How was the first-in-human dose set for approved vaccines?

“The final formulation, antigen and adjuvant doses (120 µg RSVPreF3 with 50 µg AS01E) was selected based on clinical data.”

“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 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.”

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

“The quantity of each HA antigen and excipients of RIV4 was equivalent to that of the US licensed trivalent recombinant influenza vaccine manufactured by PSC with the addition of the second B strain.”

“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.”

“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).”

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

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

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”