Arexvy

“The Applicant has provided two DART studies with RSVPreF3 (without adjuvant): one in rabbit (doses of 120 μg antigen) and one in rat (doses of 48 μg antigen). In addition, the report from a DART study with the complete product (i.e., RSVPreF3/AS01E; full human dose, 120 μg PreF3) in rabbit was provided.”

“Levels of anti-RSVPreF3 IgG antibodies were increased (measured at Day 32 and 57) in 80% of females and all males administered RSVPreF3 and in 80-90% of females and all males administered RSVPreF3 adjuvanted with AS01B in the first study.”

“The antigen dose is the same as (study COV 8363131) or twice (COV 8384096) the intended clinical dose, however, the clinical formulation is adjuvanted with AS01E instead of AS01B (120 μg RSVPreF3 with 0.5 mL AS01E). AS01B contains a double dose of (the same) immuno-enhancers compared to AS01E; therefore, the adjuvant dose can be considered more than the clinical dose.”

“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.)”

“The Applicant has provided two DART studies with RSVPreF3 (without adjuvant): one in rabbit (doses of 120 μg antigen) and one in rat (doses of 48 μg antigen). In addition, the report from a DART study with the complete product (i.e., RSVPreF3/AS01E; full human dose, 120 μg PreF3) in rabbit was provided.”

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

“The antigen dose is the same as (study COV 8363131) or twice (COV 8384096) the intended clinical dose, however, the clinical formulation is adjuvanted with AS01E instead of AS01B (120 μg RSVPreF3 with 0.5 mL AS01E). AS01B contains a double dose of (the same) immuno-enhancers compared to AS01E; therefore, the adjuvant dose can be considered more than the clinical dose.”

“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.)”

“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.)”

“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.)”

“The absence of genotoxicity studies is accepted. This is not required for vaccines.”

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

“In addition, the report from a DART study with the complete product (i.e., RSVPreF3/AS01E; full human dose, 120 μg PreF3) in rabbit was provided. In neither of the studies effects were observed on female fertility, embryo-foetal, pre- and postnatal development.”

“In addition, the AS01E adjuvant components (i.e., MPL, QS21) were evaluated in three safety pharmacology studies, ten general toxicology studies, ten genotoxicology studies, five reproductive toxicology studies, and three local tolerance studies.”

“The absence of genotoxicity studies is accepted. This is not required for vaccines.”

“The absence of genotoxicity studies is accepted. This is not required for vaccines.”

“IV1, IM1 and IM2 did not show any evidence of causing chromosome damage or bone marrow cell toxicity in this in vivo test procedure. IM3 showed no evidence of causing micronuclei but did show evidence of causing bone marrow cell toxicity in this in vivo test procedure.”

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

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

“The absence of dedicated safety PD studies can be endorsed.”

“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.”

“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).”

“Local effects at the injection site included minimal to slight myofiber degeneration/necrosis and minimal to moderate mixed inflammatory cell infiltrates, and were in general, more severe in the adjuvanted RSVPreF3 group.”

“Levels of anti-RSVPreF3 IgG antibodies were increased (measured at Day 32 and 57) in 80% of females and all males administered RSVPreF3 and in 80-90% of females and all males administered RSVPreF3 adjuvanted with AS01B in the first study.”

“After vaccination a substantial and consistent immune response was observed, with at 1-month postvaccination a ~10-fold increase in RSV-A neutralising antibody titres, an ~8-fold increase in RSV-B neutralising antibody titres, and a ~12-fold increase in binding antibody titres being observed across studies.”

“Section 15 includes a summary of available results from the ongoing pharmacology studies and the preliminary results of the GLP repeat-dose toxicity study conducted in rabbits with the”

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

“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.)”

“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.)”

“The Applicant has provided two DART studies with RSVPreF3 (without adjuvant): one in rabbit (doses of 120 μg antigen) and one in rat (doses of 48 μg antigen). In addition, the report from a DART study with the complete product (i.e., RSVPreF3/AS01E; full human dose, 120 μg PreF3) in rabbit was provided.”

“In addition, the report from a DART study with the complete product (i.e., RSVPreF3/AS01E; full human dose, 120 μg PreF3) in rabbit was provided. In neither of the studies effects were observed on female fertility, embryo-foetal, pre- and postnatal development.”

“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.”

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

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

“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 Applicant has submitted three primary PD studies to characterise the immunogenicity of the PreF3-AS01E vaccine in mice and two immuno-characterization studies.”

“The Applicant has thoroughly explained that the non-clinical studies are only intended to show immunogenicity and not to evaluate vaccine efficacy, because a good animal model that can mimic the intended human non-naïve elderly target population and the sensitivity to RSV-related disease upon infection is not present.”

“However, the clinical relevance of the observed immune responses and the corresponding conclusions (including selection of the antigen type and adjuvant system) is doubtful because the used antigen doses used in the murine studies are very low (compared to the doses used in the rabbit tox study and in clinical studies)”