Vaccines of the Future -- 2004 White Paper
Friday, April 14, 2006
Reported November 22, 2004
By Shari Levine, Ivanhoe Health Correspondent
(Ivanhoe Newswire) -- Vaccines are often considered responsible for the eradication of a number of infectious diseases that once killed millions of people and left many with chronic disabilities. “When I was a kid in the 1950s, the big fear was polio. Everyone knew someone on an iron lung, but today polio is rare and exotic,” says Myron Levine, M.D., D.T.P.H., a vaccine expert and director of The Center for Vaccine Studies at the University of Maryland School of Medicine.
Today, scientists continue to improve the quality of immunizations by:
* Creating new delivery methods
* Systematically monitoring safety and effectiveness
* Developing ground-breaking vaccines for diseases that in some way involve the immune system
Part I: No More Shots
All children in the United States are required to have more than a dozen immunizations before they enter school. As a result, vaccinations have been extraordinarily successful in reducing the rate of infection from once fatal diseases. In developing countries the high cost, lack of refrigeration, and limited supply of needles make it impossible to provide vaccines to millions of needy people. In 1990 the Children’s Vaccine Initiative was developed at the World Summit for Children in New York City. The Initiative supports development of new technologies for the creation of painless, less expensive, and more accessible vaccines.
EDIBLE VACCINES
Injected vaccines stimulate an immune response in the bloodstream. Edible vaccines created out of genetically modified plants could be used to build protection in the immune cells along the nose, throat and mouth where many air-borne germs first enter the body.
Potatoes: Researchers across the United States are looking for innovative ways to create safe and effective edible vaccines. One of the pioneers in this technology is Charles Arntzen, a plant biologist at Arizona State University in Tempe.1 He was one of the first scientists to create an edible potato vaccine, but his potatoes worked only when they were eaten raw. Arntzen is researching a way to make his vaccine-containing potatoes elicit an immune response after they are cooked.
In 1998, William Langridge, Ph.D., of Loma Linda University in California, genetically engineered potatoes to carry a vaccine against cholera.2 Unlike Arntzen’s earlier versions, this potato can be cooked and still carry the intact vaccine. When Langridge fed the vaccine-containing potatoes to mice, they produced antibodies to cholera.
Also using potatoes to create an edible vaccine are Hugh Mason, Ph.D., from the Boyce Thompson Institute at Cornell University, and Carol Tacket, M.D., from the University of Maryland School of Medicine.3 Mason has successfully created transgenic potato plants that contain the vaccines for cholera, hepatitis B, E.coli, and Norwalk virus. Dr. Tacket is conducting the clinical trials to test Mason’s edible vaccines in humans.
Tomatoes: Mason is also working to develop a tomato plant that contains the hepatitis B vaccine. His goal is to make tomato juice powder from vaccine-containing tomatoes that would be reconstituted and served as a beverage in developing countries where refrigeration is unavailable.4
Dennis Buetow, Ph.D., of the University of Illinois Urbana-Champaign, is testing an edible vaccine for respiratory syncytial virus. RSV causes a pneumonia-type disease that affects infants, young children, and older adults. Until now there has been no successful vaccine against RSV.
Buetow and colleagues have genetically engineered tomatoes to contain the RSV vaccine. “Our idea is to use a new approach and produce an 'edible' vaccine which when eaten throughout the winter months, will continually prime the immune system to produce antibodies against the virus. The edible vaccine would be consumed as part of the diet, would eliminate the need for injection by needles, and could be produced locally, thus removing the need for long-term refrigerated storage and shipping,” says Buetow.
When laboratory mice were fed the vaccine-containing tomatoes, their bodies produced antibodies to RSV. Buetow believes that, while these results offer hope, the vaccine will not be available for human consumption for at least five to seven years.
Tobacco: Henry Daniell, Ph.D., from the University of Central Florida in Orlando, studies genetically modified tobacco plants capable of producing both vaccines for diseases such as cholera and proteins such as insulin to treat diabetics. “Tobacco is a model system that we use because it is easy to genetically manipulate. We are using nicotine-free tobacco plants that taste like spinach and laboratory mice like to eat it.”
Other researchers use potatoes, corn, bananas and tomatoes to produce edible vaccines, but Daniell says he prefers to study leaves because he says, “We can introduce 10,000 copies of the gene into the plant cell, and 50 percent of the total plant protein is the foreign protein that we added. We found that each genetically engineered plant produced the same amount of protein, which means that the dosage is the same.” Daniell published the results of his research in the January 2001 issue of Nature Biotechnology.
Safety: Opponents of edible vaccines have many concerns. The Organic Consumers Union is one group concerned about how scientists will control the dosage of edible vaccines. They worry that if people get too much vaccine it could be toxic. Too little, they say, could lead to disease outbreaks.
Daniell and many other scientists are concerned about the environmental impact of genetically altered plants mixing genetic material with other plants through their pollen. “Foreign genes that are introduced in the nucleus of the plant cell are contained in the pollen, and pollen should never carry the gene that is engineered,” says Daniell. He has developed a novel approach in which he works with the DNA from chloroplasts (a component of the cell that is the site of photosynthesis) instead of altering the DNA from the plant’s nucleus. While there is hope for an edible vaccine for humans, Daniell believes that edible vaccines will first become available for animals within the next three to five years.
Nasal Flu Vaccine: The biopharmaceutical company Aviron, Inc., hopes to make flu shots obsolete in the next few years. The company has developed FluMist, a nasal spray containing the flu vaccine. Kristin Nichol, M.D., from the Minneapolis VA Hospital, led the clinical trials of FluMist and published her findings in The Journal of the American Medical Association (July 13, 1999). Since FluMist was found to be safe and effective in eliciting an immune response, the company is now seeking FDA approval.5
Vaccine Patches and Band-Aids: A simple patch may one day take the of place shots. Scientists are working on vaccines made of pure DNA that can be absorbed into the skin and elicit an immune response similar to that of injected vaccines. Large number of immune cells are found in the skin because it is the body’s first layer of defense against germs. Researchers from the Veteran’s Affairs Hospital in Palo Alto, Calif., and Stanford University are looking at a hepatitis B vaccine that would be applied directly to the skin as a shampoo or lotion.6
Gregory Glenn, M.D., at the Walter Reed Army Institute of Research, has been working with the Iomai Corporation on a DNA-based vaccine that is absorbed by the skin from a Band-Aid. The solution soaks into a layer of immune cells just under the surface of the skin that are normally bypassed by needles.7
Part II: The Vaccine Controversy
Year after year vaccines protect millions of people from sickness and death. However, this protection does not come without risks and rare adverse events. The safety and effectiveness of vaccines has come under fire from several concerned groups in the United States. One vocal skeptic of vaccinations is Representative Dan Burton, (R)IN. He is spearheading a complete review of the nation’s vaccination program.
