Progress, Hope Expressed at 2nd Annual Vaccine Conference
• Vaccines as Defense Against Germ Warfare
• Cancer Vaccines
• Transcutaneous Immunization Eliminates Needles
• Intranasal Delivery
The 2nd Annual Conference on Vaccine Research, which concluded on March 30 in Bethesda, MD, was a noncommercial scientific forum that convened specialists from such diverse disciplines as microbiology, immunology, epidemiology, and public health. The meeting is jointly sponsored by nine organizations: Centers for Disease Control and Prevention, National Foundation for Infectious Diseases, National Institute of Allergy and Infectious Diseases, the International Society for Vaccines, Center for Biologics Evaluation and Research, Children's Vaccine Initiative, the Albert B. Sabin Vaccine Initiative, and the U.S. Department of Agriculture and the World Health Organization.
More than 350 scientists from around the world gathered in Bethesda to address major issues in vaccination. Topics ranged from vaccines against major global diseases, such as malaria, tuberculosis and AIDS, to protecting against more recent threats including biological weapons of mass destruction. Preventing infectious diseases remains a key target for vaccines, but they are also being studied as treatments for life-threatening diseases such as cancer.
"This is an exciting time in vaccine research," said William J. Martone, Senior Executive Director of the National Foundation for Infectious Diseases (NFID) and co-chair of the three-day conference. "We are discovering new vaccines, new methods for administering them and new ways to use them. We are also gaining greater insight into immune response. All of these things are setting the stage for more and better vaccines in the future."
Vaccines as Defense Against Germ Warfare (Back to Top)
The deadly Sarin nerve-gas incident in the Japanese subway system four years ago moved the potential for terrorist use of chemical and biological weapons onto the front pages of newspapers. For many years, the United States Department of Defense has been developing vaccines to counteract biological threats. This is no small task given the broad range of infectious organisms that could be used as biological weapons. One way to simplify development of protective immunizations against multiple agents is to identify a generic method of vaccine delivery, or a vaccine vector system.
Jonathan F. Smith, Chief of the Department of Viral Biology at the U.S. Army Medical Research Institute of Infectious Diseases, reported on the development of an RNA replicon vector based on attenuated Venezuelan equine encephalitis virus (VEE). Genes from pathologic viruses are inserted into this "safe" virus to produce a vaccine. As the VEE RNA self-replicates, it expresses the genes from the other viruses. "The hard part is identifying the most appropriate genes from the various disease-causing viruses, that is, the genes that induce a protective immune response," said Smith.
The altered RNA of VEE is inserted into virus particles that are then administered as a vaccine. When genes of Ebola, Lassa, Marburg, Influenza and Rift Valley fever virus were inserted into the VEE RNA vector and the resulting vaccine was given to rodents, the animals promptly demonstrated an immune response and were protected from infection with these viruses. The Marburg vaccine has also been shown recently to protect monkeys. Mice given a vaccine including genes from anthrax bacteria or from the botulinum neurotoxin were also protected when challenged with these harmful agents. Dr. Smith noted that researchers at the University of North Carolina are using the same vector system to develop a vaccine for HIV.
"VEE RNA replicon vector is suitable for repeated immunization against multiple agents in the same recipient," Smith commented, pointing out that genes from several organisms can be inserted into a single replicon vector, or multiple vectors can be mixed to produce a single vaccine. He speculated that vaccines against agents of bioterrorism will probably be used only prophylactically, such as for military personnel who are entering situations where the threat of bioterrorism is great. "The vaccines in all probability will be less useful after exposure, because the incubation period of most bioterrorism agents is very short," he said.
Cancer Vaccines (Back to Top)
Vaccines have traditionally been designed to generate immune responses that have a protective effect against specific infections. In the future, however, researchers believe vaccine use will expand from disease prevention to include treatment of diseases with immunologic components. One major area where this is being explored is cancer.
