Prime-boost immunization strategies against HIV-1
Author: Bråve, Andreas
Date: 2007-11-02
Location: Gard-Aulan (SMI, Nobelsväg 18) Karolinska Institutet, Solna
Time: 09.00
Department: Institutionen för mikrobiologi, tumör- och cellbiologi / Department of Microbiology, Tumor and Cell Biology
View/ Open:
thesis.pdf (3.760Mb)
Abstract
Since the start of the global HIV epidemic in 1981, more than twentyfive
million people have succumbed to AIDS-related diseases. The epidemic is
most severe in Sub-Saharan Africa, where twentyfive million people are
currently infected and more than two million died during 2006. An
indication of the epidemic s severity is that every hour the virus
infects between 300 and 800 people. It is clear that an effective
prophylactic vaccine is desperately needed. Attempts to utilize classical
vaccine strategies against HIV-1 have proven inefficient or potentially
harmful and researchers have therefore been obliged to explore novel
vaccine approaches. Genetic immunization is a new way of inducing immune
responses against antigens deriving from microbial pathogens or tumors.
The gene encoding the antigen of interest is introduced into the body by
means of an expression vector, which commonly is a recombinant bacterial
plasmid or an attenuated recombinant microbe. This method of immunization
has the primary benefit of inducing an immune response that mimics the
response to natural infection with an intracellular pathogen. The primary
strategy we use to induce high levels of broadly reactive immune
responses against HIV-1 is immunization with naked DNA encoding multiple
viral antigens in combination with potent adjuvants. The immune responses
that are induced against plasmid-encoded antigens can be significantly
augmented by subsequently boosting with additional vaccine modalities, an
immunization protocol referred to as heterologous prime boost.
Specifically, we show in mice that it is possible to obtain both humoral
and cellular immune responses to all plasmid-encoded HIV-1 antigens in a
multi-plasmid vaccine. The cytokine granulocyte macrophage-colony
stimulating factor acted as an adjuvant. We also show that spatial
separation of the vaccine components could augment the immune responses
to some of the included antigens. Further, the responses induced by the
multi-plasmid vaccine were efficiently boosted using Modified Vaccinia
virus Ankara (MVA) carrying similar, but not identical, HIV-1 genes. The
MVA boost resulted in significantly increased levels of HIV-1 specific
antibodies as well as extremely high levels of polyfunctional CD8+ T cell
responses directed against all included HIV-1 antigens. We also show the
capacity of DNA and MVA to induce long-lived vaccine-specific
immunological memory. Importantly, DNA was shown capable of efficiently
boosting an immune response primed almost one year earlier by the same
DNA construct. Moreover, the capacity of different vaccine protocols to
induce protection against a cell-based HIV-1 challenge was demonstrated
in an experimental model. Protection against challenge was obtained by
immunizing with plasmids encoding HIV-1 Gag, Env and Tat, either alone or
by priming with the plasmids and subsequently boosting with the
corresponding proteins.
With one exception, all the vaccine constructs described here have been
or are currently being evaluated in clinical trials. In our initial phase
I trial, the multigene/multisubtype vaccine has shown great potential to
induce HIV-1 specific cellular immune responses in humans that can be
dramatically augmented and broadened by boosting with the recombinant
MVA. This vaccine protocol is currently being evaluated in a phase I
trial in Tanzania. Overall, the preclinical data presented in this thesis
have translated well into immunogenicity in clinical trials.
List of papers:
I. Bråve A, Ljungberg K, Boberg A, Rollman E, Isaguliants M, Lundgren B, Blomberg P, Hinkula J, Wahren B. (2005). "Multigene/multisubtype HIV-1 vaccine induces potent cellular and humoral immune responses by needle-free intradermal delivery." Mol Ther 12(6): 1197-205
Pubmed
II. Bråve A, Ljungberg K, Boberg A, Rollman E, Engström G, Hinkula J, Wahren B. (2006). "Reduced cellular immune responses following immunization with a multi-gene HIV-1 vaccine." Vaccine 24(21): 4524-26
Pubmed
III. Bråve A, Boberg A, Gudmundsdotter L, Rollman E, Hallermalm K, Ljungberg K, Blomberg P, Stout R, Paulie S, Sandström E, Biberfeld G, Earl P, Moss B, Cox JH, Wahren B. (2007). "A New Multi-clade DNA Prime/Recombinant MVA Boost Vaccine Induces Broad and High Levels of HIV-1-specific CD8(+) T-cell and Humoral Responses in Mice." Mol Ther 15(9): 1724-33
Pubmed
IV. Bråve A, Gudmundsdotter L, Gasteiger G, Hallermalm K, Kastenmuller W, Rollman E, Boberg A, Engström G, Reiland S, Cosma A, Drexler I, Hinkula J, Wahren B, Erfle V. (2007). "Immunization of mice with the nef gene from Human Immunodeficiency Virus type 1: Study of immunological memory and long-term toxicology." Infect Agent Cancer 2(1): 14
Pubmed
V. Bråve A, Hinkula J, Cafaro A, Eriksson LE, Srivastava IK, Magnani M, Ensoli B, Barnett SW, Wahren B, Rollman E. (2007). "Candidate HIV-1 gp140DeltaV2, Gag and Tat vaccines protect against experimental HIV-1/MuLV challenge." Vaccine 25(39-40): 6882-90
Pubmed
I. Bråve A, Ljungberg K, Boberg A, Rollman E, Isaguliants M, Lundgren B, Blomberg P, Hinkula J, Wahren B. (2005). "Multigene/multisubtype HIV-1 vaccine induces potent cellular and humoral immune responses by needle-free intradermal delivery." Mol Ther 12(6): 1197-205
Pubmed
II. Bråve A, Ljungberg K, Boberg A, Rollman E, Engström G, Hinkula J, Wahren B. (2006). "Reduced cellular immune responses following immunization with a multi-gene HIV-1 vaccine." Vaccine 24(21): 4524-26
Pubmed
III. Bråve A, Boberg A, Gudmundsdotter L, Rollman E, Hallermalm K, Ljungberg K, Blomberg P, Stout R, Paulie S, Sandström E, Biberfeld G, Earl P, Moss B, Cox JH, Wahren B. (2007). "A New Multi-clade DNA Prime/Recombinant MVA Boost Vaccine Induces Broad and High Levels of HIV-1-specific CD8(+) T-cell and Humoral Responses in Mice." Mol Ther 15(9): 1724-33
Pubmed
IV. Bråve A, Gudmundsdotter L, Gasteiger G, Hallermalm K, Kastenmuller W, Rollman E, Boberg A, Engström G, Reiland S, Cosma A, Drexler I, Hinkula J, Wahren B, Erfle V. (2007). "Immunization of mice with the nef gene from Human Immunodeficiency Virus type 1: Study of immunological memory and long-term toxicology." Infect Agent Cancer 2(1): 14
Pubmed
V. Bråve A, Hinkula J, Cafaro A, Eriksson LE, Srivastava IK, Magnani M, Ensoli B, Barnett SW, Wahren B, Rollman E. (2007). "Candidate HIV-1 gp140DeltaV2, Gag and Tat vaccines protect against experimental HIV-1/MuLV challenge." Vaccine 25(39-40): 6882-90
Pubmed
Issue date: 2007-10-12
Rights:
Publication year: 2007
ISBN: 978-91-7357-327-6
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