Effective induction of HIV-specific CTL by multi-epitope using gene gun in a combined vaccination regime
Introduction
The activity of cytotoxic T-lymphocytes (CTL) is an essential component of immune surveillance. Therefore the aim of prophylactic and therapeutic vaccines for many infectious diseases is to prime and/or expand the populations of cytotoxic effector and memory T-cells recognizing pathogen-derived epitopes. These are short usually 9-amino acid-long fragments of antigens presented to the T-cell receptor by major histocompatibility complex molecules[1]. The major obstacle to the development of such vaccines has been the difficulty in eliciting efficiently and reliably strong CTL responses.
Vaccines against acquired immunodeficiency syndrome (AIDS) will likely contain viral subunits rather than whole inactivated or attenuated human immunodeficiency virus HIV preparations as the latter approaches remain controversial for practical and safety reasons. The hopes for an effective CTL epitope-based AIDS vaccine increase with the growing evidence for a central protective role of CTL during the HIV infection2, 3, 4, 5, 6, 7, 8, 9, 10. Such a vaccine reduces the amount of protein or genetic material that needs to be delivered during vaccination, facilitates construction of combined multi-isolate vaccines, enables focusing of the immune responses towards important or conserved protein regions and reduces the chance of incorporating undesired, e.g. immunopathogenic or immunosuppressive, proteins. The polymorphism of HLA molecules causing different individuals to present different sets of peptides to T-cells can be accommodated by selecting optimal epitopes presented by the commonest HLA types. Thus, 5 epitopes are estimated to cover over 80% Caucasian and Oriental populations and 9 would cover a general population irrespective of ethnic descent[11]. If more than 1 relevant epitope for each person is required, the complexity of a broadly efficacious epitope-based vaccine will increase, but would still be feasible.
Novel HIV vaccine candidates were previously constructed. These are based on a gene coding for a string of partially overlapping epitopes recognized by CTL, designated H. This gene was delivered using plasmid pTH DNA[12]or modified virus Ankara (MVA)[13]as vaccine vehicles. Vector pTH was assembled for the purpose of DNA immunization and shown to express high levels of recombinant proteins in vitro. MVA is a strongly attenuated strain of vaccinia virus which was proven to be safe when used in over 120,000 humans[14]. The multi-CTL epitope protein H consists of 20 human (restricted by 12 different HLA alleles), 3 macaque and 1 murine epitope. Gene HM containing 1 additional murine epitope derived from Plasmodium berghei was constructed as a model multi-epitope immunogen so that a parallel induction of CTL specific for two different epitopes could be followed in mice[12]. It was shown that both a single intramuscular (i.m.) vaccination using pTH.HM DNA and a single intravenous (i.v.) or i.m. administration of MVA.HM induced consistently CTL specific for both HIV and Plasmodium epitopes12, 13. When successive prime-boost immunizations to augment the CTL induction were explored, a combined regime of i.m. DNA priming and MVA boosting was found to be the most potent protocol for the elicitation of CTL15, 16.
Gene gun-mediated immunization using the Accell® device (PowderJect Vaccines) is an alternative way of nucleic acid vaccination[17]. This approach has important advantages over the needle injection of DNA intramuscularly. It delivers DNA-coated gold particles into the dermis, a major immunological inductive site and requires 100- to 1000-fold less DNA compared to the i.m. route18, 19, 20, 21. Here, vaccination regimes employing the gene gun in a combination with i.m. DNA or MVA delivery of the multi-CTL epitope immunogen were tested in mice in the search for an efficient and reliable vaccination protocol for induction of CTL prior to commencing primate studies.
Section snippets
The pTH.HM DNA vaccine
The construction of the multi-CTL epitope vector pTH.HM was described previously[12]. The HM gene contains 36 epitopes derived from human and simian immunodeficiency virus, and Plasmodium antigens, which include 2 epitopes recognized by murine CTL. In the pTH vector, the expression of the HM gene is driven by an enhancer/immediate early promoter/intron A region derived from the human cytomegalovirus. The HM open reading frame is followed by a bovine growth hormone polyadenylation site. The
Multi-epitope DNA vaccine delivered by gene gun induced CTL
An effective induction of CTL in mice by i.m. injection of the multi-CTL epitope DNA vaccine pTH.HM was demonstrated previously[12]. However, intramuscular DNA immunization of primates is proving to be more difficult and as much as 2 mg of the vector DNA may be needed to induce detectable levels of CTL activity24, 25. In contrast, gene gun-mediated delivery induces immune responses in mice and larger animals including primates using less than 10-μg quantities of DNA17, 26, 27, 28, 29. It was
Discussion
In the course of this work, the Accell® particle delivery device- or gene gun-mediated DNA immunization using multi-epitope vectors12, 13carried out alone or in combined vaccination regimes effectively induced CTL responses. It was shown in mice that gene gun-induced CTL responses using the multi-epitope DNA vector were boostable (Fig. 1) and that 3 immunizations were required to reach levels of CTL activity comparable to those achieved by a single i.m. injection[12]. Boosted CTL were also
Acknowledgements
Grant support from MRC U.K. (A.McM., T.H., G.L.S., T.J.B.) and The Wellcome Trust (A.V.S.H.) are fully acknowledged.
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