Shingrix
zoster vaccine recombinant, AS01B-adjuvanted
Species
RatRabbit
Longest study
12 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 and rabbit
“Most studies were done in rat and rabbit, as both species demonstrated a good antibody response.”
Why that species
Both rat and rabbit mount a good antibody response to the vaccine
“Most studies were done in rat and rabbit, as both species demonstrated a good antibody response.”
Surrogate molecule
No surrogate; gE/AS01B vaccine, AS01 adjuvant system and QS-21/MPL tested directly
“Nonclinical studies were performed with the gE/AS01B candidate vaccine formulation, the AS01 adjuvant system and its immunoenhancers QS-21 and MPL.”
Species: general tox
Rabbit (vaccine; one relevant species)
“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).”
Species: DART
Rat (vaccine: pre/postnatal and male fertility); rat and rabbit EFD for QS-21 and MPL
“gE/AS01B and AS01B reproductive toxicity was assessed in two studies both performed in rats, one covering pre-, peri- and post-natal development and one covering male fertility.”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies were not performed. As carcinogenicity studies are not required for final vaccine formulations, adjuvants systems and/or immunoenhancers based on current guidelines, this was considered acceptable.”
Surrogate used in
No surrogate used
“Nonclinical studies were performed with the gE/AS01B candidate vaccine formulation, the AS01 adjuvant system and its immunoenhancers QS-21 and MPL.”
Study lengthopen answer page →
Longest pivotal study
12 (AS01B alone in rabbit, seven IM doses 14 days apart)
“Group of 10 male and 10 female rabbits were treated with AS01B by intramuscular injection into the muscles of each hind limb on seven occasions 14 days apart. They were given a dose volume of 500 µL of the formulation and thus received 50 µg MPL and 50 µg QS-21 in a liposomal formulation per dose. Five rabbits per sex per group (including control group) were euthanized 3 or 28 days after the last dose.”
Pivotal GLP studies
Two rabbit IM repeat-dose vaccine studies, rat EFD/pre-postnatal and male fertility studies, rabbit local tolerance, rat safety pharmacology
“SHINGRIX has been evaluated in two repeat dose toxicity studies in rabbits, one reproductive-developmental toxicity study in rats, one male fertility study in rats, two local tolerance studies in rabbits, and one safety pharmacology study in rats.”
Route in tox
Intramuscular (clinical route)
“The toxicity studies were usually performed by the IM route of administration since this is the proposed route of administration for clinical use.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted on the final vaccine formulation (considered acceptable)
“The Applicant did not provide genotoxicity data for the final vaccine formulation gE/AS01B, which is considered acceptable.”
Carcinogenicity
Not conducted (not required for vaccines, adjuvant systems or immunoenhancers)
“Carcinogenicity studies were not performed. As carcinogenicity studies are not required for final vaccine formulations, adjuvants systems and/or immunoenhancers based on current guidelines, this was considered acceptable.”
Reproductive & developmental
Rat EFD/pre-postnatal at 40% of human dose: no maternal toxicity or offspring effects
“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.”
Safety pharmacology
Dedicated studies: ICH S7 conscious dog with AS01B at full human dose, no cardiovascular or respiratory concern
“An ICH S7-compliant safety pharmacology study in the conscious Beagle dog with the AS01B adjuvant did not raise any concern on cardiovascular and respiratory function when a full human dose was administered.”
Genotox: Ames
DQ/QS-21 negative in Ames assay
“DQ and/or QS-21 were non-mutagenic in the Ames assay and mouse lymphoma assay.”
Genotox: in vitro mammalian
DQ/QS-21 negative in mouse lymphoma assay
“DQ and/or QS-21 were non-mutagenic in the Ames assay and mouse lymphoma assay.”
Genotox: in vivo
AS01B negative in rat micronucleus assay
“In a rat micronucleus assay, AS01B showed no evidence of causing micronuclei.”
Carcinogenicity model
Not conducted (not required for vaccines or adjuvants)
“Carcinogenicity studies were not performed. As carcinogenicity studies are not required for final vaccine formulations, adjuvants systems and/or immunoenhancers based on current guidelines, this was considered acceptable.”
Carcinogenicity timing
Not required for vaccines, adjuvant systems or immunoenhancers
“Carcinogenicity studies were not performed. As carcinogenicity studies are not required for final vaccine formulations, adjuvants systems and/or immunoenhancers based on current guidelines, this was considered acceptable.”
hERG / QT
No cardiovascular concern for AS01B in ICH S7 conscious dog study at full human dose
“An ICH S7-compliant safety pharmacology study in the conscious Beagle dog with the AS01B adjuvant did not raise any concern on cardiovascular and respiratory function when a full human dose was administered.”
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 Shingrix 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 vaccines outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: No vaccine NOAEL stated; rabbit CRP up to 9-fold (males) and 5-fold (females), transient (FDA summary basis for approval, p. 14)
NOAEL / key findings
No vaccine NOAEL stated; rabbit CRP up to 9-fold (males) and 5-fold (females), transient
“A transient but statistically significant increase in C-Reactive Protein (CRP) levels was observed in rabbits receiving SHINGRIX with levels up to 9 times (male animals) and 5 times (female animals) higher compared to control animals.”
