Type 2-polarized memory B cells hold allergen-specific IgE memory.

Allergen-specific immunoglobulin E (IgE) antibodies mediate pathology in diseases such as allergic rhinitis and food allergy. Memory B cells (MBCs) contribute to circulating IgE by regenerating IgE-producing plasma cells upon allergen encounter. Here, we report a population of type 2-polarized MBCs defined as CD23hi, IL-4Rαhi, and CD32low at both the transcriptional and surface protein levels. These MBC2s are enriched in IgG1- and IgG4-expressing cells while constitutively expressing germline transcripts for IgE. Allergen-specific B cells from patients with allergic rhinitis and food allergy were enriched in MBC2s. Furthermore, MBC2s generated allergen-specific IgE during sublingual immunotherapy, thereby identifying these cells as a major reservoir for IgE. The identification of MBC2s provides insights into the maintenance of IgE memory, which is detrimental in allergic diseases but could be beneficial in protection against venoms and helminths.

Different human vaccine adjuvants promote distinct antigen-independent immunological signatures tailored to different pathogens.

The majority of vaccine candidates in clinical development are highly purified proteins and peptides relying on adjuvants to enhance and/or direct immune responses. Despite the acknowledged need for novel adjuvants, there are still very few adjuvants in licensed human vaccines. A vast number of adjuvants have been tested pre-clinically using different experimental conditions, rendering it impossible to directly compare their activity. We performed a head-to-head comparison of five different adjuvants Alum, MF59®, GLA-SE, IC31® and CAF01 in mice and combined these with antigens from M. tuberculosis, influenza, and chlamydia to test immune-profiles and efficacy in infection models using standardized protocols. Regardless of antigen, each adjuvant had a unique immunological signature suggesting that the adjuvants have potential for different disease targets. Alum increased antibody titers; MF59® induced strong antibody and IL-5 responses; GLA-SE induced antibodies and Th1; CAF01 showed a mixed Th1/Th17 profile and IC31® induced strong Th1 responses. MF59® and GLA-SE were strong inducers of influenza HI titers while CAF01, GLA-SE and IC31® enhanced protection to TB and chlamydia. Importantly, this is the first extensive attempt to categorize clinical-grade adjuvants based on their immune profiles and protective efficacy to inform a rational development of next generation vaccines for human use.

Tuberculosis vaccine with high predicted population coverage and compatibility with modern diagnostics.

A central goal in vaccine research is the identification of relevant antigens. The Mycobacterium tuberculosis chromosome encodes 23 early secretory antigenic target (ESAT-6) family members that mostly are localized as gene pairs. In proximity to five of the gene pairs are ESX secretion systems involved in the secretion of the ESAT-6 family proteins. Here, we performed a detailed and systematic investigation of the vaccine potential of five possible Esx dimer substrates, one for each of the five ESX systems. On the basis of gene transcription during infection, immunogenicity, and protective capacity in a mouse aerosol challenge model, we identified the ESX dimer substrates EsxD-EsxC, ExsG-EsxH, and ExsW-EsxV as the most promising vaccine candidates and combined them in a fusion protein, H65. Vaccination with H65 gave protection at the level of bacillus Calmette-Guérin, and the fusion protein exhibited high predicted population coverage in high endemic regions. H65 thus constitutes a promising vaccine candidate devoid of antigen 85 and fully compatible with current ESAT-6 and culture filtrate protein 10-based diagnostics.