Cervarix
human papillomavirus bivalent (types 16, 18) vaccine, recombinant, AS04-adjuvanted
Species
RatDogRabbit
Longest study
8 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rabbit (four repeat-dose studies) and rat (one repeat-dose, DART, safety pharmacology); dog for MPL alone
“Four repeated-dose toxicity studies were carried out in rabbits and one in rats.”
Why that species
Rat for DART: predictor of reproductive toxicity and regulatory rodent requirement
“Animal model: As stated by the sponsor, the rat was chosen “because of its use as a predictor of reproductive toxic change in man and the requirement for a rodent species by regulatory agencies.”
Surrogate molecule
No surrogate; toxicity materials comparable in purity to clinical and commercial lots
“Materials used in the non-clinical safety pharmacology, pharmacokinetics and toxicological studies overall had comparable purity levels as the materials used for clinical studies and the materials proposed for marketing.”
Species: general tox
Rabbit (four studies) and rat (one study)
“Four repeated-dose toxicity studies were carried out in rabbits and one in rats.”
Species: DART
Rat (fertility, embryo-fetal, peri/postnatal; vaccine and AS04 alone)
“The reproductive and developmental toxicity of Cervarix and the AS04 adjuvant alone was assessed in a study in female rats of the CD strain. The influence of Cervarix on fertility, embryo-fetal, peri-natal and post-natal survival and development was examined.”
Species: carcinogenicity
Not conducted
“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.”
Surrogate used in
No surrogate used; vaccine, AS04 and MPL tested directly
“Pharmacological and toxicological studies were performed on HPV-16/18 L1 VLP AS04, AS04 as well as on MPL.”
Study lengthopen answer page →
Longest pivotal study
8 (rabbit IM, 4 injections days 1-57, plus 13-week recovery)
“and included a 13-week recovery period. Animals were allocated randomly to 4 groups of 10 animals each, and received intramuscular injections in the paravertebral muscles on Days 1, 15, 29 and 57.”
Pivotal GLP studies
Rabbit IM repeat-dose (up to 4 injections at 2-week intervals, up to 3x human dose); rat DART; rat safety pharmacology
“The treatment regimen of up to 4 vaccine injections at 2 week intervals with up to three times the human dosage exceeds the total number of intended clinical injections.”
Route in tox
Intramuscular (vaccine and AS04); intravenous and subcutaneous for MPL-alone studies
“Repeated-dose toxicity studies have been performed with Cervarix and AS04 (intramuscular administration in rabbits).”
Skipped studiesopen answer page →
Genotoxicity
Vaccine not tested; MPL adjuvant negative in Ames, CHO clastogenicity and in vivo micronucleus
“The in vitro mutagenicity (Ames) and clastogenicity (CHO cells) tests, and in vivo micronucleus assay demonstrated no genotoxic potential of the MPL adjuvant.”
Carcinogenicity
Not conducted; accepted as the vaccine is L1 protein without HPV oncoproteins
“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.”
Reproductive & developmental
Rat combined fertility, embryo-fetal and pre/postnatal study with vaccine and AS04: no effects
“The reproductive toxicity study in CD rats did not show any effects of vaccination or AS04 administration on fertility, embryofoetal development and pre- and post-natal development.”
Safety pharmacology
Dedicated studies: vaccine in anaesthetised rats, MPL in dogs; no cardiovascular or respiratory effects
“Safety pharmacology studies were performed on HPV-16/18 L1 VLP AS04 in rats and on MPL in dogs.”
Genotox: Ames
MPL adjuvant: Ames negative (vaccine not tested)
“The in vitro mutagenicity (Ames) and clastogenicity (CHO cells) tests, and in vivo micronucleus assay demonstrated no genotoxic potential of the MPL adjuvant.”
Genotox: in vitro mammalian
MPL adjuvant: chromosomal aberration (CHO cells) negative
“The in vitro mutagenicity (Ames) and clastogenicity (CHO cells) tests, and in vivo micronucleus assay demonstrated no genotoxic potential of the MPL adjuvant.”
Genotox: in vivo
MPL adjuvant: in vivo micronucleus negative
“The in vitro mutagenicity (Ames) and clastogenicity (CHO cells) tests, and in vivo micronucleus assay demonstrated no genotoxic potential of the MPL adjuvant.”
Carcinogenicity model
Not conducted (L1 protein vaccine without HPV oncoproteins)
“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.”
Carcinogenicity timing
Not required (L1 protein vaccine without HPV oncoproteins)
“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.”
hERG / QT
No effects on blood pressure, heart rate, ECG or respiration in anaesthetised rats
“Intramuscular administration of 0.1ml/animal of the HPV-16/18 L1 VLP AS04 vaccine did not produce any treatment-related effects on blood pressure, heart rate, ECG (lead II) or respiration depth and rate”
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 Cervarix 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; vaccine and AS04 well tolerated with no consistent systemic findings in rabbits (EMA assessment report, p. 11)
NOAEL / key findings
No NOAEL stated; vaccine and AS04 well tolerated with no consistent systemic findings in rabbits
“The HPV-16 /18 L1 VLP AS04 vaccine and the AS04 adjuvant were well tolerated. The organ-weight data, macroscopic pathology evaluation, and evaluation of systemic effects showed no consistent treatment-related findings.”
