Antibody Responses Elicited by DNA Prime-Protein Boost HIV Vaccines: A Dissertation
2010
The best known correlate of protection provided by vaccines is the presence of
pathogen specific antibodies after immunization. However, against the Human
Immunodeficiency Virus-1 (HIV-1) the mere presence of antibodies specific for the viral
Envelope (Env) protein is not sufficient to provide protection. This necessitates in depth
study of the humoral responses elicited during infection and by vaccination. While a
significant amount of effort has been invested in studying the evolution of antibody
responses to viral infection, only limited progress in understanding antibody responses
elicited through vaccination has been made. In the studies described here, I attempt to
rectify this deficiency by investigating how the quality of a humoral response is altered
with the use of different immunization regimens, in particular a DNA prime-protein boost
regimen, or with the use of different model HIV-1 Env gp120 immunogens. In a New
Zealand White (NZW) rabbit model, we demonstrate that the broader neutralizing
activity elicited with the DNA prime-protein boost regimen may be the result of the
elicitation of a higher avidity antibody response and a unique profile of antibody
specificities. Specifically, use of a DNA prime-protein boost regimen elicits antibodies
targeted to the CD4 binding domain of the HIV-1 Env, a specificity that was not
frequently observed when only protein based immunizations were administered.
We extended this analysis to sera from healthy human volunteers who
participated in early phase HIV vaccine trials utilizing either a protein alone
immunization regimen, a canarypox prime-protein boost immunization regimen, or a
DNA prime-protein boost immunization regimen. Evaluation of sera from these trials
demonstrated that the use of a DNA prime-protein boost regimen results in an antibody
response with greater neutralization breadth characterized by an increased frequency and
titer of antibodies targeted toward the CD4 binding site (CD4bs). In addition to this, the
antibody response elicited by the DNA prime-protein boost regimen also exhibited the
capability to mediate antibody dependent cell-mediated cytotoxicity (ADCC) activity as
well as activation of the complement system.
Additionally, in an attempt to better understand the capabilities of antibodies
elicited by a DNA prime-protein boost regimen, we generated gp120 specific monoclonal
antibodies (mAbs) from a single DNA primed-protein boosted NZW rabbit. Analysis of
mAbs produced from this animal revealed that use of this immunization regimen elicits
an antibody repertoire with diverse epitope specificity and cross reactivity. Furthermore,
these select mAbs are capable of neutralizing heterologous HIV isolates. Further
application of mAb generation in rabbits may provide a valuable tool to study
immunogenicity of different vaccines and immunization regimens.
Concurrently, while demonstrating that a DNA prime-protein boost regimen
elicits a higher quality antibody response than that observed with other leading
techniques, we also…
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