Vaxine Pty Ltd, Flinders Medical Centre, Bedford Park, Adelaide, South Australia 5042
Flinders Medical Centre and Flinders University, Bedford Park, Adelaide, South Australia 5042
The scope of therapeutic vaccines has increased dramatically in recent years. No longer are vaccines restricted to infectious disease applications, with vaccines under development for treatment of a wide range of chronic diseases that include cancer, allergy, asthma, diabetes mellitus, autoimmunity, atherosclerosis, obesity, degenerative neurological diseases and drug addiction. These vaccines work by stimulating neutralizing antibodies or in some cases T cells against relevant self or non-self molecules. This commentary reviews the latest state of the art in the area of therapeutic vaccines.
All vaccines work by the administration of a target substance called an 'antigen', typically a protein but also a sugar or lipid. This triggers production of antibodies able to bind the antigen and neutralize it or remove it from the body. Vaccines also activate immune T lymphocytes (T cells) that then attack any cells expressing the antigen. While the immune system has primarily evolved to attack and neutralize foreign pathogens, this does not mean that it cannot respond against molecules derived from self-tissues, a process called autoimmunity. This phenomena is exploited by cancer vaccines which seek to break tolerance to self-antigens and drive an immune response against antigens expressed by the tumour cells allowing them to be targeted and killed by T cells. By contrast allergy vaccines attempt to switch an existing immune response against a relevant allergen such as house dust mite from an IgE- to an IgG-dominant phenotype. Vaccines against drug addiction attempt to induce immune responses against non-protein small molecules such as nicotine or cocaine. The following sections detail vaccine development currently going on each of these areas. In all cases if the immune response elicited by a vaccine by itself is not strong enough then it can be formulated with an enhancing substance called an 'adjuvant' to enhance its potency.
Cancer vaccines typically comprise tumor-expressed antigens combined with an adjuvant designed to trigger a cellular immune response against the cancer cells. To be successful a cancer vaccine must break self-tolerance, which can be hard to achieve as normally the body tries to avoid self-reactivity. This generally requires use of a powerful adjuvant to drive the immune system to attack tumor-expressed antigens. One particular technique for administering cancer vaccines is to incubate the cancer antigen with dendritic cells in vitro thereby enabling them to uptake antigen and become activated. The antigen-stimulated cells are then injected back into the patient. This is the basis of Sipuleucel-T vaccine (Provenge), currently the only approved human cancer vaccine used for treatment of prostrate cancer. However many other cancer vaccines are under development. Whilst the vast majority of attempts to date have been unsuccessful, glimmers of hope are appearing suggesting most of the hard lessons have been learned from the failures and we can look forward to ore and more success stories in the cancer vaccine domain.
In the United States alone approximately 65 million people have an allergy. These are most commonly to grasses, animals or foods. Vaccination with small doses of the relevant allergen to induce de-sensitisation is an effective treatment that has been practiced for decades. One area of recent progress has been in application of immune adjuvants to allergy immunotherapy.
Alzheimer's and Parkinson's Disease Vaccines
Chronic degenerative disease is another target for vaccines. An Alzheimer's disease vaccine based on the amyloid-β peptide successfully reversed memory loss in a mouse model. However, a human trial was halted in 2002 after some patients developed brain inflammation, potentially related to brain-reactive T cells. Similarly, a mid-stage study of another experimental Alzheimer's disease vaccine (ACC-001) was halted after one of the patients developed brain lesions. Despite all these setbacks, vaccine approaches to Alzheimer's disease have not been completely abandoned, but it is now recognized as critical that a successful vaccine must not stimulate T cells that might cause brain inflammation. Parkinson's disease is another incurable degenerative neurological disorder that leads to movement and cognition disorders. A clinical trial has already been started in patients with Parkinson's disease of a vaccine (PD01A) that targets alpha synuclein, mutant forms of which protein clump together in the brain of patients with Parkinson's disease and are thought to mediate the disease. Time will tell if this strategy is successful.