Also concerned about the safety of immunizations is Barbara Loe Fischer, founder of the National Vaccine Information Center (NVIC) based in Vienna, Virginia. She started the organization after two of her children were injured by what she believes were complications from vaccines. In an interview published by the New York Times Magazine on May 6, 2001, Fischer says that while vaccines have helped to decrease the number of cases of childhood infectious diseases in the last 40 years, “We have at the same time seen a doubling of asthma and learning disabilities, a tripling of diabetes. Autism is affecting one in 500 children. We need to look at whether an intervention used with every child is perhaps contributing to the background rate of chronic disease and disability.”8
Fischer says that the NVIC is “Pro-education and pro-informed consent, not anti-vaccine. There is a difference. It is immoral to write off an unknown number of children as expendable in the name of the greater good to justify public health.”9
Vaccine and Disease: Is There a Link?
Public health experts are trying to determine whether or not certain diseases are caused by vaccines. For years, patients and their doctors wondered if the hepatitis B vaccine was linked to multiple sclerosis. In February 2001, a team led by Alberto Ascherio, M.D., from Harvard University School of Public Health, published a study in The New England Journal of Medicine that found no link between the hepatitis B vaccine and multiple sclerosis.10
Whether or not there is a connection between the measles, mumps, rubella vaccine and autism in children is perhaps the most highly debated question in vaccine science. The MMR vaccine is required in all 50 states before a child is admitted to public school or day-care centers. The vaccine has helped to control a common disease that once affected about 400,000 American children a year. In countries where the vaccine is not used, measles was blamed for about 1 million childhood deaths last year.
The MMR vaccine is generally given to children just prior to the second birthday. It is around this time that children display the signs and symptoms of autism. Concerns about a link between MMR vaccine and autism began when British researchers noticed that a few dozen autistic children had developed inflamed bowels after receiving the MMR vaccine, just prior to showing the first signs of autism. Andrew Wakefield, M.D., a British gastroenterologist, believes that he has discovered the missing MMR-autism link: The live virus from the MMR vaccine has damaged autistic children’s gastrointestinal tract allowing fragments of the measles virus to circulate in the blood and enter the brain.11 Harold Buttram, M.D., an outspoken physician in Quakertown, Penn., agrees with Dr. Wakefield’s theory that the link between MMR vaccine and autism is real.
Two recent studies found no connection between MMR and autism. One was published in the March 7, 2001, issue of The Journal of the American Medical Association. A team led by Loring Dales, M.D., found no link between the vaccine for measles, mumps and rubella (MMR) and the development of autism in children.12 In this study a team of experts from the California Department of Health Services looked at the number of children in California who were diagnosed with autism each year from 1980 and 1994. After comparing these figures to the number who received the MMR vaccine, they found that the rate of vaccinations rose 14 percent while the rate of autism jumped 600 percent. The team concluded that there could be no link between the vaccine and autism.13
One month later the Institute of Medicine’s Immunization Safety Review Committee, chaired by Marie C. McCormick, M.D., of the Harvard School of Public Health, issued a report saying it examined all studies about the health effects of the MMR vaccine in young children and concluded that there is no connection to autism.14
Vaccine Testing and Regulation
Like all medications, vaccines are rigorously studied prior to being used in humans. In a telephone interview Bruce Gellin, M.D., a pediatrician at Vanderbilt University and executive director of the National Network of Immunization Information, explained the process like this: Pre-clinical tests are done on animals to test safety and effectiveness. If the vaccine is not found to be safe in animals, all testing is stopped. If it is found to be safe in animals, phase I clinical trials test the safety of the vaccine on about 10 to 100 people. If the vaccine is found to have no harmful effects, phase II clinical trials begin to determine how the vaccine is optimally provided, including the correct dose and repetition. Phase III clinical trials determine if the vaccine does what it is supposed to do in a large population (10,000 to 100,000 study participants). After phase III trials, a company can apply for FDA approval. Phase IV trials, also called post-marketing evaluations, study the performance of a vaccine after it has been distributed.
To ensure public safety, the United States government requires additional monitoring of all FDA licensed vaccines and drugs. The Center for Biologics Evaluation and Research (CBER) strictly regulates vaccine products. The CDC and FDA jointly manage the Vaccine Adverse Events Recording System (VAERS). This is a safety surveillance program that collects information about adverse events or side effects that occur after the administration of FDA-approved vaccines. When a report is filed with VAERS, experts will do an investigation to determine the cause.15
Vaccines are quickly removed from the market when adverse events occur. For example, the rotavirus vaccine was discontinued in 1999 because it was found to cause bowel obstruction in 15 infants.
The United States government offers compensation to those injured by vaccines through the National Vaccine Injury Compensation program established by The National Childhood Vaccine Injury Act of 1986.
Part III: New Vaccine Research
Today, advances in science and technology allow researchers to design vaccines that may prevent and/or treat any disease using an immunologic component.
Diabetes Vaccine: William Langridge, Ph.D., a researcher at the Loma Linda University’s Center for Molecular Biology and Gene Therapy, is working to develop a vaccine that could prevent type 1 diabetes in people at high-risk for the disease. Type 1 diabetes results from an autoimmune reaction in which the body destroys beta cells in the pancreas that are needed to produce insulin. Langridge developed one of the first edible potato vaccines that successfully protected laboratory animals from becoming diabetic.16
Also working on a diabetes vaccine are researchers at the University of North Carolina at Chapel Hill. Roland Tisch, Ph.D., created a diabetes vaccine that suppresses the body’s autoimmune response, while leaving the rest of the immune system intact.17 The vaccine was effective in preventing the disease in laboratory mice bred to develop diabetes. His research was published in the February 2001 Journal of Immunology.
Addiction Vaccines: Researchers at Cantab Pharmaceuticals in Cambridge, England, are working to develop a vaccine that will treat cocaine addiction. The vaccine is designed to make the immune system recognize cocaine as a foreign substance. The body then produces antibodies that attach to the drug in the bloodstream, preventing cocaine from reaching the brain, thus blocking the high feeling produced by the cocaine.18
Professionals who treat drug addiction have several concerns about this new treatment. First, the addict will be able to reduce the vaccine’s effectiveness by increasing the amount of cocaine ingested. Second, the body can take up to two months to create the antibodies needed for an effective immune response, which can delay treatment. Finally, because drug dependence is a complex problem involving physiological and psychological issues, experts worry that addicts may switch to alternative drugs to get high.
