Prime-boost immunization strategies against HIV-1
Year: 2007
Type: dissertation
Abstract: Since the start of the global HIV epidemic in 1981, more than twentyfive\nmillion people have succumbed to AIDS-related diseases. The epidemic is\nmost severe in Sub-Saharan Africa, where twentyfive million people are\ncurrently infected and more than two million died during 2006. An\nindication of the epidemic s severity is that every hour the virus\ninfects between 300 and 800 people. It is clear that an effective\nprophylactic vaccine is desperately needed. Attempts to utilize classical\nvaccine strategies against HIV-1 have proven inefficient or potentially\nharmful and researchers have therefore been obliged to explore novel\nvaccine approaches. Genetic immunization is a new way of inducing immune\nresponses against antigens deriving from microbial pathogens or tumors.\nThe gene encoding the antigen of interest is introduced into the body by\nmeans of an expression vector, which commonly is a recombinant bacterial\nplasmid or an attenuated recombinant microbe. This method of immunization\nhas the primary benefit of inducing an immune response that mimics the\nresponse to natural infection with an intracellular pathogen. The primary\nstrategy we use to induce high levels of broadly reactive immune\nresponses against HIV-1 is immunization with naked DNA encoding multiple\nviral antigens in combination with potent adjuvants. The immune responses\nthat are induced against plasmid-encoded antigens can be significantly\naugmented by subsequently boosting with additional vaccine modalities, an\nimmunization protocol referred to as heterologous prime boost.\n\nSpecifically, we show in mice that it is possible to obtain both humoral\nand cellular immune responses to all plasmid-encoded HIV-1 antigens in a\nmulti-plasmid vaccine. The cytokine granulocyte macrophage-colony\nstimulating factor acted as an adjuvant. We also show that spatial\nseparation of the vaccine components could augment the immune responses\nto some of the included antigens. Further, the responses induced by the\nmulti-plasmid vaccine were efficiently boosted using Modified Vaccinia\nvirus Ankara (MVA) carrying similar, but not identical, HIV-1 genes. The\nMVA boost resulted in significantly increased levels of HIV-1 specific\nantibodies as well as extremely high levels of polyfunctional CD8+ T cell\nresponses directed against all included HIV-1 antigens. We also show the\ncapacity of DNA and MVA to induce long-lived vaccine-specific\nimmunological memory. Importantly, DNA was shown capable of efficiently\nboosting an immune response primed almost one year earlier by the same\nDNA construct. Moreover, the capacity of different vaccine protocols to\ninduce protection against a cell-based HIV-1 challenge was demonstrated\nin an experimental model. Protection against challenge was obtained by\nimmunizing with plasmids encoding HIV-1 Gag, Env and Tat, either alone or\nby priming with the plasmids and subsequently boosting with the\ncorresponding proteins.\n\nWith one exception, all the vaccine constructs described here have been\nor are currently being evaluated in clinical trials. In our initial phase\nI trial, the multigene/multisubtype vaccine has shown great potential to\ninduce HIV-1 specific cellular immune responses in humans that can be\ndramatically augmented and broadened by boosting with the recombinant\nMVA. This vaccine protocol is currently being evaluated in a phase I\ntrial in Tanzania. Overall, the preclinical data presented in this thesis\nhave translated well into immunogenicity in clinical trials.
Source: Figshare
Author: Andreas Bråve
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2149619741