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The aftermath of the Merck's HIV vaccine trial.

Iaccino E, Schiavone M, Fiume G, Quinto I, Scala G - Retrovirology (2008)

Bottom Line: The recently released results of the Merck's Phase IIb "test-of concept" vaccine trials have shown no protection from HIV-1 infection in the vaccinated group compared with a control group vaccinated with placebo.The study was designed to test the Merck's MRKAd5 trivalent candidate vaccine.The vaccine formulation was expected to stimulate a HIV-specific T cell immune response and to either prevent infection, or to reduce the levels of the viral load in vaccinated subjects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Experimental and Clinical Medicine, University of Catanzaro Magna Graecia, 88100, Catanzaro, Italy. iaccino@unicz.it

ABSTRACT
The recently released results of the Merck's Phase IIb "test-of concept" vaccine trials have shown no protection from HIV-1 infection in the vaccinated group compared with a control group vaccinated with placebo. The study was designed to test the Merck's MRKAd5 trivalent candidate vaccine. The vaccine formulation was expected to stimulate a HIV-specific T cell immune response and to either prevent infection, or to reduce the levels of the viral load in vaccinated subjects. Upon the first evaluation of the interim data, the independent Data and Safety Monitoring Board (DSMB) underscored no protection from HIV-1 infection in the vaccine-inoculated volunteers compared with the control group; accordingly, the vaccine trial was stopped. This disappointing outcome warrants a critical analysis of the current vaccine studies and calls for a renewed effort toward a rational design of novel immunogens to be tested in large primate trials.

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Lymph node histomorphology and in situ hybridization in vaccinated monkeys challenged with SHIV-89.6PD viral RNA. A, Representative lymph node of monkey 493 (vaccine protected) [13]. Inguinal lymph nodes were removed at day 70 after challenge, stained with hematoxylin-eosin and subjected to in situ hybridization. The picture shows the conserved lymph-node architecture and the presence of secondary follicles with expanded germinal centers and well-represented paracortical T cell regions. No SHIV viral RNA is detected. B, Representative lymph node of monkey 480 (unprotected). The picture shows the follicular depletion, paracortical atrophy and abundant presence of SHIV viral copies. Reprinted by permission from Macmillan Publishers Ltd: Nature Medicine, Chen, X. et al., 2001, copyright 2001, Nature Publishing Group [13].
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Figure 1: Lymph node histomorphology and in situ hybridization in vaccinated monkeys challenged with SHIV-89.6PD viral RNA. A, Representative lymph node of monkey 493 (vaccine protected) [13]. Inguinal lymph nodes were removed at day 70 after challenge, stained with hematoxylin-eosin and subjected to in situ hybridization. The picture shows the conserved lymph-node architecture and the presence of secondary follicles with expanded germinal centers and well-represented paracortical T cell regions. No SHIV viral RNA is detected. B, Representative lymph node of monkey 480 (unprotected). The picture shows the follicular depletion, paracortical atrophy and abundant presence of SHIV viral copies. Reprinted by permission from Macmillan Publishers Ltd: Nature Medicine, Chen, X. et al., 2001, copyright 2001, Nature Publishing Group [13].

Mentions: These results represent a grim setback for the HIV vaccine field; however, they came with no surprise within the vaccine community. Indeed, such an outcome was predicted given the nature of the HIV-1 infection and by previous preclinical trials in monkeys. HIV-1 infection is characterized by an acute phase of infection where the virus integrates into the host CD4-positive cell genome and establishes an early viral reservoir characterized by a HIV latency in memory CD4+ T cells [2,3]. However, upon a stochastic activation of CD4 T cells by multiple stimuli, the HIV latency is overcome by the Tat-mediated transactivation of the LTR, which promotes the virus gene transcription and production of infection-competent viral particles that spread to uninfected T cells thereby reconstituting the viral reservoir [3-6]. Reactivation of viral infection occurs preferentially in activated memory T cells [7-9], and results in a limited T-cell repertoire and in a reduced immune competence [10]. In this setting, the immune system mounts a robust anti-HIV T cells immune response that decreases significantly the acute plasma viremia to a lower set point; however, shortly after the primary infection, the T cell-mediated immune pressure generates escape mutants that mediate new rounds of infection that result in increased virus spreading and further deletion of CD4+ susceptible cells [11-14] (shown in Figure 1, 2).


