To be approved for general use, a candidate vaccine must go through a long period of testing and validation. The time between discovery of a disease agent and production
of a widely available vaccine has been as long as 50 years. Today, with biological synthesis and recombinant vaccine development techniques, the length of time from
basic research to availability of a licensed product can sometimes be greatly reduced.
Basic research focuses on biochemistry and physiology and on mechanisms that disease-causing microbes use to cause damage. Such research also takes into account the
biophysical characteristics of the organisms that might be used in vaccines or drugs to prevent or interrupt the disease process.
To develop a candidate vaccine, scientists test vaccine preparations in cell-culture, and often eventually in animals such as mice, guinea pigs, or even monkeys. In some
cases, computers can help researchers visualize the vaccine candidates in three dimensions to predict how vaccine antigens will interact with the immune system. If the
vaccine candidate is shown to be promising throughout the preclinical evaluations, it can become an investigational vaccine.
An investigational vaccine is one that successfully has gone through basic research and developmental processes, often including preclinical trials in animals, and has
been approved by the U.S. Food and Drug Administration (FDA) for use in human volunteers in clinical trials.
Clinical studies rely entirely upon the participation of volunteers, people who contribute their time and energy for the advancement of science and improved health care
for all. Thousands of volunteers of all ages and from all walks of life have participated in these studies. A typical volunteer in a vaccine study agrees to be given the
vaccine, makes frequent visits to a clinic for evaluation, participates in medical testing, and provides blood or tissue samples that will be used in assessing the
vaccine’s safety and potential effectiveness. Unlike the boy vaccinated by Dr. Jenner 200 years ago, volunteers today must sign an informed consent document indicating
their understanding of the study, its risks, and their willingness to participate.
A candidate vaccine undergoes three phases of clinical trials before it can be licensed for public use. Phase I trials, to determine the safety of various doses of the
vaccine, usually begin with small numbers of volunteers, and then expand to include more volunteers if the vaccine appears to be safe.
Phase II trials, to determine whether the vaccine is safe and immunogenic, are open to hundreds of volunteers. The vaccine is tested for safety, for its ability to evoke
an immune response, and for its potential to prevent disease.
Phase III trials are large-scale efficacy studies, often in thousands of individuals, to confirm that the vaccine safely prevents disease. A vaccine is considered
successful if its overall effect is beneficial; it should prevent disease, and any side effects should be minimal. If the disease the vaccine is designed to prevent is
rare in the United States, Phase III trials may be conducted in a country where the disease is prevalent. In the cases of such international cooperation, each government
signs an agreement and expects its citizens to benefit from the study.
The most common side effects of vaccines include low-grade fever, soreness and redness at the site of the injection, or sometimes body aches for up to 24 hours after
vaccination. These minor side effects of a vaccine are far preferable to having the disease.
The extensive testing that a vaccine undergoes before it is licensed for public use is conducted, in part, to assure safety as much as possible by closely observing
large numbers of volunteers for harmful side effects. But no matter how thorough the testing, it is impossible to allow completely for the extensive variation among
individuals, their immune systems, and their reactions to the introduction of new substances into their bodies. Serious systemic reactions to vaccines can occur,
although they are very rare. The FDA and the Centers for Disease Control and Prevention monitor vaccine distribution and use. Information about adverse reactions to a
vaccine is collected even after the vaccine is licensed for general use. Both organizations record any incident of a serious reaction and follow up on any re-evaluation
of the vaccine that is necessary.
Currently scientists are pursuing many promising new strategies in vaccine development and exploring novel ways to administer vaccines. The following descriptions of
just a few of these innovative ideas provide a preview of safer, more effective ways to fight disease.
Exposing mucosal membranes to vaccines is a strategy that can produce an immune response in a less-stressful and better targeted manner. Mucosal membranes are
located throughout our bodies, but are most accessible in the lungs, nose, mouth, throat, gastrointestinal tract, rectum and vagina. The oral polio vaccine, in use since
the 1950s, is an early example of the effectiveness of this strategy. Another possible mucosal route of administration is through the nose, and flu vaccines may soon be
widely available in a nasal spray. Researchers have shown that the route of entry a disease-causing organism takes is often an effective vaccine route as well. Many
vaccine improvements may result from progress in designing better adjuvants. At present, only an aluminum salt called alum is approved as an adjuvant by the FDA, but
scientists are studying many new natural and synthetic compounds.
Scientists are also looking at new ways of presenting the vaccine to the immune system. Microspheres, tiny spheres containing bits of antigenic material, show
promise in that they can release small doses of vaccine over extended periods of time as the microspheres gradually dissolve in the body. This means that someone may be
able to receive two or three doses in just one administration of vaccine.
Perhaps the most exciting new vaccine technique is introducing pure genetic material directly into the body. This genetic material, called “naked DNA,” encodes a few
proteins from a disease-causing organism. The DNA is then incorporated into the body’s own cells, which make the proteins encoded by the new DNA. It is these proteins
that are recognized as foreign and stimulate the immune system. In this way, the DNA will have an effect similar to that of a live, attenuated vaccine. In effect, the
DNA will produce antigens for years and induce strong, long-lasting immunity. At the same time, the exclusion of genes that are critical to the disease-causing
organism’s survival will assure that the vaccines are safe and do not actually cause disease.
Researchers are also exploring ways to create edible vaccines. By genetically engineering plants to incorporate synthetic antigens, scientists may be able to develop a
banana or potato, for example, that will produce protective immunity when eaten. Obviously, such a vaccine technique would greatly simplify immunization for many people
of the world.
Vaccines remain among the most powerful tools we have for disease prevention, and advances in biotechnology have ushered in a new era in vaccine development that holds
even more promise for improving public health. NIAID remains a leader in the discovery and testing of new and improved vaccines and will continue to nourish this
exciting renaissance in vaccine development. |
