What tox package did approved vaccines have, from first-in-human to approval?

“2019nCoV-101 Part 1 (completed) Australia Initiated: May 6, 2020”

“In the 57-day repeat intramuscular toxicity study, rabbits were administered intramuscularly 4 doses (3 weekly and one additional 21 days later) of 50 ug SARS-CoV-2 rS with 50 ug Matrix-M or 50 ug Matrix-M alone.”

“The DART study confirmed that SARS-CoV-2 rS + Matrix-M1 or Matrix-M1 does not affect reproductive or developmental parameters and no adverse findings on pregnancy/lactation, or development of the embryo/foetus and offspring through post-natal Day 21 were identified.”

“No carcinogenicity studies have been performed with the SARS-CoV-2 rS vaccine and Matrix-M1 adjuvant in accordance with the WHO Guidelines on Non-clinical Evaluation of Vaccines (2005) and Guidelines on the Non-clinical Evaluation of Vaccine Adjuvants and Adjuvanted Vaccines (2014).”

“The studies were conducted inIsrael, Thailand, and Singapore. They were open-label, comprising two dose regimens, 5 and 10 µg. One had a preliminary phase 1 FIH part with a dosage up to 20 µg.”

“Animals were sacrificed 2 days after the last dose (= 4-week time point) or at 8 weeks following recovery.”

“A GLP-compliant embryo-fetal and pre/post-natal reproductive toxicity study was conducted with the current vaccine formulation of PreHevbri in female Sprague-Dawley rats.”

“There were no studies on genotoxicity and carcinogenicity, which is in line with applicable guidelines.”

“Two GLP-compliant repeated dose toxicity studies (and) were conducted in New Zealand White rabbits (10/sex/group), which received three intramuscular injections (Day 1, Day 15 and Day 29, followed by a 4- week recovery period.)”

“Study number 3: A Developmental Toxicity Study (Including Teratogenicity and Postnatal Investigations) of RSVPreF3 or AS01B by Intramuscular Injection in Rabbits. Study number: 20152506. Performing laboratory: . Study initiation date: November 08, 2018 Final report date: September 17, 2019”

“The absence of carcinogenicity studies is accepted and not required for vaccines.”

“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.”

“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).”

“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.”

“Repeated-dose toxicity studies were presented, up to 7 days in rats and 14 days in Beagle dogs, where MPL was given once daily by the intravenous route, maximising the exposure.”

“Reproductive toxicity studies including a teratogenicity study in the rabbit and a pre-and postnatal study in the rat showed no evidence of maternal toxicity, teratogenicity or any effect on the in utero development of the F1 offspring.”

“The pivotal repeat-dose toxicity study was conducted with the SC route. Results showed that five weekly SC injections with RIV3 were locally and systemically well tolerated in rats.”

“Reproductive toxicity study for FluBLOk, recombinant trivalent influenza vaccine: final report, review memorandum”

“Studies evaluating genotoxicity and carcinogenicity are normally not required for viral vaccines. Since no adjuvants or novel excipients are used in this product absence of those studies is considered acceptable.”

“A 10-week repeat-dose toxicity study was performed in BALB/c mice. Vaccine-treated mice received 1 or 3 doses of Gardasil at a concentration of 160/160/80/160 μg/ml of the HPV types 6/11/16/18 L1 VLPs.”

“The reproductive and developmental toxicity was assessed in a study in female Sprague-Dawley rats addressing all phases of reproduction and foetal development. An immune response to the vaccine was observed, and antibodies were shown to be transferred to the offspring during gestation and also lactation.”

“No carcinogenicity studies were conducted, and this is in line with CPMP/SWP/465/95.”

“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.”

“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).”

“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.”

“The absence of toxicity was evaluated after repeated administrations in the rat according to treatment schedules mimicking a human vaccination scheme (i.e., 3 injections at monthly intervals).”

“Animal reproduction studies have not been conducted.”

“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””

“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”

“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.”

“Five males and five females from each group were killed on Day 45 (3 days after the last injection) and the remainder on Day 70 of study (28 days after the last injection) in order to study recovery.”

“and developmental toxicity studies were not included in this Application since the RTS,S/ AS01E candidate vaccine containing, AS01E, MPL, QS-21 is not intended for administration to women of childbearing potential.”

“According to the WHO Guidelines on Nonclinical Evaluation of Vaccines (WHO, 2005), the EMEA Note for Guidance on Preclinical Pharmacological and Toxicological testing of Vaccines (CPMP/SWP/465/95) and the Guideline on adjuvants in vaccines for human use (EMEA/CHMP/VEG/134716/2004), carcinogenicity studies are not required for final vaccine formulations, Adjuvants Systems and/or immunoenhancers.”

“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.”

“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 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.”