New Low-Cost Method to Deliver Vaccine Shows Promise

/PRNewswire/ -- Researchers have developed a promising new approach to vaccination for rotavirus, a common cause of severe diarrheal disease that is responsible for approximately 500,000 deaths among children in the developing world every year. In a study published in the November issue of Clinical and Vaccine Immunology, a vaccine delivered as nasal drops effectively induced an immune response in mice and protected them from rotavirus infection. The new vaccine delivery system has also been tested successfully and found to be heat stable with tetanus and is currently being tested with diphtheria and pertussis.

The team from the Cummings School of Veterinary Medicine at Tufts University and Tufts University School of Medicine collaborated with researchers from Boston and Tulane Universities to test the effectiveness of immunization with harmless bacteria that were engineered to display rotavirus protein.

"The new vaccine, in conjunction with an agent that enhances immunity, induced sufficient antibody formation against rotavirus to protect mice against infection when the mice were exposed to rotavirus three weeks after their third immunization," explained John E. Herrmann, Ph.D., research professor in the infectious diseases division of the department of biomedical sciences at the Cummings School of Veterinary Medicine at Tufts University and the senior author of the published study.

"We created the rotavirus vaccine using a harmless bacterium called Bacillus subtilis (B. subtilis), which we can modify to display on its surface or in its cytoplasm proteins from infectious bacteria and viruses. When people are exposed to these proteins, they develop antibodies against them and therefore become immune to the bacteria and viruses," said the study's first author Sangun Lee, Ph.D., DVM, research associate at the Cummings School. "The B. subtilis bacteria are so harmless that they are part of the normal diet in several Asian countries."

"The vaccine with the Bacillus bacteria is very inexpensive to produce in large quantities and, unlike most traditional vaccines, requires no special purification steps before use. As a result, the cost of vaccine production is unusually low," explained Saul Tzipori, BVSc (DVM), DSc, Ph.D., Agnes Varis University Chair in Science and Society, distinguished professor of microbiology and infectious diseases, and director of the infectious diseases division of the department of biomedical sciences at the Cummings School. These findings are consistent with the team's previous studies in which they demonstrated that B. subtilis bacteria displaying a fragment of tetanus toxin protein completely protect mice from tetanus. Tetanus vaccines have been stored for more than a year at 113(o)F without any loss of potency, a property that may be common to all B. subtilis vaccines.

Vaccines currently available have to be stored in refrigerators or freezers until the moment they are administered. This cold chain is difficult and costly to maintain. In many parts of the world, there is insufficient refrigeration or electricity to keep vaccines cold. The lack of refrigeration combined with the lack of trained personnel, especially in rural areas in developing countries, make it impossible for many children and adults to be vaccinated against standard infections, such as tetanus, rotavirus, diphtheria, pertussis (whooping cough) and other diseases.

"In addition to being heat-stable and low-cost, the B. subtilis vaccines are given in the form of nasal drops or spray. A needle-free approach to vaccination is particularly advantageous in developing countries where clean needles and syringes and trained personnel are not always available," said team leader Abraham L. (Linc) Sonenshein, Ph.D., professor and acting chair of molecular biology and microbiology at TUSM and member of the genetics and microbiology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

"This vaccine project is still in the developmental stage," he continued. "The next major step for these vaccines is to show that they are safe and work well in humans, and then to extend the rotavirus and tetanus vaccine technology to include diphtheria, pertussis and other infectious diseases. Those diseases cause tens of thousands of deaths, particularly in newborns and in South-East Asia. We are actively looking for partners in the U.S. and around the world to help us pursue our goal of reaching the point where many childhood and adult vaccines can be manufactured in a way that avoids the need for injection or refrigeration. Jerry Keusch of Boston University School of Public Health and I started this project 15 years ago, and it has taken a long time to reach the stage where we now have effective needle-free vaccines. The technology has now advanced enough that we can expect to be successful with many other vaccines in a short time frame."

