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Antibody Sequencing and Immune Responses.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Antibody Sequencing and Immune Responses./
Author:	Joyce, Collin M.
Description:	1 online resource (469 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-04, Section: B.
Contained By:	Dissertations Abstracts International85-04B.
Subject:	Bioinformatics. -
Online resource:	click for full text (PQDT)
ISBN:	9798380472258

Antibody Sequencing and Immune Responses.
Joyce, Collin M.

Antibody Sequencing and Immune Responses. - 1 online resource (469 pages)

Source: Dissertations Abstracts International, Volume: 85-04, Section: B.

Thesis (Ph.D.)--The Scripps Research Institute, 2023.

Includes bibliographical references

Millions of people continue to die from HIV despite wide-spread use of antiretroviral drugs, signaling the need to develop an effective vaccine. It is well established that neutralizing antibodies play a large role in anti-viral protection and will need to be induced by successfully designed immunogens. Nevertheless, extreme diversity of circulating HIV strains has made this goal difficult to achieve. Therefore, the reliable vaccine elicitation of broadly neutralizing antibodies (bnAbs) that work to confer protection against vastly diverse viral strains represents a promising contributor to ending or controlling the HIV pandemic. Additionally, although a small subset of naturally infected individuals develops potent bnAbs, the antibodies themselves are often associated with rare features of the antibody response to infections which may act as a barrier for successful vaccine design. Thus, the focus of this thesis is to identify and characterize components of the antibody repertoire that are important for the elicitation of bnAbs.In Chapter 1, I use high-throughput antibody next-generation sequencing to characterize the baseline antibody repertoire of an immunoglobulin-loci knock-in rodent, the OmniRat. The goal of this study is to understand its relevance for modeling the human antibody repertoire for vaccination studies. By leveraging our previously published largest single collection of human antibody gene sequences I was able to make comparisons to humans and demonstrate that although the OmniRat may be useful for monoclonal antibody discovery, it has a distinct repertoire from that of humans. Therefore, it is not well suited for use in approximating the human antibody response to candidate vaccine immunogens. Chapter 2 is a longitudinal follow-up to our original description of the baseline human antibody repertoire. Here I aim to describe how features of the baseline human antibody repertoire change over time. To do this, I re-sequenced the antibody repertoires of two healthy human donors from our original study. I show that after ~4 years within a single individual, features of the antibody repertoire had shifted enough to look like that of a different individual. Additionally, we found that most antibody sequences and clonotypes were replaced within that time and characterized a small number of persistent public clonotypes. Our results reveal a stable size and overall diversity of the antibody repertoire, but a significant turnover in the fine composition of the repertoire over time.In Chapter 3 I studied the case of an individual living with HIV-1 who was infected with two similar related founder viruses and went on to mount a broadly neutralizing immune response after 9-11 months of infection. From this individual, a potent lineage of bnAbs was isolated that features different lengths of genetic insertions within a single position. The phenotype of memory B cells from this lineage was also described. By characterizing the antibody-virus co-evolution that occurs within this individual, I offer insight into how a bnAb response might be facilitated through vaccination.Chapter 4 addresses the need for rapid development of neutralizing antibodies against diseases like SARS-CoV-2 and HIV through in vitro affinity maturation. To achieve this end, I wrote an open-source Python package, 'NNK', which is used for processing next-generation sequencing data derived from in vitro affinity maturation experiments and for the identification of enriched mutations. Its application is demonstrated by improving the potency of the anti-HIV bnAb, N49P7. This system will be useful for future pandemic preparedness and the elucidation of features important for bnAb breadth.Chapter 5 explores vaccine induced genetic insertions and deletions (indels) from somatic hypermutation. These indels are rare in memory B cells in part due to the risk of non-productive frameshift mutations. Here through the use two antibody heavy and light chain double knock-in mouse models I show that genetic insertions can be readily induced by immunization and begin to explore the genetic origins of these insertions. These findings, although preliminary, indicate that the creation of indels through vaccination may be less challenging for generating bnAbs than previously thought, significantly impacting future HIV bnAb vaccine design.In conclusion, this thesis provides a comprehensive exploration of the complexities inherent in the antibody repertoire and its potential applications in the design and prediction of effective responses to HIV immunogens. Through a series of detailed investigations, it underscores the significant challenges, as well as the promising opportunities, in the quest to develop a reliable HIV vaccine.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798380472258Subjects--Topical Terms:

583857
Bioinformatics.
Subjects--Index Terms:

Antiretroviral drugsIndex Terms--Genre/Form:

554714
Electronic books.

Antibody Sequencing and Immune Responses.
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