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New Drug for Treating Hepatitis B, but Problems with Hepatitis A Vaccines

Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Md., recently learned that a deliberately weakened version of the hepatitis A virus (HAV) can rapidly revert to its former virulence—a bad sign for scientists trying to develop a live attenuated HAV vaccine. In a separate development, the Food and Drug Administration (FDA) has approved a drug, which initially was studied as a potential treatment for HIV, for treating patients with chronic hepatitis B infections.

The drug, Adefovir dipivoxil, proved toxic for the kidneys when tested at high doses in AIDS patients, according to representatives from Gilead Sciences Inc. of Foster City, Calif., which developed the drug. However, in lower doses, it appears to be safe and effective when evaluated in patients with chronic hepatitis B infections. The drug, a nucleotide analog, blocks production of DNA polymerase, an enzyme needed for replication of the viral genome.

AIDS activist and writer Larry Kramer made an unusual appearance last August during a meeting of the FDA advisory committee whose members were evaluating the drug. "I consider [Adefovir] to be a wonder drug," he told panel members. Kramer received a liver transplant last year and claims that treatments with the experimental drug prolonged his life, making the transplant procedure possible.

More than drama, the current search for a better vaccine to protect against hepatitis A involves frustrations. Although a killed-virus vaccine is available, it is short of ideal. For example, to gain even limited protection individuals must routinely undergo multiple intramuscular injections, making the vaccine costly and cumbersome to use, particularly in developing nations. Hence, researchers are seeking to develop a live, attenuated virus-based vaccine—ideally one that could impart immunity after a single dose.

Oddly, improvements in sanitation conditions throughout much of the developing world are increasing the need for such a vaccine. Hepatitis A, which is transmitted through contaminated food and water, was once so common that children routinely became infected with the virus and thus tended to develop immunity, typically, by age 5. However, as sanitation practices improve, fewer people develop natural immunity, meaning they face greater health consequences when they do become infected when older. "The older you get, the more severe and life-threatening the disease," says Suzanne Emerson, the leader of the NIAID team that is seeking to develop a live attenuated vaccine.

Emerson and her colleagues, in trying to determine key functions of HAV genes, compared the genetic makeup of a virulent version of human HAV with that of closely related attenuated versions. They looked at 14 different chimeric viruses, each containing a different combination of genes taken from the parent strain. Monkeys exposed to a virus containing either of two genes, 2C or VP1/2A, develop hepatitis symptoms. When both those genes are present, the disease is more severe. Conversely, chimeras containing mutated forms of 2C and VP1/2A do not cause disease.

From those results the researchers reasoned that altering these two genes could yield a live, weakened HAV strain that would induce immunity. However, when they injected monkeys with that strain, it reverted to its original potency within the monkeys. Although it does not cause disease in the injected monkeys, they shed infectious particles that can infect other animals. Such a reversion is not unique to HAV, Emerson points out. For example, the live attenuated oral polio vaccine behaves similarly.

Insights about the behavior of attenuated HAV strains in humans could soon emerge from studies that Emerson and her collaborators are beginning with a live attenuated HAV vaccine that is being used in China, but is not licensed elsewhere. When asked about the nature of that vaccine, how widely it is being used, and whether it can revert to a virulent form, she says, "We do not have that much information about the Chinese vaccine[and] not much information about its side effects. Who knows how good the reporting is?"

Marlene Cimons
Marlene Cimons is a freelance writer in Bethesda, Md.