Additional authors include Boris R. Belitsky, Ph.D., assistant research professor in the department of molecular biology and microbiology at TUSM; James P. Brinker, M.P.H, in the department of biomedical sciences at the Cummings School; Kathryn O. Kerstein, MS, senior research associate in the department of molecular biology and microbiology at TUSM; David W. Brown, Ph.D., DVM, clinical assistant professor in the infectious diseases division of the department of biomedical sciences at the Cummings School; Gerald T. Keusch, MD, professor in the department of international health at Boston University School of Public Health, professor of medicine at Boston University School of Medicine and U.S. chairman of the Indo-U.S. Vaccine Action Program at the National Institutes of Health; and John D. Clements, Ph.D., professor and chair of the department of microbiology and immunology at Tulane University Health Sciences Center.

This study was supported by a grant from the Grand Challenges in Global Health program of the Bill and Melinda Gates Foundation, and this grant was administered by the Foundation for the National Institutes of Health. Patent applications related to the discoveries reported in these studies have been filed by Tufts University.

Lee S, Belitsky BR, Brinker JP, Kerstein KO, Brown DW, Clements JD, Keusch GT, Tzipori S, Sonenshein AL, Herrmann JE. Clinical and Vaccine Immunology.. 2010 (November); 17 (11): 1647-1655. "Development of a Bacillus subtilis-based rotavirus vaccine." DOI: 10.1128/CVI/00135-10.

Lee S, Belitsky BR, Brown DW, Brinker JP, Kerstein KO, Herrmann JE, Keusch GT, Sonenshein AL, Tzipori S. Vaccine. 2010 (September 24); 28 (41), 6658-6665. "Efficacy, heat stability and safety of intranasally administered Bacillus subtilis spore or vegetative cell vaccines expressing tetanus toxin fragment C." DOI:10.1016/j.vaccine.2010.08.016.

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FDA Revises Recommendations for Rotavirus Vaccines

The U.S. Food and Drug Administration today revised its recommendations for rotavirus vaccines for the prevention of the disease in infants and has determined that it is appropriate for clinicians and health care professionals to resume the use of Rotarix and to continue the use of RotaTeq.

The agency reached its decision based on a careful evaluation of information from laboratory results from the manufacturers and the FDA’s own laboratories, a thorough review of the scientific literature, and input from scientific and public health experts, including members of the FDA’s Vaccines and Related Biological Products Advisory Committee that convened on May 7, 2010 to discuss these vaccines.

The FDA also considered the following in its decision:

* Both vaccines have strong safety records, including clinical trials involving tens of thousands of patients as well as clinical experience with millions of vaccine recipients.
* The FDA has no evidence that PCV1 or PCV2 pose a safety risk in humans, and neither is known to cause infection or illness in humans.
* The benefits of the vaccines are substantial, and include prevention of death in some parts of the world and hospitalization for severe rotavirus disease in the United States. These benefits outweigh the risk, which is theoretical.

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Components of Extraneous Virus Detected in Rotarix Vaccine; No Known Safety Risk

FDA is recommending that healthcare practitioners temporarily suspend use of the Rotarix vaccine for rotavirus immunization in the United States while the agency learns more about components of an extraneous virus detected in the vaccine. There is no evidence at this time that this finding poses a safety risk.

The agency recently became aware that an independent U.S. academic research team, using a novel technique, has found DNA from porcine circovirus 1 (PCV1) in Rotarix, which is manufactured by GlaxoSmithKline. PCV1 is not known to cause illness in humans or other animals. In addition, Rotarix has been studied extensively, before and after approval, and found to have an excellent safety record.

Follow-up tests by GlaxoSmithKline and FDA scientists confirmed the academic team’s findings and confirmed that viral components have been present since the early stages of the vaccine’s development, including during clinical studies. Preliminary testing by both the academic researchers and FDA scientists of another licensed vaccine against rotavirus infection, RotaTeq, has not detected components of PCV1.

"We are making clinicians aware of information recently received by FDA about the Rotarix vaccine,” said Dr. Margaret A. Hamburg, Commissioner for Food and Drugs. “There is no evidence at this time that there is a safety concern. FDA is recommending that clinicians temporarily suspend use of Rotarix until we can learn more about the situation. We will keep the public and the clinical community updated on our findings.”

