Phase 1 Safety and Immunogenicity Study of a Quadrivalent Seasonal Flu Vaccine Comprising Recombinant Hemagglutinin-Flagellin Fusion Proteins

Abstract

Background. We evaluated the safety and immunogenicity of VAX2012Q, a quadrivalent influenza vaccine comprising 4 hemagglutinin subunits fused to flagellin.Methods. In this dose-ranging, open-label study, healthy adults (18–40 years) were divided into 7 cohorts for evaluation of 5 dose levels and 3 component ratios. Dose levels were as follows: (1) 1 mcg per component of VAX128C (H1N1), VAX181 (H3N2), VAX173 (B-YAM), and VAX172 (B-VIC), respectively; (2) 2 mcg per component, respectively; (3) 2, 4, 4, and 4 mcg of each component, respectively; (4) 2, 4, 6, and 6 mcg of each component, respectively; and (5) 3 mcg per component, respectively. Tolerability and immunogenicity data were analyzed.Results. Three hundred sixteen subjects received VAX2012Q (309 per protocol). At all dose levels, 54% to 65% of subjects reported mild injection site pain, the most common local reaction. Moderate injection site pain increased at dose levels 2 through 5 (22%–42%, compared with 20% at dose level 1). Systemic symptoms were mostly mild to moderate with moderate symptoms increasing in dose levels 3 and 4. Three dose level 3 subjects (6%) reported severe, transient chills and or fever. Mean fold rises in hemagglutination inhibition titers ranged from 2.5 to 6.9 despite high baseline titers. Mean seroprotection rates were ≥90% and mean seroconversion rates were ≥40% for all strains in all groups postvaccination.Conclusions. VAX2012Q elicited immune responses at all dose levels with no significant safety concerns. Doses of 2 or 3 mcg per component provided a favorable balance of tolerability and immunogenicity.

Bioconjugation Approaches to Producing Subunit Vaccines Composed of Protein or Peptide Antigens and Covalently Attached Toll-Like Receptor Ligands

“…For example, influenza vaccines VAX 102/125/2012Q, all containing the TLR5 agonist Flagellin, cause no safety issues at the doses assessed in multiple phase I/II studies. [17][18][19] Trumenba ® , which incorporates an N-terminal bacterial lipopeptide TLR2 agonist, was also well tolerated in human clinical trials. 68 Many other antigen-adjuvant conjugate vaccine candidates have also been demonstrated to be effective in animal models.…”

“…Numerous (bio)chemical strategies have been developed to covalently attach adjuvant molecules onto antigen peptides or proteins, most of which can be summarized into three categories: synthetic, recombinant fusion proteins, and semisynthetic approaches. 12,[14][15][16][17][18][19] The selection of one of these approaches needs to be rationally chosen based on the properties of the antigen and adjuvant. For example, chemical synthesis offers a cost-effective and feasible way to produce short peptides and small proteins and offers significant opportunities to engineer in non-natural components, while the routine synthesis of large peptides and proteins are less accessible due to synthetic difficulties.…”

Second-generation Flagellin-rPAc Fusion Protein, KFD2-rPAc, Shows High Protective Efficacy against Dental Caries with Low Potential Side Effects

“…The flagellin–TLR5 axis might also trigger cardiac innate immune responses and result in cardiovascular dysfunction 27 . To balance tolerability and immunogenicity, only doses of 2 or 3 μg per component is favorable 28 . To offer efficient and safe protection, an effort must be made to reduce the inflammatory response but maintain the adjuvanticity induced by flagellin.…”

Safety and Immunogenicity of an Egg-Cultivated Quadrivalent Inactivated Split-virion Influenza Vaccine (GC3110A) in Healthy Korean Children: a Randomized, Double-blinded, Active-controlled Phase III Study

“…In the U.S., there are currently 3 pharmaceutical manufacturers producing quadrivalent influenza vaccines, and the development of new vaccines is in the works. 14 15 In terms of approval age, split-virion vaccines have been approved for individuals 6 months and older or 3 years and older depending on the manufacturer, while live attenuated vaccines have been approved for individuals between 2 and 49 years of age. In December 2014, the MFDS approved the first Korean quadrivalent influenza vaccine for use in individuals aged 3 years and older.…”