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The results of a 48-weeks interim analysis of a randomized phase II clinical trial suggest that the Tat vaccine can normalize, in a specific and selective manner, the immune functions of HIV-infected patients being treated with antiretroviral drugs.
These are the key findings of the study conducted by the team of Dr. Barbara Ensoli, Director of the National AIDS Center of the Istituto Superiore di Sanitą, and President Prof. Enrico Garaci, which are published today in the journal PLoS ONE. (
The Tat vaccine has already shown to be safe and capable of inducing specific antibody and cellular immune responses in preclinical studies in monkeys and in previous phase I trials, and now appears to be a promising tool to improve immune functions in HIV-infected subjects treated with antiretroviral drugs (HAART).
"The results published today in PLoS ONE demonstrate that it was worth it to pursue the Tat vaccine strategy - says the President Enrico Garaci -. The improvement of the immunological parameters upon vaccination of patients being treated with antiretroviral drugs represents a key milestone. This is - concludes the President - a first possible indication for use of this vaccine that, today, thanks to the ad interim results of the phase II trial, we are even more determined to move forward".
The interim results of the randomized phase II trial, conducted in 87 HAART-treated patients, 48 weeks after vaccination indicate that not only is the Tat vaccine safe and capable of inducing specific antibody and cellular immune responses, but it also has a key and novel role in reducing immune system alterations observed in HIV infection, which usually persist even under successful HAART. Further, those patients who are the most immunocompromised may benefit the most from Tat vaccination.
This interim analysis shows that vaccinated patients have a significant increase of both B cells and CD4+ T cells (key players of the immune system hit hardest by HIV), as compared to non-vaccinated HAART-treated subjects. Moreover, vaccinated patients show a significant recovery of immune functions (an increase of regulatory and memory T cells) and a reduction of immune activation (CD38 expression on CD8+ T cells and biochemical markers), which is considered to be the primary cause of the clinical manifestations of HIV infection, even under successful antiretroviral therapy.
"These results, obtained with the precious support of the clinical centers involved in the study - says Dr. Barbara Ensoli - suggest that therapeutic vaccination with the Tat vaccine, combined with HAART, can significantly improve the recovery of the immune system in patients with HIV".
The phase II trial is presently ongoing in 11 Italian clinical centers. It has been amended to increase the number of vaccinated patients from 128 to 160 and to include more immunocompromised individuals. Patients fulfilling the inclusion criteria will receive 3 or 5 intradermal administrations of either 7.5 or 30 mg of the Tat vaccine at monthly intervals.
The sites involved in the conduction of the clinical trial are the following: Division of Infectious Diseases, University Policlinic of Modena (Prof. R. Esposito, Prof. C. Mussini), Clinic of Infectious Diseases, Amedeo di Savoia Hospital, Turin (Prof. G. Di Perri), Division of Infectious Diseases, S. Raffaele Hospital, Milan (Prof. A. Lazzarin), Institute of Tropical and Infectious Diseases, University of Milan L. Sacco Hospital (Prof. M. Galli), Division of Tropical and Infectious Diseases, Spedali Civili, Brescia (Prof. G. Carosi), Division of Infectious Diseases, San Gerardo Hospital, Monza (Dr. A. Gori), Unit of Infectious Diseases, University Hospital of Ferrara (Dr. L. Sighinolfi), Unit of Infectious Diseases, S.M. Annunziata Hospital, Florence (Prof. F. Mazzotta), Department of Infectious Dermatology, San Gallicano Hospital, Rome (Prof. G. Palamara), Department of Infectious Diseases, S. Maria Goretti Hospital, Latina (Dr. Mercurio), Division of Infectious Diseases, Policlinic Hospital, University of Bari (Prof. G. Angarano).
The Istituto Superiore di Sanitą is the sponsor of the trial, which is being conducted with special funds from the Italian Ministry of Health. Official information on Tat vaccine and Dr. Ensoli's research program can be found at the website and, or by calling the AIDS Toll Free Number of the Istituto Superiore di Sanitą (Tel. +39.800.86.10.61, from 1.00 p.m. to 6.00 p.m.). From November 12 until December 10, 2010, the AIDS Toll Free Number will extend its opening time from 10.00 a.m. to 6.00 p.m. Furthermore, from 10.00 a.m. to 4.00 p.m. information will be provided also in English.
