Abstract
Ig gene repertoire studies enable us to infer information about the development of a humoral
immune response to different challenges, be it infection or vaccination. The COVID-19
pandemic has placed immeasurable burden on healthcare systems and questions arose
about how the humoral response forms. In this thesis I have studied the Ig gene repertoire
from hospitalised COVID-19 patients, as well as volunteers vaccinated against SARS-CoV-
2. The COVID-19 patients’ Ig gene repertoire had immature-like characteristics within its
class-switched sequences, including low or no level of somatic hypermutation and antigen
binding sites (CDRH3s) that were longer and more hydrophobic than healthy controls. A
comparison was made between COVID-19 patients, convalescent Ebola virus (EBOV)
patients and volunteers challenged with live respiratory syncytial virus or yellow fever
vaccine. Despite the lack of commonality between two very different viruses, both EBOV and
COVID-19 patients showed expansion of the gene IGHV4-39, hinting at the possibility of a
generic antiviral response. The study into the mRNA-1273 COVID-19 vaccination showed
the immediate response to the first dose also looked immature, with an expansion in
unmutated, class-switched Ig gene sequences with longer, more hydrophobic CDRH3s.
Significant changes in the repertoire are observed in the blood as soon as day 5 after
vaccine. The repertoire characteristics were similar to those observed in the COVID-19
patient cohort. Despite serological expansion of antibodies after the booster dose, changes
to the repertoire in the blood were minimal. The current pandemic also highlighted the need
for quicker and easier methods to measure adaptive immune memory. Preliminary results
suggested that dielectrophoresis measurements of antigen-stimulated immune cells could be
used to rapidly measure cellular immunity. However, single cell transcriptomics revealed the
stimulation method activated the immune cells non-specifically. This thesis has highlighted
some previously unappreciated characteristics of the B cell repertoire in a primary immune
response.