Mosquirix
RTS,S/AS01 malaria vaccine
Sources:EMA assessment report ↗
Species
RatRabbit
Longest study
6 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rabbit (vaccine repeat-dose); rat and rabbit for adjuvant components
“As given in the WHO and EMA guidance, rat and rabbit are considered acceptable species for vaccine nonclinical safety studies and therefore generally chosen for the single dose/local tolerance and repeat dose toxicology studies.”
Why that species
Rabbit is an immunological responder species: all vaccinated rabbits seroconverted
“Serological analysis demonstrated seroconversion in all vaccine treated animals and none in the saline-treated controls, confirming that the rabbit is an immunological responder species for the RTS,S/AS01B candidate vaccine formulation.”
Surrogate molecule
No surrogate; tested RTS,S/AS01B contains twice the antigen and adjuvant amounts of Mosquirix (AS01E)
“The tested RTS,S/AS01B formulation consists of 50 μg of RTS,S antigen combined with AS01B containing 50 μg of MPL and 50 μg of QS-21 in liposomes and therefore contains twice the amounts of these constituents than the RTS,S/AS01E (Mosquirix) candidate vaccine.”
Species: general tox
Rabbit (vaccine); rat and rabbit (adjuvant components)
“As given in the WHO and EMA guidance, rat and rabbit are considered acceptable species for vaccine nonclinical safety studies and therefore generally chosen for the single dose/local tolerance and repeat dose toxicology studies.”
Species: DART
Not conducted: not intended for women of childbearing potential
“and developmental toxicity studies were not included in this Application since the RTS,S/ AS01E candidate vaccine containing, AS01E, MPL, QS-21 is not intended for administration to women of childbearing potential.”
Species: carcinogenicity
Not conducted (not required per WHO/EMA vaccine guidance)
“According to the WHO Guidelines on Nonclinical Evaluation of Vaccines (WHO, 2005), the EMEA Note for Guidance on Preclinical Pharmacological and Toxicological testing of Vaccines (CPMP/SWP/465/95) and the Guideline on adjuvants in vaccines for human use (EMEA/CHMP/VEG/134716/2004), carcinogenicity studies are not required for final vaccine formulations, Adjuvants Systems and/or immunoenhancers.”
Surrogate used in
No surrogate used
“The tested RTS,S/AS01B formulation consists of 50 μg of RTS,S antigen combined with AS01B containing 50 μg of MPL and 50 μg of QS-21 in liposomes and therefore contains twice the amounts of these constituents than the RTS,S/AS01E (Mosquirix) candidate vaccine.”
Study lengthopen answer page →
Longest pivotal study
6 (rabbit RTS,S/AS01B, necropsy Day 45; recovery to Day 70)
“Five males and five females from each group were killed on Day 45 (3 days after the last injection) and the remainder on Day 70 of study (28 days after the last injection) in order to study recovery.”
Pivotal GLP studies
GLP rabbit IM RTS,S/AS01B, 4 doses at 2-week intervals (Days 0-42); AS01B, QS-21 and MPL component studies
“Two groups of 20 New Zealand White rabbits (10 males + 10 females) were administered 4 intramuscular (IM) injections at 2 weeks interval (Day 0, 14, 28 and 42) of the candidate vaccine.”
Route in tox
Intramuscular
“Two groups of 20 New Zealand White rabbits (10 males + 10 females) were administered 4 intramuscular (IM) injections at 2 weeks interval (Day 0, 14, 28 and 42) of the candidate vaccine.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted on the final vaccine; adjuvant system components tested instead
“Vaccines are not used in the long term and this reduces risk from consequences of genotoxicity. However, the genotoxic potential of the Adjuvant System and its components should be understood.”
Carcinogenicity
Not conducted (not required for vaccines, adjuvant systems or immunoenhancers per WHO/EMA guidance)
“According to the WHO Guidelines on Nonclinical Evaluation of Vaccines (WHO, 2005), the EMEA Note for Guidance on Preclinical Pharmacological and Toxicological testing of Vaccines (CPMP/SWP/465/95) and the Guideline on adjuvants in vaccines for human use (EMEA/CHMP/VEG/134716/2004), carcinogenicity studies are not required for final vaccine formulations, Adjuvants Systems and/or immunoenhancers.”
Reproductive & developmental
Not conducted: vaccine not intended for women of childbearing potential
“and developmental toxicity studies were not included in this Application since the RTS,S/ AS01E candidate vaccine containing, AS01E, MPL, QS-21 is not intended for administration to women of childbearing potential.”
Safety pharmacology
Three dedicated GLP studies: RTS,S/AS01B, AS01B and MPL
“Three dedicated safety pharmacology studies were performed with RTS,S/AS01B, AS01B and with MPL (Table 6) all conducted under GLP.”
Genotox: Ames
MPL negative in bacterial reverse mutation test
“MPL did not induce mutations in any of the five tester strains, when tested under the conditions employed in this study.”
Genotox: in vitro mammalian
MPL negative in CHO chromosome aberration assay
“MPL did not increase the proportion of cells with structural aberrations.”
