Another key AIDS vaccine is abandoned before phase III trial. This latest setback comes at the end of a string of failures in developing vaccines that may be worse than useless. Dr. Mae-Wan Ho reports.
The US government has abandoned a controversial AIDS vaccine trial and announced it will combine the work of two federal institutions, the National Institutes of Health and the Department of Defence. Both institutions had proposed trials to test a combination of similar vaccines - a dose of canarypox virus engineered to carry HIV-1 proteins with a booster shot of the HIV protein gp120 [1]. The trial was designed to compare the types of immune responses the vaccine evoked with the protection it provided. That required the vaccine to produce an immune response in at least 30 per cent of volunteers. But analysis of the data suggests the response did not come up to scratch. “It didn't even come very close,” said Anthony Fauci, director of the NIH's National Institute of Allergy and Infectious Diseases. The cancelled NIH trial, which would have involved 11,000 volunteers, was anticipated to cost $60 to $80 million dollars. The Department of Defence trial, which was designed to test only the efficacy of the vaccine, will still go ahead. But that may be a grave mistake.
The canary pox vaccine was Aventis Pasteur's ALVAC-HIV (vDP1452), and the booster, VaxGen's AIDSVAX B/B. The ALVAC vector failed to provoke a strong immune reaction, and new evidence from Harriet Robinson's team at Emory University, announced at the 9th Conference on Retroviruses and Opportunistic Infections (Seattle, 24-28 February 2002), demonstrated that adding a gp120 booster to another vaccine actually reduced the vaccine's efficacy rather than improving it. These disappointing results were to be expected, according to AIDS virologists who have been studying the problems of AIDS vaccines for years [2].
More bad news comes from vaccine trials in non-human primates. Vaccines that induce only cellular immunity through cytotoxic lymphocytes (CTL) - immune cells that destroy cells infected with virus - without circulating antibodies in the plasma gave only partial protection. In a study carried out by researchers in the Merck Research Laboratories in Pennsylvania, Duke University and Harvard Medical School, two out of 15 immunised macaque monkeys became ill with AIDS-related symptoms six months after being challenged with the pathogenic HIV-SIV hybrid virus (SHIV) [3].
The best vaccine based on an adenovirus vector “greatly attenuated” viral infection, but did not prevent it. Despite that, the authors claim that the vector was “promising” for development of an HIV-1 vaccine. Though they admitted that the relevance of their model system to human HIV-1 infection is not “firmly established”, and “cannot be extrapolated to predict human immunogenicity or efficacy”. This assessment must be done in clinical trials, they stated. The SHIV hybrid virus, routinely used in such studies is an especially virulent form of the AIDS virus that kill victims in weeks, and its safety has been strongly questioned [4].
Another study by researchers based in Harvard Medical School, Northwestern University of Chicago, Duke University Medical Center and the Sourthern Research Institute in Maryland is less optimistic [5]. One out of eight immunised rhesus monkeys died as the challenge virus mutated and escaped from the CTL. Such mutations in the virus that escape immune recognition have been described in more than a dozen reports in the literature in trials involving both humans and non-human primates. The authors conclude, “These data indicate that viral escape from CTL recognition may be a major limitation of the CTL-based AIDS vaccines that are likely to be administered to large human populations over the next several years.”
Some virologists have been warning for years that the entire class of AIDS vaccines based on the HIV gp120 gene or protein is not only ineffective, but also dangerous for the recipients and the human populations [6]. The vaccines are acting as “slow bioweapons” in populations undergoing clinical trials. There is evidence suggesting that gp120 can interfere with and undermine the immune system and can readily recombine with viruses and bacteria (used as vectors) to generate new pathogens.
The reason is that the envelope glycoprotein, gp120 of HIV-1 is similar to the region of human immunoglobulins that binds antigen, a crucial feature of the immune response. Thus, any AIDS vaccine containing the gp120 could interfere with the immune system and make people more vulnerable to the virus. And in the long term, it could accelerate disease progression in HIV patients that do not yet have symptoms.
The envelope glycoprotein, gp120 of HIV-1, is similar to the region of human immunoglobulins that binds antigen, a crucial feature of the immune response. Thus, any AIDS vaccine containing the gp120 could interfere with the immune system and make people more vulnerable to the virus. And in the long term, it could accelerate disease progression in HIV patients that do not yet have symptoms.
Recombinant viruses expressing gp120 could also be a source of potential new pathogens. The gp120 gene contains genetic elements that stimulate recombination or are 'recombination hotspots'. These elements are similar to certain 'Chi' (pronouned 'kye') sequences found in bacteria and viruses such as Haemophilus influenzae, Mycobacterium tuberculosis, hepatitis B virus and herpes simplex virus that often co-infect with the HIV, and are also similar to immunoglobulin recombination elements in the human host. Recombination of HIV with bacteria and viruses mediated by Chi sequences would generate new pathogens, and such recombinants have been found.
Within the human host, recombination with human genes would promote chromosomal rearrangements and formation of aberrant immunoglobulins, leading to inadequate immune responses. Furthermore, HIV-1 sequences integrated into the genome have the potential to initiate a wide variety of diverse genetic effects caused by all mobile genetic elements, especially mutations of genes due to random insertion, some of which might trigger cancer.
A recent theoretical study adds further fuel to their warning. Partially effective vaccines that inhibit the growth of the pathogen, such as the AIDS vaccines described here may leave death rates unchanged, or worse, increase deaths with the level of vaccination (see “Health warning over partially effective vaccines”, this issue). But a company in Texas, Prodigene, is putting gp120 into GM maize as a cheap, edible oral vaccine against HIV [7]. This will surely lead to widespread contamination of our food crops with disastrous consequences. Not only is this extremely hazardous for human beings. It will affect all organisms in the food chain and multiply the opportunities for this gene to recombine with bacteria and viruses in the environment, of which 99% cannot be cultured and are hence completely unknown. An edited version of our response was published in the internet journal AIDScience [8].
Article first published 01/05/02
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