What safety margins were accepted for approved vaccines?

“It should be noted that other systemic manifestations of TLR9 immunostimulation were seen in monkeys (i.e. spleen hyperplasia from 2.5 mg/kg/w and lymph node hyperplasia and liver inflammation at 12.5 mg/kg/w). Of importance, a NOAEL of 0.5 mg/kg 1018 ISS (>10-fold the clinical dose on mg/kg basis) for systemic immunostimulatory effects was identified in this study.”

“It should be noted that other systemic manifestations of TLR9 immunostimulation were seen in monkeys (i.e. spleen hyperplasia from 2.5 mg/kg/w and lymph node hyperplasia and liver inflammation at 12.5 mg/kg/w). Of importance, a NOAEL of 0.5 mg/kg 1018 ISS (>10-fold the clinical dose on mg/kg basis) for systemic immunostimulatory effects was identified in this study.”

“a This dose was expected to give an approximate 20X dose multiple assuming a 3kg average rabbit weight and a 60 kg average human weight.”

“The vaccine resulted in effects on clinical pathology parameters and histopathology that are consistent with immune stimulation following administration of a vaccine, amongst others changes in white blood cell and absolute neutrophil counts, minimally to mildly decreased albumin, increased lymph node weights (ileac and popliteal), CRP and fibrinogen.”

“The administered dose was the maximum volume of clinical formulation (used for the early clinical studies) and, although the dose is smaller than the absolute dose that will be administered to humans, it does exceed the human dosage on a weight-adjusted basis by 40-fold.”

“Transient elevations of C-reactive protein (CRP) and fibrinogen and local inflammation reactions were observed at the injection sites, indicative of acute reactions as expected.”

“No other vaccine- or adjuvant-associated adverse systemic effect was noted, even though the studied dosages exceeded the human dosage (up to more than 50-fold factor on a body weight basis), as well as the immunization schedule.”

“The HPV-16 /18 L1 VLP AS04 vaccine and the AS04 adjuvant were well tolerated. The organ-weight data, macroscopic pathology evaluation, and evaluation of systemic effects showed no consistent treatment-related findings.”

“A safety pharmacology study did not show any effect on respiratory or cardiovascular parameters when the HBsAg was administered intravenously or when the HB-AS04C vaccine was given intramuscularly, up to a 63-fold of the human dose expressed on a bodyweight basis.”

“The effects seen were minor and consistent with an immunostimulatory action. The minor effects seen were dose-related.”

“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.”

“The only treatment-related effects were indicative of the immune response and injection site reactions.”

“On a body weight basis, the dose of the vaccine administered to mice was approximately 1450-fold the projected human dose.”

“There was a treatment-related enlargement of the iliac lymph nodes. Treatment-related microscopic changes were noted in lymph nodes (hyperplasia) and in the muscle at the injection sites (inflammation).”

“There were no local reactions and no signs of systemic toxicity including clinical pathology parameters, organ weights and macroscopic findings. The main related findings were transient microscopic changes at the injection sites, which is expected.”

“revealed changes attributed to the vaccine properties of the reference and tested vaccines. None of these findings had a toxicological significance.”

“The tested RTS,S/AS01B formulation consists of 50 μg of RTS,S antigen combined with AS01B containing 50 μg of MPL and 50 μg of QS-21 in liposomes and therefore contains twice the amounts of these constituents than the RTS,S/AS01E (Mosquirix) candidate vaccine.”

“In conclusion, intramuscular administration of RTS,S/AS01B on four occasions at 2-week intervals triggered an acute inflammatory response at injection sites that increased with the vaccine dose and volume administered. Nonetheless, full recovery was observed 28 days after the last administration.”

“Developmental toxicity study has been performed in female rats at a dose equivalent to the adult human dose.”

“Based on the limited data submitted, the vaccine caused typical location reactions at the injection sites but did not cause any systemic effects other than the expected lymphoid hyperplasia.”

“Repeated dose toxicity has thus been evaluated in one relevant animal species (rabbits) and the studies have been conducted according to the relevant WHO and EMA guidelines, including recommendations on dose (full human dose), number of doses (exceeding proposed number in the clinic) and of route of administration (IM is proposed route of administration for licensure).”

“A transient but statistically significant increase in C-Reactive Protein (CRP) levels was observed in rabbits receiving SHINGRIX with levels up to 9 times (male animals) and 5 times (female animals) higher compared to control animals.”