Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful HCMV vaccine tested to date, demonstrating ∼50% efficacy in preventing HCMV acquisition in multiple phase 2 trials. However, the mechanism of vaccine protection remains unknown. Plasma from 33 postpartum women gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope specificity as well as neutralizing and nonneutralizing anti-HCMV effector functions and compared with an HCMV-seropositive cohort. gB/MF59 vaccination elicited IgG responses with gB-binding magnitude and avidity comparable to natural infection. Additionally, IgG subclass distribution was similar with predominant IgG1 and IgG3 responses induced by gB vaccination and HCMV infection. However, vaccine-elicited antibodies exhibited limited neutralization of the autologous virus, negligible neutralization of multiple heterologous strains, and limited binding responses against gB structural motifs targeted by neutralizing antibodies including AD-1, AD-2, and domain I. Vaccinees had high-magnitude IgG responses against AD-3 linear epitopes, demonstrating immunodominance against this nonneutralizing, cytosolic region. Finally, vaccine-elicited IgG robustly bound membrane-associated gB on the surface of transfected or HCMV-infected cells and mediated virion phagocytosis, although were poor mediators of NK cell activation. Altogether, these data suggest that nonneutralizing antibody functions, including virion phagocytosis, likely played a role in the observed 50% vaccine-mediated protection against HCMV acquisition.

Background The frequencies, cellular phenotypes, epitope specificity and clonal diversity of allergen-specific B cells in food allergic patients are not fully understood, but are of major pathogenic and therapeutic significance. Objective To characterize peanut allergen-specific B cell populations, and the sequences and binding activities of their antibodies, before and during immunotherapy. Methods B cells binding fluorescently labeled Ara h 1 or Ara h 2 were phenotyped and isolated by flow cytometric sorting from 18 patients at baseline and 13 during therapy. 57 monoclonal antibodies derived from allergen-binding single B cells were evaluated by ELISA, Western blotting and peptide epitope mapping. Deep sequencing of B cell repertoires identified additional members of the allergen-specific B cell clones. Results Median allergen-binding B cell frequencies were 0.0097% (Ara h 1) or 0.029% (Ara h 2) of B cells in baseline allergic patient blood, and were approximately three-fold higher during immunotherapy. Five of 57 allergen-specific cells belonged to clones containing IgE-expressing members. Almost all allergen-specific antibodies were mutated, and binding to both conformational and linear allergen epitopes was detected. Increasing somatic mutation of IgG4 members of a clone was seen in immunotherapy, while IgE mutation levels in the clone did not increase. Conclusion Most peanut allergen-binding B cells isolated by antigen-specific flow sorting express mutated and isotype-switched antibodies. Immunotherapy increases their frequency in the blood, and even narrowly-defined allergen epitopes are recognized by numerous distinct B cell clones in a patient. The results also suggest that oral immunotherapy can stimulate somatic mutation of allergen-specific IgG4.

Previous evidence suggests that a homeostatic germinal center (GC) response may limit bortezomib desensitization therapy. We evaluated the combination of costimulation blockade with bortezomib in a sensitized non-human primate kidney transplant model. Sensitized animals were treated with bortezomib, belatacept, and anti-CD40 mAb twice weekly for a month (n = 6) and compared to control animals (n = 7). Desensitization therapy-mediated DSA reductions approached statistical significance (P = .07) and significantly diminished bone marrow PCs, lymph node follicular helper T cells, and memory B cell proliferation. Graft survival was prolonged in the desensitization group (P = .073). All control animals (n = 6) experienced graft loss due to antibody-mediated rejection (AMR) after kidney transplantation, compared to one desensitized animal (1/5). Overall, histological AMR scores were significantly lower in the treatment group (n = 5) compared to control (P = .020). However, CMV disease was common in the desensitized group (3/5). Desensitized animals were sacrificed after long-term follow-up with functioning grafts. Dual targeting of both plasma cells and upstream GC responses successfully prolongs graft survival in a sensitized NHP model despite significant infectious complications and drug toxicity. Further work is planned to dissect underlying mechanisms, and explore safety concerns.

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The main function of the immune system is to fight off potential infections, but also to maintain its activity below a level that would trigger self-reactivity. Regulatory T cells (Tregs) such as forkhead box P3+ (FOXP3) Tregs and type 1 regulatory T cells (Tr1) play an essential role in this active process, using several distinct suppressive mechanisms. A wide range of pathologies have been associated with altered Treg cell function. This is best exemplified by the impact of mutations of genes essential for Treg function and the associated autoimmune syndromes. This review summarizes the main features of different subtypes of Tregs and focuses on the clinical implications of their altered function in human studies. More specifically, we discuss abnormalities affecting FOXP3+ Tregs and Tr1 cells that will lead to autoimmune manifestations and/or allergic reactions, and the potential therapeutic use of Tregs.