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
Gardasil 9: what was done before first-in-human, and what came after?
human papillomavirus 9-valent vaccine, recombinant · HPV 9-valent L1 VLPs
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 Gardasil 9 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 oncology vaccines (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: No NOAEL stated; only immune-response and injection-site effects in rats (EMA assessment report, p. 24)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week IM rat study (4 doses every 21 days) with 21-day recovery
“A recovery group consisting of 10 males and 10 females rats per group were sacrificed 21 days after the interim necropsy (day 67). Study duration was 13 weeks.”
Pivotal GLP studies
13-week IM rat repeat-dose (with local tolerance); rat fertility/embryo-foetal study; rat postnatal developmental study
“Toxicology studies supporting the safety of the 9vHPV vaccine included 3 GLP-compliant studies in rats consisting of: i) a repeat-dose toxicity study (with local tolerance and non-GLP immunogenicity assessments), ii) an intramuscular developmental toxicity and immunogenicity study with female fertility and embryo-foetal evaluation and iii) an intramuscular developmental toxicity and immunogenicity study with postnatal evaluation.”
DART package
Species: DART
Rat (female fertility/embryo-foetal and postnatal development)
“The reproductive and developmental toxicity of the 9vHPV vaccine was assessed in two GLP-compliant studies using female rats.”
Reproductive & developmental
Two GLP rat studies (fertility/EFD and postnatal); no adverse effects; up to 240 and 160 times human dose (mg/kg)
“Reproduction studies have been performed in rats at doses up to 240 and 160 times the human dose on mg/kg basis and revealed no evidence of impaired fertility or harm to the fetus due to V503 vaccine.”
PPND / ePPND: when
Rat postnatal developmental study (dosing to lactation day 7) completed before the marketing application
“In the second developmental toxicity study, female rats (F0) received 0.5 mL (0.25 mL administered to each quadriceps muscle) intramuscular injection with 9vHPV vaccine on 4 occasions (Premating Week -5 and -2 plus GD 6 and LD 7).”
Carcinogenicity
Species: carcinogenicity
Not conducted
“The oncogenic/carcinogenic potential of the 9vHPV vaccine in long and short-term studies was not evaluated. According to current requirements as mentioned above, carcinogenicity studies are generally not required for vaccines and this is acceptable also for Gardasil 9.”
Carcinogenicity model
Not conducted (not required for vaccines)
“The oncogenic/carcinogenic potential of the 9vHPV vaccine in long and short-term studies was not evaluated. According to current requirements as mentioned above, carcinogenicity studies are generally not required for vaccines and this is acceptable also for Gardasil 9.”
Carcinogenicity timing
Not required for vaccines
“The oncogenic/carcinogenic potential of the 9vHPV vaccine in long and short-term studies was not evaluated. According to current requirements as mentioned above, carcinogenicity studies are generally not required for vaccines and this is acceptable also for Gardasil 9.”
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
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
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