MEMP PhD Thesis Defense (3:00 PM): Eric Wang

Computational Design of Vaccines against Mutable Pathogens

Although vaccination has saved hundreds of millions of lives and virtually eradicated numerous pathogens that once plagued humanity, some viruses such as SARS-CoV-2, influenza, and HIV remain difficult targets due to their ability to quickly mutate and evade previous immune responses. Consequently, the development of vaccines that remain effective against diverse viral strains is a critical challenge for improving human health.

The vastness of protein sequence space presents both an exciting opportunity and a significant challenge for designing vaccine antigens. To navigate this complexity, integrating computational methods with experimental data and a mechanistic understanding of the adaptive immune response offers a promising approach for identifying optimal sequences for new vaccines. In this thesis, we develop three new vaccine antigens using computational techniques specifically tailored to address the unique challenges posed by viral mutability and to take advantage of modern vaccine platforms.

First, we present the development of a cocktail of antigens based on the SARS-CoV-2 receptor-binding domain (RBD), designed to protect against future mutations. Although these antigens were created prior to the emergence of the Omicron variant, they include the majority of mutated residues found in Omicron. Computational modeling of the antibody response suggests that our cocktail elicits more robust protection against SARS-CoV-2 variants than vaccines based on the unmutated RBD. In the second project, we describe the development of mosaic RBD-nanoparticles that promote antibodies targeting conserved epitopes. These designs were stably expressed and tested in both naïve mice and mice with prior COVID-19 vaccinations. Our designed mosaic RBD-nanoparticles generated broader antibody responses than previous state-of-the-art RBD-nanoparticles and significantly broader responses than bivalent mRNA vaccines. Deep mutational scanning revealed that these responses were indeed concentrated on conserved epitopes. Lastly, our third project focuses on the development of antigens that may elicit potent T-cell responses targeting HIV. The antigens were designed to include regions that are both immunogenic and difficult for the virus to mutate without compromising fitness. We show that our design features regions that are both highly conserved and contain antagonistic fitness interactions, and that it is immunogenic for the majority of HLA haplotypes in the Caucasian population.

Thesis Supervisor:
Arup K. Chakraborty, PhD
John M. Deutch Institute Professor
Professor of Chemical Engineering, Physics and Chemistry, MIT

Thesis Committee Chair:
Karl Dane Wittrup, PhD
Carbon P. Dubbs Professor in Chemical Engineering, MIT

Thesis Reader:
Daniel Lingwood, PhD
Associate Professor of Medicine, Harvard Medical School
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Topic: Eric Wang MEMP PhD Thesis Defense
Time: Friday, November 22, 2024, 3:00 PM Eastern Time (US and Canada)

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