Thomas Kosten, M.D., a psychiatrist at Yale University, is doing the first clinical trials on this cocaine vaccine (called TA-CD). In phase I clinical trials, he found that the vaccine did not cause major side effects. He is now conducting phase II clinical trials to test the vaccine’s effectiveness on cocaine addicts in an outpatient treatment center.19
AIDS Vaccine: An estimated 5,000 people become infected with HIV each day. AIDS prevention efforts that use behavior modification have been only moderately effective in reducing the spread of HIV. Therefore, researchers around the world have been working to create a vaccine that will prevent HIV infection or slow the progression of the disease. The challenge for scientists is that there are many different strains of the virus, and it mutates often. As of February 2001, there were 35 HIV vaccines undergoing human clinical trials. VaxGen Pharmaceuticals has created one of the first HIV vaccines to be tested on humans. Called GP120, or AIDSVax, the vaccine closely mimics the outer envelope of the virus, creating an immune response when an antibody binds to the vaccine’s coating. To test the efficacy of GP120, about 8,000 people at high-risk for infection in the United States, Canada and Thailand have been given the vaccine and will be monitored over the time.20
The pharmaceutical company Merck & Co has been testing a vaccine in monkeys that appears to prevent the progression of HIV infection. Positive results from their research were presented at a 2001 scientific meeting in Keystone, Colorado, by researchers John Shiver and Emilio Emini. Phase I clinical trials are underway.21
At Duke University, Bart Haynes, M.D. and colleagues are working to develop an HIV vaccine that would be administered as a nasal spray. This vaccine will create a strong immune response in both the mucous membranes (i.e. the genitals where contact with HIV is first made) and the general immune system.22
Norman Letvin, M.D., from the Beth Israel Deaconess Medical Center and Harvard University, is developing a different kind of AIDS vaccine. Letvin’s vaccine is not designed to prevent HIV infection, rather to control the amount of virus in the body, allowing the person to live a longer, healthier life.23 To do this, he uses a specific type of T-cell lymphocyte that kills HIV-infected cells already in the body.
Alzheimer’s Vaccine: Dave Morgan, Ph.D., from the University of South Florida in Tampa, is developing a vaccine to slow and hopefully stop memory loss caused by Alzheimer’s disease. The vaccine, developed by Elan Pharmaceuticals in San Francisco, Calif., was tested on mice bred to develop the disease. The vaccinated mice produced antibodies to beta amyloid - a protein scientists believe accumulates in the brain and causes Alzheimer’s. The vaccine triggers the immune system to remove the amyloid plaques in the brain and may keep them from developing at all. The vaccine is being tested for safety in phase I clinical trials.24, 25
Cancer Vaccines: Genetically engineered vaccines are being used to activate cancer patient’s immune systems to attack and destroy tumors. These are what researchers call therapeutic research. A team at Stanford Medical School led by Lawrence Fong, M.D., created a vaccine called dendritic cell therapy that would help the body’s immune system to recognize cancerous tumor cells as an “enemy” and attack.
The National Cancer Institute is sponsoring about 100 studies of cancer vaccines, the majority of them in patients with melanoma, a type of skin cancer. Donald Morton, M.D., a surgeon from the John Wayne Cancer Institute in Santa Monica, Calif., has developed CancerVax, a vaccine made from melanoma cells that are dying from radiation. Successful trials have led this vaccine to be tested on 1,000 patients with melanoma.26
New Vaccines for Developing Countries
Myron Levine, M.D., director of the Center for Vaccine Research at the University of Maryland School of Medicine, has made substantial contributions to the development of new vaccines. He says, “We would like to see that all vaccines of the future would be given by mouth, on the skin, or through nasal spray.”
The Center for Vaccine Development makes vaccines for children who live in developing countries. Diseases like cholera, typhoid and shigella are virtually non-existent in industrialized nations, but these infections kill millions of children in developing nations. Dr. Levine says, “We are currently working on several projects that include:
* Exploring the widespread use of a live oral cholera vaccine that has already been used by the World Health Organization during a cholera outbreak in Oceania,
* Typhoid vaccine that is in phase II clinical trials,
* Another typhoid vaccine that is just completing phase I clinical trials
* Shigella vaccine that is in phase I clinical trials.
Part IV: Vaccine Shortages
The United States government closely monitors safety and effectiveness of vaccines, but private companies manufacture these products for a profit. As a result, financial issues affecting private pharmaceutical companies can dictate the supply of vaccines while the demand remains constant.
Tetanus: In January 2001, the tetanus vaccine was suddenly in short supply. Until then, two pharmaceutical companies produced the vaccine: Wyeth-Ayerst (a division of American Home Products) and Aventis-Pasteur.
The vaccine business is not profitable because they are expensive to make, research and develop, and the return is very low. The Vaccines for Children Program, established in 1994, helps the CDC distribute vaccines to families that otherwise could not afford them. The program stipulated that the price of vaccines may only rise in accordance with the Consumer Price Index. So when vaccine manufacturers raised the price, the CDC was unable to afford it.27
The tetanus vaccine shortage resulted when Wyeth-Ayerst stopped producing the product after the FDA halted manufacturing at one of the company’s plants in Tennessee. The FDA found problems with the packaging of the vaccine and seized thousands of syringes. In October 2000, the FDA and Wyeth-Ayerst agreed to bring the manufacturing plant up to FDA standards, and the company was fined $30 million. Then in January 2001, Wyeth-Ayerst announced that it was stopping production of tetanus vaccines.28
Flu Vaccine Shortage: The 2000 influenza vaccine was delayed by a month, leaving many Americans at risk early in the flu season. The CDC reported several reasons for the delay, including:29
* The manufacturers of the flu vaccine had difficulty growing one strain of the live virus. As a result the early supply of vaccine was given to those at high risk for flu (older adults, people with suppressed immune systems, and health care workers).
* The FDA found one of the four flu vaccine-manufacturing plants in violation of safety standards and closed it.
* The vaccine was shipped to larger corporations, which delayed the delivery to smaller clinics and physician offices.30
Conclusion: Vaccine use has changed the medical landscape and has contributed to a significant decrease in infectious disease morbidity and mortality in the United States. Experts continue to enhance the quality of vaccines while making great strides to improve access to immunizations for people around the world.
The Global Alliance for Vaccines and Immunization is new organization dedicated to ensuring that all children have equal access to vaccines. The Alliance brings together public health experts from the World Health Organization, UNICEF, the World Bank and others to develop new vaccines against major killers that primarily affect the world’s poorest people. Financial support for GAVI comes from The Global Fund for Children’s Vaccines, which was created with a $750 million grant from The Bill and Melinda Gates Foundation. In time, scientific advances, technology, and financial support hopefully will improve worldwide immunizations. 31
ENDNOTES
1. Lee Dye, "Eating away disease: A scientist hopes specially modified fruits and vegetables can vaccinate the world," ABC News Online, 11 October 2000.
2. Reuters Staff, "Potatoes engineered to carry cholera 'shot,'" 26 Feb 1998.
3. Cat Lazaroff, "Edible Vaccines Carry Flavor of Danger," Environmental News Service, 11 July 2000.
4. Lazaroff, July 2000.
5. Associated Press Staff, "Nasal spray effective at preventing flu," CNN.com http://cnn.com/HEALTH/9907/13/nasal.flu.vaccine.ap, 13 July 1999.
