Question 1

Which animal species did regulators accept for approved vaccines?

Accepted Answer

6 of 13 approved vaccines ran pivotal tox in: other species. Details for each product, quoted from FDA and EMA reviews: https://precedia.bio/m/vaccine/species.

Question 2

How long were the pivotal tox studies for approved vaccines?

Accepted Answer

Most common longest pivotal study for approved vaccines: ~1 month (4 wk) (8 of 13). Details for each product, quoted from FDA and EMA reviews: https://precedia.bio/m/vaccine/study-length.

Question 3

Which nonclinical studies did approved vaccines skip?

Accepted Answer

11 of 13 approved vaccines skipped carcinogenicity; 8 of 13 skipped genotoxicity. Details for each product, quoted from FDA and EMA reviews: https://precedia.bio/m/vaccine/skipped-studies.

Question 4

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

Accepted Answer

Rarely public: 0 of 13 reviews of approved vaccines say even partly how the first human dose was set. Standard methods inside. Details for each product, quoted from FDA and EMA reviews: https://precedia.bio/m/vaccine/first-dose.

Question 5

Which risks did regulators probe for approved vaccines?

Accepted Answer

The modality-specific risks FDA and EMA reviewers probed for 13 of 13 approved vaccines, with verbatim quotes. Details for each product, quoted from FDA and EMA reviews: https://precedia.bio/m/vaccine/risks.

Question 6

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

Accepted Answer

13 approved vaccines: 2 first dosed humans outside the US; 8 had recovery in the longest repeat-dose study; 0 finished PPND after filing. Details for each product, quoted from FDA and EMA reviews: https://precedia.bio/m/vaccine/tox-package.

Question 7

What safety margins were accepted for approved vaccines?

Accepted Answer

7 of 13 reviews of approved vaccines state a safety margin: median 50× human exposure at the NOAEL, by condition. Details for each product, quoted from FDA and EMA reviews: https://precedia.bio/m/vaccine/safety-margin.

Question 8

Animal model or human cells: efficacy evidence for approved vaccines

Accepted Answer

11 of 13 approved vaccines never tested the clinical molecule in an animal disease model; 0 rested on human cells or in vitro data alone. Details for each product, quoted from FDA and EMA reviews: https://precedia.bio/m/vaccine/efficacy.

Question 9

What flexibility did FDA and EMA accept for approved vaccines?

Accepted Answer

12 of 13 approved vaccines had a departure from the guideline that regulators accepted. What, and why. Details for each product, quoted from FDA and EMA reviews: https://precedia.bio/m/vaccine/flexibility.

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Arexvyrespiratory syncytial virus vaccine, adjuvanted (AS01E) · RSV preF3; TLR4 (AS01E adjuvant)							→
Cervarixhuman papillomavirus bivalent (types 16, 18) vaccine, recombinant, AS04-adjuvanted · HPV 16/18 L1 VLPs; TLR4 (AS04 adjuvant)							→
Cyfendusanthrax vaccine adsorbed, adjuvanted · B. anthracis PA; TLR9 (CpG 7909 adjuvant)							→
Fendrixhepatitis B vaccine (rDNA), AS04C-adjuvanted · HBsAg VLPs; TLR4 (AS04C adjuvant)							→
Flublokinfluenza vaccine, recombinant hemagglutinin · Influenza HA							→
Gardasilhuman papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant · HPV 6/11/16/18 L1 VLPs							→
Gardasil 9human papillomavirus 9-valent vaccine, recombinant · HPV 9-valent L1 VLPs							→
HBVaxProhepatitis B vaccine (rDNA) · HBsAg VLPs							→
Heplisav-Bhepatitis B vaccine (recombinant), adjuvanted · HBsAg; TLR9 (CpG 1018 adjuvant)							→
MosquirixRTS,S/AS01 malaria vaccine · P. falciparum CSP-HBsAg (RTS,S) VLPs; TLR4 (AS01 adjuvant)							→
NuvaxovidCOVID-19 vaccine, recombinant spike protein nanoparticle, Matrix-M-adjuvanted · SARS-CoV-2 spike (nanoparticle)							→
PreHevbriohepatitis B vaccine (recombinant), 3-antigen · HBsAg S/pre-S1/pre-S2 VLPs							→
Shingrixzoster vaccine recombinant, AS01B-adjuvanted · VZV glycoprotein E; TLR4 (AS01B adjuvant)							→

Approved protein and VLP vaccines (FDA and EMA)

Longest pivotal study, every precedent