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
Heplisav-B: what was done before first-in-human, and what came after?
hepatitis B vaccine (recombinant), adjuvanted · HBsAg; TLR9 (CpG 1018 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 Heplisav-B 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: Monkey NOAEL 0.5 mg/kg CpG 1018 (>10-fold clinical) for systemic immunostimulation; spleen and lymph node hyperplasia, liver inflammation at higher doses (EMA assessment report, p. 28)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
8-week SC cynomolgus monkey and rat (CpG 1018 adjuvant alone), each with 4-week recovery
“Study no. 00-157 “A 8-Week Subcutaneous Toxicity Study of 1018 ISS Adjuvant in Cynomolgus Monkeys, with a 4-Week Recovery Period” 7. Study no. 00-158 “An 8-Week Subcutaneous Toxicity Study of 1018 ISS Adjuvant in Rats, with a 4-Week Recovery Period””
Pivotal GLP studies
Adjuvanted vaccine IM repeat-dose studies in mice (3 doses, days 0, 14, 28) and rats (4 doses, days 0-42)
“The general safety of the 1018 ISS adjuvanted HBsAg vaccine was investigated in two pivotal studies were the vaccine was administrated by the IM injection, the clinical route of administration: a repeated-dose toxicity study in mice (study 00-95) where 3 IM doses were given (at day 0, 14 and 28) and a repeated dose toxicity study in rats (study 12-728) where 4 IM doses were given (at day 0, 14, 28 and 42).”
DART package
Species: DART
Rat (fertility, embryo-fetal and pre/postnatal development in a single combined study)
“HBsAg plus CpG 1018 was also tested in rats in a reproductive and developmental toxicity study which assessed the potential effects on mating behavior, fertility, gestation, embryo-fetal development, parturition, lactation and maternal behavior”
Reproductive & developmental
Rat multigeneration DART study: stillbirths and skeletal anomalies only secondary to maternal toxicity at 200-fold the clinical CpG 1018 dose
“In a multigeneration reprotoxicological study in rats, effects on the offspring (stillborn pups and skeletal abnormalities) occurred secondary to maternal toxicity at a dose 200-fold the proposed clinical dose of Heplisav B with respect to 1018 ISS on a body weight basis.”
PPND / ePPND: when
Combined developmental and perinatal/postnatal study in rat (HBsAg + 1018 ISS) completed before the marketing application
“Study title: Developmental and Perinatal/Postnatal Reproduction Toxicity Study of Intramuscularly Administered HBsAg + 1018 ISS in Rats, Including a Postnatal Behavioral/Functional and Immunological Evaluation”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No studies assessing the carcinogenicity of Heplisav B or 1018 ISS adjuvant have been performed. This is acceptable for this type of product in line with EMAs guidelines for vaccines and adjuvants and compliant with ICH S1A, considering that the exposure to this vaccine will be sporadic.”
Carcinogenicity model
Not conducted (ICH S1A; sporadic vaccine exposure)
“No studies assessing the carcinogenicity of Heplisav B or 1018 ISS adjuvant have been performed. This is acceptable for this type of product in line with EMAs guidelines for vaccines and adjuvants and compliant with ICH S1A, considering that the exposure to this vaccine will be sporadic.”
Carcinogenicity timing
Not required for this type of product (vaccine, sporadic exposure; ICH S1A)
“No studies assessing the carcinogenicity of Heplisav B or 1018 ISS adjuvant have been performed. This is acceptable for this type of product in line with EMAs guidelines for vaccines and adjuvants and compliant with ICH S1A, considering that the exposure to this vaccine will be sporadic.”
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
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