Phase 1 safety and immunogenicity study of a quadrivalent seasonal flu vaccine comprising recombinant hemagglutinin-flagellin fusion proteins

摘要: Control of seasonal and pandemic influenza represents a global public health challenge due to the virus's ability circumvent protective immune responses through frequent mutation subunit recombination. These characteristics, coupled with influenza's spread rapidly during outbreaks, require continuous surveillance, vaccine reformulation, tightly scheduled manufacturing. Egg- cell-culture–based production methods are resource- time-intensive, leaving little room for error in selection components or timing production. For example, 2014–2015, long manufacturing lead times prevented industry from addressing discrepancy between H3 virus predominantly circulating northern hemisphere included licensed [1]. Furthermore, low effectiveness 2012–2013 season was attributed mutations introduced as part egg-based [2]. Rapid response, high-yield that remain faithful sequences therefore needed address shortcomings current approaches. Recombinant technologies have potential such include recombinant HA [3], virus-like particles consisting hemagglutinin (HA), neuraminidase (NA), matrix (M1) proteins [4, 5], vaccinia virus-based expression NA [6], HA1 fragment [7], HA2 stalk [8], well DNA vector-based multiple antigens [9]. To date, none has achieved combination rapid, production, potency, sequence is sufficient deficiencies associated egg- cell-based approaches. We developed platform whereby globular head domain major antigen, HA, fused Toll-like receptor (TLR)5 agonist, flagellin (Salmonella typhimurium type 2 [STF2]) [10–12]. The binding STF2 TLR5 on surface sentinel cells activates innate system and, turn, enhances adaptive response [10]. moiety serves built-in adjuvant. relatively simple fusion can be inexpensively produced standard Escherichia coli systems at high yield. Specifically, yields range 0.3 1 mg purified bulk drug substance per liter fermentation, cycle time under weeks (unpublished observations). In animal models humans, individual HA-STF2 elicit HA-specific neutralizing antibodies microgram doses [13]. We reproduced these results using variety A B strains, we also determined optimal, subtype type-specific placement each within protein [12–17]. dose antigen required, rapidity efficiency further demonstrate capacity vaccines. Extending this work, developing prototypic quadrivalent flu vaccine, VAX2012Q. report Phase I dose-ranging study designed identify total component ratio provides optimal tolerability immunogenicity profiles.