PLoS ONE is the first journal of primary research from all areas of science to employ a combination of peer review and post-publication rating and commenting, to maximize the impact of every report it publishes. PLoS ONE is published by the Public Library of Science (PLoS), the open-access publisher whose goal is to make the world's scientific and medical literature a public resource.
Barbara Ensoli, Director of the National AIDS Center, and Enrico Garaci, President of the Istituto Superiore di Sanitą (ISS), are publishing today in PloS ONE ( the data of the interim analysis on the Phase II Clinical Trial with the Tat vaccine.
The results of the 48-weeks interim analysis conducted in 87 patients on HAART therapy show that the immunization with Tat "is capable of arriving where therapy alone cannot".
The strategy based on the use of Tat as a vaccine ( " Tat vaccine") had already shown a remarkable potential during the pre-clinical testing (1, 2). After the phase I results (3-8), which confirmed the safety of the vaccine used for the first time in humans, the data from the interim analysis of the ongoing phase II trial allow to consider therapeutic immunization with Tat vaccine as a promising tool to potentiate HAART. Tat immunization of HAART-treated patients appears to restore the equilibrium (homeostasis) of the immune system, which is severely compromised by HIV, and to enhance the drugs' effects.
The rationale
The antiretroviral therapy suppresses HIV replication, but it is often unable to restore the "immune system homeostasis", as it was before the HIV infection. Thus, despite successful HAART, HIV-positive individuals have an increased risk to develop non-AIDS-related illnesses such as cardiovascular, neurological, liver, kidney, tumoral diseases, which generally appear in elderly people (premature aging). In fact, although upon HAART the HIV viral load is reduced to undetectable levels and the CD4+ T cell counts are restored to almost normal values, the subjects often remain still compromised by a kind of continuous "alert" of the immune system, called "immune activation". This is probably a consequence of HIV persistence in those cells/sites where the virus resides and resists to therapy (the so called sanctuaries).
In fact, even under effective HAART, CD4+ T cells, the main viral target, as well as other cell types hit by the virus, continue to express HIV regulatory proteins, including Tat, even when viral replication is undetectable in blood. What is the role of Tat?
Tat is a regulatory protein necessary for HIV replication. Tat contributes to increase immune activation that is necessary for the virus to infect new target cells both at the beginning of infection or under effective HAART when the virus tries to reactivate infection, explaining the persistent viral reactivation. The chronic expression of Tat, which is also released in the extracellular fluids, exerts a "continuous pressure" on viral replication and causes an hyperactivation of the immune system. This, in turn, leads to the persistence of the disease and the appearance of new non-AIDS-related pathologies that are now seen in successfully HAART-treated individuals.
Immunization with the Tat vaccine appears as a very promising new therapeutic approach since it acts, in a selective and focused fashion, against a viral product (Tat) that promotes virus replication and the continuous activation of the immune system.
Main results
The publication shows results of the 48-weeks interim analysis on 87 virologically-suppressed HAART-treated individuals, enrolled in the ongoing phase II multicentric clinical trial of therapeutic immunization with Tat. The Tat vaccine was administered monthly 3 or 5 times by the intradermal route at the dose of 7.5 or 30 mg. An intergroup comparison was performed with 88 virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study conducted at the same clinical sites and evaluated by the same centralized core laboratory.
The data of the phase II clinical trial indicate that immunization with Tat is safe, induces durable humoral and cellular immune responses, and can act in synergy with HAART to restore the homeostasis of the immune system. Of note, more immune-compromised individuals experience greater therapeutic effects from Tat immunization.
For a long time immunologists have aimed at contrasting the immune activation and restoring proper immunological functions which too often are not achieved by HAART since, although it suppresses virus replication, HAART does not entirely control HIV infection. Therefore, it is probable that the immunization with Tat will considerably reduce the risk to develop new and severe pathologies associated with the residual and persistent immune activation that the antiretroviral drugs are unable to eliminate.
In fact, as compared to the Reference Group, Tat-immunized patients show, in addition to an increase of CD4+ T cells, significant increments of B cells, both key players of the immune system that are severely reduced during the infection. Furthermore, the patients immunized with Tat vaccine show a significant recovery of the immune system function (regulatory and memory T cells increase) and a marked reduction of the chronic immune activation status (CD8+ CD38+ lymphocytes, serum beta2-microglobulin and neopterin) considered as a primary cause of non-AIDS-related pathologies and complications as the premature aging. Which are the implications?
