Which risks did regulators probe for approved vaccines?

“In combination with especially AS01B, RSVPreF3 induced F-specific CD4+ and CD8+ T cell responses and RSV-specific neutralising antibody titres after the second and third vaccination and induced proinflammatory cytokines as measured after the first and second vaccination.”

“No dedicated PK or ADME studies for RSVPreF3 OA are performed. This is endorsed. The adjuvant system AS01 is not a novel adjuvant, since several products using the adjuvant system have already been registered (a.o., Shingrix, using AS01B).”

“GSK’s 3rd table in their response lists the preclinical studies conducted with vaccine formulations containing MPL. GSK concluded that none of these studies show evidence of adverse neurological, immunological or autoimmune-based (AID) reactions.”

“In conclusion the pharmacokinetic studies conducted in rats have shown that MPL-related material is widely distributed throughout the body, notably to the fat and spleen, and is then likely eliminated mainly via the expired air, with only low levels of radioactivity remaining in the carcass.”

“Furthermore, rat dams and offspring were shown to be exposed to high titres of circulating anti-HBs antibodies during the reproductive toxicity study.”

“Neither distribution nor excretion data are available for the final HB-AS04C vaccine or the AS04C adjuvant. However, the applicant assumes that aluminium salt particles containing adsorbed materials follow the same distribution and elimination as for unadsorbed aluminium particles.”

“Theoretically, the vaccine could give rise to antibodies, which cross-react to self-structures, resulting in autoimmune events. Such possibility is not readily studied in experimental animal models, but can only be studied in the clinical situation.”

“Experimental studies to demonstrate absorption, distribution, metabolism, and excretion of the active ingredients in Gardasil have not been performed for any of the component viruses. This is in line with Note for guidance on preclinical pharmacological and toxicological testing of vaccines (CPMP/SWP/465/95).”

“The increase in splenic weights was considered an expected secondary effect to the stimulation of the immune system by vaccination and was converted to normal range following a 21-day recovery. Theoretically, immune stimulation holds a risk of causing/exacerbating autoimmune diseases, but such a risk can only be characterized in post-marketing settings.”

“No studies on absorption, distribution, metabolism or excretion were performed. This is in line with the CHMP Note for Guidance on Preclinical Pharmacological and Toxicological Testing of Vaccines and is therefore acceptable.”

“Based on the design of this repeated dose toxicology study, no immuno-toxicological findings such as autoimmune reactions were observed. It is noted that this animal study revealed no kidney or vascular lesions justifying further examinations or indicating potential immune complex deposition.”

“The 300 mcg 1018 ISS + HBsAg dose (approximately 20 times the human dose) induced only a 2-fold increase in IL-12p40 levels over baseline, and the 15 mcg 1018 ISS + HBsAg dose (a 1 X human dose) did not induce an increase in either IL-12p40 or IFN-g levels after the first or last injection.”

“According to published data the rapid decline is due to initial low affinity binding to plasma proteins (95%) and to significant distribution to kidney (up to 20 % of the dose), liver, and to a minor extent spleen.”

“The neutrophil counts and fibrinogen concentrations showed evidence of a return to levels similar to those recorded before treatment commenced within three days after dosing.”

“[14C]-QS-21 was almost exclusively eliminated via urinary excretion with >99 % of the injected dose recovered in urine by 72 h after dosing.”

“The findings were considered consistent with immune system stimulation consequent to administration of an active adjuvant, and comprised: local injection site inflammation, reversible enlargement of the lymph nodes draining the injection sites (but not elsewhere), and chemical markers of inflammation (i.e., CRP, fibrinogen, and globulin).”

“As the Matrix-M1 adjuvant is not currently marketed in a human vaccine in the EU market, Novavax is planning to conduct a biodistribution study in mice to evaluate the Matrix-M1 adjuvant, which may be of value in further understanding the mode of action of the adjuvant.”

“There were no vaccine-related adverse gross or microscopic pathologic findings observed at terminal necropsy other than isolated incidence of slight discrete lymphoid hyperplasia in the spleens and lymph nodes of the vaccine treated rats, which represented an expected immunostimulatory property of the vaccine.”

“Pharmacokinetic studies were not performed with PreHevbri. This was considered acceptable by the CHMP.”

“These changes in CRP levels reflect an activation of the acute-phase response and indicate increasing levels of systemic inflammation, which potentially may be correlated with clinical adverse events such as malaise, fatigue, and nausea.”

“Taken together, the biodistribution studies with QS-21 and MPL administered in solution have shown that QS-21 and MPL are widely distributed throughout the body and are eliminated within several hours (48-168 h).”

“In accordance with current guidelines, pharmacokinetic studies are not required for the vaccine assessment. No non-clinical pharmacokinetic studies have been performed to evaluate absorption, distribution, metabolism and excretion of the active ingredients of RIV4.”