Chapter 5: Research Advances
Recent and Prospective


by From the Dana Sourcebook of Immunology

January, 2006

In 1967 the surgeon general of the United States, William Stewart, declared that it was time to “close the book on infectious diseases.” At that time— thanks to vaccines, drugs, and improved sanitation— we seemed to have won the war against germs. Although many infectious diseases have indeed been conquered, the last few decades have brought new threats.

  • Previously unknown diseases are appearing (AIDS, SARS, and Lyme disease).
  • Familiar diseases are becoming resistant to treatment (tuberculosis and malaria).
  • Uncommon diseases are becoming more widespread (West Nile virus).

The microbial world is continuously evolving and producing new infectious agents, and with an increase in travel and the shipping of goods worldwide, the new agents can spread like wildfire.

 pub_immunologysrcbk_img_40
Vaccines are used to stimulate the immune system to produce antibodies that protect the body from later attacks by the same invader. Bill Branson

To meet these challenges, scientists have developed powerful new techniques in molecular biology and genetic engineering. Improved understanding of disease processes has led to new vaccines and drugs—as well as entirely new ideas about the fight against disease.

Vaccines of the Future

To develop new vaccines, scientists identify protective antigens, which are parts of microbes likely to stimulate immunity that will protect against disease. Then, using genetic engineering, they make many copies of the corresponding genes (DNA). That DNA can be used to make DNA vaccines and vector vaccines, which may soon be available for use in humans.

DNA vaccines are often “naked” DNA (not associated with a cell or a virus) that carry instructions for making protective antigens. When the DNA is injected into tissue, nearby cells take it up and produce the antigens. The immune response against the protective antigens will defend the body against future infection with the living organism.

To make vector vaccines, the genes for the protective antigens are inserted into or recombined with the genetic material of otherwise harmless bacteria or viruses (vectors) and injected into people. As the vectors multiply in the body, they expose the immune system to the protective antigens, stimulating active immunity against the harmful organism.

Dendritic cell-based vaccines are also being developed, notably to fight cancer and infectious diseases on a large geographic scale. Dendritic cells are antigen-presenting cells, able to show or present bits of foreign proteins to the immune system. In addition, dendritic cells are the body’s sentinels and sensors, performing dozens of other tasks that lead to the initiation and control of most immune responses. To harness the biology of dendritic cells in vaccine design, two approaches are being developed. In treating cancer, and recently AIDS, dendritic cells removed from the patient’s blood are stimulated to reproduce in the laboratory, “loaded” with protective antigens, and then returned to the body. In another approach being developed for HIV and malaria, vaccine proteins are being directly guided to dendritic cells in the body, making antigen presentation hundreds of times more efficient. Vaccine designers are now turning to principles of immunology to devise better and more effective strategies.

Therapeutic Vaccines

Preventive vaccines thwart infections and diseases a person might get in the future, but researchers are also working on vaccines to fight diseases a person already has. These are called therapeutic vaccines. For example, several experiments are under way to develop vaccines that may help stimulate the immune system to fight the long-term effects of HIV infection. Therapeutic vaccines against hepatitis B, hepatitis C, tuberculosis, and malaria are also under investigation.

 pub_immunologysrcbk_img_41
When adults experience a resurgence of the chicken pox virus, they develop shingles. It is a more severe form of the disease and is accompanied by pain not experienced with chicken pox.  CDC / Dr. K.L. Hermann

A promising experimental vaccine can help prevent shingles, a painful condition caused by reactivation of latent chicken pox virus. After a bout of chicken pox, the virus may not be completely eliminated from the body, remaining latent in nerve cells for decades. When the body ages, and the immune system starts to decline, the virus may reactivate. The reactivated virus spreads along the infected nerves to the skin, causing shingles, a painful rash that may result in permanent, painful nerve damage. The shingles vaccine, a stronger version of the children’s chicken pox vaccine, has been shown to decrease the incidence of shingles or result in milder disease with fewer complications. 

Researchers also hope to use therapeutic vaccines to treat Alzheimer’s disease, heart disease, and some allergic and autoimmune diseases. These vaccines can target specific cells and molecules (rather than an infectious organism) to interrupt the disease process.