Risksopen answer page →
Immune & cytokine safety
No neurological, immunological or autoimmune adverse reactions in MPL-containing preclinical studies (FDA concurred)
“GSK’s 3rd table in their response lists the preclinical studies conducted with vaccine formulations containing MPL. GSK concluded that none of these studies show evidence of adverse neurological, immunological or autoimmune-based (AID) reactions.”
Biodistribution & persistence
Radiolabelled MPL in rat widely distributed (fat, spleen), likely eliminated via expired air; no vaccine ADME
“In conclusion the pharmacokinetic studies conducted in rats have shown that MPL-related material is widely distributed throughout the body, notably to the fat and spleen, and is then likely eliminated mainly via the expired air, with only low levels of radioactivity remaining in the carcass.”
Modality-specific risk
TLR4-agonist adjuvant (AS04/MPL): strong local inflammatory reaction at the injection site, amplified by up to 3x human dose
“This local effect is most likely the sign of the strong adjuvant effect induced by AS04. Furthermore, up to three times the full human dosage was used in the rabbit studies, probably amplifying this local reaction.”
Anti-drug antibodies: animals
Immune response in vaccinated rats; antibodies transferred to offspring in gestation and lactation
“An immune response to the vaccine was observed, and antibodies were transferred to the offspring during gestation and also during lactation.”
Anti-drug antibodies: patients
99.9% of initially seronegative subjects seroconverted to HPV 16 and 18 one month after the third dose
“In clinical trials assessing immunogenicity, 99.9% of initially seronegative subjects had seroconverted to both HPV types 16 and 18 one month after the third dose.”
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 Cervarix 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; vaccine and AS04 well tolerated with no consistent systemic findings in rabbits (EMA assessment report, p. 11)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Rabbit IM repeat-dose, 4 injections (days 1, 15, 29, 57), with 13-week recovery
“and included a 13-week recovery period. Animals were allocated randomly to 4 groups of 10 animals each, and received intramuscular injections in the paravertebral muscles on Days 1, 15, 29 and 57.”
Pivotal GLP studies
Rabbit IM repeat-dose (up to 4 injections at 2-week intervals, up to 3x human dose); rat DART; rat safety pharmacology
“The treatment regimen of up to 4 vaccine injections at 2 week intervals with up to three times the human dosage exceeds the total number of intended clinical injections.”
DART package
Species: DART
Rat (fertility, embryo-fetal, peri/postnatal; vaccine and AS04 alone)
“The reproductive and developmental toxicity of Cervarix and the AS04 adjuvant alone was assessed in a study in female rats of the CD strain. The influence of Cervarix on fertility, embryo-fetal, peri-natal and post-natal survival and development was examined.”
Reproductive & developmental
Rat combined fertility, embryo-fetal and pre/postnatal study with vaccine and AS04: no effects
“The reproductive toxicity study in CD rats did not show any effects of vaccination or AS04 administration on fertility, embryofoetal development and pre- and post-natal development.”
PPND / ePPND: when
Rat pre- and postnatal study with fertility assessment completed before the marketing application (protocol to IND in 2002)
“For this purpose, a pre- and post-natal toxicity study in rats, including an assessment of the potential impact of vaccination on fertility was performed. The protocol for the investigation was submitted to IND -(b)(4)- (Serial No. 0065, December 9, 2002).”
Carcinogenicity
Species: carcinogenicity
Not conducted
“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.”
Carcinogenicity model
Not conducted (L1 protein vaccine without HPV oncoproteins)
“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.”
Carcinogenicity timing
Not required (L1 protein vaccine without HPV oncoproteins)
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
No adverse systemic effects at dosages up to more than 50-fold the human dose (body weight basis)
“No other vaccine- or adjuvant-associated adverse systemic effect was noted, even though the studied dosages exceeded the human dosage (up to more than 50-fold factor on a body weight basis), as well as the immunization schedule.”
NOAEL / key findings
No NOAEL stated; vaccine and AS04 well tolerated with no consistent systemic findings in rabbits
“The HPV-16 /18 L1 VLP AS04 vaccine and the AS04 adjuvant were well tolerated. The organ-weight data, macroscopic pathology evaluation, and evaluation of systemic effects showed no consistent treatment-related findings.”
Efficacy evidenceopen answer page →
Efficacy evidence
Immunogenicity in mice and rhesus monkeys (AS04 superior to aluminium alone); no protection model
“Primary pharmacodynamic studies in mice and monkeys show that the activation of the innate immunity by AS04 is paralleled by the induction of a strong and persistent specific immune response by the Cervarix vaccine.”
Why that model
HPV species specificity precludes animal protection models
“Given the species specificity of HPV precluding the evaluation of any human HPV-16/18 vaccine in protection animal models, primary pharmacodynamic studies aimed at the preclinical evaluation of the immunogenicity of the HPV-16/18 L1 VLP AS04 vaccine were carried out in mice and Rhesus monkeys.”
Reviewer's view of the efficacy data
No animal model exists, so Cervarix was not tested for protection
“No animal model exists for human papilloma virus infection. Consequently Cervarix has not been tested for protection.”
Flexibilityopen answer page →
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.”
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