PreHevbrio
hepatitis B vaccine (recombinant), 3-antigen · HBsAg S/pre-S1/pre-S2 VLPsIsrael, Thailand and Singapore: legacy dose-ranging studies, one with a first-in-human part up to 20 µg
Nuvaxovid: what was done before first-in-human, and what came after?
COVID-19 vaccine, recombinant spike protein nanoparticle, Matrix-M-adjuvanted · SARS-CoV-2 spike (nanoparticle)
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).”
Same question, other vaccines
Arexvy
respiratory syncytial virus vaccine, adjuvanted (AS01E) · RSV preF3; TLR4 (AS01E adjuvant)Not stated in public reviews
Cervarix
human papillomavirus bivalent (types 16, 18) vaccine, recombinant, AS04-adjuvanted · HPV 16/18 L1 VLPs; TLR4 (AS04 adjuvant)Not stated in public reviews
Cyfendus
anthrax vaccine adsorbed, adjuvanted · B. anthracis PA; TLR9 (CpG 7909 adjuvant)Not stated in public reviews
Fendrix
hepatitis B vaccine (rDNA), AS04C-adjuvanted · HBsAg VLPs; TLR4 (AS04C adjuvant)Not stated in public reviews
Flublok
influenza vaccine, recombinant hemagglutinin · Influenza HANot stated in public reviews
Gardasil
human papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant · HPV 6/11/16/18 L1 VLPsNot stated in public reviews
Gardasil 9
human papillomavirus 9-valent vaccine, recombinant · HPV 9-valent L1 VLPsNot stated in public reviews
HBVaxPro
hepatitis B vaccine (rDNA) · HBsAg VLPsNot stated in public reviews
Heplisav-B
hepatitis B vaccine (recombinant), adjuvanted · HBsAg; TLR9 (CpG 1018 adjuvant)Not stated in public reviews
Mosquirix
RTS,S/AS01 malaria vaccine · P. falciparum CSP-HBsAg (RTS,S) VLPs; TLR4 (AS01 adjuvant)Not stated in public reviews
Shingrix
zoster vaccine recombinant, AS01B-adjuvanted · VZV glycoprotein E; TLR4 (AS01B adjuvant)Not stated in public reviews