Another HIV vaccine has failed.

On 21 September 2007, the pharmaceutical giant Merck called a halt to a phase II trial of a new vaccine candidate against HIV [3]. An interim assessment showed that the vaccine, long considered the most promising in development, failed both in preventing HIV infection and in reducing the viral load of those infected.

The vaccine candidate (Merck V520) is a mixture of three components, each a weakened adenovirus vector carrying one of the three synthetic HIV genes gag, pol and nef. The vaccine is designed to elicit a cell-mediated immune response, to stimulate the body’s own CD8 T-cells that recognize and kill the HIV-infected cells. No further details on the precise nature of the vaccine could be found on the Merck website or in the published scientific literature.

The multi-centre, randomised, double-blind, placebo-controlled phase II trial enrolled 3 000 HIV-negative volunteers from diverse background between 18 and 45 years of age at high risk of HIV infection.

The interim assessment was on approximately 1 500 volunteers expected to have the best response to the vaccine because they had low levels of pre-existing immunity to adenovirus 5.

The results were devastating. The vaccine did not prevent infection, if anything there were more infections among those given the vaccine. In 741 volunteers who received at least one dose of the three-dose vaccine series, 24 cases of HIV infection were found, compared to 21 cases of HIV infection in the 762 of the placebo group. In the subgroup of 672 who had received at least two vaccinations and who were HIV negative for at least the first 12 weeks of the trial, 19 cases of HIV infection were found, compared to 11 cases in the 691 volunteers who received placebo. The vaccine did not reduce the amount of virus in the bloodstream of those who became infected. The HIV RNA levels at approximately 8 to 12 weeks after diagnosis of infection expressed as geometric means were about 40 000 copies/mL in the vaccine group and 37 000 copies/mL in the placebo group.

Concern over the ethics of vaccine trials heightens as doubt gathers over the vaccine strategy

This latest vaccine failure came less than two months after headlines resounded across the globe that the world is losing the fight against AIDS. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases and US’ top advisor on AIDS, said at the 4^th International AIDS Society Conference held in Sydney Australia that for everyone one person placed on therapy, six people get infected with HIV; and he agreed with the UNAIDS Executive Director Peter Piot that the discrepancy between the number of individuals being put on therapy and the number becoming infected “is not sustainable”, and means that “we are losing the battle” against HIV and AIDS [4]. Fauci later qualified his remarks by referring to “advances” made, including new approaches in vaccine development.

The failure of the Merck vaccine heightens ethical concerns over the continuation of a range of HIV vaccine trials, and raises doubt over the vaccine strategy itself [2], as both old and new approaches to vaccine development are increasingly mired in controversy [5] (see Controversy over European Framework Programme AIDS Vaccines, SiS 36).

The International AIDS Vaccine Initiative (IAVI) recognizes “challenges” facing an AIDS vaccine [6], chief among which is the hypervariability of HIV both on a population basis and within HIV-infected individuals, the virus can differ between tissue compartments within the same individual host, and several forms could co-exist in the same tissue compartment. The other challenges are that both the immune response to the virus and how it causes disease remain poorly understood; and there are multiple routes of transmission, which complicates the vaccine strategy.

One main feature against the vaccine strategy is that HIV is a retrovirus that integrates into the host cell genome, and could remain in a latent form, thereby escaping immune surveillance [7, 8]. The virus’ homologies to host genes could also provoke autoimmune responses against the host.

An international team of scientists led by Vejkov Veljokovic at the Institute for Nuclear Sciences Belgrade in Serbia reviewed the evidence on the hazards of gp120 vaccines extensively in 2000 [9]. They highlighted the homologies of gp120 to the human immunoglubulins, hence its potential for participating in, and destabilizing, the immune network. Gp120-based vaccines caused ‘deceptive imprinting’ of the immune system, disarming it against a subsequent HIV infection and accelerating progression to AIDS disease. Such vaccines were also found to elicit auto-antibodies in the host, to impair cytotoxic T lymphocytes, and to eliminate 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. (The dangers of horizontal gene transfer and recombination apply to all recombinant vaccines against HIV.) On the basis of the extensive evidence of actual and potential hazards, Veljkovic and colleagues called for a moratorium on gp120 vaccines, and for a new vaccine strategy that avoids the dangers specific to gp120, as well as those general to HIV as an integrated retrovirus.

Above all, it remains unclear as to exactly how HIV causes AIDS disease, as IAVI admits (see above) and as borne out by a recent review of the evidence [10, 11] (On Quitting HIV, Beyond the HIV-Causes-AIDS Model, SiS 34). In the absence of this knowledge, any vaccine strategy based on HIV is inappropriate and potentially dangerous.

A rethink of the vaccine strategy is in order in view of the harm that can be caused to participants in clinical trials; and the failed Merck vaccine is perhaps the clearest example of that to-date. Bearing in mind that only a subset of the volunteers – those expected to give the best response to the vaccine – has been assessed, the full clinical picture could be considerably worse.

Merck should now disclose the results in full, including the precise nature of the vaccine used, to ensure that the same mistakes are not made again. For the same reasons, full reporting of the clinical and scientific data from all vaccine trials should be made mandatory.

Disproportionate resources poured into anti-HIV vaccines at the expense of other safer and more effective interventions

There is now substantial evidence that nutritional interventions and exercise are effective in both preventing HIV infection and in delaying disease progression, as described in many chapters of our report, Unraveling AIDS [2]. Since then, new supporting evidence has accumulated.

Naturally occurring flavonoids in tea and fruit juices are found to have anti-HIV activity [12, 13] (Desk Top Drug Discovery, SiS 33); while certain naturally circulating auto-antibodies in HIV-negative healthy individuals are capable of neutralising HIV [14]. The enormous amounts of resources that continue to be poured into vaccine development via the IAVI, especially by mega-philanthropies such as the Gates Foundation [15] (Philanthropy Gates Style, SiS 35) would do much more to combat AIDS if diverted to eradicating poverty, improving nutrition and sanitation, and to promoting a generally healthy lifestyle.

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