6. Dana Mackenzie, "Vaccinations Without the Ouch," ScienceNOW, 20 September 1999.
7. Interview with Jim Slade, Needle Free Vaccines, http://www.pbs.org/healthweek/featurep1_318.htm, 27 August 1999.
8. Arthur Allen, "Questions for Barbara Loe Fischer on the Costs of Vaccination," The New York Times Magazine, 6 May 2001.
9. Allen, 6 May 2001
10. Bob Edwards, "Profile: Two new studies show no link between hepatitis B vaccine and multiple sclerosis," Morning Edition (NPR), 1 February 2001.
11. Centers for Disease Control and Prevention, National Immunization Program Web site, http://www.cdc.gov/nip/vacsafe/concerns/autism/autism-mmr.htm.
12. Loring Dales, Sandra Jo Hammer, Natalie J. Smith, "Time trends in Autism and in MMR Immunization Coverage in California," JAMA, March 7, 2001, vol 285, No. 9, pg. 1189.
13. Josh Fischman, "Vaccine worries get shot down but parents still fret," US News and World Report, 19 March 2001, pg. 63.
14. Institute of Medicine website, http://www.iom.edu/Imsafety, 24 April 2001.
15. Federal Drug Administration website, http://www.fda.gov/cber/vaccines.htm
16. Staff Writer, "LLU researcher receives major grant to further develop diabetes vaccine," Loma Linda University School of Medicine News, 24 August 2000.
17. Staff Writer, "Vaccine could prevent Type-1 Diabetes," United Press International, 31 January 2001.
18. Charlie Schmidt, "Newsfronts: Science and Technology: Medicine: Cocaine Vaccine," Popular Science, 1 June 1999, pg. 35.
19. Dawn Mackeen, "Immunized against addiction," Salon.com, http://www.salon.com/health/feature/2000/04/26/vaccine, 26 April 2000.
20. Julia Connors, Duke, "Other University Scientists pursue vaccine for HIV," University Wire, 19 March 2001.
21. Michael Waldholz, "Why Merck’s Experimental AIDS vaccine has scientists so excited," The Wall Street Journal, 2 April 2001.
22. Julia Connors, March 2001.
23. Julia Connors, March 2001.
24. Lindsay Peterson, "Hope in sight for fighting alzheimer’s," The Tampa Tribune, 10 April 2001, pg. 3.
25. Gina Kolata, "Separating research from news," The New York Times, 18 July 2000.
26. Daniel Q. Haney, "Vaccines show promise as powerful new cancer treatment," Naples Daily News, 27 August 2000.
27. Amy Standen, 8 March 2001
28. Amy Standen, "Ready for some lockjaw?" Salon.com, http://www.salon.com/tech/feature/2001/03/08/tetanus, 8 March 2001.
29. David Pitt, "Should production problems delay distribution, doctors have to prioritize their patients," Associated Press, 22 June 2000.
30. Mary Ann Elchisak, "Flu shots and influenza vaccine: vaccine shortage," http://pharmacology.about.com, 26 October 2000.
31. Global Alliance for Children’s Vaccines (GAVI) Web site, http://www.vaccinealliance.org.
WEB SITES
Sabin Vaccine Institute -- http://www.sabin.org
Bill and Melinda Gates Children’s Vaccine Program --http://www.childrensvaccine.org/homepage.htm
Boyce Thompson Institute for Plant Research -- http://bti.cornell.edu/
Centers for Disease Control National Vaccine Program Office --http://www.cdc.gov/od/nvpo/default.htm
CDC National Immunization Program -- http://www.cdc.gov/nip/
Food and Drug Administration -- http://www.fda.gov
Global Alliance for Vaccines and Immunizations -- http://www.vaccinealliance.org/
The Dale and Betty Bumpers Vaccine Research Center at the National Institutes of Allergy and Infectious Disease/National Institutes of Health -- http://www.niaid.nih.gov/vrc/default.htm
VaxGen -- http://www.vaxgen.com/
Parents Requesting Open Vaccine Education (PROVE) -- http://www.vaccineinfo.net/
National Vaccine Information Center -- http://www.909shot.com/
World Health Organization Vaccine Initiatives -- http://www.who.int/vaccines
National Network for Immunization Information -- http://www.immunizationinfo.org/index.cfm
Iomai Corporation -- http://www.iomai.com
http://search.ivanhoe.com/archives/p_archive.cfm?storyid=10094&channelid=CHAN-100013
Reported November 22, 2004
By Shari Levine, Ivanhoe Health Correspondent
(Ivanhoe Newswire) -- Vaccines are often considered responsible for the eradication of a number of infectious diseases that once killed millions of people and left many with chronic disabilities. “When I was a kid in the 1950s, the big fear was polio. Everyone knew someone on an iron lung, but today polio is rare and exotic,” says Myron Levine, M.D., D.T.P.H., a vaccine expert and director of The Center for Vaccine Studies at the University of Maryland School of Medicine.
Today, scientists continue to improve the quality of immunizations by:
* Creating new delivery methods
* Systematically monitoring safety and effectiveness
* Developing ground-breaking vaccines for diseases that in some way involve the immune system
Part I: No More Shots
All children in the United States are required to have more than a dozen immunizations before they enter school. As a result, vaccinations have been extraordinarily successful in reducing the rate of infection from once fatal diseases. In developing countries the high cost, lack of refrigeration, and limited supply of needles make it impossible to provide vaccines to millions of needy people. In 1990 the Children’s Vaccine Initiative was developed at the World Summit for Children in New York City. The Initiative supports development of new technologies for the creation of painless, less expensive, and more accessible vaccines.
EDIBLE VACCINES
Injected vaccines stimulate an immune response in the bloodstream. Edible vaccines created out of genetically modified plants could be used to build protection in the immune cells along the nose, throat and mouth where many air-borne germs first enter the body.
Potatoes: Researchers across the United States are looking for innovative ways to create safe and effective edible vaccines. One of the pioneers in this technology is Charles Arntzen, a plant biologist at Arizona State University in Tempe.1 He was one of the first scientists to create an edible potato vaccine, but his potatoes worked only when they were eaten raw. Arntzen is researching a way to make his vaccine-containing potatoes elicit an immune response after they are cooked.
In 1998, William Langridge, Ph.D., of Loma Linda University in California, genetically engineered potatoes to carry a vaccine against cholera.2 Unlike Arntzen’s earlier versions, this potato can be cooked and still carry the intact vaccine. When Langridge fed the vaccine-containing potatoes to mice, they produced antibodies to cholera.
Also using potatoes to create an edible vaccine are Hugh Mason, Ph.D., from the Boyce Thompson Institute at Cornell University, and Carol Tacket, M.D., from the University of Maryland School of Medicine.3 Mason has successfully created transgenic potato plants that contain the vaccines for cholera, hepatitis B, E.coli, and Norwalk virus. Dr. Tacket is conducting the clinical trials to test Mason’s edible vaccines in humans.
