Nuvaxovid
COVID-19 vaccine, recombinant spike protein nanoparticle, Matrix-M-adjuvanted
Species
RatRabbit
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 for the adjuvanted vaccine; rats and rabbits for Matrix-M1 adjuvant studies
“A repeat-dose GLP-compliant study with SARS-CoV-2 rS in rabbits was performed, with or without the adjuvant Matrix-M1. In addition, 6 GLP-compliant repeated dose toxicity studies in rats and rabbits with other vaccines in combination with Matrix-M1, or Matrix-M1 alone, were provided, in which the toxicity of Matrix-M1 was evaluated.”
Why that species
Rat chosen for DART after a pilot study showed the adjuvanted vaccine is immunogenic in male and female rats
“A non-GLP pilot study in rats indicated that SARS-CoV-2 rS adjuvanted with Matrix-M1 is immunogenic in female and male rats following one and two immunisations.”
Surrogate molecule
No surrogate; clinical antigen tested with and without Matrix-M1 adjuvant
“A repeat-dose GLP-compliant study with SARS-CoV-2 rS in rabbits was performed, with or without the adjuvant Matrix-M1.”
Species: general tox
Rabbit (adjuvanted vaccine); rat and rabbit (Matrix-M1 adjuvant studies)
“A repeat-dose GLP-compliant study with SARS-CoV-2 rS in rabbits was performed, with or without the adjuvant Matrix-M1. In addition, 6 GLP-compliant repeated dose toxicity studies in rats and rabbits with other vaccines in combination with Matrix-M1, or Matrix-M1 alone, were provided, in which the toxicity of Matrix-M1 was evaluated.”
Species: DART
Rat (combined fertility, embryo-fetal and postnatal study, females dosed before mating and in gestation)
“A DART study in rats with SARS-CoV-2 rS + Matrix-M1 or Matrix- M1 alone (administered 27 and 13 days prior to cohabitation and on gestation day (GD) 7 and 15) has been performed.”
Species: carcinogenicity
Not conducted (WHO vaccine guidelines)
“No carcinogenicity studies have been performed with the SARS-CoV-2 rS vaccine and Matrix-M1 adjuvant in accordance with the WHO Guidelines on Non-clinical Evaluation of Vaccines (2005) and Guidelines on the Non-clinical Evaluation of Vaccine Adjuvants and Adjuvanted Vaccines (2014).”
Surrogate used in
No surrogate used; clinical antigen with Matrix-M1 and Matrix-M1 alone tested
“A DART study in rats with SARS-CoV-2 rS + Matrix-M1 or Matrix- M1 alone (administered 27 and 13 days prior to cohabitation and on gestation day (GD) 7 and 15) has been performed.”
Study lengthopen answer page →
Longest pivotal study
8 weeks
“In the 57-day repeat intramuscular toxicity study, rabbits were administered intramuscularly 4 doses (3 weekly and one additional 21 days later) of 50 ug SARS-CoV-2 rS with 50 ug Matrix-M or 50 ug Matrix-M alone.”
Pivotal GLP studies
57-day IM repeat-dose study in rabbits (with and without Matrix-M); IM DART study in rats (vaccine or Matrix-M alone)
“The sponsor submitted two toxicity study reports (57-day repeat intramuscular toxicity study with and without Matrix-M adjuvant in rabbits and developmental and reproductive toxicology study of intramuscular administration of SARS-C0V-2 rS nanoparticle vaccine with Matrix-M adjuvant or Matrix-M alone in rats)”
Route in tox
Intramuscular
“In the 57-day repeat intramuscular toxicity study, rabbits were administered intramuscularly 4 doses (3 weekly and one additional 21 days later) of 50 ug SARS-CoV-2 rS with 50 ug Matrix-M or 50 ug Matrix-M alone.”
Skipped studiesopen answer page →
Genotoxicity
Matrix-M1 adjuvant negative in GLP Ames and in vitro CHO micronucleus assays; in vivo testing judged unnecessary
“The confirmatory GLP-compliant bacterial reverse mutation assay and Mammalian Cell Micronucleus assay in CHO Cells with Matrix-M1 confirmed the absence of any indication for a genotoxic potential of Matrix-M1. Further in vivo studies were therefore not considered necessary.”
Carcinogenicity
Not conducted (WHO vaccine and adjuvanted vaccine guidelines)
“No carcinogenicity studies have been performed with the SARS-CoV-2 rS vaccine and Matrix-M1 adjuvant in accordance with the WHO Guidelines on Non-clinical Evaluation of Vaccines (2005) and Guidelines on the Non-clinical Evaluation of Vaccine Adjuvants and Adjuvanted Vaccines (2014).”
