Outflanking immunodominance to target subdominant broadly neutralizing epitopes

Abstract

A major obstacle to vaccination against antigenically variable viruses is skewing of antibody responses to variable immunodominant epitopes. For influenza virus hemagglutinin (HA), the immunodominance of the variable head impairs responses to the highly conserved stem. Here, we show that head immunodominance depends on the physical attachment of head to stem. Stem immunogenicity is enhanced by immunizing with stem-only constructs or by increasing local HA concentration in the draining lymph node. Surprisingly, coimmunization of full-length HA and stem alters stem-antibody class switching. Our findings delineate strategies for overcoming immunodominance, with important implications for human vaccination.

Hemagglutinin head-specific responses dominate over stem-specific responses following prime boost with mismatched vaccines

“…The dominance of HA head-specific Abs is consistent with the serological dominance of head Ab observed in humans (31), ferrets (32), and mice (33,34). Although the mechanistic basis for HA stem subdominance remains unclear (35), a study in mice suggests that under typical immunization conditions, HA-head specific naive B cells outcompete stem-specific naive B cells for limiting amounts of antigens based on the higher avidity of the B cell receptors for head versus stem epitopes (36).…”

Protective Malaria Vaccine in Mice Based on the Plasmodium vivax Circumsporozoite Protein Fused with the Mumps Nucleocapsid Protein

“…Although the mechanism involved is not within the scope of this paper, some of the following hypotheses can be taken into consideration: (i) Some protein regions may be more available to antibody binding than others in the tertiary protein structure, which would confer an advantage for B-cell activation. This is one of the most important features of B-cell responses and has been extensively studied for antigens such as HA from the influenza virus and gp120 from HIV [52,53]. While the preference of the antibody response to recognize the repeat portions of the CSP during infections has also been documented, our chimeric construct combines all repeat variants into one protein and seems to prioritize the B-cell immune response to individual components that remain ambiguous [47,54]; (ii) Furthermore, the recognition of some epitopes can interfere with the availability of the antibody binding to the other epitopes.…”

Original Antigenic Sin: How Original? How Sinful?

“…But interactions between sub-stances are always scalar: At some level, every Ab binds every antigen, just with different affinity (or avidity for multivalent ligands). Primary antibodies induced by HA typically have dissociation constants (K D ) in the 1 to 10 nM range, increasing up to 100-fold after multiple rounds of somatic mutation induced by boosting (de St Groth and Webster 1966a,b;Webster 1966;Frank et al 2015;Angeletti et al 2019). Ab affinity for cross-reacting antigens will generally be lower than inducing immunogens, but even low-affinity interactions become meaningful at high concentrations of just one of the reactants.…”

“…Is the group-specific nature of imprinting due to priming of HA stem-specific B cells (Tesini et al 2019)? If so, can it be overcome by immunogens designed to activate only B cells specific for the nonimprinted stem or avoided entirely by including group I and group II immunogens in the first vaccine a child receives ( perhaps, immunizing with each immunogen in different sites to avoid competition in individual lymph nodes [Angeletti et al 2019]).…”