Control of Simian/Human Immunodeficiency Virus Viremia and Disease Progression after IL-2-Augmented DNA-Modified Vaccinia Virus Ankara Nasal Vaccination in Nonhuman Primates

Abstract

A successful HIV vaccine may need to stimulate antiviral immunity in mucosal and systemic immune compartments, because HIV transmission occurs predominantly at mucosal sites. We report here the results of a combined DNA-modified vaccinia virus Ankara (MVA) vaccine approach that stimulated simian/human immunodeficiency virus (SHIV)-specific immune responses by vaccination at the nasal mucosa. Fifteen male rhesus macaques, divided into three groups, received three nasal vaccinations on day 1, wk 9, and wk 25 with a SHIV DNA plasmid producing noninfectious viral particles (group 1), or SHIV DNA plus IL-2/Ig DNA (group 2), or SHIV DNA plus IL-12 DNA (group 3). On wk 33, all macaques were boosted with rMVA expressing SIV Gag-Pol and HIV Env 89.6P, administered nasally. Humoral responses were evaluated by measuring SHIV-specific IgG and neutralizing Abs in plasma, and SHIV-specific IgA in rectal secretions. Cellular responses were monitored by evaluating blood-derived virus-specific IFN-γ-secreting cells and TNF-α-expressing CD8+ T cells, and blood- and rectally derived p11C tetramer-positive T cells. Many of the vaccinated animals developed both mucosal and systemic humoral and cell-mediated anti-SHIV immune responses, although the responses were not homogenous among animals in the different groups. After rectal challenge of vaccinated and naive animals with SHIV89.6P, all animals became infected. However a subset, including all group 2 animals, were protected from CD4+ T cell loss and AIDS development. Taken together, these data indicate that nasal vaccination with SHIV-DNA plus IL-2/Ig DNA and rMVA can provide significant protection from disease progression.

Generation and evaluation of a recombinant modified vaccinia virus Ankara vaccine for rabies

“…This finding appears to be in line with others, such as a study involving recombinant MVA expressing measles virus antigens, where MVA recombinants boosted low-levels of vaccine induced immunity much more efficiently than live attenuated measles virus vaccine [64]. Booster responses induced by MVA recombinants upon mucosal delivery, specifically after intranasal delivery, have also been indicated in macaques [65] and [66]. The most prominent value of recombinant MVA vaccines lie in this so-called "booster effect".…”

Differential CD4+versus CD8+T-Cell Responses Elicited by Different Poxvirus-Based Human Immunodeficiency Virus Type 1 Vaccine Candidates Provide Comparable Efficacies in Primates

“…However, vaccine-induced T-cell and humoral immune responses were not sufficient to protect animals from SHIV 89.6p infection, but immunized animals that became infected were protected from disease progression for more than a year (66 weeks), while the majority of control animals developed evidence of AIDS-like disease. Others also have previously shown vaccine-induced control of the SHIV 89.6P load and protection from disease progression (3,8,19,21,24). It is possible that protection is relatively easy to induce in the challenge model used (25).…”

HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

“…Finally, the Tat protein, both intracellular and extracellular, exerts key roles in the pathogenesis of AIDS-associated tumors [100,102] and AIDS-associated neuropathogenesis [103]. The first exon of Tat encodes aminoacids 1-72, which include the N-terminal prolinerich (aa [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], the cysteine-rich (aa 21-37 containing 7 cysteines) and the core (aa 38-48) regions, representing Tat activation domain, and the basic region (aa 49-58) for nuclear localization and binding to the HIV LTR TAR RNAs. The C-terminal region of Tat, comprising the second exon, contains the arginine-glycine-aspartic acid (RGD), which is a motif present in extracellular matrix proteins [104][105][106].…”

“…However, few have provided significant protective immunity in non human primate models [6][7][8][9][10][11][12][13] and, most importantly, results from clinical trials, including the first phase III trial (AIDSVAX carried by VacGen) based on a monomeric gp120 Env protein, have been largely disappointing [14][15][16]. These failures may be ascribed to several reasons, including the fact that i) recombinant monomeric gp120 molecules are insufficient to create the correct antigen conformation for induction of neutralizing antibodies, which indeed recognize mostly conformational epitopes on native trimeric Env proteins, and ii) neutralization sensitive conserved epitopes, mainly located in the V3 region of Env [17], are masked and not accessible to antibodies in native Env proteins because of conformation and heavy glycosylation [18,19].…”