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Tat Oyi vaccine trials to begin in 2007

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Okay, so I guess the honor of posting the first topic of this subject of the new forums falls to me!

I'll start if off with a re-post of status of the research regarding the promising Tat Oyi vaccine. I have been lucky to have been corresponding with Dr. Erwann Loret, who is in charge of the research. I've pasted some of the details of the publication he put out after his study of the effects of the Tat Oyi vaccine on SIV challeneged macaques. The summary of the status, however, was that every single macaque who received the Tat Oyi vaccine had an antibody response to Tat. One macaque was even challenged twice, yet after 6 months no viral reservoir was found. This is very important news indeed. Phase one trials are being prepared, to begin sometime in 2007. So far they will be conducted in Maresille. I'll post more on this in later posts. Read on!

Reservoir cells no longer detectable after a heterologous SHIV challenge with the synthetic HIV-1 Tat Oyi vaccine.

Three adjuvants authorized for human use trigger an immune response with Tat Oyi similar to what was observed with the complete Freund adjuvant in a former study [22]. No local or systemic toxicity or adverse effects were observed in rabbits and macaques with vaccine doses superior to those planed for clinical trials. Furthermore, the synthetic protein Tat Oyi is pharmacologically stable in solution for at least a period of one month, which is a requirement for mass vaccination (data not shown).

Although a low viremia was not achieved for all macaques, reservoir cells were no longer detectable 56 days after a heterologuous challenge. Taken together, these results suggest that a Tat Oyi synthetic protein could be an excellent component of a vaccine targeting HIV-1 and could provide an appropriate treatment against HIV- 1 in both developing and industrial countries. On a fundamental point of view, the decreased level of CD8 cells in the control macaques suggests an important role of extra cellular Tat in the immunodeficiency induced by the HIV-1. We hope to be able to confirm in phase I/II clinical trial with seropositive patients that a therapeutical effect can be obtained from the Tat Oyi vaccination.

This therapeutic effect might result, firstly, in a reduced viremia and stable CD4 cells level following an interruption of the antiretroviral treatment. We believe this vaccine will not prevent sero negative people from HIV infection, however it could avoid the collapse of the cellular immunity, and therefore a therapeutic effect could be expected with the eradication of the virus titres and viral reservoir as is observed with HEPS patients. This vaccine could be also the only affordable therapy for millions of seropositive patients that have no access to antiretroviral treatment.

I finally found out what is exactly going on in Madrid (clinica sandoval) with the testing of a vaccine. They are just recruiting volunteers to test a vaccine (any vaccine anytime in the future). But nothing else...They believe a vaccine is decades away.

Too bad, I was looking forward to seeing the Ensoli trials being conducted in Spain as well (besides Italy and Africa).

As far as what you were told about the expected timeline for a vaccine, you know where I stand on that! An outright cure/ eradication might take longer, but we are just around the corner regarding therapeutic vaccines that will make haart medications a thing of the past.

Let's hope, J220...let's hope...

What exactly is going on with the Ensoli trials?  Has it officially entered Phase II yet?

And what about Remune?  A press release last year indicated that it was about to (re-)enter Phase III as a medication-sparing therapeutic vaccine (either as a first treatment option or as something that could be taken after meds are discontinued):

That is interesting news about the Tat Oyi vaccine.

No, I have no information from the Ensoli trial, only:

A) the last official release from her team was when they announced they were cutting the phase one trial short because of "surpassed expectations".

B) All patients had both cellular and immune responses (can't remember the number, but I believe it was something like 80% and 100 % of subjects, respectively.)

C) They said they were moving forward with phase two, wider-scale tests in both Italy and Africa. Last I heard- albeit through third parties- was that phase two would start sometime in September.

All indications are that anti-Tat therapy is effective. Below I copy a little information on Tat itself, and why this is now a prime target of HIV therapy. This comes from one of the many recent publications that have identified the crucial role of Tat.


What is Tat?

Tat is an 86- to 102-amino-acid transcriptional activator that is encoded by two exons and is highly conserved among HIV isolates. It is produced early during the virus life cycle and is essential for efficient virus replication (4, 9). Several in vitro studies have demonstrated that Tat is secreted from virus-infected cells and exerts its biological effects on neighboring cells by (i) inhibiting T-cell proliferation, (ii) inducing apoptotic cell death, and (iii) increasing permissiveness for infection by both macrophage-tropic and T-cell-tropic HIV isolates as a result of enhanced expression of CXCR4 and CCR5 on susceptible cells. Thus, Tat appears to be involved in both host immune suppression and viral dissemination.

Why use Tat as a vaccine?

The rationale for using Tat as a vaccine target for HIV is supported by the following. First, Tat induces both humoral and cellular immune responses in humans (16, 17, 28). Second, anti-Tat antibodies protect against the increased permissiveness for HIV infection and the inhibitory effects on T-cell proliferation (12, 31, 36) and thus may control disease progression. Third, in HIV-1-infected individuals, anti-Tat antibodies correlate inversely with progression to AIDS (25, 36). In addition, in a recent study of 57 HIV-1-infected subjects, CD8+ T-cell responses against Tat were evident in 19% of these individuals, indicating that Tat is frequently targeted by HIV-1-specific cytotoxic T lymphocytes (CTL) (1). Furthermore, in nonhuman primates, there appears to be selective pressure on Tat CTL epitopes during the acute phase of SIV infection, suggesting that CTL against Tat may play an important role in disease control (2).


Anyway, I have links to many publications regading Tat research, both in vitro and vivo. The conclusions of all research so far are universal, in that targeting Tat results in inhibition of replication and an increase in immune system response. I cannot say much about Ensoli's trial, other than what is publicaly known already, because I have not been able to communicate with anyone associated with that research. I have however, as I stated earlier in the thread, had the good fortune to link up with Dr. Loret. In short, and regarding his testing of the Tat Oyi vaccine in macaques, he states:

The resistance of this macaque [number 966] to SHIV was so impressive that it was challenged twice with another SHIV strain. This second SHIV challenge made possible to see the retroconversion and to reproduce experimentally the serological phenotype observed in Gabon and reported in 1989 by Huet et al.

For those that don't know, the Tat Oyi variant used for Loret's vaccine was identified in a group of individuals in Gabon who retroconverted (sp?). He wrote:

The base of our approach is to have selected the Tat Oyi variant identified in seropositif patients who became seronegative. This cohort was identified in 1986 in Gabon and they were cleared of infection in 1996

So, these are the reasons why anti-Tat therapy is so promising. Indeed, Ensoli's vaccine certainly seems to be doing very well. Ensoli's research began a bit earlier, with some of the first papers which identified Tat antibodies as an important marker for disease progression (i.e. most patients with significant Tat antibodies had a slower, or nonexistent, disease progression).

Loret's phase one trial is set to begin in 2007. If human subjects have a response anywhere close to what was seen in the SHIV models, we should be seeing extremely significant results, perhaps even better that Ensoli's, due to the specificity of the Tat Oyi variant (identified in the patients who became seronegative). In any case, I think anti-Tat is the next big thing, and could very well mean, at the very least, a dramatic shift from present treatment methods (haart), in particular when you consider that anti-Tat therapy is not affected by any resistance issues. And all this with no side effects...not bad. J.


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