Tomatoes: Mason is also working to develop a tomato plant that contains the hepatitis B vaccine. His goal is to make tomato juice powder from vaccine-containing tomatoes that would be reconstituted and served as a beverage in developing countries where refrigeration is unavailable.4
Dennis Buetow, Ph.D., of the University of Illinois Urbana-Champaign, is testing an edible vaccine for respiratory syncytial virus. RSV causes a pneumonia-type disease that affects infants, young children, and older adults. Until now there has been no successful vaccine against RSV.
Buetow and colleagues have genetically engineered tomatoes to contain the RSV vaccine. “Our idea is to use a new approach and produce an 'edible' vaccine which when eaten throughout the winter months, will continually prime the immune system to produce antibodies against the virus. The edible vaccine would be consumed as part of the diet, would eliminate the need for injection by needles, and could be produced locally, thus removing the need for long-term refrigerated storage and shipping,” says Buetow.
When laboratory mice were fed the vaccine-containing tomatoes, their bodies produced antibodies to RSV. Buetow believes that, while these results offer hope, the vaccine will not be available for human consumption for at least five to seven years.
Tobacco: Henry Daniell, Ph.D., from the University of Central Florida in Orlando, studies genetically modified tobacco plants capable of producing both vaccines for diseases such as cholera and proteins such as insulin to treat diabetics. “Tobacco is a model system that we use because it is easy to genetically manipulate. We are using nicotine-free tobacco plants that taste like spinach and laboratory mice like to eat it.”
Other researchers use potatoes, corn, bananas and tomatoes to produce edible vaccines, but Daniell says he prefers to study leaves because he says, “We can introduce 10,000 copies of the gene into the plant cell, and 50 percent of the total plant protein is the foreign protein that we added. We found that each genetically engineered plant produced the same amount of protein, which means that the dosage is the same.” Daniell published the results of his research in the January 2001 issue of Nature Biotechnology.
Safety: Opponents of edible vaccines have many concerns. The Organic Consumers Union is one group concerned about how scientists will control the dosage of edible vaccines. They worry that if people get too much vaccine it could be toxic. Too little, they say, could lead to disease outbreaks.
Daniell and many other scientists are concerned about the environmental impact of genetically altered plants mixing genetic material with other plants through their pollen. “Foreign genes that are introduced in the nucleus of the plant cell are contained in the pollen, and pollen should never carry the gene that is engineered,” says Daniell. He has developed a novel approach in which he works with the DNA from chloroplasts (a component of the cell that is the site of photosynthesis) instead of altering the DNA from the plant’s nucleus. While there is hope for an edible vaccine for humans, Daniell believes that edible vaccines will first become available for animals within the next three to five years.
Nasal Flu Vaccine: The biopharmaceutical company Aviron, Inc., hopes to make flu shots obsolete in the next few years. The company has developed FluMist, a nasal spray containing the flu vaccine. Kristin Nichol, M.D., from the Minneapolis VA Hospital, led the clinical trials of FluMist and published her findings in The Journal of the American Medical Association (July 13, 1999). Since FluMist was found to be safe and effective in eliciting an immune response, the company is now seeking FDA approval.5
Vaccine Patches and Band-Aids: A simple patch may one day take the of place shots. Scientists are working on vaccines made of pure DNA that can be absorbed into the skin and elicit an immune response similar to that of injected vaccines. Large number of immune cells are found in the skin because it is the body’s first layer of defense against germs. Researchers from the Veteran’s Affairs Hospital in Palo Alto, Calif., and Stanford University are looking at a hepatitis B vaccine that would be applied directly to the skin as a shampoo or lotion.6
Gregory Glenn, M.D., at the Walter Reed Army Institute of Research, has been working with the Iomai Corporation on a DNA-based vaccine that is absorbed by the skin from a Band-Aid. The solution soaks into a layer of immune cells just under the surface of the skin that are normally bypassed by needles.7
Part II: The Vaccine Controversy
Year after year vaccines protect millions of people from sickness and death. However, this protection does not come without risks and rare adverse events. The safety and effectiveness of vaccines has come under fire from several concerned groups in the United States. One vocal skeptic of vaccinations is Representative Dan Burton, (R)IN. He is spearheading a complete review of the nation’s vaccination program.
Also concerned about the safety of immunizations is Barbara Loe Fischer, founder of the National Vaccine Information Center (NVIC) based in Vienna, Virginia. She started the organization after two of her children were injured by what she believes were complications from vaccines. In an interview published by the New York Times Magazine on May 6, 2001, Fischer says that while vaccines have helped to decrease the number of cases of childhood infectious diseases in the last 40 years, “We have at the same time seen a doubling of asthma and learning disabilities, a tripling of diabetes. Autism is affecting one in 500 children. We need to look at whether an intervention used with every child is perhaps contributing to the background rate of chronic disease and disability.”8
Fischer says that the NVIC is “Pro-education and pro-informed consent, not anti-vaccine. There is a difference. It is immoral to write off an unknown number of children as expendable in the name of the greater good to justify public health.”9
Vaccine and Disease: Is There a Link?
Public health experts are trying to determine whether or not certain diseases are caused by vaccines. For years, patients and their doctors wondered if the hepatitis B vaccine was linked to multiple sclerosis. In February 2001, a team led by Alberto Ascherio, M.D., from Harvard University School of Public Health, published a study in The New England Journal of Medicine that found no link between the hepatitis B vaccine and multiple sclerosis.10
Whether or not there is a connection between the measles, mumps, rubella vaccine and autism in children is perhaps the most highly debated question in vaccine science. The MMR vaccine is required in all 50 states before a child is admitted to public school or day-care centers. The vaccine has helped to control a common disease that once affected about 400,000 American children a year. In countries where the vaccine is not used, measles was blamed for about 1 million childhood deaths last year.
The MMR vaccine is generally given to children just prior to the second birthday. It is around this time that children display the signs and symptoms of autism. Concerns about a link between MMR vaccine and autism began when British researchers noticed that a few dozen autistic children had developed inflamed bowels after receiving the MMR vaccine, just prior to showing the first signs of autism. Andrew Wakefield, M.D., a British gastroenterologist, believes that he has discovered the missing MMR-autism link: The live virus from the MMR vaccine has damaged autistic children’s gastrointestinal tract allowing fragments of the measles virus to circulate in the blood and enter the brain.11 Harold Buttram, M.D., an outspoken physician in Quakertown, Penn., agrees with Dr. Wakefield’s theory that the link between MMR vaccine and autism is real.
