Vaccines: A Paradigm Shift

Vaccines have been used to prevent a host of diseases for hundreds of years. But, more recently, vaccines are being utilized to help evaluate and diagnose patients with primary immunodeficiency disease (PIDD). And, it is hoped that in the future, research that is being conducted will determine how vaccines can be used as a treatment option for immune-deficient and autoimmune diseases.

Vaccines as a Diagnostic Tool

The first pneumococcal vaccine was licensed in 1977. A short time later in 1980, Dr. Gerald Schiffman and colleagues published a paper on the antibody response to pneumococcal vaccines in the Journal of Immunological Methods.¹ This led to using vaccines to test a patient’s ability to mount a protective antibody response as the standard of care when diagnosing a patient with a suspected immunodeficiency. According to the authors of Essentials of Clinical Immunology (5th edition), “Failure to make specific antibody after immunization is fundamental to the diagnosis.… Measurements of IgG subclasses are meaningless unless backed up by test immunizations and detection of specific IgG response.”²

To determine the level of functional antibodies, a patient’s serum levels are measured pre- and post-vaccination. If the serotypes do not reach a protective level after vaccination, the patient could be susceptible to recurrent and opportunistic infections. Therefore, even if the patient has normal immunoglobulin levels, it is important to measure the functionality of the antibodies.

A number of factors should be considered when deciding which vaccine to use when evaluating a patient’s functional immunity. Infants, for instance, are not able to formulate a response to all polysaccharide antigens. To compensate, polysaccharides are coupled with peptides to form a conjugated vaccine. Peptides cause helper T cells to be activated and proliferate. In turn, B cells can recognize molecules of the polysaccharide component, which leads to antibody production and formation of memory cells.³ The memory cells can then be measured to determine if the child is able to formulate a protective response. (See Table 1.)

Therapeutic Vaccines

Historically, immunotherapy using vaccines has widely been viewed as disease prevention, rather than disease treatment. And, although vaccines have been used to diagnose immunological diseases, immunology itself has not played a large role in the development of vaccines. Most successful vaccines have utilized the induction of protective antibodies. Therapeutic vaccines of the future, however, will require the induction of T cell immunity.⁴

Dendritic Cell Vaccines

Dendritic vaccines hold a great deal of hope for cancer patients by using T cells to help destroy cancer cells. Dendritic vaccines are made by extracting the patient’s dendritic cells and exposing them to immune stimulants, which in turn reproduces large amounts of dendritic cells. Those cells are then exposed to antigens from the patient’s cancer cells and injected back into the patient. The vaccine works by breaking down the antigens on the cell surface into smaller pieces, which allows the antigens to be more visible to the killer T cells that ultimately destroy the cancer cells. Provenge, recently approved for the treatment of prostate cancer, is an example of a dendritic vaccine.⁵

Tumor Cell Vaccines

Tumor cell vaccines also hold hope for cancer patients. Tumor vaccines are made by removing tumor cells, killing them to prevent recurrence, modifying the cells and reintroducing them back into the patient. It is hoped that the patient’s own immune system will then attack only the cancer cells, leaving other healthy tissue unharmed. These vaccines can be both allogeneic and autologous.

DNA Vaccines

DNA vaccines hold out promise to treat autoimmune diseases. In 1990, John Wolff and associates discovered that an injection of plasmids produces a protein response in mice⁶ that appears to stimulate T cells. As a result, labs can now insert the genes of an antigenic component of a pathogen into plasmids in order to test the effectiveness of vaccines.

The first human trial of a DNA vaccine used to treat an autoimmune disease was reported in the August 2007 issue of Annals of Neurology. Rather than stimulate the immune system as had traditionally been done with vaccines, principal investigator Hideki Garren, MD, PhD, from Stanford University and Bayhill Therapeutics sought to down-regulate an already overactive immune system in patients with relapsing/remitting multiple sclerosis. The study showed that the vaccine was safe and well-tolerated. In addition, the study showed a trend toward the reduction of brain lesions for patients on the active vaccine versus the placebo.⁷

Antigen Vaccines

Antigen-based vaccines incite the immune system to fight against it by creating antibodies. Research is focused on creating vaccines that will take specific antigens from, for instance, a cancer cell, and force the immune system to eradicate it. Eventually, it is hoped that therapeutic vaccines will treat diseases such as Alzheimer’s, HIV/AIDS, Crohn’s disease and Huntington’s disease, as well as many other devastating and costly diseases.

New Pathways Using Immunotherapy Principles

The concept of immunotherapy also is being studied as a possible treatment method for a rare immunodeficiency. In studies recently published in the Journal of Clinical Investigation, it was reported that immunologists have discovered that using an alternative signal pathway significantly improved the function in a 13-year-old boy with WiskottAldrich syndrome (WAS). Mutations in the WAS gene prevent the body from producing the WAS protein. Consequently, the body’s ability to use cells such as natural killer (NK) cells is compromised, leaving the patient prone to recurrent infections, cancer and premature death. The only known cure for WAS is a stem cell transplant.

Instead of other more well-known therapeutic pathways of treating disease, such as DNA vaccines, researchers identified and used an alternative pathway to restore the normal immune function. They were able to show that by treating the patient with pharmaceutically produced interleukin-2 (IL-2), the patient’s own NK cell cytoxicity matched the level to that of a healthy control subject. In an article published on April 15 by Science Daily, Dr. Jordan Orange of Children’s Hospital of Philadelphia stated: “Although follow-up studies will be necessary to investigate long-range benefits and test IL-2 in additional patients, the initial results are encouraging. If cytokines can provide clinical benefits with low toxicity, this may represent an important advance and opportunity for all patients with Wiskott-Aldrich syndrome.”⁸

Hope for the Future

While the focus on therapeutic vaccines for immune-deficient and autoimmune disease patients represents a paradigm shift by researchers, it appears to be one of rapid acceptance and endless possibilities. Vaccinology has the potential to revolutionize patient treatments, targeting currently incurable diseases and rendering them powerless against the human body.