Therapeutic vaccine trials and patient safety

Since its foundation in 1992 EATG members have been involved in the discourse on patient safety in trials aimed at immunising people with HIV against their virus by means of vaccination. The first European multi-centre trials on therapeutic vaccines received intensive community input. One of these trials (US-funded) went through US community constituency group procedures. The other trial sponsored by an Austrian company set up a European Community Advisory Board and provided even for independent work of this group in conjunction with the EATG. Outcomes included reviewed patient material, study designs and presentation of results.

The differences between trials of pharmaceutical substances and vaccines are plenty. Therefore, when research into therapeutic vaccines began to find new momentum with the preventive AIDS vaccine drive (in Europe beginning 1999) EATG established a Vaccine Working Group (VWG) to identify the relevant differences and issues. The VWG found major obstacles in the community that were based on misunderstandings about the nature of vaccination and of efforts in immunotherapy.

The common misperceptions were:
• The invariable outcome of the immunologic reaction to therapeutic vaccination is viral sterility. This is not true. Rather an unimpaired ”natural“ immune response supported by therapeutic vaccination should be able to control viral replication down to a level, where there is only ”insignificant“ replication which will result in a decay of the reservoir. Trials of therapeutic vaccination will therefore invariably have to consider the longerterm outcomes of such efforts. This is also and particularly true for the long-term outcomes of immune responses initiated by vaccination in people with HIV. Particularly in new vaccination constructs based on DNA and viral vectors safety concerns about potential damage caused by the immune response to the vaccine or the vector need to be heeded. The misconceptions about sterility also need to be addressed in the informed consent process in order to counter the common assumption that therapeutic vaccination automatically reduces the risk of passing on the HIV-infection. There is no clinical evidence yet to support this assumption.

• Anybody can be vaccinated. This is not true. The immunological damage done by HIV during the course of an infection typically leads to an incapacity of the individual with low CD4-counts to produce an adequate immune response to HIV. The commonly assumed threshold of CD4-Nadir before entering a therapeutic vaccine trial is well above 250 cells/μl. The trials thus focus on individuals with a lot to lose from undue interference with their immunity which may only just be able to keep their own virus in check and themselves from more rapid progression.

• Therapeutic vaccine trials contribute to the development of preventive vaccines. This is partially true. However, some vaccines such as ”anti-tat“ are modelled from long-term progressors and are aiming to turn the switch from rapid to slow rather than leading to a complete halt in the disease development. This approach can therefore only indirectly (e.g. technology of production) contribute to preventive vaccine research.

• Therapeutic vaccination has been proven to work. It has been proven in a small number of patients that a rather complex course of HAART, IL-2 and vaccination can result in better virological outcomes than HAART and IL-2 alone. This is a proof of principle that antiviral, immunotherapeutic and vaccination principles can have a synergistic effect on viral load. Therapeutic vaccination by itself has not been shown to have such effects. While immune responses to various therapeutic vaccines have been elicited in a number of clinical trials there is still no evidence of any therapeutic effect.

Since these common misperceptions were reported from several Western and Eastern European countries, they pointed to a need for increased education and advocacy. Such information deficits were identified in immunology, vaccinology, politics and ethics of vaccine research in general.

In 2003 the VWG commissioned Julian Meldrum to clarify some of the issues. In ”Successes and failures in vaccine trials“ he pointed out that a therapeutic vaccine – if it does not cure disease, or removes the need for any further treatment of any other kind - can only be called ‘partially effective’. The main goal of a partially effective therapeutic vaccine will always be, to reduce the burden of the disease and of its treatment. This effect is measurable in different ways. In theory, it could be of benefit to prevent onward transmission or re-infection of a positive person with different strains of HIV, although there could be great difficulty in assessing this and its clinical importance.

It would be a success:
If disease burden, including the burden of treatment, is reduced through the use of a therapeutic vaccine by people with HIV, then that therapeutic vaccine will have been a success. This success could be experienced as the opportunity to interrupt treatment and allow the body to recover from its effects. It could equally be experienced through people being able to benefit for longer from the least toxic and most easily managed combinations available to them. In countries where cost restricts access to antiretrovirals, a successful therapeutic vaccine might also enable people to minimize the cost of treatment, since first-line combined formulations will always be cheaper than those reserved for second- and thirdline use. Monitoring costs might also be reduced, if the frequency of tests could be reduced.

It would be a failure:
If it is not possible to show that a vaccine has a significant effect on viral load, CD4 levels and (above all) on patterns of other treatment that are needed, then there can be no justification for providing that vaccine to people with HIV. This remains true, even if some laboratory marker of immunological response appears to show a ”response“ in those who are vaccinated.

Also in 2003 the VWG published an overview of therapeutic vaccine trials in Europe, Warsaw. Call for establishment of an international register.

Recent efforts in compiling data on ongoing and planned therapeutic vaccine trials in Europe have come to a much more limited insight into the developing research scene. While a German company gladly provided the requested data on their four trials, no such data were forwarded from other partners – confidentiality issues being quoted by more than one of the individuals involved in the search. Thus the results of this effort vary very much in depth.

Table Bavarian Nordic (data complete)

EuroVacc (no info)

TheraVacc (some info)

Anti-Tat (some info)

The larger part of data on ongoing research thus has the quality of hearsay. Efforts are urgently needed to bring therapeutic vaccine research in Europe up to the standard of the US with regard to gaining access to information on ongoing research and assuring targeted education efforts to the respective trial populations in time.

Matthias Wienold

EATN - European AIDS Treatment News, Volume 15, I – Spring 2006

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