In 2003, the first preventive vaccines to go into full scale trials were shown conclusively not to work. It is unlikely that anything as clear and definite will be reported next year, but there should still be plenty of news to follow, with a pipeline of vaccine candidates that is expanding by the month.
AIDSVAX B/B, tested in North America and Amsterdam, and AIDSVAX B/E, tested in Thailand, each mixed the surface proteins (gp120) from two strains of HIV.
There was some confusion after VaxGen, the manufacturer of AIDSVAX, claimed “success” among some non-Caucasian trial volunteers given AIDSVAX B/B, on the basis of hotly contested statistical assumptions. The nearly identical HIV incidence among Thai trial volunteers, seen when vaccine and placebo groups were compared, is likely to put an end to such claims, however irrational it might be to make the connection.
As of December 2003, it seems that one more AIDSVAX B/E trial is still going forwards, in Thailand, using it to boost immune responses from a canarypox-based vaccine made by Aventis Pasteur. The scientific basis for including AIDSVAX in this 16,000 volunteer trial, co-sponsored by the Royal Thai Army and the US National Institutes of Health in Rayong and Chonburi provinces, now looks weaker than it did. The level of immune response from the canarypox vaccine, used as a primer in this way, was seen as insufficient to justify a large-scale American trial of a similar vaccine combination. If it does go ahead as planned, results will take several more years to obtain.
Neutralising antibodies: still worth pursuing
The idea behind AIDSVAX was to create antibody responses that can keep virus particles out of cells and so block infection. People with HIV are often capable of producing such antibodies as well as the “binding” antibodies used to diagnose HIV infection, though usually too late to protect against long-term infection. In monkeys, “passive immunisation” with monoclonal neutralising antibodies can sometimes protect against infection and further reports of this kind may appear in the next year. Antibodies may have their clinical uses, for example, in the way hepatitis B antibodies are currently used to protect babies born to mothers with hepatitis B. Provided the antibodies can be made in bulk and at very low cost, for example, in genetically modified plants, they may also have a role as microbicides.
The best bet for an antibody-making vaccine is likely to be a modified form of gp120 and/or gp41, or perhaps something else which mimics a structure on the surface of transmitted viruses. Several research groups are working towards this goal, but until animal studies can show high levels of protective antibodies against a wide variety of HIV strains, there will not be further clinical trials based on this concept.
Killer T-cells: towards a test of concept
The main alternative to a vaccine for antibodies is a vaccine for “cellular immune responses” that kill infected cells, by recognising fragments of the HIV proteins that are made inside them. Greater or lesser cellular immune responses seem to be an important reason why people progress at different rates from HIV infection to AIDS. Cellular immune responses are sometimes found in antibody-negative people who are heavily exposed to HIV.
The main current challenge for the vaccines field is to find the best way to get an immune response that kills HIV-infected cells. The goal is to get HIV-specific killer T-cell responses (CD8) and also strong helper T-cell (CD4) responses to support them. This might be enough to abort infection, especially where exposure is to small quantities of HIV. However, animal tests suggest that their greatest value could be in slowing the course of HIV disease and preventing onward transmission of the virus.
The next step is to show strong immune responses in human volunteers to vaccines that include genes for multiple HIV proteins. This is almost certainly achievable, but not as straightforward as first hoped. The hardest question will be whether to go into full-scale trials with a product that goes part way to meet these criteria, or to hold out for one that clearly does so, even if it means extending trials for a year or two.
First into trials were systems designed to use a DNA prime followed by a boost made up using a harmless vaccine strain of a virus as a “vector”. The most advanced of these is the DNA/MVA system based on subtype A virus sequences that the International AIDS Vaccine Initiative (IAVI) is now sponsoring in early-stage trials in the UK, Kenya, Uganda, Switzerland and South Africa. We’re still waiting for the results of using this combination, but early indications are that more trials may be needed to get the dosing right. At worst, IAVI may need to consider replacing its DNA primer with another kind of vaccine incorporating the same gene sequence. Such vaccines are being made and the most likely candidate would be a “replicon” system placing key HIV-related gene sequences inside the protein shell of something called Semliki Forest Virus. This would not be an easy decision, given the urgent need to move towards full-scale trials.
The trouble with DNA
The main problem with DNA vaccines seems to be one of scale. The vaccine dose needed to achieve in humans the same kind of immune response that is routinely seen in mice may not, in practice, be deliverable. Only a little DNA can be dissolved into the volume that can safely be injected into even the biggest of our muscles. If that dose is multiplied for each extra HIV protein or variant strain needed in a “real world” vaccine, the end result could be a rash of injections too painful for words.