The aftermath of the Merck's HIV vaccine trial.

Iaccino E, Schiavone M, Fiume G, Quinto I, Scala G - Retrovirology (2008)

Lymph node histomorphology and in situ hybridization in vaccinated monkeys challenged with SHIV-89.6PD viral RNA. A, Representative lymph node of monkey 493 (vaccine protected) [13]. Inguinal lymph nodes were removed at day 70 after challenge, stained with hematoxylin-eosin and subjected to in situ hybridization. The picture shows the conserved lymph-node architecture and the presence of secondary follicles with expanded germinal centers and well-represented paracortical T cell regions. No SHIV viral RNA is detected. B, Representative lymph node of monkey 480 (unprotected). The picture shows the follicular depletion, paracortical atrophy and abundant presence of SHIV viral copies. Reprinted by permission from Macmillan Publishers Ltd: Nature Medicine, Chen, X. et al., 2001, copyright 2001, Nature Publishing Group [13].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483718&req=5

Figure 1: Lymph node histomorphology and in situ hybridization in vaccinated monkeys challenged with SHIV-89.6PD viral RNA. A, Representative lymph node of monkey 493 (vaccine protected) [13]. Inguinal lymph nodes were removed at day 70 after challenge, stained with hematoxylin-eosin and subjected to in situ hybridization. The picture shows the conserved lymph-node architecture and the presence of secondary follicles with expanded germinal centers and well-represented paracortical T cell regions. No SHIV viral RNA is detected. B, Representative lymph node of monkey 480 (unprotected). The picture shows the follicular depletion, paracortical atrophy and abundant presence of SHIV viral copies. Reprinted by permission from Macmillan Publishers Ltd: Nature Medicine, Chen, X. et al., 2001, copyright 2001, Nature Publishing Group [13].
Mentions: These results represent a grim setback for the HIV vaccine field; however, they came with no surprise within the vaccine community. Indeed, such an outcome was predicted given the nature of the HIV-1 infection and by previous preclinical trials in monkeys. HIV-1 infection is characterized by an acute phase of infection where the virus integrates into the host CD4-positive cell genome and establishes an early viral reservoir characterized by a HIV latency in memory CD4+ T cells [2,3]. However, upon a stochastic activation of CD4 T cells by multiple stimuli, the HIV latency is overcome by the Tat-mediated transactivation of the LTR, which promotes the virus gene transcription and production of infection-competent viral particles that spread to uninfected T cells thereby reconstituting the viral reservoir [3-6]. Reactivation of viral infection occurs preferentially in activated memory T cells [7-9], and results in a limited T-cell repertoire and in a reduced immune competence [10]. In this setting, the immune system mounts a robust anti-HIV T cells immune response that decreases significantly the acute plasma viremia to a lower set point; however, shortly after the primary infection, the T cell-mediated immune pressure generates escape mutants that mediate new rounds of infection that result in increased virus spreading and further deletion of CD4+ susceptible cells [11-14] (shown in Figure 1, 2).

Bottom Line: The recently released results of the Merck's Phase IIb "test-of concept" vaccine trials have shown no protection from HIV-1 infection in the vaccinated group compared with a control group vaccinated with placebo.The study was designed to test the Merck's MRKAd5 trivalent candidate vaccine.The vaccine formulation was expected to stimulate a HIV-specific T cell immune response and to either prevent infection, or to reduce the levels of the viral load in vaccinated subjects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Experimental and Clinical Medicine, University of Catanzaro Magna Graecia, 88100, Catanzaro, Italy. iaccino@unicz.it

ABSTRACT
The recently released results of the Merck's Phase IIb "test-of concept" vaccine trials have shown no protection from HIV-1 infection in the vaccinated group compared with a control group vaccinated with placebo. The study was designed to test the Merck's MRKAd5 trivalent candidate vaccine. The vaccine formulation was expected to stimulate a HIV-specific T cell immune response and to either prevent infection, or to reduce the levels of the viral load in vaccinated subjects. Upon the first evaluation of the interim data, the independent Data and Safety Monitoring Board (DSMB) underscored no protection from HIV-1 infection in the vaccine-inoculated volunteers compared with the control group; accordingly, the vaccine trial was stopped. This disappointing outcome warrants a critical analysis of the current vaccine studies and calls for a renewed effort toward a rational design of novel immunogens to be tested in large primate trials.

Show MeSH
Related in: MedlinePlus