Global Effort Takes Aim at RabiesGlobal Effort Takes Aim at Rabies

Atlanta—Despite a major milestone in public health—the elimination of canine rabies in the United States—rabies control experts caution that continued vigilance is needed worldwide to reduce the 55 000 human deaths that occur annually from the preventable viral illness transmitted by dogs and such wildlife as raccoons, bats, and skunks.

Researchers who gathered here on the Centers for Disease Control and Prevention (CDC) campus for the first World Rabies Day symposium in early September reported that canine transmission remains the leading cause of human rabies cases in developing countries and that importation of unvaccinated dogs from rabies-endemic areas could endanger humans and animals in the United States.

“We have to acknowledge the hidden burden of rabies,” said Deborah Briggs, PhD, executive director of the United Kingdom–based Alliance for Rabies Control and a leading organizer of the symposium. “Countries don't realize what this disease costs them, not only in human lives, but also in prevention, hospitalizations, and dog control.”

In Latin America, rabies spending totals about $40 million per year, said Cristina Schneider, DVM, ScD, an epidemiologist and regional advisor with the Veterinary Public Health Unit of the Pan American Health Organization (PAHO), in Washington, DC. With PAHO support, she said, Latin America launched a campaign in 1983 to eliminate rabies transmission from dogs to humans. Annual spending covers free medical care for nearly 1 million people, vaccination of nearly 44 million dogs, surveillance systems, and other activities such as training and education.

The payoff has been a dramatic decrease in dog-to-human rabies transmission. In 2006, 29 human cases from dogs were reported in Latin America, down from 355 in 1982, before the campaign began. Even so, the 2006 figure represents recent increases: 20 cases were reported in 2004 and 11 in 2005.

Schneider said PAHO has surveyed health officials in Brazil, Haiti, El Salvador, and Bolivia, which have had some of the highest numbers of reported cases, to investigate why dog-to-human transmission has not been eliminated in these countries.

The survey revealed a number of obstacles that hinder elimination of dog-to-human rabies transmission. They include discontinued dog vaccinations and other control measures due to lack of resources, lack of public awareness of disease risks, and difficulties in obtaining postexposure prophylaxis in areas just beyond urban centers. “Even if postexposure prophylaxis is free, some people cannot afford transportation to get it, or they cannot afford to lose time from work” to get the shots, said Schneider.

In addition to helping Latin American countries step up canine vaccination programs, make postexposure prophylaxis more widely available, and provide more public education about rabies, PAHO is encouraging technical cooperation among the affected countries. For example, Schneider said, Brazil has donated 800 000 doses of canine vaccine to Haiti's rabies control program.

Charles Ruprecht, VDM, PhD, chief of the CDC Rabies Program, said Latin America's rabies successes offer a model for Asia and sub-Saharan Africa, where nearly all human rabies deaths occur. According to the World Health Organization, Asia carries the greatest public health burden of rabies, with 31 000 annual deaths and $560 million spent each year, primarily on postexposure prophylaxis.

Elimination of canine rabies in the United States is the result of widespread dog vaccination and licensing, as well as stray dog control. Even though the United States experienced an 8.2% increase in reported rabies cases last year—6940 cases in animals and 3 in humans—no cases of the dog/coyote rabies virus variant have been identified in the United States since 2004. “We have demonstrated that canine rabies can be eliminated,” said Ruprecht.

But the importation of dogs for resale into the United States from endemic countries is posing new risks for exposure. Ben Sun, DVM, MPVM, state veterinarian with the California Department of Public Health, said dogs are being imported “by the truckloads” and often are sold in airport parking lots. According to the CDC, dogs are subject to inspection but not automatic quarantine on entry to the continental United States. Sun estimated that 4000 to 5000 dogs are imported into California annually.

Researchers reported in a poster presentation that 8376 dogs were imported through Chicago's O’Hare International Airport in the first 9 months of 2006. About half of the dogs were from Mexico, where rabies is endemic. What's more, said Ingrid Trevino, DVM, MPH, an epidemiologist with the Illinois Department of Public Health who reported the data, 13% of the dogs received confinement agreements, which are issued by CDC, customs, or border protection personnel if the dog has no proof of vaccination, is too young to be vaccinated, or was vaccinated fewer than 30 days before entry into the country. Owners fill out the confinement forms, which specify that the dog be kept away from humans and other animals until 30 days after it has been vaccinated. Importers must provide addresses where dogs will be confined if the dog is not being sold immediately.

Trevino and her colleagues surveyed state agencies to determine their follow-up procedures on confinement agreements. They found that only 11 of 32 states that responded to the survey perform any kind of follow-up when a dog is ordered confined on arrival in the United States, Trevino said.

For underdeveloped countries, researchers are exploring new vaccine approaches for both preexposure and postexposure prophylaxis. Hildegund Ertl, MD, Immunology Program Leader at the Wistar Institute in Philadelphia, Pa, and colleagues are working to develop a long-lasting, single-dose vaccine for preexposure use. The agent they are focusing on is made with adenovirus of the C68 serotype, isolated from a chimpanzee. In mice, it produces an effective immune response if given orally. The vaccine has not been tested in humans yet, but Ertl hopes it can be adapted for use in “bite clinics” in remote areas of endemic countries.

Also, CDC teams are investigating the use of monoclonal antibodies as a replacement for rabies immune globulin (RIG), which currently is used with vaccine in postexposure prophylaxis regimens. RIG's drawbacks are that it is expensive and unavailable in many parts of the world. Findings from animal studies reported at the symposium showed that monoclonal antibodies appear safe and effective, but the challenge is in developing a monoclonal product that will be less expensive than RIG.

Along with new vaccines, researchers and clinicians need a new animal model in which to study rabies treatment. Rodney Willoughby, MD, associate professor of pediatrics at the Medical College of Wisconsin, Milwaukee, who successfully treated the first unvaccinated survivor of rabies in 2004, said many of the disease mechanisms “don't make sense” and that the current medical literature on rabies is not useful for clinicians caring for patients with rabies virus infection.

Willoughby said the protocol used in the successful treatment of the teenager who survived (as well as in the treatment of 10 subsequent patients, none of whom survived) is uncovering clinical details about rabies that were not previously recognized. For example, tetrahydrobiopterin deficiency occurs, as a result of either rabies infection or the treatment, which includes induced coma and administration of antiviral medications. The deficiency can lead to low levels of neuronal nitric oxide synthase, reduced cranial blood flow, and resulting cerebral artery spasms. “We're still actively learning,” said Willoughby.

An appropriate animal model could expedite the learning process, Willoughby noted. Mice, monkeys, and dogs have served as models for the study of rabies, but none has proved optimal. Researchers at the CDC are planning to launch new studies using 6 ferrets that will be infected with rabies virus and treated with the Milwaukee protocol. The CDC is building a special intensive care unit for use in the ferret research. Boonlert Lumlertdacha, DVM, an infectious diseases fellow at the CDC, said ferrets are appropriate for animal studies because they are susceptible to more than 20 domestic and wildlife variants of rabies virus.

“The one clear deficit is that we need an animal model,” said Willoughby, “and we needed it yesterday.”