One possible answer is to deliver the DNA in ways that make it more immunogenic. For example, Chiron is testing a delivery system called PLG which seems to do this – though it isn’t clear if this would be available to other vaccine developers. Also, some systems – like DNA injection into the skin – simply don’t work to prime other immune responses, even though they allow a radical reduction in the amount of DNA needed to get an immune response as a vaccine in its own right.
The Merck-Aventis Pasteur collaboration
A better answer may be, to dispense with DNA vaccines in favour of including the genes in different vector systems, chosen for the immune response they can generate. This is the path that Merck, now the leading commercial HIV vaccine developer, is taking through its collaboration with Aventis Pasteur. While a DNA primer added little to the immune response seen with Merck’s adenovirus type 5 (MrkAd5) vector, it was found that the response to the gag gene proteins in Ad5 is greatly boosted in monkeys by giving an ALVAC canarypox vaccine, also including a gag gene. This worked even though the gene sequences in the two vaccines were not the same, which is how such a system would normally be designed.
Merck and Aventis Pasteur are now collaborating closely, so Merck will develop gene sequences to be included both in adenovirus systems produced by Merck and in canarypox systems produced by Aventis Pasteur.
The US government-funded HIV Vaccine Trials Network is now assisting with expanded international early phase trials of the Merck adenovirus vaccine. One issue is to test how far existing immunity to adenovirus type 5 will interfere with its use for an HIV vaccine. For this reason, Merck may yet shift to another form of adenovirus. The other question, which may get an answer this year, is whether the adenovirus/canarypox combination works as well in humans as it does in monkeys. If it does, then the development path towards vaccines to enter trials is relatively clear.
More projects to watch
- a DNA/adenovirus multi-subtype, multi-protein HIV vaccine under development at the US National Institutes of Health Vaccine Research Center. Will this hit the same problems as the Merck DNA/adenovirus combination?
- a DNA/MVA multi-protein vaccine candidate being developed by Harriet Robinson’s group at Emory University, which has done some of the most impressive animal studies on this kind of vaccine. Will they, too, give up on DNA?
- a slew of vaccines set for early stage clinical trials in South Africa, under the auspices of the South African AIDS Vaccine Initiative, SAAVI – following a first trial which has already begun, with a replicon vaccine (a fragment of subtype C HIV DNA in a viral coat from Venezuelan Equine Encephalitis) originally developed in an IAVI-sponsored project but now backed by the US NIH.
- an interesting group of vaccine candidates based on subtype B and subtype C virus sequences, developed in Europe and now beginning to enter trials in London and Lausanne, Switzerland, coordinated by the EuroVacc Foundation with European Union support.
Beyond prime-boost systems
IAVI has begun clinical trials in Belgium with a vaccine that uses the outer coat of something called adeno-associated virus – which is totally unrelated to the adenovirus strains used by various vaccine developers. This seems to have the knack of getting DNA into cells in a way that allows it to be expressed for longer periods than happens with other vectors. The hope is that it can provide a one-shot vaccine which does not need boosters – a very important goal for any vaccine that is going to be used in a large-scale public health programme.
And the biggest challenge of all
Will be to test any of these products in full scale clinical trials in Africa, where political and economic stability cannot be guaranteed.
For example, Kenyan tea estates have been studied as possible locations for HIV vaccine trials and other health research, because they provide a relatively stable community with access to health care that can be used as a foundation for clinical trial infrastructure. Unfortunately, global tea prices are now so low that mechanisation and mass redundancy are real prospects in such communities.
For another example, Cote d’Ivoire has long been one of the most prosperous countries in francophone West Africa – but half the country is now held by rebel forces and basic services to the people in that region are no longer what they were.
The best prospect must be, to connect the development and testing of vaccines and other prevention methods to the World Health Organization’s push to get 3 million people with HIV on ARV treatment by 2005. Whether this happens will depend on a readiness to go the extra mile, on the part of governments in the wealthy North, that remains to be demonstrated.
Preventive vaccines background information on aidsmap
Vaxgen announces second phase III trial failure in its AIDSVAX programme aidsmap news report
AIDS Vaccine 2003 conference website with abstracts
HIV Vaccine Trials Network US-funded international collaborations
International AIDS Vaccine Initiative with a database of preventive vaccines in clinical trials