"We have a two-fold victory in world public health," said Duane Alexander, M.D., Director of the NICHD. "Not only is this the first vaccine to protect young children against typhoid fever, it appears to be the most effective typhoid vaccine ever developed. And in contrast to other typhoid vaccines, it is virtually free of side effects."

Untreated, typhoid fever is a debilitating and life- threatening illness caused by the bacteria, "Salmonella typhi". Vaccine development for typhoid fever has been difficult, because "S. typhi" inhabits and causes illness only in human beings -- there are no animal models for the disease. Typhoid fever is spread by fecal contamination of drinking water or food, or by person to person contact. The disease is common in developing countries lacking adequate sewage and sanitation facilities. Symptoms include fever, stomach pains, weight loss, loss of appetite, delirium, severe diarrhea (in children), and constipation (in adults). According to the U.S. Centers for Disease Control and Prevention, about 16 million people worldwide develop typhoid each year, and 600,000 die from it. Roughly 400 cases of typhoid fever occur in the U.S. each year, about 70 percent of which are acquired by Americans traveling abroad. (http://www.cdc.gov/ncidod/dbmd/diseaseinfo/typhoidfever_g.htm)

The NICHD researchers chose to do the study in the Dong Thap province of the Mekong Delta, a rural area which lacks a public sewage system and therefore has a high incidence of typhoid fever-roughly 413 cases for every 100,000 children under age 15. More than 90 percent of the typhoid strains present in the area are resistant to the antibiotics used to treat the disease.

In developing the vaccine, the NICHD researchers used an approach they had earlier pioneered. The approach involves chemically linking a polysaccharide from the disease- causing bacteria with a protein molecule. Ordinarily, the polysaccharide would slip past the defenses of a child's immature immune system. But adding the protein to the polysaccharide allows the immune system to produce antibodies that inactivate the bacteria. Antibodies are immune system proteins that recognize a particular substance. Together with another protein called complement, antibodies begin the first steps in the complex sequences of events by which the immune system destroys disease-causing organisms.

Two of the researchers, Dr. John Robbins and Dr. Rachel Schneerson, received the prestigious Pasteur and Lasker Awards for using this approach to develop a vaccine that virtually eliminated disease caused by the deadly and debilitating bacteria, "Haemophilus influenzae" type B (Hib), from the developed world. (http://www.nichd.nih.gov/new/releases/cviawar2.htm). Hib vaccination also is being implemented in Africa, South and Central America, and in Southeast Asia. Dr. Robbins is the recipient of this year's Albert B. Sabin Gold Medal for dedicating his career to preventing diseases that afflict children, such as meningitis, pertusis, typhoid, and several others.

In all, 11,091 Vietnamese children ranging from age 2 to age 5 took part in the study. The children received two injections, 6 weeks apart. Half received the vaccine, and the other half, a placebo. In the following two years, both groups were observed by their physicians throughout the study. Those who developed typhoid fever received the standard treatment of antibiotic therapy for the disease. "S. typhi" was isolated from only 4 children who had received both injections of the vaccine. The placebo group had 47 cases, for an effectiveness rate of 91.5 percent. By comparison, typhoid vaccines currently on the market have a 70 percent effectiveness rate and do not protect children under age 5 against the disease. Fewer than 2 percent of children experienced any side effects, all of which were mild, and limited to swelling at the injection site, or to mild fever that resolved within 48 hours.

The study authors wrote that they next plan to test the vaccine in children under two, to see if it can be administered at the same time as the routine vaccination for Diphtheria, Tetanus, and Pertussis. Because of the high levels of protective antibodies the vaccine brought about in young children, the study authors also wrote that the vaccine would probably be at least 90 percent effective in individuals above 5 years of age, "including the military and travelers to areas with high rates of typhoid fever."

Authors of the study were Feng Ying C. (Kimi) Lin, M.D., M.P.H, Zuzana Kossaczka, Ph.D., Delores A. Bryla, M.P.H., John B. Robbins, M.D., Rachel Schneerson, M.D., and Shousun C. Szu, Ph.D, all of the National Institute of Child Health and Human Development, NIH; Joseph Shiloach, Ph.D., National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Vo Anh Ho, M.D., Phan Van Bay, M.D., Mai Ngoc Lanh, M.D., Dong Thap Province Hospital; Ha Ba Khiem, M.D., Tran Cong Thanh, M.D., Pasteur Institute, Ho Chi Min City; and Dan Duc Trach, M.D., Ph.D., National Institute of Hygiene and Epidemiology, Hanoi.