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ISIS Report 12/10/07

Controversy Over European Framework Programme AIDS Vaccines

One Italian researcher is taking another to court over criticisms of an AIDS vaccine

Dr. Mae-Wan Ho uncovers a dangerous vaccine project funded by the European Union and demands a halt on all clinical trials and a suspension of the project

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Italian drama ends up in court

Several AIDS vaccines are caught up in controversy as the most promising new candidate is halted mid-way through its phase II trial [1] (New Strategy HIV Vaccine Fails, SiS 36). But potentially more damaging vaccines are in the pipelines, funded by the Framework Programme 6 of the European Union at the taxpayer’s expense.

A recent issue of Science (10 August 2007) carried a news item on a dispute over an AIDS vaccine that ended up in court [2]. A leading Italian researcher Barbara Ensoli of the Istituto Superiore di Sanità (ISS) in Rome has developed the vaccine; and Ensoli is suing another prominent researcher, immunologist Fernando Aiuti at the University of Rome for damage to her reputation. Aiuti, a former collaborator of Ensoli, sees critical flaws in the early trials of the vaccine and has made his views known in the public media.

Ensoli’s vaccine is based on the HIV protein Tat, which helps the virus replicate. She hopes that bolstering the immune response to Tat can prevent infections and also help people already infected. Ensoli has reported some success in monkey studies with her vaccine, but several other labs had not had the same success.

Aiuti is not alone in his criticism of the vaccine. Genoveffa Franchini at the US National Cancer Institute Bethesada Maryland had worked on a Tat vaccine that failed, and also collaborated with Ensoli in the laboratory of Robert Gallo (co-discovery of HIV). Franchini does not think Ensoli’s vaccine has any chance of success, and neither does Gallo, who has long warned that the form of Tat in her vaccine could actually suppress some immune responses. Others have warned of even more dire consequences of exposing human subjects to the Tat protein (see below).

In January 2004, the ISS launched a phase I trial of Ensoli’s Tat vaccine to test for toxicity in both HIV-infected and uninfected individuals. But the trial was terminated in November over Aiuti’s objections, and because only 47 of the 88 intended number of volunteers had been recruited. Ensoli agreed to terminate the trial declaring that the endpoints were reached: no serious safety issue had surfaced, and blood tests showed that a significant number of participants had developed immune response to Tat.

However, inspectors at the regulatory agency, Agenzia Italiana del Farmaco (AIFA) wrote a harsh report on the conduct of the clinical trial, highlighting several important deviations from the original protocol. This report was sent to Aiuti from several difference sources, including the hospital he works with. Aiuti distributed the report widely, and continued to do so despite a subsequent letter from the director of AIFA stating that he had accepted ISS’s explanation, and that the trial did hit their endpoints.

Aiuti maintains, however, that the AIFA director, Netto Martini, had dismissed the criticisms of the inspectors too readily. The inspectors’ data were very specific, and none of the inspectors had withdrawn their criticisms. This story had been widely reported in the Italian media, which is why Ensoli decided to sue, seeking €2.5 m for damages to her reputation.

Meanwhile, phase II therapeutic studies on the vaccine are in the pipelines. Glenda Gray, head of a unit at Chris Hani Baragwanath Hospital in Soweto, South Africa, has been considering conducting phase II studies of the vaccine. She wrote to Ensoli, and is now wondering why enrolment for the phase I trials was stopped so abruptly after receiving no satisfactory reply from Ensoli, except an apprehension of legal action. 

Ensoli says phase II therapeutic studies will start in Italy in the next few months, and she is now making a second generation vaccine that will contain the HIV envelop protein as well as Tat, a vaccine that is even more controversial (see below).

Tat vaccine strategy potentially disastrous

What the Science report [2] failed to mention are serious safety concerns over the HIV Tat protein in the vaccine (see Box 1). The Tat protein not only leads to immune deficiency, but also causes programmed cell death of T and B (thymus and bone-marrow derived) lymphocytes. Moreover, it is neurotoxic, and strongly implicated in HIV-associated encephalitis (inflammation of the brain) and dementia.


Tat and HIV

Tat protein is a trans-activator of HIV-1, i.e., it can activate HIV-1 even when the protein is not made by the virus, but for example, supplied in a vaccine. It supports efficient viral replication by stabilizing the transcription of viral genes. Tat can also be released from HIV-infected cells to affect uninfected cells.

More importantly, researchers at Rockefeller University New York in the United States and the Institute for Human Genetics and Biochemistry Vesenaz in Switzerland have found in studies dating back to the early 1990s that normal healthy HIV- individuals, from neonates to adults, contain antibodies against Tat protein, that are part of the human innate immune system [3, 4]. On being infected with HIV, these innate Tat-reactive antibodies decline after a latent period, without other ‘adaptive’ antibodies arising against the Tat protein. The same pattern of Tat protein immunity is found in chimpanzees, but not in other mammals such as monkeys and mice. These other mammals have no natural Tat antibodies and on being exposed to Tat protein, will develop adaptive antibodies to it. Consequently, test results based on the wrong animal model can be quite misleading.

