Engineering B cells to provide protection against infection

As an alternative approach to protect against infection, we have developed approaches where B cells are genetically engineered to produce protective antibodies. This approach could be helpful in situations where vaccination fail to induce protection, or is not possible due to immunodeficiency. Our initial work has been promising, and current work is focused upon improving the protective capabilities of these “emAb” B cells as move this approach towards the clinic to help protect people from infection.

Identification of naive B cells specific for candidate vaccine antigens

The traditional vaccine development process has focused upon designing the pathogen component of the vaccine. This meant either developing ways to weaken or inactivate the pathogen, or developing a process to produce an immunogenic subunit of the pathogen. While these approaches have been incredibly successful for some pathogens, protective vaccines for many infections remain elusive. Recent, evidence suggests that one reason that previous HIV-1 vaccines many have failed is that the HIV-1 antigen included in these vaccines did not stimulate naïve B cells that express antibodies with the ability to protect against HIV-1. If true, this means that vaccine failure could have been predicted if researchers had been able to assess the repertoire of naïve B cells able to bind to the candidate HIV-1 vaccine immunogen prior to vaccination. In light of this, we have begun to utilize our rare antigen-specific enrichment approaches to isolate B cells able to bind to candidate vaccine antigens. These enrichments allow for a robust analysis of the binding abilities of the antibodies expressed by these antigen-specific B cells as well as the phenotype and function of the cells themselves.

Understanding factors limiting B cell activation following vaccination

Protective vaccines rely on the ability of host B cells to recognize foreign antigen and respond, generating effector subsets that can produce antibody and neutralize invading pathogens. However, the critical first step in this process is that the naïve B cell must bind antigen and become activated. Surprisingly, we recently found that in mice 60%-80% of naïve antigen-specific B cells fail to expand in response to vaccination. Current work is aimed at understanding the intrinsic and extrinsic factors that limit the activation of naïve B cells after vaccination. To investigate these questions, we probe the phenotypes and functions of rare antigen-specific human and murine B cells using our antigen-specific enrichment techniques. The goal of this work is to understand the factors that limit naïve B cell activation allowing for activation of all potentially protective naïve B cells after vaccination.

Understanding the differentiation of B cells following vaccination

Naïve B cell activation and proliferation is only the first step in a protective response. Activated B cells must also undergo a complicated process of differentiation in order to produce long-lived antibody-secreting plasma cells and long-lived memory B cells. In previous work we have assessed the number and phenotype of memory B cells generated through the germinal center-dependent and germinal center-independent pathways. Using an in vivo limited dilution approach we have found that a single antigen-specific naïve murine B cell usually does not produce progeny that differentiate down each developmental pathway. Current work is focused upon understanding the B cell intrinsic and extrinsic mechanisms that control differentiation. The ultimate goal of this work is to be able to direct B cell differentiation to ensure that B cells expressing potentially-protective antibodies enter the optimal differentiation pathway to produce long-lived protective progeny.