Improving the immunogenicity of HIV-1 DNA vaccines
Author: Hallengärd, David
Date: 2010-02-26
Location: MTCs seminarierum (A302), Nobels väg 16
Time: 13.00
Department: Institutionen för mikrobiologi, tumör- och cellbiologi / Department of Microbiology, Tumor and Cell Biology
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thesis.pdf (1.487Mb)
Abstract
Nearly 30 years have passed since the start of the global HIV epidemic
and we are still unable to control the spread of the virus. HIV
predominately infects cells crucial for the function of the immune
system, integrates into the host genome and demonstrates a huge genetic
variability, and the use of therapeutic antiretroviral drugs can restrain
but not clear the infection. Therefore a protective vaccine is considered
the best approach to counteract HIV. The failure of HIV vaccine
candidates based on classical vaccine strategies have paved the way for
novel vaccine modalities, such as genetic vaccines. These vaccines have
induced broad and robust immune responses in animals but need to be
optimized to ultimately induce protection against HIV infection.
Furthermore, no definite correlates of protection against HIV infection
are yet identified and this severely complicates the vaccine development.
Nevertheless, the licensure of several DNA vaccines for veterinary use
and the induction of protection against SIV infection/disease in
non‐human primate models raise hope for the possibility to induce
protection against HIV‐1/AIDS by DNA vaccination also in humans. This
thesis describes both the effect of optimizing the gene insert and the
use of adjuvants to augment the immune responses after immunization with
HIV‐1 plasmids.
A HIV‐1 protease gene was genetically optimized by changing the amino acid composition. By altering the enzymatic active site, rendering the protein inactive, it was possible to greatly increase the in vitro protein expression and significantly increase the immunogenicity of the gene in various mouse strains, including mice transgenic for the human HLA‐A0201 molecule. We thus identified a rather simple strategy to drastically increase the immunogenicity of HIV‐1 protease and induce strong immune responses against wild type protease as well as against protease carrying drug resistance mutations. The optimized protease construct will be integrated into the clinically evaluated multigene vaccine, HIVIS, and initial results have shown that the immunogenicity of the protease construct, as well as the immunogenicity of the other constructs in the vaccine, is not negatively affected by the addition of the new plasmid. Also, by administering our multigene vaccine formulated in a lipid‐based adjuvant intranasally to young mice we could increase both the systemic cellular and humoral immune responses. In addition, antibody responses could be detected at mucosal sites distant from the intranasal mucosa, demonstrating the ability of DNA vaccines to induce broad immune responses in different compartments of the body. The induction of these mucosal anti‐HIV antibodies presents a possible means to prevent infection at the mucosal surface where the majority of HIV transmissions take place. These and other ways to augment the induction of strong immune responses by DNA vaccination will hopefully provide clues on how to construct and deliver the next generation of potent DNA vaccines against HIV as well as against other infectious diseases and cancers.
A HIV‐1 protease gene was genetically optimized by changing the amino acid composition. By altering the enzymatic active site, rendering the protein inactive, it was possible to greatly increase the in vitro protein expression and significantly increase the immunogenicity of the gene in various mouse strains, including mice transgenic for the human HLA‐A0201 molecule. We thus identified a rather simple strategy to drastically increase the immunogenicity of HIV‐1 protease and induce strong immune responses against wild type protease as well as against protease carrying drug resistance mutations. The optimized protease construct will be integrated into the clinically evaluated multigene vaccine, HIVIS, and initial results have shown that the immunogenicity of the protease construct, as well as the immunogenicity of the other constructs in the vaccine, is not negatively affected by the addition of the new plasmid. Also, by administering our multigene vaccine formulated in a lipid‐based adjuvant intranasally to young mice we could increase both the systemic cellular and humoral immune responses. In addition, antibody responses could be detected at mucosal sites distant from the intranasal mucosa, demonstrating the ability of DNA vaccines to induce broad immune responses in different compartments of the body. The induction of these mucosal anti‐HIV antibodies presents a possible means to prevent infection at the mucosal surface where the majority of HIV transmissions take place. These and other ways to augment the induction of strong immune responses by DNA vaccination will hopefully provide clues on how to construct and deliver the next generation of potent DNA vaccines against HIV as well as against other infectious diseases and cancers.
List of papers:
I. Hallengärd D, Hallermalm K, Boberg A, Petersson S, Roos AK, Wahren B, Bråve A (2010). "Increased expression and immunogenicity of HIV ]1 protease following inactivation of the enzymatic activity." (Manuscript)
II. Bråve A, Hallengärd D, Schröder U, Blomberg P, Wahren B, Hinkula J (2008). "Intranasal immunization of young mice with a multigene HIV-1 vaccine in combination with the N3 adjuvant induces mucosal and systemic immune responses." Vaccine 26(40): 5075-8. Epub 2008 Apr 15
Pubmed
I. Hallengärd D, Hallermalm K, Boberg A, Petersson S, Roos AK, Wahren B, Bråve A (2010). "Increased expression and immunogenicity of HIV ]1 protease following inactivation of the enzymatic activity." (Manuscript)
II. Bråve A, Hallengärd D, Schröder U, Blomberg P, Wahren B, Hinkula J (2008). "Intranasal immunization of young mice with a multigene HIV-1 vaccine in combination with the N3 adjuvant induces mucosal and systemic immune responses." Vaccine 26(40): 5075-8. Epub 2008 Apr 15
Pubmed
Issue date: 2010-02-05
Rights:
Publication year: 2010
ISBN: 978-91-7409-799-3
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