Two recent studies found no connection between MMR and autism. One was published in the March 7, 2001, issue of The Journal of the American Medical Association. A team led by Loring Dales, M.D., found no link between the vaccine for measles, mumps and rubella (MMR) and the development of autism in children.12 In this study a team of experts from the California Department of Health Services looked at the number of children in California who were diagnosed with autism each year from 1980 and 1994. After comparing these figures to the number who received the MMR vaccine, they found that the rate of vaccinations rose 14 percent while the rate of autism jumped 600 percent. The team concluded that there could be no link between the vaccine and autism.13
One month later the Institute of Medicine’s Immunization Safety Review Committee, chaired by Marie C. McCormick, M.D., of the Harvard School of Public Health, issued a report saying it examined all studies about the health effects of the MMR vaccine in young children and concluded that there is no connection to autism.14
Vaccine Testing and Regulation
Like all medications, vaccines are rigorously studied prior to being used in humans. In a telephone interview Bruce Gellin, M.D., a pediatrician at Vanderbilt University and executive director of the National Network of Immunization Information, explained the process like this: Pre-clinical tests are done on animals to test safety and effectiveness. If the vaccine is not found to be safe in animals, all testing is stopped. If it is found to be safe in animals, phase I clinical trials test the safety of the vaccine on about 10 to 100 people. If the vaccine is found to have no harmful effects, phase II clinical trials begin to determine how the vaccine is optimally provided, including the correct dose and repetition. Phase III clinical trials determine if the vaccine does what it is supposed to do in a large population (10,000 to 100,000 study participants). After phase III trials, a company can apply for FDA approval. Phase IV trials, also called post-marketing evaluations, study the performance of a vaccine after it has been distributed.
To ensure public safety, the United States government requires additional monitoring of all FDA licensed vaccines and drugs. The Center for Biologics Evaluation and Research (CBER) strictly regulates vaccine products. The CDC and FDA jointly manage the Vaccine Adverse Events Recording System (VAERS). This is a safety surveillance program that collects information about adverse events or side effects that occur after the administration of FDA-approved vaccines. When a report is filed with VAERS, experts will do an investigation to determine the cause.15
Vaccines are quickly removed from the market when adverse events occur. For example, the rotavirus vaccine was discontinued in 1999 because it was found to cause bowel obstruction in 15 infants.
The United States government offers compensation to those injured by vaccines through the National Vaccine Injury Compensation program established by The National Childhood Vaccine Injury Act of 1986.
Part III: New Vaccine Research
Today, advances in science and technology allow researchers to design vaccines that may prevent and/or treat any disease using an immunologic component.
Diabetes Vaccine: William Langridge, Ph.D., a researcher at the Loma Linda University’s Center for Molecular Biology and Gene Therapy, is working to develop a vaccine that could prevent type 1 diabetes in people at high-risk for the disease. Type 1 diabetes results from an autoimmune reaction in which the body destroys beta cells in the pancreas that are needed to produce insulin. Langridge developed one of the first edible potato vaccines that successfully protected laboratory animals from becoming diabetic.16
Also working on a diabetes vaccine are researchers at the University of North Carolina at Chapel Hill. Roland Tisch, Ph.D., created a diabetes vaccine that suppresses the body’s autoimmune response, while leaving the rest of the immune system intact.17 The vaccine was effective in preventing the disease in laboratory mice bred to develop diabetes. His research was published in the February 2001 Journal of Immunology.
Addiction Vaccines: Researchers at Cantab Pharmaceuticals in Cambridge, England, are working to develop a vaccine that will treat cocaine addiction. The vaccine is designed to make the immune system recognize cocaine as a foreign substance. The body then produces antibodies that attach to the drug in the bloodstream, preventing cocaine from reaching the brain, thus blocking the high feeling produced by the cocaine.18
Professionals who treat drug addiction have several concerns about this new treatment. First, the addict will be able to reduce the vaccine’s effectiveness by increasing the amount of cocaine ingested. Second, the body can take up to two months to create the antibodies needed for an effective immune response, which can delay treatment. Finally, because drug dependence is a complex problem involving physiological and psychological issues, experts worry that addicts may switch to alternative drugs to get high.
Thomas Kosten, M.D., a psychiatrist at Yale University, is doing the first clinical trials on this cocaine vaccine (called TA-CD). In phase I clinical trials, he found that the vaccine did not cause major side effects. He is now conducting phase II clinical trials to test the vaccine’s effectiveness on cocaine addicts in an outpatient treatment center.19
AIDS Vaccine: An estimated 5,000 people become infected with HIV each day. AIDS prevention efforts that use behavior modification have been only moderately effective in reducing the spread of HIV. Therefore, researchers around the world have been working to create a vaccine that will prevent HIV infection or slow the progression of the disease. The challenge for scientists is that there are many different strains of the virus, and it mutates often. As of February 2001, there were 35 HIV vaccines undergoing human clinical trials. VaxGen Pharmaceuticals has created one of the first HIV vaccines to be tested on humans. Called GP120, or AIDSVax, the vaccine closely mimics the outer envelope of the virus, creating an immune response when an antibody binds to the vaccine’s coating. To test the efficacy of GP120, about 8,000 people at high-risk for infection in the United States, Canada and Thailand have been given the vaccine and will be monitored over the time.20
The pharmaceutical company Merck & Co has been testing a vaccine in monkeys that appears to prevent the progression of HIV infection. Positive results from their research were presented at a 2001 scientific meeting in Keystone, Colorado, by researchers John Shiver and Emilio Emini. Phase I clinical trials are underway.21
At Duke University, Bart Haynes, M.D. and colleagues are working to develop an HIV vaccine that would be administered as a nasal spray. This vaccine will create a strong immune response in both the mucous membranes (i.e. the genitals where contact with HIV is first made) and the general immune system.22
Norman Letvin, M.D., from the Beth Israel Deaconess Medical Center and Harvard University, is developing a different kind of AIDS vaccine. Letvin’s vaccine is not designed to prevent HIV infection, rather to control the amount of virus in the body, allowing the person to live a longer, healthier life.23 To do this, he uses a specific type of T-cell lymphocyte that kills HIV-infected cells already in the body.
Alzheimer’s Vaccine: Dave Morgan, Ph.D., from the University of South Florida in Tampa, is developing a vaccine to slow and hopefully stop memory loss caused by Alzheimer’s disease. The vaccine, developed by Elan Pharmaceuticals in San Francisco, Calif., was tested on mice bred to develop the disease. The vaccinated mice produced antibodies to beta amyloid - a protein scientists believe accumulates in the brain and causes Alzheimer’s. The vaccine triggers the immune system to remove the amyloid plaques in the brain and may keep them from developing at all. The vaccine is being tested for safety in phase I clinical trials.24, 25
Cancer Vaccines: Genetically engineered vaccines are being used to activate cancer patient’s immune systems to attack and destroy tumors. These are what researchers call therapeutic research. A team at Stanford Medical School led by Lawrence Fong, M.D., created a vaccine called dendritic cell therapy that would help the body’s immune system to recognize cancerous tumor cells as an “enemy” and attack.
