Cause of hepatitis A virulence pinpointed

Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) have located two genes that give hepatitis A virus (HAV) its virulent properties. The team, led by Suzanne Emerson, Ph.D., also has discovered that deliberately weakened HAV can quickly revert to its naturally occurring, infection-causing form. To be published in the September 1 issue of Journal of Virology, and appearing online this week, these findings indicate that making an improved vaccine for HAV will be a very difficult task.

“As sanitation improves in developing countries, there will be an increased need for inexpensive and easy-to-administer vaccines to prevent hepatitis A, which is transmitted through contaminated food and water,” notes Dr. Emerson. HAV is so common in developing countries that almost everyone is infected during childhood (often without becoming noticeably ill) and thereafter is immune to the virus. Improvements in sanitation and water quality, though, make such naturally acquired immunity less likely. Unfortunately, if HAV infection occurs for the first time later in life, it can result in dangerous illness, including severe liver damage.

A vaccine made from killed HAV does exist, but it requires multiple booster shots to be given intramuscularly-an expense and inconvenience that inhibits its use in less developed countries. Scientists at NIAID have been attempting to develop a live, attenuated HAV vaccine. An attenuated vaccine-one made from a deliberately weakened form of the virus-could be given orally in a single dose, a clear advantage to the existing vaccine.

To develop such a vaccine, Dr. Emerson and her coworkers first had to determine which genes give HAV its punch. They compared the genetic make-up of a virulent version of human HAV with that of an attenuated version of the same strain of virus by creating 14 artificial “chimeric” viruses, each of which contained a different combination of genes taken from the parent strains. Monkeys exposed to a virus that contained either of two genes, 2C or VP1/2A, from the virulent parent developed symptoms of hepatitis. When both genes from the virulent parent were present, the disease was markedly more severe. Conversely, chimeras containing mutated forms of 2C and VP1/2A did not cause disease.

Weakening HAV by altering its two virulence-determining genes would seem to be a logical way to produce a hepatitis A vaccine. But when the researchers infected monkeys with just such an attenuated virus, it mutated within those animals, although it did not cause disease. Feces from the animals, however, contained infectious particles that could cause hepatitis in other monkeys.

“Although these results suggest that a live, attenuated HAV vaccine may be difficult to develop, they do help us better understand what controls HAV growth,” notes Dr. Emerson. “Ultimately, this knowledge may provide us with a roadmap to a less expensive and more potent killed vaccine that could be used worldwide.”

NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

Reference: SU Emerson et al. Identification of VP1/2A and 2C as virulence genes of hepatitis A and demonstration of genetic instability of 2C. Journal of Virology. 76 (17), pp. 8551-59 (2002).
Available online at http://jvi.asm.org/.

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institute of Allergy and Infectious Diseases
is a component of the National Institutes of Health,
U.S. Department of Health and Human Services