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
Shingrix: what was done before first-in-human, and what came after?
zoster vaccine recombinant, AS01B-adjuvanted · VZV glycoprotein E; TLR4 (AS01B 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 Shingrix 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 vaccine NOAEL stated; rabbit CRP up to 9-fold (males) and 5-fold (females), transient (FDA summary basis for approval, p. 14)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
AS01B alone in rabbit: seven IM doses 14 days apart, necropsy 3 or 28 days after last dose
“Group of 10 male and 10 female rabbits were treated with AS01B by intramuscular injection into the muscles of each hind limb on seven occasions 14 days apart. They were given a dose volume of 500 µL of the formulation and thus received 50 µg MPL and 50 µg QS-21 in a liposomal formulation per dose. Five rabbits per sex per group (including control group) were euthanized 3 or 28 days after the last dose.”
Pivotal GLP studies
Two rabbit IM repeat-dose vaccine studies, rat EFD/pre-postnatal and male fertility studies, rabbit local tolerance, rat safety pharmacology
“SHINGRIX has been evaluated in two repeat dose toxicity studies in rabbits, one reproductive-developmental toxicity study in rats, one male fertility study in rats, two local tolerance studies in rabbits, and one safety pharmacology study in rats.”
DART package
Species: DART
Rat (vaccine: pre/postnatal and male fertility); rat and rabbit EFD for QS-21 and MPL
“gE/AS01B and AS01B reproductive toxicity was assessed in two studies both performed in rats, one covering pre-, peri- and post-natal development and one covering male fertility.”
Reproductive & developmental
Rat EFD/pre-postnatal at 40% of human dose: no maternal toxicity or offspring effects
“Treatment of female CD rats with the candidate vaccine at 40% of the full human dose per occasion was well tolerated, did not lead to maternal toxicity, and did not adversely affect embryo-fetal or pre- and post-natal survival, growth or development of the offspring.”
PPND / ePPND: when
Combined EFD and pre/postnatal study in rat (gE/AS01B) completed before the marketing application
“Treatment of female CD rats with the candidate vaccine at 40% of the full human dose per occasion was well tolerated, did not lead to maternal toxicity, and did not adversely affect embryo-fetal or pre- and post-natal survival, growth or development of the offspring.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies were not performed. As carcinogenicity studies are not required for final vaccine formulations, adjuvants systems and/or immunoenhancers based on current guidelines, this was considered acceptable.”
Carcinogenicity model
Not conducted (not required for vaccines or adjuvants)
“Carcinogenicity studies were not performed. As carcinogenicity studies are not required for final vaccine formulations, adjuvants systems and/or immunoenhancers based on current guidelines, this was considered acceptable.”
Carcinogenicity timing
Not required for vaccines, adjuvant systems or immunoenhancers
“Carcinogenicity studies were not performed. As carcinogenicity studies are not required for final vaccine formulations, adjuvants systems and/or immunoenhancers based on current guidelines, this was considered acceptable.”
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
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