The National Cancer Institute is sponsoring about 100 studies of cancer vaccines, the majority of them in patients with melanoma, a type of skin cancer. Donald Morton, M.D., a surgeon from the John Wayne Cancer Institute in Santa Monica, Calif., has developed CancerVax, a vaccine made from melanoma cells that are dying from radiation. Successful trials have led this vaccine to be tested on 1,000 patients with melanoma.26
New Vaccines for Developing Countries
Myron Levine, M.D., director of the Center for Vaccine Research at the University of Maryland School of Medicine, has made substantial contributions to the development of new vaccines. He says, “We would like to see that all vaccines of the future would be given by mouth, on the skin, or through nasal spray.”
The Center for Vaccine Development makes vaccines for children who live in developing countries. Diseases like cholera, typhoid and shigella are virtually non-existent in industrialized nations, but these infections kill millions of children in developing nations. Dr. Levine says, “We are currently working on several projects that include:
* Exploring the widespread use of a live oral cholera vaccine that has already been used by the World Health Organization during a cholera outbreak in Oceania,
* Typhoid vaccine that is in phase II clinical trials,
* Another typhoid vaccine that is just completing phase I clinical trials
* Shigella vaccine that is in phase I clinical trials.
Part IV: Vaccine Shortages
The United States government closely monitors safety and effectiveness of vaccines, but private companies manufacture these products for a profit. As a result, financial issues affecting private pharmaceutical companies can dictate the supply of vaccines while the demand remains constant.
Tetanus: In January 2001, the tetanus vaccine was suddenly in short supply. Until then, two pharmaceutical companies produced the vaccine: Wyeth-Ayerst (a division of American Home Products) and Aventis-Pasteur.
The vaccine business is not profitable because they are expensive to make, research and develop, and the return is very low. The Vaccines for Children Program, established in 1994, helps the CDC distribute vaccines to families that otherwise could not afford them. The program stipulated that the price of vaccines may only rise in accordance with the Consumer Price Index. So when vaccine manufacturers raised the price, the CDC was unable to afford it.27
The tetanus vaccine shortage resulted when Wyeth-Ayerst stopped producing the product after the FDA halted manufacturing at one of the company’s plants in Tennessee. The FDA found problems with the packaging of the vaccine and seized thousands of syringes. In October 2000, the FDA and Wyeth-Ayerst agreed to bring the manufacturing plant up to FDA standards, and the company was fined $30 million. Then in January 2001, Wyeth-Ayerst announced that it was stopping production of tetanus vaccines.28
Flu Vaccine Shortage: The 2000 influenza vaccine was delayed by a month, leaving many Americans at risk early in the flu season. The CDC reported several reasons for the delay, including:29
* The manufacturers of the flu vaccine had difficulty growing one strain of the live virus. As a result the early supply of vaccine was given to those at high risk for flu (older adults, people with suppressed immune systems, and health care workers).
* The FDA found one of the four flu vaccine-manufacturing plants in violation of safety standards and closed it.
* The vaccine was shipped to larger corporations, which delayed the delivery to smaller clinics and physician offices.30
Conclusion: Vaccine use has changed the medical landscape and has contributed to a significant decrease in infectious disease morbidity and mortality in the United States. Experts continue to enhance the quality of vaccines while making great strides to improve access to immunizations for people around the world.
The Global Alliance for Vaccines and Immunization is new organization dedicated to ensuring that all children have equal access to vaccines. The Alliance brings together public health experts from the World Health Organization, UNICEF, the World Bank and others to develop new vaccines against major killers that primarily affect the world’s poorest people. Financial support for GAVI comes from The Global Fund for Children’s Vaccines, which was created with a $750 million grant from The Bill and Melinda Gates Foundation. In time, scientific advances, technology, and financial support hopefully will improve worldwide immunizations. 31
ENDNOTES
1. Lee Dye, "Eating away disease: A scientist hopes specially modified fruits and vegetables can vaccinate the world," ABC News Online, 11 October 2000.
2. Reuters Staff, "Potatoes engineered to carry cholera 'shot,'" 26 Feb 1998.
3. Cat Lazaroff, "Edible Vaccines Carry Flavor of Danger," Environmental News Service, 11 July 2000.
4. Lazaroff, July 2000.
5. Associated Press Staff, "Nasal spray effective at preventing flu," CNN.com http://cnn.com/HEALTH/9907/13/nasal.flu.vaccine.ap, 13 July 1999.
6. Dana Mackenzie, "Vaccinations Without the Ouch," ScienceNOW, 20 September 1999.
7. Interview with Jim Slade, Needle Free Vaccines, http://www.pbs.org/healthweek/featurep1_318.htm, 27 August 1999.
8. Arthur Allen, "Questions for Barbara Loe Fischer on the Costs of Vaccination," The New York Times Magazine, 6 May 2001.
9. Allen, 6 May 2001
10. Bob Edwards, "Profile: Two new studies show no link between hepatitis B vaccine and multiple sclerosis," Morning Edition (NPR), 1 February 2001.
11. Centers for Disease Control and Prevention, National Immunization Program Web site, http://www.cdc.gov/nip/vacsafe/concerns/autism/autism-mmr.htm.
12. Loring Dales, Sandra Jo Hammer, Natalie J. Smith, "Time trends in Autism and in MMR Immunization Coverage in California," JAMA, March 7, 2001, vol 285, No. 9, pg. 1189.
13. Josh Fischman, "Vaccine worries get shot down but parents still fret," US News and World Report, 19 March 2001, pg. 63.
14. Institute of Medicine website, http://www.iom.edu/Imsafety, 24 April 2001.
15. Federal Drug Administration website, http://www.fda.gov/cber/vaccines.htm
16. Staff Writer, "LLU researcher receives major grant to further develop diabetes vaccine," Loma Linda University School of Medicine News, 24 August 2000.
17. Staff Writer, "Vaccine could prevent Type-1 Diabetes," United Press International, 31 January 2001.
18. Charlie Schmidt, "Newsfronts: Science and Technology: Medicine: Cocaine Vaccine," Popular Science, 1 June 1999, pg. 35.
19. Dawn Mackeen, "Immunized against addiction," Salon.com, http://www.salon.com/health/feature/2000/04/26/vaccine, 26 April 2000.
20. Julia Connors, Duke, "Other University Scientists pursue vaccine for HIV," University Wire, 19 March 2001.
21. Michael Waldholz, "Why Merck’s Experimental AIDS vaccine has scientists so excited," The Wall Street Journal, 2 April 2001.