Reproductive & developmental
Rat DART (dosing before mating and in gestation): no effects on reproduction, embryo-fetal or postnatal development to day 21
“The DART study confirmed that SARS-CoV-2 rS + Matrix-M1 or Matrix-M1 does not affect reproductive or developmental parameters and no adverse findings on pregnancy/lactation, or development of the embryo/foetus and offspring through post-natal Day 21 were identified.”
Safety pharmacology
Not conducted (WHO vaccine guideline); physiological functions assessed within the rabbit repeat-dose study
“Safety pharmacology studies were not conducted with SARS-CoV-2 rS with Matrix-M1 adjuvant vaccine, which is in line with the recommendation of the WHO Guidelines on Non-clinical Evaluation of Vaccines (2005), also given the availability of supporting non-clinical and clinical data, which indicated that the vaccine did not affect physiological functions other than those of the immune system.”
Genotox: Ames
Matrix-M1: GLP bacterial reverse mutation assay negative
“The confirmatory GLP-compliant bacterial reverse mutation assay and Mammalian Cell Micronucleus assay in CHO Cells with Matrix-M1 confirmed the absence of any indication for a genotoxic potential of Matrix-M1. Further in vivo studies were therefore not considered necessary.”
Genotox: in vitro mammalian
Matrix-M1: GLP micronucleus assay in CHO cells negative
“The confirmatory GLP-compliant bacterial reverse mutation assay and Mammalian Cell Micronucleus assay in CHO Cells with Matrix-M1 confirmed the absence of any indication for a genotoxic potential of Matrix-M1. Further in vivo studies were therefore not considered necessary.”
Genotox: in vivo
Not conducted (judged unnecessary after negative in vitro results)
“The confirmatory GLP-compliant bacterial reverse mutation assay and Mammalian Cell Micronucleus assay in CHO Cells with Matrix-M1 confirmed the absence of any indication for a genotoxic potential of Matrix-M1. Further in vivo studies were therefore not considered necessary.”
Carcinogenicity model
Not conducted (WHO vaccine and adjuvant guidelines)
“No carcinogenicity studies have been performed with the SARS-CoV-2 rS vaccine and Matrix-M1 adjuvant in accordance with the WHO Guidelines on Non-clinical Evaluation of Vaccines (2005) and Guidelines on the Non-clinical Evaluation of Vaccine Adjuvants and Adjuvanted Vaccines (2014).”
Carcinogenicity timing
Not required under WHO vaccine and adjuvanted vaccine guidelines
“No carcinogenicity studies have been performed with the SARS-CoV-2 rS vaccine and Matrix-M1 adjuvant in accordance with the WHO Guidelines on Non-clinical Evaluation of Vaccines (2005) and Guidelines on the Non-clinical Evaluation of Vaccine Adjuvants and Adjuvanted Vaccines (2014).”
hERG / QT
Not conducted; no effects on physiological functions in the repeat-dose study
“Safety pharmacology studies were not conducted with SARS-CoV-2 rS with Matrix-M1 adjuvant vaccine, which is in line with the recommendation of the WHO Guidelines on Non-clinical Evaluation of Vaccines (2005), also given the availability of supporting non-clinical and clinical data, which indicated that the vaccine did not affect physiological functions other than those of the immune system.”
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 Nuvaxovid 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; transient CRP and fibrinogen elevations and injection-site inflammation in rabbits, as expected for a vaccine (FDA summary basis for approval, p. 17)
NOAEL / key findings
No NOAEL stated; transient CRP and fibrinogen elevations and injection-site inflammation in rabbits, as expected for a vaccine
“Transient elevations of C-reactive protein (CRP) and fibrinogen and local inflammation reactions were observed at the injection sites, indicative of acute reactions as expected.”
Risksopen answer page →
Immune & cytokine safety
Matrix-M1: injection-site inflammation, reversible draining lymph node enlargement, raised CRP, fibrinogen and globulin (immune stimulation)
“The findings were considered consistent with immune system stimulation consequent to administration of an active adjuvant, and comprised: local injection site inflammation, reversible enlargement of the lymph nodes draining the injection sites (but not elsewhere), and chemical markers of inflammation (i.e., CRP, fibrinogen, and globulin).”