Dendritic cells, which are found throughout the body, are able to induce and enhance the body's immune response. Researchers theorize that loading these cells with tumor-derived antigens might produce rejection immune responses and cure the disease. Preliminary trials in patients with cancer have used dendritic cells isolated from blood and loaded with lymphoma-specific antigen. Dendritic cells can also be generated in vitro by culturing blood monocytes. In recent trials, these cells have been loaded with peptides specific for melanoma and prostate cancer. Clinical responses have been observed. Another strategy to generate dendritic cells is to culture CD34+ hematopoietic progenitor cells.
At Baylor Institute for Immunology Research in Dallas, Jaques Banchereau and colleagues are beginning clinical trials with different preparations of dendritic cells in patients with melanoma, prostate cancer and breast cancer. During his talk at the vaccine conference, Banchereau expressed hope that his studies would "demonstrate that dendritic cells are a potentially valuable therapeutic approach in cancer and, eventually, in other conditions that affect the immune system."
Transcutaneous Immunization Eliminates Needles (Back to Top)
With a few notable exceptions, such as the oral polio vaccine, most vaccines are given by injection. One potential new route of administration is transcutaneous immunization, in which an antigen and an adjuvant are applied to the skin surface. According to Tanya M. Scharton-Kersten of Iomai Corp. (Washington, DC), the vaccine can be delivered in as little as 15 minutes in animal models with a maximal response occurring within 30 minutes. When this technique was used with cholera toxin in animals, a potent serum antibody response was observed.
"Although antibody production is an important component of immunity," said Scharton-Kersten, "protection against many microbes requires the immune system to mount a defense using T-cells." To determine whether transcutaneous immunization can elicit a T-cell response, she used this technique with mice. The animals were studied after they received three topical immunizations on the skin surface at four-week intervals. This method did indeed induce proliferation of certain important immune cells know as CD4+ cells.
Scharton-Kersten noted that host immune responses (both B- and T-cell) have been observed with more than 30 antigens using this technique. "Transcutaneous immunization technology appears to be broadly applicable to current vaccine development," she said.
Phase I trials have begun in healthy humans. Scharton-Kersten hopes vaccines based on this technique will be available in patch form within two to three years for animals and within three to five years for humans. "They will be so easy to use that mass vaccination should be possible without highly trained medical professionals. Also, because the skin surface remains intact, there is minimal risk of adverse reaction."
Intranasal Delivery (Back to Top)
Another needle-less route for immunization is being explored for childhood respiratory illnesses. The second most common cause of croup, bronchiolitis and pneumonia in infants, after respiratory syncytial virus (RSV), is parainfluenza virus type 3 (PIV3). David Greenberg, Associate Professor of Pediatrics at Children's Hospital of Pittsburgh, reported on a clinical study of bovine PIV3 vaccine that is administered by intranasal spray.
In the study, 192 infants were randomized to receive the intranasal vaccine or placebo at ages 2, 4, 6 and 12–15 months. Other regularly scheduled childhood immunizations, such as the diptheria-tetanus-pertussis vaccine, were administered at the same time. The high rates of nasal shedding of bovine PIV3 indicated that the virus was reproducing in the noses of children, meaning that a local immune response was possible. Serum antibodies increased in vaccinated infants compared to infants given placebo. The intranasal vaccine, currently in development by Aviron, was well tolerated, with no serious adverse effects.
"Parainfluenza virus is responsible for many physician visits and is a common cause of infant hospitalization," Greenberg stated. "This study offers hope that we may be able to prevent the disease caused by the infection." He noted that a trial is necessary to prove the efficacy of the vaccine. "Being able to administer a vaccine by intranasal spray has great appeal because it spares infants additional shots."
For more information: Leonard Novick, Executive Director, National Foundation for Infectious Diseases, 4733 Bethesda Ave., Suite 750, Bethesda, MD 20814. Tel: 301-656-0003. Fax: 301-907-0878. Email: nfid@aol.com.