22. Julia Connors, March 2001.
23. Julia Connors, March 2001.
24. Lindsay Peterson, "Hope in sight for fighting alzheimer’s," The Tampa Tribune, 10 April 2001, pg. 3.
25. Gina Kolata, "Separating research from news," The New York Times, 18 July 2000.
26. Daniel Q. Haney, "Vaccines show promise as powerful new cancer treatment," Naples Daily News, 27 August 2000.
27. Amy Standen, 8 March 2001
28. Amy Standen, "Ready for some lockjaw?" Salon.com, http://www.salon.com/tech/feature/2001/03/08/tetanus, 8 March 2001.
29. David Pitt, "Should production problems delay distribution, doctors have to prioritize their patients," Associated Press, 22 June 2000.
30. Mary Ann Elchisak, "Flu shots and influenza vaccine: vaccine shortage," http://pharmacology.about.com, 26 October 2000.
31. Global Alliance for Children’s Vaccines (GAVI) Web site, http://www.vaccinealliance.org.
WEB SITES
Sabin Vaccine Institute -- http://www.sabin.org
Bill and Melinda Gates Children’s Vaccine Program --http://www.childrensvaccine.org/homepage.htm
Boyce Thompson Institute for Plant Research -- http://bti.cornell.edu/
Centers for Disease Control National Vaccine Program Office --http://www.cdc.gov/od/nvpo/default.htm
CDC National Immunization Program -- http://www.cdc.gov/nip/
Food and Drug Administration -- http://www.fda.gov
Global Alliance for Vaccines and Immunizations -- http://www.vaccinealliance.org/
The Dale and Betty Bumpers Vaccine Research Center at the National Institutes of Allergy and Infectious Disease/National Institutes of Health -- http://www.niaid.nih.gov/vrc/default.htm
VaxGen -- http://www.vaxgen.com/
Parents Requesting Open Vaccine Education (PROVE) -- http://www.vaccineinfo.net/
National Vaccine Information Center -- http://www.909shot.com/
World Health Organization Vaccine Initiatives -- http://www.who.int/vaccines
National Network for Immunization Information -- http://www.immunizationinfo.org/index.cfm
Iomai Corporation -- http://www.iomai.com
ENDNOTES
1. Lee Dye, "Eating away disease: A scientist hopes specially modified fruits and vegetables can vaccinate the world," ABC News Online, 11 October 2000.
2. Reuters Staff, "Potatoes engineered to carry cholera 'shot,'" 26 Feb 1998.
3. Cat Lazaroff, "Edible Vaccines Carry Flavor of Danger," Environmental News Service, 11 July 2000.
4. Lazaroff, July 2000.
5. Associated Press Staff, "Nasal spray effective at preventing flu," CNN.com http://cnn.com/HEALTH/9907/13/nasal.flu.vaccine.ap, 13 July 1999.
6. Dana Mackenzie, "Vaccinations Without the Ouch," ScienceNOW, 20 September 1999.
7. Interview with Jim Slade, Needle Free Vaccines, http://www.pbs.org/healthweek/featurep1_318.htm, 27 August 1999.
8. Arthur Allen, "Questions for Barbara Loe Fischer on the Costs of Vaccination," The New York Times Magazine, 6 May 2001.
9. Allen, 6 May 2001
10. Bob Edwards, "Profile: Two new studies show no link between hepatitis B vaccine and multiple sclerosis," Morning Edition (NPR), 1 February 2001.
11. Centers for Disease Control and Prevention, National Immunization Program Web site, http://www.cdc.gov/nip/vacsafe/concerns/autism/autism-mmr.htm.
12. Loring Dales, Sandra Jo Hammer, Natalie J. Smith, "Time trends in Autism and in MMR Immunization Coverage in California," JAMA, March 7, 2001, vol 285, No. 9, pg. 1189.
13. Josh Fischman, "Vaccine worries get shot down but parents still fret," US News and World Report, 19 March 2001, pg. 63.
14. Institute of Medicine website, http://www.iom.edu/Imsafety, 24 April 2001.
15. Federal Drug Administration website, http://www.fda.gov/cber/vaccines.htm
16. Staff Writer, "LLU researcher receives major grant to further develop diabetes vaccine," Loma Linda University School of Medicine News, 24 August 2000.
17. Staff Writer, "Vaccine could prevent Type-1 Diabetes," United Press International, 31 January 2001.
18. Charlie Schmidt, "Newsfronts: Science and Technology: Medicine: Cocaine Vaccine," Popular Science, 1 June 1999, pg. 35.
19. Dawn Mackeen, "Immunized against addiction," Salon.com, http://www.salon.com/health/feature/2000/04/26/vaccine, 26 April 2000.
20. Julia Connors, Duke, "Other University Scientists pursue vaccine for HIV," University Wire, 19 March 2001.
21. Michael Waldholz, "Why Merck’s Experimental AIDS vaccine has scientists so excited," The Wall Street Journal, 2 April 2001.
22. Julia Connors, March 2001.
23. Julia Connors, March 2001.
24. Lindsay Peterson, "Hope in sight for fighting alzheimer’s," The Tampa Tribune, 10 April 2001, pg. 3.
25. Gina Kolata, "Separating research from news," The New York Times, 18 July 2000.
26. Daniel Q. Haney, "Vaccines show promise as powerful new cancer treatment," Naples Daily News, 27 August 2000.
27. Amy Standen, 8 March 2001
28. Amy Standen, "Ready for some lockjaw?" Salon.com, http://www.salon.com/tech/feature/2001/03/08/tetanus, 8 March 2001.
29. David Pitt, "Should production problems delay distribution, doctors have to prioritize their patients," Associated Press, 22 June 2000.
30. Mary Ann Elchisak, "Flu shots and influenza vaccine: vaccine shortage," http://pharmacology.about.com, 26 October 2000.
31. Global Alliance for Children’s Vaccines (GAVI) Web site, http://www.vaccinealliance.org.
WEB SITES
Sabin Vaccine Institute -- http://www.sabin.org
Bill and Melinda Gates Children’s Vaccine Program --http://www.childrensvaccine.org/homepage.htm
Boyce Thompson Institute for Plant Research -- http://bti.cornell.edu/
Centers for Disease Control National Vaccine Program Office --http://www.cdc.gov/od/nvpo/default.htm
CDC National Immunization Program -- http://www.cdc.gov/nip/
Food and Drug Administration -- http://www.fda.gov
Global Alliance for Vaccines and Immunizations -- http://www.vaccinealliance.org/
The Dale and Betty Bumpers Vaccine Research Center at the National Institutes of Allergy and Infectious Disease/National Institutes of Health -- http://www.niaid.nih.gov/vrc/default.htm
VaxGen -- http://www.vaxgen.com/
Parents Requesting Open Vaccine Education (PROVE) -- http://www.vaccineinfo.net/
National Vaccine Information Center -- http://www.909shot.com/
World Health Organization Vaccine Initiatives -- http://www.who.int/vaccines
National Network for Immunization Information -- http://www.immunizationinfo.org/index.cfm
Iomai Corporation -- http://www.iomai.com
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