T cells control the generation of nanomolar-affinity anti-glycan antibodies

Abstract

Vaccines targeting glycan structures at the surface of pathogenic microbes must overcome the inherent T cell-independent nature of immune responses against glycans. Carbohydrate conjugate vaccines achieve this by coupling bacterial polysaccharides to a carrier protein that recruits heterologous CD4 T cells to help B cell maturation. Yet they most often produce low- to medium-affinity immune responses of limited duration in immunologically fit individuals and disappointing results in the elderly and immunocompromised patients. Here, we hypothesized that these limitations result from suboptimal T cell help. To produce the next generation of more efficacious conjugate vaccines, we have explored a synthetic design aimed at focusing both B cell and T cell recognition to a single short glycan displayed at the surface of a virus-like particle. We tested and established the proof of concept of this approach for 2 serotypes of Streptococcus pneumoniae. In both cases, these vaccines elicited serotype-specific, protective, and long-lasting IgG antibodies of nanomolar affinity against the target glycans in mice. We further identified a requirement for CD4 T cells in the anti-glycan antibody response. Our findings establish the design principles for improved glycan conjugate vaccines. We surmise that the same approach can be used for any microbial glycan of interest.

T Cell–Mediated Humoral Immune Responses to Type 3 Capsular Polysaccharide of Streptococcus pneumoniae

“…Through in vitro expansion, this T cell population could be enriched. In addition to our own studies, multiple past and present studies demonstrate the presence of T cell populations that recognize carbohydrate epitopes of glycoconjugate vaccines (21–24). This work contributes to the broader application of Tcarb mediated immune responses and next-generation vaccine development strategies against bacterial pathogens.…”

The challenges of glycan recognition with natural and artificial receptors

“…[30][31][32] Typically, glycan-binding antibodies exhibit lower affinities (with equilibrium dissociation constant (K D ) values in the micromolar range for monovalent interactions) than protein-specific antibodies (with K D values in the nanomolar range). 33,34 However, affinities can be enhanced by generating antibodies containing two or more glycan binding sites, or through non-covalent assembly into oligomers with multiple binding sites. 35,36 The formation of a multivalent complex can result in higher affinities and enhanced selectivities.…”

“…A growing understanding of the immunological mechanisms by which the immune system refines its antibodies, together with recent technological advances in carbohydrate chemistry and bioconjugation are also enabling the production of highaffinity anti-glycan antibodies. 48,49 By using Qb virus-like particles (VLPs) conjugated via copper-catalyzed azide-alkyne cycloaddition with short synthetic glycans, anti-glycan IgG antibodies with nanomolar affinity were produced (Fig. 3).…”

“…3). 48 The controlled glycan density displayed on the virus-like particles facilitated not only B but also T cell recognition, which subsequently provided T cells with help in promoting affinity maturation in B cells.…”

Overexpression of O‐polysaccharide chain length regulators in Gram‐negative bacteria using the Wzx‐/Wzy‐dependent pathway enhances production of defined modal length O‐polysaccharide polymers for use as haptens in glycoconjugate vaccines

“…; Polonskaya et al . ). Manipulation of the OPS synthesis pathway represents an efficient and economical approach to achieve high yields of homogenous polysaccharides of a predetermined size, with clear advantages over the prior approaches.…”