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
Cervarix: what was done before first-in-human, and what came after?
human papillomavirus bivalent (types 16, 18) vaccine, recombinant, AS04-adjuvanted · HPV 16/18 L1 VLPs; TLR4 (AS04 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 Cervarix 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; vaccine and AS04 well tolerated with no consistent systemic findings in rabbits (EMA assessment report, p. 11)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Rabbit IM repeat-dose, 4 injections (days 1, 15, 29, 57), with 13-week recovery
“and included a 13-week recovery period. Animals were allocated randomly to 4 groups of 10 animals each, and received intramuscular injections in the paravertebral muscles on Days 1, 15, 29 and 57.”
Pivotal GLP studies
Rabbit IM repeat-dose (up to 4 injections at 2-week intervals, up to 3x human dose); rat DART; rat safety pharmacology
“The treatment regimen of up to 4 vaccine injections at 2 week intervals with up to three times the human dosage exceeds the total number of intended clinical injections.”
DART package
Species: DART
Rat (fertility, embryo-fetal, peri/postnatal; vaccine and AS04 alone)
“The reproductive and developmental toxicity of Cervarix and the AS04 adjuvant alone was assessed in a study in female rats of the CD strain. The influence of Cervarix on fertility, embryo-fetal, peri-natal and post-natal survival and development was examined.”
Reproductive & developmental
Rat combined fertility, embryo-fetal and pre/postnatal study with vaccine and AS04: no effects
“The reproductive toxicity study in CD rats did not show any effects of vaccination or AS04 administration on fertility, embryofoetal development and pre- and post-natal development.”
PPND / ePPND: when
Rat pre- and postnatal study with fertility assessment completed before the marketing application (protocol to IND in 2002)
“For this purpose, a pre- and post-natal toxicity study in rats, including an assessment of the potential impact of vaccination on fertility was performed. The protocol for the investigation was submitted to IND -(b)(4)- (Serial No. 0065, December 9, 2002).”
Carcinogenicity
Species: carcinogenicity
Not conducted
“The mutagenic and carcinogenic potential of the Cervarix vaccine was not further evaluated, which is accepted since the vaccine is based on L1 protein and HPV oncoproteins are absent.”
Carcinogenicity model
Not conducted (L1 protein vaccine without HPV oncoproteins)
“The mutagenic and carcinogenic potential of the Cervarix vaccine was not further evaluated, which is accepted since the vaccine is based on L1 protein and HPV oncoproteins are absent.”
Carcinogenicity timing
Not required (L1 protein vaccine without HPV oncoproteins)
“The mutagenic and carcinogenic potential of the Cervarix vaccine was not further evaluated, which is accepted since the vaccine is based on L1 protein and HPV oncoproteins are absent.”
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
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