Abstract
Mutational changes that mostly occur at the head region of hemagglutinin (HA) lead to the emergence of new epidemic influenza viruses, whereas HA antigens have been modified to generate broadly neutralizing antibodies toward highly conserved epitopes in the HA stem. Interestingly, a recent analysis of serum antibody repertoires showed that broadly neutralizing antibodies bind to HA monomer at a conserved region occluded at the intermonomer interface of HA trimer and confer protection in animal models. We showed previously that the recombinant HA ectodomain from a pandemic strain A/Korea/01/2009 was monomeric in solution and crystal structure. In order to examine the potential antigenicity of a monomeric form, we designed HA monomer that incorporates mutations to destabilize trimer conformations. Starting with the HA trimer from a seasonal strain A/Thailand/CU44/2006, mutations were introduced at the intermonomer interface, Ser199 of HA1 and Gly47, Arg75, Phe88, Val91, and Arg106 of HA2. Two mutants, F88E and V91W, were characterized to form a monomer and their double mutant F88E/V91W monomer was selected as an antigen. Animal studies showed that the HA monomer induced protective immunity in vivo, comparable to the trimer, albeit low antibody titers in sera.
Highlights
Mutational changes that mostly occur at the head region of hemagglutinin (HA) lead to the emergence of new epidemic influenza viruses, whereas HA antigens have been modified to generate broadly neutralizing antibodies toward highly conserved epitopes in the HA stem
We previously showed that the purified recombinant HA ectodomain from a pandemic H1N1 (pH1N1) isolate, A/Korea/01/2009 (KR01), was a monomer in solution[18]
A recent analysis of serum antibody repertoires in young adults before and after seasonal influenza vaccination showed that broadly neutralizing cross-reactive antibodies bind to a monomeric HA at a highly conserved region occluded in HA trimer, which conferred full protection against influenza challenge[31]
Summary
Mutational changes that mostly occur at the head region of hemagglutinin (HA) lead to the emergence of new epidemic influenza viruses, whereas HA antigens have been modified to generate broadly neutralizing antibodies toward highly conserved epitopes in the HA stem. A recent analysis of serum antibody repertoires showed that broadly neutralizing antibodies bind to HA monomer at a conserved region occluded at the intermonomer interface of HA trimer and confer protection in animal models. A recent analysis of serum antibody repertoires in young adults before and after seasonal influenza vaccination showed that broadly neutralizing cross-reactive antibodies bind to a monomeric HA at a highly conserved region occluded in HA trimer, which conferred full protection against influenza challenge[31]. This observation is contrary to that of earlier research showing that cross-reactive epitope sites require HA trimerization to attain full antigenicity. These HA trimer-dependent antibodies were bound to monomeric HA with KDs in the range of nM, with slightly decreased affinity compared to the trimer[32]
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