In humans, the decline of Tat natural antibodies is correlated with progression to AIDS disease, including the decrease of CD4+ T cells. This is thought to involve immune tolerance to the Tat protein being recognized as “self”, and so the T and B cells producing those antibodies are deleted as a defence against autoimmune disease when the host is faced with excess Tat protein and a potentially massive autoimmune response.

It is thought that genomes of current humans and chimpanzees may include remnants of viral sequences that have become established as species-specific “self” genome components. Thus, innate antibodies may represent the legacy of a retroviral ancestor of HIV that has integrated into the common ancestor of chimpanzees and humans. The continued introduction of Tat may then result in an overload, resulting in the squelching of antibody production as a defence against autoimmunity.

Tat protein itself also induces apoptosis ((programmed cell death) of T cells. Thus long-term non-progressors (to AIDS) show little evidence of T cell loss and maintain normal levels of the Tat natural antibodies.          

In addition, Tat protein is neurotoxic, and is strongly implicated in HIV associated dementia and inflammation of the brain. The protein induces massive apoptosis of neurons even though HIV does not directly infect neurons [5].

The researchers have already concluded in 2001 [4] that, “the introduction of HIV Tat protein comprises a double-edged sword: destruction of lymphocytes in general by apoptosis and particular tolerance-based destruction of T or B cells that produce the potentially protective innate antibodies.” (p.1008).

Another potential danger is that Tat may trans-activate a plethora of dormant viruses lurking in the human genome, as pointed out in the chapter, HIV and latent viruses, in ISIS’ Report [6] Unraveling AIDS.

Vested interest in dangerous vaccines

Ensoli has obvious stakes in the success of the Tat vaccine. She is the coordinator of European Union’s Framework Programme 6 (FP6) AIDS Vaccines Integrated Project (AVIP), costing €10.3 million, which concentrates on combining structural and regulatory genes and gene products in making AIDS vaccines (see Box 2).

In the European Commission description of the AVIP, it is acknowledged that vaccines based on viral structural products (Env/Gag/Pol) alone have failed to prevent infection by HIV/Simian Immunodeficiency Virus (SIV); but claims that vaccines based on viral regulatory gene products (Tat/Rev/Nef) have been shown to limit virus replication and to prevent disease onset (presumably in preclinical animal experiments). Therefore, a vaccine combining both regulatory and structural viral antigens (combined vaccine) is likely to be superior as it induces immune responses to both early and late viral products.


AIDS Vaccine Integrated Project

The AVIP (AIDS Vaccine Integrated Project) is funded by European Union Framework programme 6 (Project number LSHP-CT-2004-503487) to the tune of €10.3 million over 5 years starting 1 February 2004. Its aim is to generate novel HIV-1 vaccine candidates and carry out standardized clinical trials in Europe and the developing world, as stated: “Comparative analysis in both preclinical studies and phase I therapeutic and preventive trials of these vaccines will be key for the selection of vaccine candidates for phase II/III trials in DC [developing countries].”

Clinical sites have been set up in Estonia, Finland, Germany, Italy, Sweden and the United Kingdom. Four novel vaccines have been selected based the combination of HIV regulatory (Tat and/or Rev, and/or Nef) with structural (Env and/or Gag/Pol) genes or gene products, on ground that they will be more effective than those developed up to then.

Included in its major objectives are to perform feasibility studies and technology transfer in developing countries for future phase II/III trials; to carry out training in EU countries and developing countries through the establishment of the AVIP International School; and to ensure community involvement both in EU countries and developing countries, to guarantee the correct ethical information of the volunteers, counselling, quality of life evaluation and risk assessment. 

New generation of combination vaccines doubly dangerous

Within the AVIP is a DNA vaccine that contains Env/Gag/Tat genes. The Tat protein essentially disarms the immune system completely through immune tolerance, and is at the same time toxic to T and B lymphocytes and to neurons (see Box 1). The hazards of the Env gene or gp120 is well-known, and includes the disarming and destabilization of the immune system, auto-immune response, impairment of cytotoxic T lymphocytes, and elimination of CD4+ T cells.  Further, the presence of recombination hotspots in gp120 facilitates horizontal gene transfer and recombination to create new HIV strains and other viruses and bacteria (see [1] (New Strategy HIV Vaccine Fails, SiS 36).

Obviously, the combination vaccines promoted by the AVIP are seriously and doubly dangerous.

All trials involving such vaccines should be halted, and the AVIP project suspended pending independent review on the risks and ethics of promoting the vaccines.

I thank Dr. Veljko Veljkovic for his advice and for sending me key publications for this report.

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