Abstract
(1) Influenza viruses constantly change and evade prior immune responses, forcing seasonal re-vaccinations with updated vaccines. Current FDA-approved vaccine manufacturing technologies are too slow and/or expensive to quickly adapt to mid-season changes in the virus or to the emergence of pandemic strains. Therefore, cost-effective vaccine technologies that can quickly adapt to newly emerged strains are desirable. (2) The filamentous fungal host Thermothelomyces heterothallica C1 (C1, formerly Myceliophthora thermophila) offers a highly efficient and cost-effective alternative to reliably produce immunogens of vaccine quality at large scale. (3) We showed the utility of the C1 system expressing hemagglutinin (HA) and a HA fusion protein from different H1N1 influenza A virus strains. Mice vaccinated with the C1-derived HA proteins elicited anti-HA immune responses similar, or stronger than mice vaccinated with HA products derived from prototypical expression systems. A challenge study demonstrated that vaccinated mice were protected against the aggressive homologous viral challenge. (4) The C1 expression system is proposed as part of a set of protein expression systems for plug-and-play vaccine manufacturing platforms. Upon the emergence of pathogens of concern these platforms could serve as a quick solution for producing enough vaccines for immunizing the world population in a much shorter time and more affordably than is possible with current platforms.
Highlights
Influenza virus infections account for 3–5 million cases of severe respiratory disease worldwide, associated with 300,000 to 600,000 deaths annually [1,2]
We developed the protein expression system based on the novel filamentous fungal Thermothelomyces heterothallica C1
Several full-length membrane-linked HA proteins were expressed in C1, including those derived from the pre-2009 pandemic A/H1N1/(Puerto Rico/8/1934) and A/H1N1/(New Caledonia/20/99), the A/H3N2/ (Texas/1/1977) and the 2009 pandemic A/H1N1/(California/7/2009) strains, as well as the B (Florida/4/2006) strain
Summary
Influenza virus infections account for 3–5 million cases of severe respiratory disease worldwide, associated with 300,000 to 600,000 deaths annually [1,2]. Seasonal influenza virus infections are caused by type A and B influenza viruses (IAV and IBV, respectively), both containing eight −ssRNA segments encoding at least 10–12 ORFs. IAVs are further divided into subtypes based on the antigenic profile of the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) [3]. Due to the segmented nature of their genomes, influenza viruses can re-assort and generate novel strains [6,7]. Pandemic influenza strains are IAVs with HA segments derived from strains in the animal reservoir [8,9] and for which humans carry little to non-existent immunity due to the divergent immunological properties of the HA and NA subtypes. Humans are considered the only natural reservoir of IBVs, but have diverged into two antigenically distinct lineages known as Victoria and Yamagata lineages [10]. The HA1 region contains the receptor binding site [13,14] and is the major target of the neutralizing immune responses against influenza [15]
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