In the increasingly complex and expensive quest to find new medicines, the immune system – with its unique power to prevent, cure and cause disease – deserves more attention. Vaccines, which work by triggering the immune system to produce antibodies, have saved millions of lives since they were discovered by Edward Jenner in 1796. They are rightfully described by the World Health Organization (WHO) as the most effective health intervention after safe water. But conventional vaccines give us only a glimpse into the amazing power of our immune system. When it is out of balance, it destroys healthy cells, causing severe autoimmune diseases such as Type-1 diabetes or multiple sclerosis. When it is exhausted, cancers and chronic infections can take hold. The immune system plays a central role in these and many other diseases.
Looking at advances in immunology, we are about to see a shift from Jenner’s initial preventive vaccines to an era where a next generation of vaccines successfully orchestrate our bodies’ defences to cure and eliminate diseases.
Thanks to the work of Professor Ralph Steinman, the 2011 Nobel Prize winner, we now understand that specific immune system cells, called dendritic cells, instruct other cells to either fight diseases or to initiate tolerance to the body’s own proteins that it might erroneously attack. Many other scientists have added complementary knowledge, which has enabled vaccines to go far beyond the prevention of infections. Indeed, there are now 527 vaccines in clinical development covering not only 49 infectious diseases but also 28 types of cancers, 10 autoimmune diseases or allergies and 17 other diseases.
Four emerging next-generation vaccine technologies stand out for their potential to unlock the power of the immune system: DNA; computational antigen discovery; immune response boosting adjuvants; and nanoparticles.
In cancer, DNA vaccines carry genetic instructions to enable the production of proteins that are specific to tumour cells. Upon vaccination, target cells start to produce these proteins in much larger quantities. The vaccine-induced proteins (antigen) are danger signals to the immune system, which elicit a more effective, amplified immune attack on the tumour. While the principle of DNA vaccines has been confirmed in human trials, selective delivery of DNA vaccines to the target cells must be accomplished to commercialize this approach safely and effectively.
The power of antibodies
For many diseases, effective antibodies can be found in the blood of patients. However, the concentration levels of these antibodies are often too low to prevent the disease. To help the immune system produce more of these antibodies, an alarm signal (antigen) is required. Researchers, such as Professor William Schief, at The Scripps Research Institute, are developing methods to identify these unknown antigens. They visualize the antibodies found in the blood of infected patients and use computational biology to identify the antigen sequences that effectively bind to these antibodies. This and similar approaches open up prevention strategies for unresolved infectious diseases such as HIV, hepatitis C or tuberculosis. The main challenge is that the antigen molecules that have been discovered are too small to be recognized by the immune system and, therefore, larger carriers are needed to present these antigens to immune cells.
We now understand that dendritic cells regulate the strength of the immune system’s response via specific proteins called toll-like receptors (TLR). Stimulating these TLRs can boost the immune response dramatically. Novel cancer vaccine candidates can use the boost effect of TLR-targeting molecules and use other immune-modulated strategies to strengthen the immune response to the cancer. However, these potent immune-boosting molecules can have severe side effects, especially if their delivery is not targeted directly to the dendritic cells.
Nanoparticle vaccines have the potential to bring together all benefits of the technologies discussed so far. Their size is similar to that of naturally occurring pathogens such as viruses, which facilitate preferential absorption by dendritic cells. Novel manufacturing methods, developed at the laboratories of Professor Robert Langer at MIT, enable the design of the nanoparticle surface structure, payload and release characteristics to induce the desired immune response. For example, novel antigens can be displayed on the outside shell of the particle and an immune-boosting adjuvant encapsulated inside. Both components, antigen and booster, reach the immune cell at the same time and induce a powerful antibody immune response. The vaccine and immunotherapy developer can also use particles to design a “tolerogenic” vaccine that stops erroneous immune attacks. In this instance, a molecule signalling tolerance is encapsulated together with a benign antigen; for example, an allergen. The nanoparticles deliver the tolerogenic instructions inside target cells so that the immune system stops overreacting to the allergen, effectively blunting the allergy.
In clinical and pre-clinical experiments, nanoparticle vaccines have shown their potential to shape immune responses to influenza viruses, pneumococcal bacteria, cancer related antigens, nicotine, house dust mites and antigens causing symptoms of multiple sclerosis.
The next decades will see a radical change in our thinking about vaccines. New categories of therapeutic and tolerogenic vaccines will be added to improved preventive vaccines. Together, they will safely harness the previously underestimated power of the body’s own defences.
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Image: A nurse prepares an injection of the influenza vaccine at Massachusetts General Hospital in Boston, Massachusetts January 10, 2013. REUTERS/Brian Snyder