PhD Thesis Proposal: Jennifer Lai

Friday, January 17, 2020, 3:30–5:30pm

Rm 232 (Jackson Conf Rm), Cummings Hall

“Engineering Precision Immunogens to Target the Vaccine Antibody Response to Vulnerable Viral Epitopes”

Abstract

The goal of many vaccines is to elicit antibody-mediated protection, yet for certain pathogens not all antibodies are equal. While some antibodies may provide broad protection against many viral strains, others may provide only narrow protection, or even worse, enhance infection. In these cases, a vaccine must selectively elicit protective antibodies from a sea of possible suboptimal or detrimental antibody responses. To this end, this work takes a structure-based immunogen design approach: utilizing structural data of protective antibodies recognizing their cognate viral epitopes, protein engineering tools are employed to develop precision immunogens for human immunodeficiency virus-1 (HIV-1) and Dengue virus.

For HIV-1, major challenges to vaccine design are (1) eliciting antibodies with broad reactivity and function, and (2) targeting antibody responses to vulnerable epitopes amidst irrelevant immunodominant epitopes. Here, a minimal immunogen was engineered to stabilize the b-stranded conformation of the structurally plastic variable loops 1-2 (V1V2), an epitope known to be associated with potent broadly neutralizing and cross-reactive antibody responses. This conformationally stabilized V1V2 loop immunogen exhibits a superior capacity to elicit cross-reactive antibody responses in mouse models.

For Dengue virus, that non-neutralizing and serotype-specific antibodies may mediate enhanced infection poses a challenge to vaccine development. To reduce the risk of eliciting antibodies to epitopes known to be associated with non-neutralizing or serotype-specific responses, a Dengue envelope protein domain III-based immunogen was successfully engineered to ablate undesired epitopes while maintaining an epitope known to elicit broadly neutralizing antibodies. In a mouse model, this domain III immunogen elicits cross-reactive antibody responses to all Dengue serotypes. Epitope-specificity of antibody responses as a result of immunization will be delineated to determine which epitopes, desired or undesired, may contribute to antibody cross-reactivity. Precision immunogens with fine-grained epitope presentation such as those developed here thus have the potential to tailor the vaccine-elicited antibody response.

Thesis Committee

For more information, contact Daryl Laware at daryl.a.laware@dartmouth.edu.