Taking Aim against Cancer

Cancer is one of the most active areas of research into therapeutic vaccines, and researchers hope their findings will lead to the development of preventive vaccines as well. Current therapies for cancer, such as radiation and chemotherapy, can damage healthy cells and cause severe side effects. Researchers hope to develop vaccines that teach the immune system to recognize and destroy cancer cells more effectively, without damaging healthy cells. This can be tricky, because cancer cells are not foreign invaders but the body’s own cells gone awry.

Tumor cell vaccines use killed cancer cells that are altered to make them better at stimulating the immune system. Tumor antigen vaccines use tumor-specific proteins to stimulate immune responses against living tumor cells. To make them, scientists identify proteins that are present in cancer cells but not in normal cells. They then must find ways to use these proteins or antigens to stimulate a strong immune response from the patient’s immune system, in other words, by targeting them to reach appropriate dendritic cells. Additional exciting strategies include drawing on the ways the tumor suppresses an immune attack; these evasion mechanisms can be neutralized, allowing for more effective immunity.               

Dendritic cell vaccines against cancer have shown promise in clinical trials. DNA vaccines are also being developed to treat cancer. Some of these vaccines use naked DNA, like the vaccines described above. Other DNA vaccines use a more complicated approach: cells taken from the patient are engineered with appropriate genetic material to make tumor-specific proteins and then returned to the patient. DNA vaccines against some human cancers, including melanoma, leukemia, and prostate cancer, are being tested in clinical trials

A Growing Threat from Within

Another new threat to our health has come not from infectious organisms or cancer, but from our own immune systems. Since the 1950s, Western industrialized countries have seen a doubling of allergic diseases (such as asthma, hay fever, and eczema) and autoimmune diseases (such as type 1 diabetes, multiple sclerosis, and Crohn’s disease, a disease of the small intestine characterized by diarrhea, cramping, and loss of appetite and weight). The reason for this increase is not well understood.

 pub_immunologysrcbk_img_42
As people have become more concerned about bacteria in the home, companies have started offering antibacterial products such as this soap. However, bacteria are always mutating, and new strains arise that are resistant to antibiotics and antibacterials.  Kenneth C. Zirkel

Some scientists say these diseases have been around all along, but doctors are diagnosing them more often. Others blame pollution, stress, or the presence of more allergens in our homes. It may be all of these, but it may also be because we are, in fact, too clean.

Life for most people in the developed world has changed dramatically in the last century. Fewer people live on farms, our water supply is safer, and people are having fewer children. Researchers, noting that people who grew up on farms, with many siblings, or with serious childhood diseases are less likely to develop allergies and asthma, have proposed the “hygiene hypothesis,” which states that the absence of childhood diseases might somehow increase the likelihood of developing allergies. Others have proposed that harmless microbes found in the soil, on farms, and in our intestines teach the immune system to react appropriately to the antigens it encounters. Researchers are attempting to identify the “friendly bacteria” or other environmental factors that might help prevent allergic disease.

A Delicate Balance

To keep us healthy, the elements of the immune response must be carefully controlled. Too little immune activity leaves the body susceptible to infections and cancer. Too much activity may result in autoimmunity or allergic diseases. A special group of T cells called regulatory T cells, or Treg cells, are attracting significant attention because of their critical role in keeping the immune system balanced. They seem to be able to dampen harmful immune responses in a selective way. Regulatory T cells are part of the immune tolerance system mentioned previously, but unlike the T cells discussed earlier, they do not generate protective immunity. Instead they suppress immunity, particularly immunity to self and harmless proteins in the environment. Without Treg cells we would all suffer, and could even die, from autoimmune diseases such as inflammatory bowel disease.

Research is under way to prevent or treat allergic and autoimmune diseases and to improve the success rate for organ transplants by improving Treg cell function. Without effective Treg cells, the immune response is more likely to overreact to harmless antigens (resulting in allergy) or react against the body itself (causing autoimmunity).

Many current treatments for allergic and autoimmune diseases suppress the immune system in a nonspecific way, leaving patients more susceptible to infections. The aim with Treg cells is to reduce harmful immune functions specifically, leaving disease-fighting functions intact.

In contrast, scientists are also researching ways to inhibit or destroy specific Treg cells. This might stimulate the immune system to fight cancer or infectious diseases, or make vaccines more effective.

Modern technologies have allowed new insights into health and disease. New understanding may also allow us to control the immune system, preventing and treating allergic and autoimmune diseases. New strategies to strengthen the immune system may help us at last “close the book” on cancer, infectious diseases, and even autoimmune diseases.

New Approaches for Hindering Viruses