Biodistribution & persistence
No biodistribution data at approval; mouse biodistribution study of Matrix-M1 adjuvant planned
“As the Matrix-M1 adjuvant is not currently marketed in a human vaccine in the EU market, Novavax is planning to conduct a biodistribution study in mice to evaluate the Matrix-M1 adjuvant, which may be of value in further understanding the mode of action of the adjuvant.”
Modality-specific risk
Vaccine-induced enhanced disease: none seen after SARS-CoV-2 challenge in animals given low (0.01-1 µg) antigen doses
“In animals vaccinated with low doses (i.e., 0.01 µg, 0.1 µg or 1 µg) of Wuhan rS prior to challenge with SARS-CoV-2, no evidence of exacerbation of disease was found in necropsy and histopathology, thus alleviating earlier concerns about potential occurrence of vaccine-induced enhanced disease in vaccine recipients after a subsequent exposure to SARS-CoV-2.”
Anti-drug antibodies: animals
High anti-S IgG titers in rabbits, enhanced by Matrix-M1, confirming exposure
“SARS-CoV-2 rS vaccine was administered on day 1, 8, 15, and 36 and induced high anti-S IgG titers. Addition of Matrix-M1 adjuvant significantly enhanced anti-S IgG responses.”
Anti-drug antibodies: patients
Two-dose schedule produced seroconversion in almost all participants
“Clinical phase 3 data confirm that the vaccine is immunogenic and the studied two dose schedule resulted in seroconversion in almost all participants.”
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Australia: Study 2019nCoV-101 Part 1, started May 2020
“2019nCoV-101 Part 1 (completed) Australia Initiated: May 6, 2020”
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 Nuvaxovid 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; transient CRP and fibrinogen elevations and injection-site inflammation in rabbits, as expected for a vaccine (FDA summary basis for approval, p. 17)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
57-day IM rabbit study with 4 doses of adjuvanted vaccine or Matrix-M alone
“In the 57-day repeat intramuscular toxicity study, rabbits were administered intramuscularly 4 doses (3 weekly and one additional 21 days later) of 50 ug SARS-CoV-2 rS with 50 ug Matrix-M or 50 ug Matrix-M alone.”
Pivotal GLP studies
57-day IM repeat-dose study in rabbits (with and without Matrix-M); IM DART study in rats (vaccine or Matrix-M alone)
“The sponsor submitted two toxicity study reports (57-day repeat intramuscular toxicity study with and without Matrix-M adjuvant in rabbits and developmental and reproductive toxicology study of intramuscular administration of SARS-C0V-2 rS nanoparticle vaccine with Matrix-M adjuvant or Matrix-M alone in rats)”
DART package
Species: DART
Rat (combined fertility, embryo-fetal and postnatal study, females dosed before mating and in gestation)
“A DART study in rats with SARS-CoV-2 rS + Matrix-M1 or Matrix- M1 alone (administered 27 and 13 days prior to cohabitation and on gestation day (GD) 7 and 15) has been performed.”
Reproductive & developmental
Rat DART (dosing before mating and in gestation): no effects on reproduction, embryo-fetal or postnatal development to day 21
“The DART study confirmed that SARS-CoV-2 rS + Matrix-M1 or Matrix-M1 does not affect reproductive or developmental parameters and no adverse findings on pregnancy/lactation, or development of the embryo/foetus and offspring through post-natal Day 21 were identified.”
PPND / ePPND: when
Rat combined DART with postnatal follow-up to day 21, completed before the marketing application
“The DART study confirmed that SARS-CoV-2 rS + Matrix-M1 or Matrix-M1 does not affect reproductive or developmental parameters and no adverse findings on pregnancy/lactation, or development of the embryo/foetus and offspring through post-natal Day 21 were identified.”
Carcinogenicity
Species: carcinogenicity
Not conducted (WHO vaccine guidelines)
“No carcinogenicity studies have been performed with the SARS-CoV-2 rS vaccine and Matrix-M1 adjuvant in accordance with the WHO Guidelines on Non-clinical Evaluation of Vaccines (2005) and Guidelines on the Non-clinical Evaluation of Vaccine Adjuvants and Adjuvanted Vaccines (2014).”
Carcinogenicity model
Not conducted (WHO vaccine and adjuvant guidelines)
“No carcinogenicity studies have been performed with the SARS-CoV-2 rS vaccine and Matrix-M1 adjuvant in accordance with the WHO Guidelines on Non-clinical Evaluation of Vaccines (2005) and Guidelines on the Non-clinical Evaluation of Vaccine Adjuvants and Adjuvanted Vaccines (2014).”