These data indicate that HAART can work better when the HIV-1 Tat protein is blocked, and further suggest that the more immune-compromised HAART-treated individuals may benefit the most from the immunization with the Tat vaccine. Therefore, thanks to these results, the regulatory bodies supervising the trial conduction recently approved an amendment to the clinical protocol, to expand patient recruitment to more immune compromised subjects, and to increase the number of participants from 128 to 160. Thus, it is now possible and of utmost importance to enrol new patients for the study completion, in order to accelerate the initiation of further trials based on the Tat vaccine.
Who are the actors of this discovery?
The ISS National AIDS Center directed by Barbara Ensoli; San Gallicano Hospital, the core lab for all the immunological and virological testing; the 10 (now 11) Italian Clinical Centres conducting the trial (all co-authors of the paper); the vaccine production staff (Diatheva) and the staff of the vaccine formulation and kit preparation (Injectalia); the enrollent patients; all the control and supporting organizations such as the Contract Research Organization (OPERA), the Data Safety Monitoring Board (DSMB), the Community Advisory Boards (CAB), the International Advisory Board (IAB), and the AIDS toll-free Help line. The Istituto Superiore di Sanitą, directed by Prof. Garaci, is the sponsor of the trial that was conducted with special funds of the Italian Ministry of Health.
1. Cafaro A., Caputo A., Fracasso C., Maggiorella M.T., Goletti D., Baroncelli S., Pace M., Sernicola L., Koanga-Mogtomo M.L., Betti M., Borsetti A., Belli R., Ākerblom L., Corrias F., Buttė S., Heeney J., Verani P., Titti F., and Ensoli B. Control of SHIV89.6P-infection of cynomolgus monkeys by HIV-1 Tat protein vaccine. Nat. Med. 5:643-650, 1999.
2. Cafaro A, Bellino S, Titti F, Maggiorella MT, Sernicola L, Wiseman RW, Venzon D, Karl JA, O'Connor D, Monini P, Robert-Guroff M, Ensoli B. Impact of Viral Dose and Major Histocompatibility Complex Class IB Haplotype on Viral Outcome in Mauritian Cynomolgus Monkeys Vaccinated with Tat upon Challenge with Simian/Human Immunodeřciency Virus SHIV89.6P J Virol, 84: 8953-8958, 2010.
3. Ensoli B, Fiorelli V, Ensoli F, Cafaro A, Titti F, Buttė S, Monini P, Magnani M, Caputo A, Garaci E. Candidate HIV-1 Tat vaccine development: from basic science to clinical trials. AIDS 20 :2245-2261, 2006.
4. Ensoli B, Fiorelli V, Ensoli F, Lazzarin A, Visintini R, Narciso P, Di Carlo A, Monini P, Magnani M, Garaci E. The therapeutic phase I trial of the recombinant native HIV-1 Tat protein. AIDS 22: 2207-2209, 2008.
5. Longo O., Tripiciano A., Fiorelli V., Bellino S., Scoglio A., Collacchi B., Ruiz Alvarez M.J., Francavilla V., Arancio A., Paniccia G., Lazzarin A., Tambussi G., Tassan Din C., Visintini R., Narciso P., Antinori A., D'Offizi G., Giulianelli M., Carta M., Di Carlo A., Palamara G., Giuliani M., Laguardia M.E., Monini P., Magnani M., Ensoli F., and Ensoli B. Phase I therapeutic trial of the HIV-1 Tat protein and long term follow-up. Vaccine, 27:3306-3312, 2009.
6. Caputo A., Gavioli R., Bellino S., Longo O., Tripiciano A., Francavilla V., Sgadari C., Paniccia G., Titti F., Cafaro A., Ferrantelli F., Monini P., Ensoli F., and Ensoli B. HIV-1 Tat-based vaccines: an overview and perspectives in the field of HIV/AIDS vaccine development. Int. Reviews Immunol., 28:285-334, 2009.
