Simian immunodeficiency virus DNA vaccine trial in macaques

Abstract

An experimental vaccine consisting of five DNA plasmids expressing different combinations and forms of simian immunodeficiency virus-macaque (SIVmac) proteins has been evaluated for the ability to protect against a highly pathogenic uncloned SIVmac251 challenge. One vaccine plasmid encoded nonreplicating SIVmac239 virus particles. The other four plasmids encoded secreted forms of the envelope glycoproteins of two T-cell-tropic relatives (SIVmac239 and SIVmac251) and one monocyte/macrophage-tropic relative (SIV-mac316) of the uncloned challenge virus. Rhesus macaques were inoculated with DNA at 1 and 3, 11 and 13, and 21 and 23 weeks. Four macaques were inoculated intravenously, intramuscularly, and by gene gun inoculations. Three received only gene gun inoculations. Two control monkeys were inoculated with control plasmids by all three routes of inoculation. Neutralizing antibody titers of 1:216 to 1:768 were present in all of the vaccinated monkeys after the second cluster of inoculations. These titers were transient, were not boosted by the third cluster of inoculations, and had fallen to 1:24 to 1:72 by the time of challenge. Cytotoxic T-cell activity for Env was also raised in all of the vaccinated animals. The temporal appearance of cytotoxic T cells was similar to that of antibody. However, while antibody responses fell with time, cytotoxic T-cell responses persisted. The SIVmac251 challenge was administered intravenously at 2 weeks following the last immunization. The DNA immunizations did not prevent infection or protect against CD4 ؉ cell loss. Long-term chronic levels of infection were similar in the vaccinated and control animals, with 1 in 10,000 to 1 in 100,000 peripheral blood cells carrying infectious virus. However, viral loads were reduced to the chronic level over a shorter period of time in the vaccinated groups (6 weeks) than in the control group (12 weeks). Thus, the DNA vaccine raised both neutralizing antibody and cytotoxic T-lymphocyte responses and provided some attenuation of the acute phase of infection, but it did not prevent the loss of CD4 ؉ cells.

A DNA vaccine producing LcrV antigen in oligomers is effective in protecting mice from lethal mucosal challenge of plague

“…While it is well known that DNA vaccines can be highly effective in the induction of cell-mediated responses [23,33,34], our data argue strongly that DNA immunization is also effective in the induction of protective antibody responses critical for the development of vaccines against bacterial infections. The level of antibody produced by the tPA-V construct was comparable to that reported for the most effective protein vaccine formulations containing LcrV [35].…”

“…The F1 gene includes a natural leader sequence (aa 1-22) which was also unchanged to keep the two F1 gene designs compatible with those for V and Pla. Y. pestis gene inserts were incorporated individually into the DNA vaccine vector pJW4303 which has been widely used in a very broad range of DNA vaccine studies [23][24][25][26]. It contains the CMV immediate early promoter, an Intron A sequence, and the bovine growth hormone polyA tail as previously reported [27].…”

“…Our previous DNA vaccine studies against other infectious agents have demonstrated that a proper leader sequence was important in inducing high level antibody responses by increasing soluble antigen production in mammalian cell systems [23][24][25][26]. In particular, we have described a molecular approach to enhance the secretion and thus the immunogenicity of the HIV-1 gp120 antigen by linking the human tissue plasminogen activator (tPA) leader sequence to the N terminus of the gp120 protein [23,24,27]. Since LcrV gene does not encode a typical signal peptide, the focus of this study was to determine if the immunogenicity of an LcrV-based DNA vaccine could be improved when engineered to include the signal sequence from tPA.…”

Modulating the immune response to genetic immunization

“…These vaccines, however, were not protective, though they did alter the time course of infection (23,24). DNA vaccines encoding simian immunodeficiency virus (SIV) proteins have elicited neutralizing antibodies and CTL responses in rhesus macaques, although these vaccines also did not protect animals from pathogenic viral challenge (25,26). Immune responses to HIV-1 antigens have been generated in macaques by using genetic immunization (27,28), and multicomponent HIV-1 DNA vaccines have successfully protected macaques from challenge with chimeric SHIV virus (29).…”

Multigene DNA prime‐boost vaccines for SHIV89.6P

“…Notable successes of DNA vaccines in primate models of disease include complete protection of macaques from lethal doses of Plasmodium knowlesi malaria [27] and rabies virus [17]. Several macaque studies have shown reduced simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) viral load in animals vaccinated with DNA alone [5,9,11,18,19,26]. However, DNA vaccines alone generally induce low-level immune responses; these can be boosted by using a different type of vaccine, such as recombinant protein or poxvirus vectors [10,19,26].…”