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<p>The evolution of antigenically variable viruses cannot be understood without studying
the interaction between viruses and the host immune system. Viral evolution is driven
by their fast acquisition of genetic variation as well as by the strong selection
imposed by the host immune response. Moreover, understanding viral evolution dynamics
and its interplay on the host immune response can provide essential information for
vaccine development. In this dissertation, I use an integrative approach to study
various aspects of this interplay in two viral systems: influenza A (IAV) and cytomegalovirus
(CMV), both ubiquitous in humans and significant public health threats. </p><p>Congenital
cytomegalovirus infection is the leading infectious cause of congenital defects. As
such, the study of viral dynamics is essential to develop better treatment and prevention
procedures. In a monkey challenge study for congenital cytomegalovirus infection,
I investigated viral transmission between maternal and fetal compartments. Using high-coverage
sequencing data, I examined viral evolutionary dynamics in time and space. I found
evidence of large transmission bottleneck sizes between maternal compartments and
in congenital transmission. I also inquire about the role of preexistent CMV-specific
antibodies in the virus population, finding no apparent effect in the viral genetic
make-up but reduced viral load and also reduced congenital transmission. </p><p>One
of the more promising vaccine formulation for CMV until now is the gB-MF59 vaccine,
which is based on a soluble version of the immunodominant gB protein. To understand
immune and viral factors contributing to vaccine efficacy for this formulation, I
examined immunoglobulin G binding to a gB-specific peptide microarray from seropositive
individuals and vaccinees prior to and after vaccination. The antibody profile observed
from binding clustered by individual immune exposure history. While the antibody profile
elicited by vaccination show high agreement with the one from seropositive individuals,
I also identified regions in gB preferentially targeted in vaccinees. Moreover, I
observe no difference between the antibody profiles of vaccinees with different clinical
outcomes and instead found further evidence for reduced cross-immunity between divergent
genotypes. </p><p>Original antigenic sin (OAS) refers to the tendency of the host
immune system to focus on previously recognized viral epitopes during secondary challenges
with related viral strains. This preference is sustained by antibody memory and can
result in suboptimal immune protection. Mounting evidence highlights the importance
of the initial viral strain encountered during childhood, which primes the antibody
repertoire to contend against further infections. Here, the goal was to identify OAS-driven
cohort effects in IAV driven by at least one antigenic mutation. Using sequence data
and host's age information from individuals infected with H1N1 in the U.S. from 2009
to the present, we searched for potential signatures of birth year cohort changes
driven by new variants with nonsynonymous mutations. We identified multiple variants
with such properties and studied the age groups with differential abundance after
such variant arose.</p>
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