Rotarix and RotaTeq are given by mouth to young infants to prevent rotavirus disease, which can cause severe diarrhea and dehydration and is estimated to be responsible for the deaths of more than 500,000 infants around the world each year, primarily in low- and middle-income countries. Before the introduction of a rotavirus vaccine, rotavirus resulted in more than 50,000 hospitalizations and several dozen deaths in the United States each year. FDA licensed RotaTeq in 2006 and Rotarix in 2008. Most children vaccinated in the United States received RotaTeq.

“In many countries, rotavirus causes so much severe illness and death that the known benefits of continued use of Rotarix far outweigh any theoretical risk of harm from the vaccine,” said Dr. Thomas Frieden, Director of the Centers for Disease Control and Prevention. “We anticipate that many countries will decide to continue vaccinating with Rotarix while more information becomes known.”

FDA will continue to gather more information about the PCV1 components in Rotarix, including whether intact virus, as opposed to DNA fragments, is present. The agency is assessing current vaccine testing methods. In four to six weeks, FDA will convene an expert advisory committee and make additional recommendations on the use of rotavirus vaccines.

FDA will provide updates to patients, providers, and the general public as more information becomes available. The agency will also continue to communicate with the World Health Organization and counterpart regulatory agencies in other countries.

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Unusual Rotavirus Season May Be Due to Newly Introduced Vaccine

Rotavirus activity in the ongoing 2007-2008 season appears to have started later than usual and have been less severe than during any of the previous seasons for which data are available, according to an interim report issued in today's early release edition of the Centers for Disease Control and Prevention's Morbidity and Mortality Weekly Report (MMWR).

Rotavirus is the leading cause of severe gastroenteritis (vomiting and diarrhea) in infants and young children, annually causing about 410,000 physician office visits, 205,000-272,000 emergency department visits, 55,000-70,000 hospitalizations, and between 20 and 60 deaths among US children less than 5 years of age. Worldwide, rotavirus causes approximately 1,600 deaths each day among children less than 5 years of age.

Data from around the United States indicate that during the ongoing season, rotavirus activity was delayed by about three months compared with the start time for the previous 15 years. The season began at the end of February instead of November, the usual start time, and the season peaked at the end of April instead of March, the usual peak time.

Hospitalizations, emergency department visits, and physician visits were also substantially reduced at some network of medical centers conducting prospective rotavirus surveillance. The number of laboratory tests performed for rotavirus from Jan. 1 to May 3, 2008, was 37 percent lower than usual, and the percent of all tests conducted for gastroenteritis that were positive for rotavirus was 79 percent lower than usual.

The report indicates that marked changes in rotavirus activity may be due to a newly introduced rotavirus vaccine for infants. In 2006, a new rotavirus vaccine, RotaTeq (Merck & Co. Inc.), was recommended for routine immunization of U.S. infants at 2, 4 and 6 months of age. Clinical trial results indicated that this live, oral vaccine prevented 74 percent of all rotavirus cases, about 98 percent of severe cases, and about 96 percent of hospitalizations due to rotavirus.

"The changes appear to be greater than expected based on the protective effects of the vaccine alone," said Dr. Anne Schuchat, director of the National Center for Immunization and Respiratory Diseases at CDC. "It is also possible that current levels of vaccination may be helping to decrease the spread of rotavirus to unvaccinated individuals in the community. Ongoing monitoring is needed to confirm the impact of vaccination this year and to monitor the impact of the vaccine on rotavirus disease and its epidemiology over time."

The data used in the new report were obtained from the National Respiratory and Enteric Virus Surveillance System (NREVSS) and from the New Vaccine Surveillance Network (NVSN). NREVSS is a voluntary network of U.S. laboratories that provide CDC with weekly reports of the number of tests performed and positive results obtained for a variety of
pathogens, including rotavirus.

Rotavirus is highly contagious. Large amounts of the virus are shed in the stool of infected persons and can be spread by contaminated hands and objects. Children can spread rotavirus both before and after they become sick with diarrhea, and they can pass the virus to household
members and other close contacts.