7. Bellino S., Francavilla V., Tripiciano A., Paniccia G., Arancio A., Fiorelli V., Scoglio A., Collacchi B., Campagna M., Lazzarin A., Tambussi G., Tassan Din C., Visintini R., Narciso P., Antinori A., D'Offizi G., Giulianelli M., Carta M., Di Carlo A., Palamara G., Giuliani M., Laguardia M.E., Monini P., Magnani M., Ensoli F., and Ensoli B. Parallel conduction of the phase I preventive and therapeutic trials based on the Tat vaccine candidate. Recent Rev. Clin. Trials, 4:195-204, 2009.
8. Ensoli B., Fiorelli V., Ensoli F., Lazzarin A., Visintini R., Narciso P., Di Carlo A., Tripiciano A., Longo O., Bellino S., Francavilla V., Paniccia G., Arancio A., Scoglio A., Collacchi B., Ruiz Alvarez M.J., Tambussi G., Tassan Din C., Palamara G., Latini A., Antinori A., D'Offizi G., Giuliani M., Giulianelli M., Carta M., Monini P., Magnani M., and Garaci E. The preventive phase I trial with the HIV-1 Tat based vaccine. Vaccine, 28:371-378, 2009.
On the publication Journal PLoS (Public Library of Science) ONE is a prestigious peer-reviewed journal, co-founded by the Nobel Laureate Harold E. Varmus in 2006. PLoS ONE is an open-access journal, publishing only on the web, supported by an Advisory Board of the highest international caliber. PLoS ONE uses a novel reviewing process starting with a pre-review by the Editorial board, a subsequent review by qualified referees, and a post-review step, which represents a novel tool open to the scientific community through an on-line forum.
Supplementary information
1) What are the effects of Tat vaccination?
The data obtained at 48 weeks from the ongoing phase II clinical trial indicate that the Tat vaccine, administered to HIV infected HAART-treated individuals with suppressed plasma viremia, is capable of restoring the homeostasis, that is the proper equilibrium, of the immune system, which is heavily compromised by HIV infection, thus optimizing and intensifying the effects of antiretroviral drugs.
2) On the basis of the results recently published in PLoS ONE, can one say that the Tat vaccine is effective?
The results of the phase II study indicate that the Tat vaccine, used in association with the antiretroviral therapy in patients with suppressed plasma viremia, reduces the immune activation in a selective and targeted manner, and improves the immune function in HIV-infected patients. Further studies will be needed to determine whether the Tat vaccine may be effective in the different clinical stages of HIV disease.
3) Can the Tat vaccine replace the antiretroviral therapy?
This is not known at present. Additional studies are needed to give an answer to this question. In this phase II study the Tat vaccine has been tested on HIV-infected HAART-treated individuals with suppressed plasma viremia. Therefore, the subjects immunized with the vaccine continued to take the antiretroviral drugs. The synergistic effect of vaccination and antiretroviral treatment is the subject of the scientific publication in PLoS ONE:
4) How many patients have received the Tat vaccine?
In the study published in PLoS ONE the vaccinees are 87. Considering also the previous phase I trial, a total of 114 HIV+ patients have been vaccinated with Tat so far. Nevertheless the phase II study is still ongoing and the number of Tat immunized individuals is growing.
5) Which are the main benefits of the Tat vaccine?
Tat vaccine administration induces a significant improvement of several clinical parameters such as an increase of CD4+ Tcell and B cell number, as well as a reduction of immune activation markers (i.e. the presence on the cell surface of the CD38 molecule and the beta2-microglubina or neopterin levels, which are serum proteins increased during inflammation and immune activation).
6) Which are the main results of the phase II trial?
The data of the phase II trial obtained so far indicate that Tat vaccination is safe and induces a specific and durable immune response against Tat, which, by operating in synergy with the antiretroviral treatment, contributes to the restoration of the proper equilibrium of the immune system that HAART alone is often unable to re-establish.
7) Where does the Tat vaccination operate?
The present data indicate that Tat vaccine acts on the immune activation and regulation, restoring the proper behavior of the cells of the immune system. It is likely that, thanks to Tat vaccination, the risks of developing those novel and serious diseases associated with the immune activation and dysregulation, which HAART cannot overcome, are considerably reduced.
8) What is the immune activation?
It is like a "continuous alarm" of the immune system that seems to be consequent to the HIV persistence in those cells/sites (the so called "sanctuaries") in which it resides and resists to therapy.
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