Abstract
Seasonal influenza vaccines are often ineffective because they elicit strain-specific antibody responses to mutation-prone sites on the hemagglutinin (HA) head. Vaccines that provide long-lasting immunity to conserved epitopes are needed. Recently, we reported a nanoparticle-based vaccine platform produced by solid-phase peptide synthesis (SPPS) for targeting linear and helical protein-based epitopes. Here, we illustrate its potential for building broadly protective influenza vaccines. Targeting known epitopes in the HA stem, neuraminidase (NA) active site, and M2 ectodomain (M2e) conferred 50-75% survival against 5LD50 influenza B and H1N1 challenge; combining stem and M2e antigens increased survival to 90%. Additionally, protein sequence and structural information were employed in tandem to identify alternative epitopes that stimulate greater protection; we report three novel HA and NA sites that are highly conserved in type B viruses. One new target in the HA stem stimulated 100% survival, highlighting the value of this simple epitope discovery strategy. A candidate influenza B vaccine targeting two adjacent HA stem sites led to >104-fold reduction in pulmonary viral load. These studies describe a compelling platform for building vaccines that target conserved influenza epitopes.
Highlights
The rapid mutation rate of influenza viruses fuels seasonal epidemics that cause >0.25 million deaths annually and facilitates occasional pandemic outbreaks that can lead to >20 million fatalities [1,2,3,4,5]
Protocol #2019–17 was approved by the Institutional Animal Care and Use Committees (IACUC) of the Infectious Disease Research Institute which operates under a currently approved Assurance #A4337-01, which is in accordance with Public Health Service (PHS) Policy for Humane Care and Use of Laboratory Animals
We have previously reported that peptides synthesized with one B cell epitope located at either the N- or C-terminus induced equivalent antibody responses [35]
Summary
The rapid mutation rate of influenza viruses fuels seasonal epidemics that cause >0.25 million deaths annually and facilitates occasional pandemic outbreaks that can lead to >20 million fatalities [1,2,3,4,5]. Human infections are caused by type A (IAV) and B (IBV) viruses. Antigenic mismatch between vaccine and circulating strains severely limits effectiveness. Selective pressure on unstable epitopes favors escape mutants with substitutions that abrogate antibody binding, thereby undermining long-term protection. This continual antigenic drift forces vaccines to be updated annually based on prediction of the strains that will dominate the upcoming year [8]
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