Adjuvant solution for pandemic influenza vaccine production

Abstract

Extensive preparation is underway to mitigate the next pandemic influenza outbreak. New vaccine technologies intended to supplant egg-based production methods are being developed, with recombinant hemagglutinin (rHA) as the most advanced program for preventing seasonal and avian H5N1 Influenza. Increased efforts are being focused on adjuvants that can broaden vaccine immunogenicity against emerging viruses and maximize vaccine supply on a worldwide scale. Here, we test protection against avian flu by using H5N1-derived rHA and GLA-SE, a two-part adjuvant system containing glucopyranosyl lipid adjuvant (GLA), a formulated synthetic Toll-like receptor 4 agonist, and a stable emulsion (SE) of oil in water, which is similar to the best-in-class adjuvants being developed for pandemic flu. Notably, a single submicrogram dose of rH5 adjuvanted with GLA-SE protects mice and ferrets against a high titer challenge with H5N1 virus. GLA-SE, relative to emulsion alone, accelerated induction of the primary immune response and broadened its durability against heterosubtypic H5N1 virus challenge. Mechanistically, GLA-SE augments protection via induction of a Th1-mediated antibody response. Innate signaling pathways that amplify priming of Th1 CD4 T cells will likely improve vaccine performance against future outbreaks of lethal pandemic flu.

Protection and Long-Lived Immunity Induced by the ID93/GLA-SE Vaccine Candidate against a Clinical Mycobacterium tuberculosis Isolate

“…GLA adjuvant formulations have been used with experimental vaccines for influenza, HIV (29), respiratory syncytial virus (RSV) (30), leishmaniasis (31), malaria (32), and leprosy (33) in addition to TB (34,35). Many of these vaccines using GLA formulations have also resulted in protection in preclinical animal models, including mice (34)(35)(36), ferrets (37,38), guinea pigs (34,35,39), cotton rats (30), and hamsters (40), against infectious challenge.…”

Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands as Influenza Virus Vaccine Adjuvants Induce Rapid, Sustained, and Broadly Protective Responses

“…Some influenza virus vaccine adjuvants have been demonstrated to induce cross-protective responses (13,22,45), and cross-protection has been associated with the induction of Th1-type immune responses (47). Therefore, we sought to assay whether 1V270 and 1Z105 could induce heterologous protection from influenza viruses in two different assays.…”

“…Avian-origin influenza A viruses of the H5N1 subtype are of concern for their potential to cause a human pandemic with a high mortality rate, and efforts to develop vaccines against H5 subtype avian influenza viruses have demonstrated that H5 subtype HAs are poorly immunogenic and may require the use of an adjuvant (45). Mice were immunized with 2 g of rHA derived from A/Vietnam/1203/2004 (VN/04), a highly pathogenic avian H5N1 subtype virus, plus adjuvant or in vehicle alone (Fig.…”

Vaccine Self-Assembling Immune Matrix Is a New Delivery Platform That Enhances Immune Responses to Recombinant HBsAg in Mice

“…One reason for this long gap is that the principles of adjuvant activity were largely unknown; thus, the development of adjuvants was empirical, Moreover, many adjuvants, including Freund's adjuvant, were reactogenic and not acceptable for licensure (2). Recent methods to improve vaccine delivery have taken several approaches, including the use of virosomes (3)(4)(5), vector-based methods (6)(7)(8), liposome-based methods (9)(10)(11), and the use of more traditional formulation with adjuvants (12)(13)(14)(15)(16)(17). Each of these methods has some drawbacks, in terms of reactogenicity, regulatory issues, product stability, or time required for formulation; however, each of these methods focuses on presenting the vaccine as a particulate.…”