk
Adjuvant-driven injection-site inflammation and lymph node hyperplasia; 500 µg alum versus 225 µg in Gardasil
“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.”
Anti-drug antibodies: animals
Immune response in all vaccine-treated rats, confirming exposure
“Serology testing showed an immune response in all vaccine recipient animals.”
Anti-drug antibodies: patients
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.
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 9 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 NOAEL stated; only immune-response and injection-site effects in rats (EMA assessment report, p. 24)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week IM rat study (4 doses every 21 days) with 21-day recovery
“A recovery group consisting of 10 males and 10 females rats per group were sacrificed 21 days after the interim necropsy (day 67). Study duration was 13 weeks.”
Pivotal GLP studies
13-week IM rat repeat-dose (with local tolerance); rat fertility/embryo-foetal study; rat postnatal developmental study
“Toxicology studies supporting the safety of the 9vHPV vaccine included 3 GLP-compliant studies in rats consisting of: i) a repeat-dose toxicity study (with local tolerance and non-GLP immunogenicity assessments), ii) an intramuscular developmental toxicity and immunogenicity study with female fertility and embryo-foetal evaluation and iii) an intramuscular developmental toxicity and immunogenicity study with postnatal evaluation.”
DART package
Species: DART
Rat (female fertility/embryo-foetal and postnatal development)
“The reproductive and developmental toxicity of the 9vHPV vaccine was assessed in two GLP-compliant studies using female rats.”
Reproductive & developmental
Two GLP rat studies (fertility/EFD and postnatal); no adverse effects; up to 240 and 160 times human dose (mg/kg)
“Reproduction studies have been performed in rats at doses up to 240 and 160 times the human dose on mg/kg basis and revealed no evidence of impaired fertility or harm to the fetus due to V503 vaccine.”
PPND / ePPND: when
Rat postnatal developmental study (dosing to lactation day 7) completed before the marketing application
“In the second developmental toxicity study, female rats (F0) received 0.5 mL (0.25 mL administered to each quadriceps muscle) intramuscular injection with 9vHPV vaccine on 4 occasions (Premating Week -5 and -2 plus GD 6 and LD 7).”
Carcinogenicity
Species: carcinogenicity
Not conducted
“The oncogenic/carcinogenic potential of the 9vHPV vaccine in long and short-term studies was not evaluated. According to current requirements as mentioned above, carcinogenicity studies are generally not required for vaccines and this is acceptable also for Gardasil 9.”
Carcinogenicity model
Not conducted (not required for vaccines)
“The oncogenic/carcinogenic potential of the 9vHPV vaccine in long and short-term studies was not evaluated. According to current requirements as mentioned above, carcinogenicity studies are generally not required for vaccines and this is acceptable also for Gardasil 9.”
Carcinogenicity timing
Not required for vaccines
“The oncogenic/carcinogenic potential of the 9vHPV vaccine in long and short-term studies was not evaluated. According to current requirements as mentioned above, carcinogenicity studies are generally not required for vaccines and this is acceptable also for Gardasil 9.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat reproduction studies: up to 240 and 160 times the human dose (mg/kg) without fertility or fetal effects
“Reproduction studies have been performed in rats at doses up to 240 and 160 times the human dose on mg/kg basis and revealed no evidence of impaired fertility or harm to the fetus due to V503 vaccine.”
NOAEL / key findings
No NOAEL stated; only immune-response and injection-site effects in rats
“The only treatment-related effects were indicative of the immune response and injection site reactions.”
Efficacy evidenceopen answer page →
Efficacy evidence
Immunogenicity in rhesus macaques (non-GLP): antibodies to all 9 HPV types; no protection model
“The vaccine elicited a robust immune response in all the animals resulting in the production of antibodies against each of the nine HPV types (6, 11, 16, 18, 31, 33, 45, 52 and 58) present in the vaccine.”
Why that model
No animal model of human papillomavirus infection, so protection could not be tested
“There is no animal model for human papilloma virus infection. Therefore, the vaccine could not be tested for protection in animals.”
Reviewer's view of the efficacy data
Primate immunogenicity against all 9 types supported clinical development
“The immunogenicity study PD001 in non-human primates demonstrated immunogenicity against all 9 HPV types and supported the clinical development of the product.”
Flexibilityopen answer page →
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.”
Similar precedents
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