August 2002
NIAID's Vaccine and Treatment Evaluation Units
For more than 40 years, vaccine research and development has been a vital component of the National Institute of Allergy and Infectious Diseases (NIAID) research agenda. Established in 1962, the NIAID Vaccine and Treatment Evaluation Units (VTEUs) have played a key role in this effort.The VTEUs are a network of university research hospitals across the United States that conduct Phase I and II clinical trials to test and evaluate candidate vaccines for infectious diseases. Through these sites, researchers can quickly carry out safety and efficacy studies of promising vaccines in children, adults, and specific high-risk populations, such as premature infants and the elderly. The results of these trials may have a profound effect on public health here and abroad.
The VTEU network is a critical player in the success of NIAID vaccine research and development. Through numerous studies at the VTEUs, researchers have tested and advanced vaccines for malaria, tuberculosis, pneumonia, cholera, and whooping cough. In the last six years alone, NIAID has supported more than 110 clinical studies through the VTEU network.
One of the many strengths of the VTEUs is their ability to conduct studies to address important public health questions. The VTEUs have the flexibility to focus on developing orphan vaccines for rare conditions. They also allow researchers to compare products from different manufacturers and to test the additive effects of products from different manufacturers in a prime-boost strategy.
Highlights and accomplishments
NIAID-supported research led to the development of several group A streptococcal (GAS) vaccine candidates, which are in various stages of testing. Major disorders associated with GAS infection include scarlet fever, strep throat, impetigo, pneumonia, bacteremia, acute kidney inflammation, toxic shock syndrome, necrotizing fasciitis (caused by so-called flesh-eating bacteria), and rheumatic fever. Rheumatic fever occurs in all parts of the world and is the leading cause of acquired heart disease in children in developing countries.Researchers are conducting clinical trials to evaluate the safety of a recombinant protein vaccine against GAS. In addition, the VTEU is evaluating the safety of a novel bacterial delivery system in which commensal bacteria (so-called "good" bacteria) may be engineered to produce a GAS protective antigen. In recent years, there have been few clinical trials testing GAS vaccines, adding to the importance of these studies.
NIAID has invested more than 30 years of research into developing pneumococcal vaccines. Early product development support as well as Phase I and II studies conducted by VTEU sites in infants were helpful in developing Prevnar, a vaccine to prevent pneumococcal diseases in children younger than 2 years of age.
By delivering more than one vaccine at a time, combination vaccines minimize needlesticks and trips to the doctor. A five-site VTEU trial evaluated the impact of inactivated (killed) poliovirus vaccine versus oral poliovirus vaccines when given with a combined vaccine against Haemophilus influenzae type b, pertussis, diphtheria, and tetanus. As a result of the study, health experts now recommend that children get the inactivated poliovirus vaccine as part of their routine immunizations.
Novel Delivery Systems
VTEU research has also helped usher in a new era of ways to deliver vaccines, such as a nasal spray. Six VTEUs enrolled young children in a Phase III trial of FluMist, an influenza vaccine administered by nasal spray. The vaccine proved to be 93 percent effective against the predominant flu strains of the 1996 to 1997 flu season. In 1998, researchers again inoculated the children against three flu strains thought to be circulating that season. They found the nasal spray vaccine to be 86 percent effective against not only the flu strains covered in the vaccine but also against a circulating strain not included in the vaccine.Issues such as lack of refrigeration can make immunizing people using traditional vaccines very difficult in developing countries. To help address this issue, scientists have developed plants genetically engineered to contain an antigen for the Escherichia coli bacteria and the Norwalk virus. This development shows that safe and effective edible vaccines can be made.
The first clinical study of an edible vaccine was conducted at the University of Maryland VTEU in 1998. In it, potatoes were genetically engineered to produce an immune response to E. coli when eaten raw. This novel technology may be an inexpensive and effective way to safely immunize people in developing countries against vaccine-preventable illnesses.
