VAIL, Colo. – The emergence of hepatitis B vaccine escape mutant viral strains poses a possible serious threat to the success of the global hepatitis B control program of the World Health Organization, although thus far the danger remains theoretical, according to Dr. Myron J. Levin.
Dr. Myron J. Levin
“I think this is a potential crisis for us to keep track of,” Dr. Levin explained at conference on pediatric infectious diseases sponsored by the Children’s Hospital, Denver.
Hepatitis B vaccine escape mutants (VEMs) are already here, and there is considerable selection pressure for the formation of more. Under the wrong conditions, they are capable of causing breakthrough hepatitis B infection in fully immunized individuals.
VEMs occur most often in countries with high rates of endemic hepatitis B infection and universal hepatitis B vaccine immunization programs, such as Taiwan, for example. A recent report indicates that in the pre-vaccine era, 7.8% of Taiwanese patients with hepatitis B possessed mutant strains not recognized by the vaccine (Antivir. Ther. 2010;15:463-9). Fifteen years after introduction of universal infant immunization in that country, the prevalence of VEMs among individuals with hepatitis B disease was close to 25%.
On a more positive note, while the prevalence of VEMs has indeed grown, the pool of Taiwanese with serious hepatitis B infection has shrunk markedly. Indeed, the rate of seropositivity to hepatitis B surface antigen (HBsAg) among Taiwanese children has decreased by 95% since the vaccine program was introduced. Liver cancer in this population has been reduced by 60%.
“So the implication is right now there is no obvious problem. But it’s something we need to monitor,” observed Dr. Levin, professor of pediatrics and medicine at the University of Colorado, Denver.
Worst case scenario? The vaccines would have to be redesigned to recognize VEMs and incorporate hepatitis B virus proteins that aren’t vulnerable to escape mutations, he added.
Selection pressure for formation of VEMs comes from two distinct sources: immunization and lamivudine monotherapy for chronic hepatitis B.
The hepatitis B virus is a DNA virus that utilizes a reverse transcriptase enzyme to replicate its viral genome, as does HIV. Reverse transcription is a notoriously error-prone process that can lead to single amino acid mutations in HBsAg. The antibodies drawn forth by the hepatitis B vaccine specifically target the surface antigen protein. If the surface antigen protein contains a mutation, the vaccine may be unable to neutralize the virus, and a VEM is created.
Moreover, depending upon the epitopes mutated in a VEM, the VEM may not be detected by tests for HBsAg. “You could have someone with chronic hepatitis B and you wouldn’t detect it,” according to Dr. Levin.
Thus, even as the global hepatitis B immunization program continues to reduce new cases of hepatitis B infection and the enormous burden of chronic hepatitis B disease, it is simultaneously generating VEMs, thereby potentially sewing the seeds of the program’s failure.
A second, entirely separate source of selection pressure promoting the creation of VEMs stems from the fact that lamivudine frequently leads to mutations in the gene for reverse transcriptase, which happens to overlap the surface antigen gene. These mutations can result in changes in the surface antigen protein, which under the wrong conditions will result in VEMs.
“The outcome will depend on whether the new mutant is stable, whether it can cause antigenic change in the neutralization characteristics of the surface antigen, whether it’s transmissible from one person to another, and whether it can cause acute or chronic disease. But if all these things line up right, treatment with lamivudine could create a situation where you have more VEMs,” Dr. Levin continued.
Lamivudine was the first nucleoside analog approved for the treatment of chronic hepatitis B infection. It remains widely used as monotherapy in many resource-poor countries because it is inexpensive, relatively free of side effects, and effective – at least initially. As has been seen with single-agent therapy in HIV and tuberculosis, however, lamivudine monotherapy eventually results in the appearance of lamivudine-resistant hepatitis B strains.
The World Health Organization is monitoring the hepatitis B VEM situation closely (Bull. World Health Org. 2010;88:66-73). One issue that’s as yet unclear is whether emergence of VEMs will be accelerated by simultaneous use of the hepatitis B vaccine and treatment with lamivudine.
Dr. Levin disclosed that he has served as a consultant to Merck and Co. and GlaxoSmithKline. Both companies make hepatitis A and B vaccines.