Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Hildegund C. Ertl

Abstract

Human immunodeficiency virus type 1 (HIV-1) has infected 76 million people since the beginning of the epidemic. The first evidence that an HIV-1 vaccine could prevent infection in humans was provided in the RV144 vaccine efficacy trial. RV144 demonstrated 31.2% efficacy and immune correlate analyses indicated that antibodies targeting the variable 2 (V2) region of HIV-1 envelope (Env) correlated with decreased risk of infection. However, significant improvements are needed to develop a globally effective vaccine against HIV-1.

Several approaches can be employed to improve upon vaccination strategies: heterologous prime-boost regimens, immunogen design, and alternative adjuvants. To enhance Env-specific antibodies, I tested simian-derived adenovirus (SAdV) vectors expressing Env proteins and administered them in heterologous prime-boost regimens with recombinant Env in adjuvant. In the first study, I tested the SAdV vectors in prime-boost regimens with trimeric Env protein in aluminum salt. Priming with SAdV vector was advantageous over protein prime and inclusion of the trimeric protein induced neutralizing antibodies.

It has been suggested that a vaccine designed to elicit greater V2-specific antibody responses than that seen in the RV144 trial may be more effective at preventing HIV-1 infection. The variable 1 and 2 (V1/V2) region of Env has been grafted onto a protein scaffold and shown to exhibit a native conformation. In the second study, I sought to enhance the V2-specific antibody response using SAdV vectors expressing scaffolded V1/V2. SAdV vectors expressing scaffolded V1/V2 elicited greater V2-specific antibodies only transiently. However, SAdV vectors expressing either HIV-1 gp140 or scaffolded V1/V2 induced sustained response rates of V2 conformational antibodies more than one year after vaccination. This contrasts with the RV144 trial, where V2-specific antibody responses declined quickly after vaccination.

In the third study, I tested calcium phosphate (CaP) as an adjuvant to a recombinant Env protein compared to alum adjuvant. Alum, the most commonly used adjuvant, induces suboptimal immune responses. CaP has demonstrated preferential immune responses as an adjuvant in animals and humans. CaP did not elicit greater antibody responses in this study.

These studies demonstrate SAdV vectors as advantageous vaccine vector platforms and that novel immunogen design can improve HIV-1 vaccines.

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