PhD Thesis Defense: Nicholas Curtis

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"Characterization of Antibody Repertoires Developed from Naive and Recall Responses"

Abstract

Adaptive immunity, comprised in part by the antibody repertoire, is the cornerstone of our ability to remain healthy amongst the plethora of pathogenic challenges we encounter daily. Despite the importance of understanding antibody repertoire development, much remains unknown about the composition and evolution of circulating antibodies in response to viral challenges.

To better understand antibody repertoire development, we profiled the serum antibody repertoire using a combination of next-generation sequencing and serum antibody proteomics in the predominantly naïve response against SARS-CoV-2 spike and the recalled response to influenza hemagglutinin. The response to SARS-CoV-2 spike in four convalescent individuals was diverse (consisting of between 59 and 167 clonotypes) and predominately targeted regions of the protein which were inaccessible on prefusion spike and likely non-protective. Only a small fraction of these antibodies could target any tested SARS-CoV-2 variants. Few of the recombinantly expressed antibodies neutralized the virus, and those that did neutralize were orders of magnitude weaker than a representative therapeutic antibody; however, all antibodies showed robust ADCP, ADCC, and ADCD activities. In one donor, an antibody with high binding to another human coronavirus, HKU1, dominated the serum repertoire and had levels of somatic hypermutation commonly observed in recalled antibodies. This antibody was the only among a panel we characterized which maintained binding to the highly mutated B.1.1.529 variant.

Contrastingly, the response to influenza hemagglutinin in two adult vaccinees was dominated by broadly reactive antibodies which maintained binding to strains circulating at the time of the individuals’ birth. The repertoire was highly polarized, as one of these highly abundant “imprinted” antibody clonotypes accounted for up to 64% of hemagglutinin-reactive serum IgG. The inferred progenitors of these serum antibodies had considerable binding breath and evolved to acquire binding to contemporary strains. During the maturation process some antibodies maintained binding to ancestral strains while others lost binding.

This work helps to identify novel therapeutic antibodies and provides new insights to guide the development of vaccines for eliciting protective antibody responses in the short-term (i.e., following first infections and vaccinations) while also providing memory against variants which may be encountered later in life.

Thesis Committee

• Jiwon Lee (Chair)
• Margaret Ackerman
• Britt Goods
• Aaron Schmidt (Ragon Institute of Mass General, MIT, and Harvard)

Contact

For more information, contact Thayer Registrar at thayer.registrar@dartmouth.edu.