Nuvaxovid
COVID-19 vaccine, recombinant spike protein nanoparticle, Matrix-M-adjuvanted · SARS-CoV-2 spike (nanoparticle)Australia: Study 2019nCoV-101 Part 1, started May 2020
Cyfendus: what was done before first-in-human, and what came after?
anthrax vaccine adsorbed, adjuvanted · B. anthracis PA; TLR9 (CpG 7909 adjuvant)
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 Cyfendus 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: Injection-site necrosis and granulomatous inflammation judged adverse but expected to resolve (FDA summary basis for approval, p. 16)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Adult rat IM repeat-dose study (about 4 weeks of dosing) with a recovery period
“Following the recovery period, there was no evidence of progression of the necrosis or inflammation noted on SD 31, and there was no evidence of delayed toxicity.”
Pivotal GLP studies
GLP rat studies, all IM: single-dose, repeat-dose, pre/postnatal DART and juvenile repeat-dose
“The applicant conducted a single-dose acute toxicity study, a repeat-dose safety toxicity study, a pre- and post-natal developmental and reproductive toxicity (DART) study, as well as a juvenile repeat-dose toxicology study. All these GLP-compliant toxicology studies were performed in rats, and animals were dosed with CYFENDUS via IM injection, the intended route for human use.”
DART package
Species: DART
Female rat (pre/postnatal study with embryo-fetal phase, full human dose 0.5 mL)
“In a pre- and post-natal developmental study with an embryo-fetal development toxicity phase performed in female rats, a full human dose (0.5 mL) of CYFENDUS was administered by intramuscular injection on three occasions: 14 days prior to start of cohabitation, on the day of cohabitation, and on Gestation Day 7.”
Reproductive & developmental
Rat DART study: no effects on mating, fertility, pregnancy, embryo-fetal viability or postnatal survival and development
“No reproductive or developmental toxicity was noted in the DART study. There was no effect on mating, fertility, pregnancy, embryo-fetal viability, growth, or morphologic development, parturition, maternal care of offspring or postnatal survival, growth, or development.”
PPND / ePPND: when
Rat pre- and postnatal DART study completed before the marketing application
“Emergent has completed a single-dose acute toxicity study, a repeat-dose safety toxicity study in adult rats, a pre- and postnatal developmental and reproductive toxicity (DART) study in rats, as well as a juvenile repeat-dose toxicology study in rats.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“CYFENDUS has not been evaluated for carcinogenicity, mutagenic potential, or male infertility in animals.”
Carcinogenicity model
Not conducted
“CYFENDUS has not been evaluated for carcinogenicity, mutagenic potential, or male infertility in animals.”
Carcinogenicity timing
Not evaluated for carcinogenicity in animals
“CYFENDUS has not been evaluated for carcinogenicity, mutagenic potential, or male infertility in animals.”
Same question, other vaccines
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
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
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
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Shingrix
zoster vaccine recombinant, AS01B-adjuvanted · VZV glycoprotein E; TLR4 (AS01B adjuvant)Not stated in public reviews