Vaccine Safety
The evaluation of vaccine safety is an important part of every vaccine clinical trial sponsored by the National Institutes of Health, including the VTEUs. Study participants are closely monitored for any adverse effects of the vaccinations they receive. All trials include safety as a primary study objective. In addition to the rigorous evaluation of vaccine safety that takes place during every trial, VTEU research explores emerging hypotheses regarding possible vaccine-related adverse events.Recent Federal efforts to improve the safety of vaccination have found that it is prudent to remove thimerosal, a possible source of organic mercury, from vaccines routinely given to infants. The University of Rochester VTEU has conducted a study to assess mercury levels in blood, hair, and stool samples from infants who received routine vaccines containing thimerosal. Mercury levels were compared with similar samples from infants who received vaccines without thimerosal.
Several important results have been obtained from this study. Mercury levels in blood were low in all infants studied and uniformly below the Environmental Protection Agency safety guidelines for methyl mercury. Mercury levels in the stool of infants receiving vaccines containing thimerosal were relatively high compared to mercury levels in the stool of infants who were not exposed to thimerosal. These results indicate that thimerosal appears to be removed from the blood and body more rapidly than methyl mercury. Thus, exposure to thimerosal is likely less dangerous than exposure to methyl mercury - and the guidelines for methyl mercury offer an even greater margin of safety.
Biodefense
Responding to the concern that the smallpox virus could be used as a bioterrorist weapon against the United States, NIAID is exploring the best way to use existing smallpox vaccine supplies to protect military and civilian populations. Approximately 15 million doses of Dryvax smallpox vaccine have been stored since production stopped in 1983.Because the estimated amount needed to control a U.S. outbreak is 40 million doses, NIAID began a study to determine whether Dryvax vaccine could be diluted effectively to make more doses of this smallpox vaccine available. This clinical trial showed that the existing U.S. supply of smallpox vaccine could successfully be diluted up to five times and retain its potency, effectively expanding the number of individuals it could protect from the contagious disease to 75 million. Dryvax, the vaccine used in this study, was made by Wyeth Laboratories (Marietta, Pa.). The vaccine is freeze-dried, live vaccinia virus, a poxvirus related to smallpox virus.
A report describing these findings appears in the April 2002 issue of The New England Journal of Medicine. The Dryvax vaccine will soon be studied in previously vaccinated populations to determine whether any residual immunity exists from earlier vaccination.
In addition to Dryvax, NIAID is sponsoring clinical trials of another vaccine against smallpox. Eighty million doses of Wetvax or APSV, a different formulation of the vaccinia smallpox vaccine produced by Aventis Pasteur (Paris, France) has been in storage for 40 years. The VTEU studies will determine the safety and preliminary efficacy of various concentrations of Aventis Pasteur's Smallpox Vaccine, USP (APSV) in adults who have never received vaccinia.
Researchers are also working on new, improved anthrax vaccines that may be more easily given to a diverse population. NIAID is collaborating with the U.S. Department of Defense to develop a next-generation vaccine. This new vaccine is based on a laboratory-produced recombinant version of PA protein, the major component of the existing vaccine that protects against infection. The Institute will supervise phase I and phase II trials of the recombinant PA vaccine in different formulations at VTEU sites.
VTEU Sites
The VTEUs are set up to respond to changing health needs. The sites and principal investigators are listed below.
| Baylor College of Medicine Dept. of Microbiology and Immunology One Baylor Plaza, 221D Houston, TX 77030 Principal Investigator: Wendy Keitel, M.D. Phone: 713-798-4469 Fax: 713-798-6802 E-mail: wkeitel@bcm.tmc.edu Cincinnati University Children's Hospital University of California at Los Angeles Center Saint Louis University Health Sciences Center |
University of Maryland School of Medicine Center for Vaccine Development HSF Room 480 685 West Baltimore Street Baltimore, MD 21201 Principal Investigator: Myron M. Levine, M.D. Phone: 410-706-7588 Fax: 410-706-6205 E-mail: mlevine@medicine.umaryland.edu University of Rochester Vanderbilt University Medical Center |
NIAID is a component of the National Institutes of Health (NIH), which is an agency of the Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
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