Genotox: in vivo
AS01B negative in rat bone marrow micronucleus test, with bone marrow cell toxicity
“The conclusion of the applicant was that AS01B showed no evidence of causing micronuclei but did show evidence of causing bone marrow cell toxicity.”
Carcinogenicity model
Not conducted (not required per WHO/EMA vaccine guidance)
“According to the WHO Guidelines on Nonclinical Evaluation of Vaccines (WHO, 2005), the EMEA Note for Guidance on Preclinical Pharmacological and Toxicological testing of Vaccines (CPMP/SWP/465/95) and the Guideline on adjuvants in vaccines for human use (EMEA/CHMP/VEG/134716/2004), carcinogenicity studies are not required for final vaccine formulations, Adjuvants Systems and/or immunoenhancers.”
Carcinogenicity timing
Not required for vaccines, adjuvant systems or immunoenhancers (WHO/EMA guidance)
“According to the WHO Guidelines on Nonclinical Evaluation of Vaccines (WHO, 2005), the EMEA Note for Guidance on Preclinical Pharmacological and Toxicological testing of Vaccines (CPMP/SWP/465/95) and the Guideline on adjuvants in vaccines for human use (EMEA/CHMP/VEG/134716/2004), carcinogenicity studies are not required for final vaccine formulations, Adjuvants Systems and/or immunoenhancers.”
hERG / QT
AS01B in conscious dog: no relevant effect on QT/QTc or other ECG intervals over 72 hours
“AS01B administered intramuscularly, did not affect the health status and the body weight gain of the animals throughout the study period, and did not relevantly affect the arterial blood pressure, the heart rate and the duration of the RR and PR intervals, of the QRS complex and of the QT and QTc intervals, irrespective of the formula used for QT interval correction, during the 72-hour period following administration.”
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 Mosquirix 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 NOAEL stated; dose-related acute injection-site inflammation, fully recovered 28 days after last dose; no systemic toxicity (EMA assessment report, p. 51)
NOAEL / key findings
No NOAEL stated; dose-related acute injection-site inflammation, fully recovered 28 days after last dose; no systemic toxicity
“In conclusion, intramuscular administration of RTS,S/AS01B on four occasions at 2-week intervals triggered an acute inflammatory response at injection sites that increased with the vaccine dose and volume administered. Nonetheless, full recovery was observed 28 days after the last administration.”
Risksopen answer page →
Immune & cytokine safety
Transient neutrophil and fibrinogen increases after dosing, back to pre-dose levels within three days
“The neutrophil counts and fibrinogen concentrations showed evidence of a return to levels similar to those recorded before treatment commenced within three days after dosing.”
Biodistribution & persistence
Adjuvant only: QS-21 eliminated almost exclusively in urine (>99% by 72 h) in mice; antigen PK not studied
“[14C]-QS-21 was almost exclusively eliminated via urinary excretion with >99 % of the injected dose recovered in urine by 72 h after dosing.”
Modality-specific risk
Adjuvant (AS01B) haematology effects: transient haemoglobin decrease in rats; bone marrow red cell production unaffected
“These changes in haemoglobin occurred despite no change to red cell number. Based on this result, AS01B was concluded not to affect the ability of bone marrow to produce red blood cells.”
Anti-drug antibodies: animals
All vaccinated rabbits seroconverted, none of the controls; confirms immune response
“Serological analysis demonstrated seroconversion in all vaccine treated animals and none in the saline-treated controls, confirming that the rabbit is an immunological responder species for the RTS,S/AS01B candidate vaccine formulation.”
Anti-drug antibodies: patients
Intended response: 98.9% of 5-17-month-olds seroprotected for anti-HBs before and after booster
“In the 5-17 months age category, 98.9% of RTS,S/AS01E recipients (R3R group) had seroprotective levels ( ≥10 mIU/ml) of anti-HBs antibodies both pre-booster (Month 20) and one month post booster dose of RTS,S/AS01E (Month 21).”
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 Mosquirix 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 NOAEL stated; dose-related acute injection-site inflammation, fully recovered 28 days after last dose; no systemic toxicity (EMA assessment report, p. 51)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Rabbit RTS,S/AS01B IM, 4 doses; necropsy Day 45 or after 28-day recovery (Day 70)
“Five males and five females from each group were killed on Day 45 (3 days after the last injection) and the remainder on Day 70 of study (28 days after the last injection) in order to study recovery.”
Pivotal GLP studies
GLP rabbit IM RTS,S/AS01B, 4 doses at 2-week intervals (Days 0-42); AS01B, QS-21 and MPL component studies
“Two groups of 20 New Zealand White rabbits (10 males + 10 females) were administered 4 intramuscular (IM) injections at 2 weeks interval (Day 0, 14, 28 and 42) of the candidate vaccine.”
DART package
Species: DART
Not conducted: not intended for women of childbearing potential
“and developmental toxicity studies were not included in this Application since the RTS,S/ AS01E candidate vaccine containing, AS01E, MPL, QS-21 is not intended for administration to women of childbearing potential.”