Heart Disease Vaccines
Vaccines against atherosclerosis (artery blockages) are also under development. A vaccine that worked by eliciting neutralizing antibodies to cholesteryl ester transfer (CETP) successfully prevented atherosclerosis in animal models. These vaccines targeting CETP are now in human clinical trial testing. Vaccines are also being developed to target high blood pressure by inducing antibodies against angiotensin II, which is an important inducer of blood pressure. One vaccine has already reached Phase 2 human clinical trials but unfortunately achieved only modest reduction in blood pressures indicating a need to increase vaccine potency for this strategy to be successful.
Type 2 Diabetes Vaccines
Type 2 diabetes is another target of vaccine development. Interleukin (IL)1β is a pro-inflammatory cytokine implicated in the pathogenesis of insulin resistance and type 2 diabetes. Consequently, a vaccine has been designed to try and treat type 2 diabetes by induction of neutralizing antibodies against IL1β.
Obesity is a fast growing global problem. Ghrelin is an endogenous peptide that enhances appetite and food intake. Ghrelin has thereby been used as a target for an obesity vaccine, with the hope that inducing neutralizing antibodies to ghrelin will reduce appetite and thereby help with weight loss.
Autoimmune Disease Vaccines
Autoimmune diseases including multiple sclerosis, rheumatoid arthritis and type 1 diabetes are also areas potentially able to be targeted by vaccine therapies. Various approaches have been tried including development of vaccines that induce neutralizing antibodies against tumor necrosis factor-a, a key pro-inflammatory cytokine driving the pathogenesis of rheumatoid arthritis. For T1D prevention, a vaccine based on the self-protein glutamic acid decarboxylase showed some early promise in clinical trials but this has not held up under more extensive human testing.
Drug Addiction Vaccines
Drug addiction is another major global problem. Most smoking cessation vaccines attempt to induce anti-nicotine antibodies hereby blocking nicotine action in the brain. However in setback to this field a mid-phase clinical trial did not achieve its primary end point of smoking cessation. Another drug addiction vaccine targets cocaine addiction. In this approach neutralizing antibodies are induced against cocaine. These antibodies bind to cocaine molecules in the patient's blood stream and thereby prevent the cocaine getting into the brain where it acts.
Vaccine adjuvant technologies are of critical importance to successful development of therapeutic vaccines. In the case of cancer vaccines the adjuvant needs to drive a strong T-cell response, whereas for most other therapeutic vaccines the need is for an adjuvant to drive a long-lasting neutralizing antibody response. Hence adjuvant selection will be critical to success of many of the above vaccines. Currently only two adjuvant platforms are approved for human use, alum-based adjuvants (aluminium hydroxide or phosphate, alone or combined with monophosphoryl lipid A) or squalene oil emulsion adjuvants, both of which suffer from potential toxicity and safety concerns. More promising may be unconventional adjuvants made from polysaccharides such as carbohydrate-based particulate vaccine adjuvants, e.g our own AdvaxTM delta inulin adjuvants that are well tolerated and induce potent T-cell immunity. These are based on a new paradigm that suggests that inflammation may not be the best route to a robust and long-lived adaptive immune response.
The above descriptions provide an example of the wide diversity of novel vaccines that are currently under development. Space precludes a detailed discussion of the merits of each individual vaccine, or to mention many other novel vaccine technologies such as DNA or RNA vaccines or nasally administered vaccine approaches, all of which are still in their relative infancy, but may one day dramatically accelerate development and effectiveness of the therapeutic vaccines mentioned in this article. Suffice to say large pharma company and biotech vaccine pipelines have never been fuller; consistent with us currently being in a golden age of vaccines.
About the Author
Nikolai Petrovsky is Director of Endocrinology at Flinders Medical Centre, Professor of Medicine at Flinders University and founder of Vaxine, an Australian company focused on vaccine adjuvant development. He has held several large adjuvant development contracts from the National Institutes of Health and has taken vaccines for influenza, hepatitis B and allergy from the bench to the clinic. His research has won awards including 2010 Ernst & Young Entrepreneur of the Year Award, 2011 BioSpectrum Asia-Pacific Emerging Company of the Year Award, 2011 Vaccine Industry Excellence Award for Most Innovative Asian Biotech and 2013 Biopharma Asia Asian Executive of the Year. He is a regular speaker at international meetings and has authored over 100 research papers focused on the areas of adjuvants and immuno-informatics.
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