Carcinogenicity timing
Not required under WHO vaccine and adjuvanted vaccine guidelines
“No carcinogenicity studies have been performed with the SARS-CoV-2 rS vaccine and Matrix-M1 adjuvant in accordance with the WHO Guidelines on Non-clinical Evaluation of Vaccines (2005) and Guidelines on the Non-clinical Evaluation of Vaccine Adjuvants and Adjuvanted Vaccines (2014).”
Safety marginopen answer page →
Safety margin at NOAEL
Rat DART study: dose exceeds the human dose 40-fold on a weight-adjusted basis
“The administered dose was the maximum volume of clinical formulation (used for the early clinical studies) and, although the dose is smaller than the absolute dose that will be administered to humans, it does exceed the human dosage on a weight-adjusted basis by 40-fold.”
NOAEL / key findings
No NOAEL stated; transient CRP and fibrinogen elevations and injection-site inflammation in rabbits, as expected for a vaccine
“Transient elevations of C-reactive protein (CRP) and fibrinogen and local inflammation reactions were observed at the injection sites, indicative of acute reactions as expected.”
Efficacy evidenceopen answer page →
Efficacy evidence
SARS-CoV-2 live-virus challenge in mice, hamsters, cynomolgus and rhesus macaques
“Live virus challenge studies were performed in mice, hamsters, cynomolgus macaques, and rhesus macaques.”
Why that model
Mice made susceptible by intranasal adenovirus vector expressing human ACE2 before challenge
“The 2 lead antigens were tested for protective effect against SARS-CoV-2 challenge, at 10 μg level, with or without 5 ug Matrix-M1 adjuvant, in a prime-boost regime in mice sensitised for SARS-CoV-2 by intranasal instillation of adenovirus vector expressing human ACE2.”
Reviewer's view of the efficacy data
Robust immune response shown effective against disease symptoms and viral replication in hamsters and macaques
“From the studies in hamsters, cynomolgus macaques and rhesus monkeys, it emerged that vaccination with the BV2373 construct in combination with the adjuvant Matrix-M1 leads to a robust immune response that is proven to be effective against the disease symptoms of SARS-CoV-2 infection and in reducing viral replication.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
Rat DART used Matrix-M1 below the absolute human dose (maximum volume of clinical formulation)
Why: Dose exceeds the human dose 40-fold on a weight-adjusted basis and induced an immune response in rats · Pharmacology or kinetics
“The administered dose was the maximum volume of clinical formulation (used for the early clinical studies) and, although the dose is smaller than the absolute dose that will be administered to humans, it does exceed the human dosage on a weight-adjusted basis by 40-fold.”
“In addition, the final audited DART report includes data showing that the dose used in this study did induce an immune response. The study design and generated results are therefore considered acceptable.”
OtherVerdict not stated
Rabbit repeat-dose study used antigen/adjuvant 50/50 µg instead of the clinical 5/50 µg ratio
“Of note, the dosing schedule used was not in accordance with the proposed clinical schedule (the dose ratio of SARS-CoV-2 rS nanoparticle/Matrix-M1 used is different: 50/50 in the study vs 5/50 in the clinical situation).”
DARTAcceptedBeyond the letter
DART done in rat although rabbit placental antibody transfer is more similar to humans
Why: Fetal titers about 8.0% and pup titers 70-82% of maternal levels showed sufficient antibody transfer · Pharmacology or kinetics
“For the evaluation of reproduction toxicology, the applicant has used the rat as animal model. It is noted that placental transfer of antibodies in rabbits is more similar to humans compared to rodents.”
“Titers measured in foetuses were approximately 8.0% of those present in dams, whereas nursing pups had anti-S lgG levels approximately 70-82 % of the IgG levels of the dams, indicating that sufficient antibody transfer occurred via placenta and especially lactation.”
DARTVerdict not stated
No male fertility study
Why: No adverse findings in male reproductive organs in the GLP repeat-dose study · Weight of evidence
“No male fertility studies were performed given no adverse observations in male reproductive organs were observed in the GLP repeat-dose toxicology study.”
BiodistributionAcceptedBeyond the letter
Matrix-M1 adjuvant biodistribution study not completed before approval
Why: Extensive clinical package at initial marketing approval · Human data
“Considering the extensive clinical package available at the time of initial marketing approval, the safety profile of the adjuvanted vaccine was considered acceptable without finalisation of the biodistribution study.”
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