Abstract
Current influenza vaccines do not elicit broadly protective immune responses against multiple strains. New strategies to focus the humoral immune response to conserved regions on influenza antigens are therefore required for recognition by broadly neutralizing antibodies. It has been suggested that B-cells with receptors that recognize conserved epitopes would be preferentially stimulated through avidity effects by mosaic particles presenting multiple forms of a variable antigen. We adapted SpyCatcher-based platforms, AP205 virus-like particles (VLPs) and mi3 nanoparticles (NPs), to covalently co-display SpyTagged hemagglutinin (HA) trimers from group 1 and group 2 influenza A strains. Here we show successful homotypic and heterotypic conjugation of up to 8 different HA trimers to both VLPs and NPs. We characterized the HA-VLPs and HA-NPs by cryo-electron tomography to derive the average number of conjugated HAs and their separation distances on particles, and compared immunizations of mosaic and homotypic particles in wild-type mice. Both types of HA particles elicited strong antibody responses, but the mosaic particles did not consistently elicit broader immune responses than mixtures of homotypic particles. We conclude that covalent attachment of HAs from currently-circulating influenza strains represents a viable alternative to current annual influenza vaccine strategies, but in the absence of further modifications, is unlikely to represent a method for making a universal influenza vaccine.
Highlights
Each year, influenza virus infections affect 5–30% of the global population, resulting in millions of severe infections and hundreds of thousands of deaths [1]
We adapted the AP205 SpyCatcher-virus-like particles (VLPs) platform that we had previously used to conjugate a trimeric HIV-1 immunogen [21] as a way to increase the intrinsic immunogenicity of HA, mask undesired epitopes located at the bottom of the HA trimer, and attach different HA trimers to the same particle
Attempts to develop broadly protective influenza vaccines have been challenging partly due to the immunodominance hierarchy of antibody epitopes on HA
Summary
Influenza virus infections affect 5–30% of the global population, resulting in millions of severe infections and hundreds of thousands of deaths [1]. Epidemics are typically caused by the influenza type A, with a smaller number of infections resulting from type B. Vaccines can minimize the incidence of severe infections; they do not offer complete protection and have to be re-administered annually [1, 2]. The lack of complete efficacy of current vaccines can be attributed to several reasons.
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