Effective Induction of Simian Immunodeficiency Virus-Specific Cytotoxic T Lymphocytes in Macaques by Using a Multiepitope Gene and DNA Prime-Modified Vaccinia Virus Ankara Boost Vaccination Regimen

Abstract

DNA and modified vaccinia virus Ankara (MVA) are vaccine vehicles suitable and safe for use in humans. Here, by using a multicytotoxic T-lymphocyte (CTL) epitope gene and a DNA prime-MVA boost vaccination regimen, high levels of CTLs specific for a single simian immunodeficiency virus (SIV) gag-derived epitope were elicited in rhesus macaques. These vaccine-induced CTLs were capable of killing SIV-infected cells in vitro. Fluorescence-activated cell sorter analysis using soluble tetrameric major histocompatibility complex-peptide complexes showed that the vaccinated animals had 1 to 5% circulating CD8+ lymphocytes specific for the vaccine epitope, frequencies comparable to those in SIV-infected monkeys. Upon intrarectal challenge with pathogenic SIVmac251, no evidence for protection was observed in at least two of the three vaccinated animals. This study does not attempt to define correlates of protective immunity nor design a protective vaccine against immunodeficiency viruses, but it demonstrates clearly that the DNA prime-MVA boost regimen is an effective protocol for induction of CTLs in macaques. It also shows that powerful tools for studying the role of CTLs in the control of SIV and human immunodeficiency virus infections are now available: epitope-based vaccines, a protocol for an effective induction of CTLs in primates, and a simple and sensitive method for quantitation of epitope-specific T cells. The advantages of the DNA prime-MVA boost regimen as well as the correlations of tetramer staining of peripheral blood lymphocytes with CTL killing in vitro and postchallenge control of viremia are discussed.

Neurovirulence and Immunogenicity of Attenuated Recombinant Vesicular Stomatitis Viruses in Nonhuman Primates

“…Since the prime and boost vectors differ only in the surface G proteins, the VSV protein-specific CMI response to other viral proteins may have restricted replication of boosting virus. The use of fully heterologous prime-boost vaccination regimens with rVSV and either plasmid DNA or other viral vectors results in more robust postboost HIV-1-specific cellular immune responses (86)(87)(88)(89). The differences in levels of gag-specific immune responses elicited by the attenuated and prototypic vectors tested in this study probably are the outcome of a complex interplay between induction and susceptibility to host innate and acquired immune responses during vector replication and antigen priming of APC.…”

Nanotechnology in vaccine delivery

“…A malaria vaccine administered using this dosing regimen also showed promise in the clinic [48,50]. Preclinical trials of viralvectored vaccines used to immunize against tuberculosis [65], Ebola [66] and SIV [67] using a prime-boost strategy also appear promising.…”

Current situation in the development of a preventive HIV vaccine

“…The most advanced pre-clinical protocols of the new vaccine prototypes include that being developed by Aventis Pasteur in Uganda, which uses a Canarypox vector for the expression of viral structural proteins 60 . Also in Uganda, January 2003 saw the start of a phase I trial combining DNA + MVA (strain A) 61 . A similar phase I clinical trial sponsored by IAVI and KAVI is being carried out in Kenya.…”