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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  (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 .
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
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.
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.
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.
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
Tat vaccine strategy potentially disastrous
What the Science report  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
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
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.
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 .
have already concluded in 2001  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).
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  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
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.
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
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
 (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.
thank Dr. Veljko Veljkovic for his advice and for sending me key publications
for this report.