Most conventional vaccine applications are prophylactic: they prevent an infectious disease from developing. Besides prophylactic applications, vaccines may be used to treat already established diseases, such as infectious diseases, cancer, or drug addiction. Although the development and use of therapeuticvaccines is still in its infancy, some examples will be highlighted here.
Several human diseases exist in which the immune system is able to contain the disease to a certain extent, but fails to fully eradicate the pathogen that causes the disease. Both tuberculosis and AIDS are examples of such persistent infectious diseases. Proper stimulation of the immune system using therapeutic vaccines may break the status quo and shift the equilibrium towards full eradication of the disease-causing pathogen Tuberculosis is caused by infection with M. tuberculosis via the lungs. The mycobacteria are taken up by alveolar macrophages and DCs, but these cells somehow fail to destroy the pathogens. As a result, a local inflammation occurs causing influx of monocytes and the formation of granulomas, which can persist for years. Although a vaccine against tuberculosis based on an attenuated strain of Mycobacterium bovis (bacille Calmette-Gue´rin, or BCG) already exists, this vaccine is only effective in severe forms of childhood tuberculosis and not for treating latent infections with M. tuberculosis. Currently, therapeutic vaccines are under develop-ment containing the antigen HspX that is expressed during the dormant stage of the mycobacterium. Vaccines based on this antigen have proven to be effective in mice, and are currently tested in phase I clinical trials (Haile and Kallenius, 2005).
Acquired immunodeficiency syndrome (AIDS) is caused by infection with the HIV. HIV predomi-nantly resides in CD4 positive T-cells, monocytes and macrophages. The virus is cytopathic in acti-vated T-cells, but less in macrophages and not at all in latently infected cells with integrated provirus. Although HIV infection does not immediately cause AIDS, and some seropositive patients never develop AIDS, most infected patients progress to AIDS over a period of years and eventually die if not adequately treated.
Vaccines against HIV should ideally elicit both humoral and cellular immunity. The humoral response should give protection against non-infected individuals (prophylactic) or against spread or re-infection of already infected individuals, whereas the cellular immunity should reduce the intracellular virus pool by killing infected cell populations. A humoral response against HIV has proven difficult to obtain: vaccination against the viral glycoprotein gp120 has resulted in protection against the culture-adapted HIV strains, but not against a challenge with native virus (Gilliam and Redfield, 2003; Kaufmann and McMichael, 2005). Also protective cellular responses are difficult to obtain as Th-cells are the prime target of the virus.
To date, the best results with therapeutic vaccines against HIV were achieved with a replica-tion-defective recombinant adenovirus-5 (rAd5) vec-tor (Shiver et al., 2002; Shiver and Emini, 2004). Vaccination of rhesus monkeys with rAd5 vectors resulted in partial protection against reinfection with fresh isolates of infectious virus. In humans rAd5 vectors have been tested in a phase I study, showing that these vectors could induce strong cellular immune responses in humans. A recently started phase IIb clinical study should demonstrate whether these vectors can convey protection in HIV-infected patients.
Cancer is caused by the malignant outgrowth of a single transformed cell. Multiple mutations in genes may give them a growth advantage, but may also lead to different antigens or a different pattern of antigen expression, as has been demonstrated in several types of tumors. In principle specific T-cell responses can be mounted against such tumor-specific or tumor-asso-ciated antigens. However, despite the presence of tumor infiltrating lymphocytes in certain sets of tumors, the immune system somehow fails to mount an effective response that can eradicate the tumor. It is the hope that active vaccination may be able to augment the already-existing immune reaction against tumors in such a way that this will lead to eradication of the tumor (Finn, 2003). However, this is not an easy task. Patients with cancer are often of advanced age and therefore have a smaller repertoire of circulating T-cells that can mount a tumor-specific response. Anti-cancer treatments received by the patient may further suppress antitumor immune responses. Furthermore, tumor cells can evade im-mune suppression in various ways. Tumors tend to be genetically unstable and can lose their antigens by mutation. Moreover, CTL-based responses sometimes result in selection of tumor cells lacking MHC class I molecules that cannot be recognized and killed by cytotoxic T-cells. Some tumors excrete immunosup-pressive cytokines (e.g., TGF-b) to prevent or reduce immune attack.
Immunotherapy against cancer requires the activation of tumor specific T-cells, although humoral responses may in some cases (e.g., non-Hodgkin lymphoma) also be effective. There are several strate-gies to boost such a tumor-specific CTL response. Vaccines can be prepared from the patient’s tumor itself by mixing irradiated tumor cells or cell extracts with bacterial adjuvants such as BCG to enhance their immunogenicity. Alternatively, heat shock proteins isolated from the patient’s tumor that contain asso-ciated tumor antigens can be used as a tumor-specific vaccine. In combination with adjuvants, these heat-shock proteins can be very potent in stimulating CTL responses against tumor cells as has been demon-strated in several clinical trials (Liu et al., 2002). Another approach is to genetically alter tumor cells in order to make them more immunogenic. Transfection of tumor cells with the gene encoding the co-stimula-tory molecule B7 has resulted in direct activation of tumor-specific CTLs by the transformed tumor cells (Garnett et al., 2006). Similar results can be achieved bytransforming tumor cells with genes encoding cyto-kines (e.g., GM-CSF, IL-2, IL-4, and IL-12).
Therapeutic vaccines are also being developed for the treatment of drug abuse, such as addiction to nicotine, cocaine or metamphetamine (Haney and Kosten, 2004). The idea is to evoke a humoral immune reaction against the drug molecules. As most of these drugs have their addictive action within the central nervous system, antibodies raised against the drug molecules can prevent the passage of these molecules over the blood brain barrier and thus prevent the addictive effects. Most abused drugs are small non-protein substances, which generally do not elicit an immune response. In order to activate the host immune system against these substances they need to be conjugated to proteins, such as ovalbumin or diphtheria toxin. This approach has been effective in animal models. Several clinical trials to test vaccines against nicotine are ongoing. The first outcomes show large variations between neutralizing antibody levels among patients, but those with high levels can successfully remain abstinent.