Eugene, Hermancia /S
(2012)
Developing a Broadly Reactive HIV Envelope Vaccine.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
One of the challenges facing HIV vaccine development is the diversity of the envelope protein (Env). Env only vaccines protect against homologous virus infection, but have not protected from heterologous virus infection. In this project, soluble Env trimers were designed and constructed to elicit anti-Env immune responses that recognize contemporary viral isolates. Env sequences isolated from the Americas, Europe, Africa, and Asia were aligned to generate a consensus Env sequence that represents clades A, B, C, E, and group M. These Envs were truncated at the transmembrane domain (Envgp140) and stabilized with a T4 fibronectin domain from bacteriophage. The overall hypothesis is a multi-clade vaccine expressing HIV-1 envelope proteins in their trimeric structure will elicit a broad cross-reactive immune response capable of protecting from heterologous virus challenge. Two vaccine strategies were used: a polyvalent vaccine strategy, using a mixture of equal amounts of consensus Env trimers of clades A, B, C and E (Poly consensus) in equal amounts, was directly compared to a single consensus Env representing the entire group M (Con M). Initial immunogenicity studies conducted in mice showed consensus envelopes to be immunogenic. These studies were followed by immunogenicity and efficacy studies in the rhesus macaque model. The macaques were
immunized intramuscularly three times with equal amounts of total protein of either the polyvalent or consensus vaccine in combination with Imject® alum. Both vaccines were immunogenic in monkeys and sera from vaccinated animals detected and neutralized the same number of envelopes from HIV-1 isolates. After challenge with the simian-human immunodeficiency SF162p4 virus, all polyvalent vaccinated animals were infected and two of the four animals vaccinated with Con M Envgp140 showed no evidence of infection. After CD8+ T depletion of the two aviremic animals, virus emerged in one of those animals indicating potential CD8+ T cell viral control. The other animal vaccinated with Con M Envgp140 remained aviremic. The presence of cross-binding antibodies and low neutralizing antibodies elicited by two multi-clade vaccines did not provide protection to all vaccinated animals.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Eugene, Hermancia /S | hee2@pitt.edu | HEE2 | |
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| ETD Committee: |
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| Date: |
16 May 2012 |
| Date Type: |
Publication |
| Defense Date: |
11 April 2012 |
| Approval Date: |
16 May 2012 |
| Submission Date: |
23 April 2012 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
165 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Virology and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
centralized HIV vaccine |
| Date Deposited: |
16 May 2012 17:51 |
| Last Modified: |
16 May 2017 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/11983 |
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