Reproductive & developmental
Not conducted: vaccine not intended for women of childbearing potential
“and developmental toxicity studies were not included in this Application since the RTS,S/ AS01E candidate vaccine containing, AS01E, MPL, QS-21 is not intended for administration to women of childbearing potential.”
PPND / ePPND: when
Not conducted: vaccine not intended for women of childbearing potential
“and developmental toxicity studies were not included in this Application since the RTS,S/ AS01E candidate vaccine containing, AS01E, MPL, QS-21 is not intended for administration to women of childbearing potential.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not required per WHO/EMA vaccine guidance)
“According to the WHO Guidelines on Nonclinical Evaluation of Vaccines (WHO, 2005), the EMEA Note for Guidance on Preclinical Pharmacological and Toxicological testing of Vaccines (CPMP/SWP/465/95) and the Guideline on adjuvants in vaccines for human use (EMEA/CHMP/VEG/134716/2004), carcinogenicity studies are not required for final vaccine formulations, Adjuvants Systems and/or immunoenhancers.”
Carcinogenicity model
Not conducted (not required per WHO/EMA vaccine guidance)
“According to the WHO Guidelines on Nonclinical Evaluation of Vaccines (WHO, 2005), the EMEA Note for Guidance on Preclinical Pharmacological and Toxicological testing of Vaccines (CPMP/SWP/465/95) and the Guideline on adjuvants in vaccines for human use (EMEA/CHMP/VEG/134716/2004), carcinogenicity studies are not required for final vaccine formulations, Adjuvants Systems and/or immunoenhancers.”
Carcinogenicity timing
Not required for vaccines, adjuvant systems or immunoenhancers (WHO/EMA guidance)
“According to the WHO Guidelines on Nonclinical Evaluation of Vaccines (WHO, 2005), the EMEA Note for Guidance on Preclinical Pharmacological and Toxicological testing of Vaccines (CPMP/SWP/465/95) and the Guideline on adjuvants in vaccines for human use (EMEA/CHMP/VEG/134716/2004), carcinogenicity studies are not required for final vaccine formulations, Adjuvants Systems and/or immunoenhancers.”
Safety marginopen answer page →
Safety margin at NOAEL
Rabbit study used RTS,S/AS01B with twice the antigen and adjuvant content of Mosquirix; no numeric margin stated
“The tested RTS,S/AS01B formulation consists of 50 μg of RTS,S antigen combined with AS01B containing 50 μg of MPL and 50 μg of QS-21 in liposomes and therefore contains twice the amounts of these constituents than the RTS,S/AS01E (Mosquirix) candidate vaccine.”
NOAEL / key findings
No NOAEL stated; dose-related acute injection-site inflammation, fully recovered 28 days after last dose; no systemic toxicity
“In conclusion, intramuscular administration of RTS,S/AS01B on four occasions at 2-week intervals triggered an acute inflammatory response at injection sites that increased with the vaccine dose and volume administered. Nonetheless, full recovery was observed 28 days after the last administration.”
Efficacy evidenceopen answer page →
Efficacy evidence
Immunogenicity in mice and monkeys (3 IM doses, days 0, 14, 28)
“The vaccine schedule was 3 intramuscular (i.m.) injections on days 0, 14 and 28, except GSK041 study in monkeys and two mouse studies (LIMS 20110165, LIMS 20130320) designed with immunobridging objectives.”
Why that model
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.
Reviewer's view of the efficacy data
Pharmacology programme adequate; no additional studies required
“The pharmacological testing program proposed for RTS,S/AS01E candidate vaccine is considered adequate and no additional studies are required.”
Flexibilityopen answer page →
Flexibility accepted
DARTVerdict not stated
No reproductive and developmental toxicity studies
Why: Vaccine not intended for administration to women of childbearing potential · Other reason
“and developmental toxicity studies were not included in this Application since the RTS,S/ AS01E candidate vaccine containing, AS01E, MPL, QS-21 is not intended for administration to women of childbearing potential.”
OtherAcceptedBeyond the letter
Toxicity studies used RTS,S/AS01B, with twice the antigen and adjuvant amounts of the marketed AS01E formulation
Why: Higher-content formulation well tolerated, supporting safe use of Mosquirix
“The tested RTS,S/AS01B formulation consists of 50 μg of RTS,S antigen combined with AS01B containing 50 μg of MPL and 50 μg of QS-21 in liposomes and therefore contains twice the amounts of these constituents than the RTS,S/AS01E (Mosquirix) candidate vaccine.”
“The results from the toxicity studies indicate that RTS,S/AS01B, AS01B, QS-21 and MPL are well tolerated by the animals and support the safe use of Mosquirix in human subjects.”
BiodistributionAccepted
No pharmacokinetic study of the vaccine antigen
Why: Pharmacokinetic studies are normally not required for a vaccine · Within the guideline
“Pharmacokinetic studies are normally not required for a vaccine. Pharmacokinetic study of the vaccine antigen was not studied which is considered acceptable by the CHMP.”
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