Risksopen answer page →
Immune & cytokine safety
Acute-phase response (CRP rise) indicating systemic inflammation, possibly linked to malaise, fatigue and nausea
“These changes in CRP levels reflect an activation of the acute-phase response and indicate increasing levels of systemic inflammation, which potentially may be correlated with clinical adverse events such as malaise, fatigue, and nausea.”
Biodistribution & persistence
Adjuvant biodistribution only: QS-21 and MPL widely distributed, eliminated within 48-168 h
“Taken together, the biodistribution studies with QS-21 and MPL administered in solution have shown that QS-21 and MPL are widely distributed throughout the body and are eliminated within several hours (48-168 h).”
Modality-specific risk
Adjuvant QS-21: kidney and great-vessel malformations in rabbits, not rats, at doses well above clinical
“The final conclusion on the adjuvant component QS-21 is that it potentially induces treatment related adverse findings including kidney and great blood vessel malformations in rabbits but not in rats, at doses considered sufficiently in excess over the therapeutic dose to raise any concern.”
Anti-drug antibodies: animals
All vaccine-treated rabbits seroconverted (anti-gE ELISA), confirming exposure
“All gE/AS01B treated animals seroconverted as assessed by gE ELISA.”
Anti-drug antibodies: patients
Intended response: anti-gE vaccine response rate 96.5% one month after the second dose (0, 6-month schedule)
“The co-primary objectives for the 0, 6-month schedule were met: (1) the Vaccine Response Rate at one month after the second dose was 96.5% (97.5% CI: 90.4 to 99.2), with LL of the 97.5% CI ≥60%;”
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 Shingrix 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 vaccines outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: No vaccine NOAEL stated; rabbit CRP up to 9-fold (males) and 5-fold (females), transient (FDA summary basis for approval, p. 14)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
AS01B alone in rabbit: seven IM doses 14 days apart, necropsy 3 or 28 days after last dose
“Group of 10 male and 10 female rabbits were treated with AS01B by intramuscular injection into the muscles of each hind limb on seven occasions 14 days apart. They were given a dose volume of 500 µL of the formulation and thus received 50 µg MPL and 50 µg QS-21 in a liposomal formulation per dose. Five rabbits per sex per group (including control group) were euthanized 3 or 28 days after the last dose.”
Pivotal GLP studies
Two rabbit IM repeat-dose vaccine studies, rat EFD/pre-postnatal and male fertility studies, rabbit local tolerance, rat safety pharmacology
“SHINGRIX has been evaluated in two repeat dose toxicity studies in rabbits, one reproductive-developmental toxicity study in rats, one male fertility study in rats, two local tolerance studies in rabbits, and one safety pharmacology study in rats.”
DART package
Species: DART
Rat (vaccine: pre/postnatal and male fertility); rat and rabbit EFD for QS-21 and MPL
“gE/AS01B and AS01B reproductive toxicity was assessed in two studies both performed in rats, one covering pre-, peri- and post-natal development and one covering male fertility.”
Reproductive & developmental
Rat EFD/pre-postnatal at 40% of human dose: no maternal toxicity or offspring effects
“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.”
PPND / ePPND: when
Combined EFD and pre/postnatal study in rat (gE/AS01B) completed before the marketing application
“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.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies were not performed. As carcinogenicity studies are not required for final vaccine formulations, adjuvants systems and/or immunoenhancers based on current guidelines, this was considered acceptable.”
Carcinogenicity model
Not conducted (not required for vaccines or adjuvants)
“Carcinogenicity studies were not performed. As carcinogenicity studies are not required for final vaccine formulations, adjuvants systems and/or immunoenhancers based on current guidelines, this was considered acceptable.”
Carcinogenicity timing
Not required for vaccines, adjuvant systems or immunoenhancers
“Carcinogenicity studies were not performed. As carcinogenicity studies are not required for final vaccine formulations, adjuvants systems and/or immunoenhancers based on current guidelines, this was considered acceptable.”
Safety marginopen answer page →
Safety margin at NOAEL
Full human dose given to rabbits, with more doses than clinically; no numeric multiple stated
“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).”
NOAEL / key findings
No vaccine NOAEL stated; rabbit CRP up to 9-fold (males) and 5-fold (females), transient
“A transient but statistically significant increase in C-Reactive Protein (CRP) levels was observed in rabbits receiving SHINGRIX with levels up to 9 times (male animals) and 5 times (female animals) higher compared to control animals.”
Efficacy evidenceopen answer page →
Efficacy evidence
Immunogenicity (cellular and humoral anti-gE) in mice
“Primary pharmacodynamics studied in mice to evaluate cellular and humoral anti-gE antigen immune responses and to select the optimal formulations”
Why that model
No appropriate animal model of VZV pathogenesis, latency or reactivation, so no challenge studies
“There is no appropriate animal model to study Varicella Zoster Virus (VZV) pathogenesis, latency or reactivation. Hence, no non-clinical data on protection against Herpes Zoster by vaccine candidates (challenge studies) were generated.”
Reviewer's view of the efficacy data
Protection addressed only clinically; no additional nonclinical pharmacology requested
“Efficacy (protection against Herpes Zoster) is only addressed clinically, as is the functionality of the induced gE-specific antibody response. No additional nonclinical primary pharmacology data were requested from the Applicant.”
Flexibilityopen answer page →
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.”
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