Epstein-Barr Virus: Implicated in Cancer Etiology in China, Impetus for a Vaccine

Virologist Hans Wolf of the University of Regensburg in Germany has been working on the etiology of nasopharyngeal carcinoma (NPC) in areas of China since 1979. Researchers from the U.S. National Cancer Institute (NCI), too, have been working with their Chinese colleagues on cancer epidemiology and etiology. The reasons for this cooperative research vary, but as Federico Welsch, associate director for international affairs at NCI, points out, "They have some cancers that are rare in the develop

Mar 15, 1999
Myrna Watanabe

Virologist Hans Wolf of the University of Regensburg in Germany has been working on the etiology of nasopharyngeal carcinoma (NPC) in areas of China since 1979. Researchers from the U.S. National Cancer Institute (NCI), too, have been working with their Chinese colleagues on cancer epidemiology and etiology. The reasons for this cooperative research vary, but as Federico Welsch, associate director for international affairs at NCI, points out, "They have some cancers that are rare in the developed world." Among these are nasopharyngeal cancer, certain liver cancers, and esophageal cancer. Environmental factors have been implicated.

Research by Wolf and Chinese colleagues Yi Zeng, chief of the department of tumor viruses at the Institute of Virology, Chinese Academy of Preventive Medicine (CAPM) and former president of CAPM, Shu-Yan Gu, now deputy director of the National Center for AIDS Prevention and Control, and others, is leading to development of a vaccine.

In work that began in the 1970s, Zeng and colleagues found that NPC, which is more concentrated in southern China than in other parts of the country, was related to infection with the Epstein-Barr virus (EBV). "The Epstein-Barr virus probably is the most successful virus worldwide in the respect that everybody is infected," explains Wolf, who is chairman of the department of medical microbiology at the University of Regensburg and who holds visiting professorships at several universities in China. He continues explaining the prevalence of infection with EBV: "The standard disease that your society [U.S.] and my society [Europe] get is infectious mononucleosis." He states that humans become infected with EBV and come down with mononucleosis as young children or teenagers. The illness is rarely serious and, in many cases, may be asymptomatic. But if a person becomes infected as an adult, which is what occurs in China, "then we get clinically more serious, more infectious mononucleosis [with] heavy involvement of the liver and the spleen, very strong swollen lymph nodes of the neck area, very large tonsils--some people even get breathing problems--and a rash." This, he says, keeps people in bed for two weeks or perhaps even four to six weeks.

But in some areas of the world, especially parts of Asia and Africa, "the people develop nasopharyngeal carcinoma," states Wolf. And in areas of Africa where there is a high prevalence of malaria, people infected with EBV may later develop Burkitt's lymphoma. The Chinese develop NPC. Only a small percentage of those infected ever develop this cancer, but it seems that infection with EBV is one of the essential risk factors. Zeng and his colleagues found evidence of an EBV gene and EBV proteins in in vitro cell lines developed from nasopharyngeal carcinomas and in cell lines developed from NPC cells transplanted into nude mice.

The carcinomas develop in adults between the ages of 40 and 70. The question Wolf asks is, "Why do the Chinese get this tumor at much higher frequency (up to 1 percent in China, 20 to 100 times more than others)?" Zeng and colleagues have answered some of this. Along with French researcher Guy deThé of Institut Pasteur in Paris and his colleagues, Zeng's team looked at the major histocompatibility complex (called HLA antigens), a group of genes on chromosome 6 in humans that codes for antigens present on blood cells. Because HLA antigens are inherited in a Mendelian manner, the researchers looked at them in families that had several members with NPC.1 They found that "70 percent had the same HLA antigen; we named this as the HLA linkage of the NPC susceptibility gene," says Zeng. A person with this gene has a 21 times greater risk of developing NPC has a person without it has.

But this gene's presence still does not fully explain why people develop NPC. Zeng and his fellow researchers looked deeper into the problem. In mouse studies using transplanted human fetal nasopharyngeal mucosal cells, they found that malignancies can be induced in the presence of EBV with TPA (a phorbol ester, which is a tumor promoter) and butyrate, a metabolic product of anaerobic bacteria. Zeng notes that anaerobic bacteria have been found in nasopharyngeal isolates from NPC patients. Also, phorbol ester-type substances were found in 52 Chinese medicinal herbs and plants, in soil, and in salted fish, honey, and edible fungus, according to Zeng. Some of these herbs are used in medicinal teas, says Wolf.

The researchers are fairly confident that they know some of the risk factors for nasopharyngeal carcinoma. They also know that likelihood of developing this cancer can be determined by the presence of certain IgA antibodies. In a survey of more than 40,000 people aged 30 to 40, Zeng and colleagues found that 93 percent of NPC patients tested positive for the IgA/VCA (viral capsid antigen) antibody to EBV. In a 10-year follow-up, Zeng says, they found that the cancer did not develop in people whose IgA/VCA antibody levels disappeared or decreased fourfold, but developed only in those with increasing or steady levels of IgA/VCA antibody. The presence of IgA/EA (early antigen) antibody against EBV also was predictive of progression to nasopharyngeal carcinoma. The time at which the antibodies increase signifies the earliest stage of the cancer.

With a quick screening test, perhaps needing as little as a drop or so of blood, individuals who are likely to develop the cancer or whose cancers are in the earliest stages can be identified. Wolf says that such inexpensive tests, which use gene products from recombinant DNA technology and can be done in "low-equipment local clinics" or "country hospitals," are being developed.

But aside from testing, they hope to have a vaccine that will prevent EBV entirely. "We did already test a first vaccine for this virus ... . We could protect from EBV infection," says Wolf. Although that was a preliminary study done in Beijing, it gave Wolf and colleagues enough data to convince a vaccine company--SmithKline Beecham--to go forward in developing a vaccine against EBV. That vaccine is currently in safety and efficacy trials in Europe. A vaccine, says Wolf, is likely to be used worldwide for all infants. "I hope it will be a market big enough to stimulate the companies to make the vaccine," notes Wolf.

Meanwhile, Institut Pasteur's deThé convinced his friend, geneticist Stephen O'Brien of NCI, to take a closer look at the human genes involved. "[Nasopharyngeal carcinoma] clearly has some heritable aspects. We would like screen a number of candidate genes, oncogenes, cytokines, tumor supressors that might explain high incidences of NPC in certain parts of China and lower incidences in others," explains O'Brien. This work, which will use NCI's high-throughput genetic technologies and computer algorithms and Zeng's blood samples, is just getting under way. (For information on the NCI's programs with China, go to the agency's Web site [cancernet.nci.nih.gov/oia/master.html].)

The NCI's long-standing relationship with China and the numerous joint projects they fund--from a randomized trial of breast self-examination to studies on early diagnosis and treatment of hepatocellular carcinoma, among other projects--indicate fertile ground for international cooperation.

The NCI's Welsch intends to visit China later this month to discuss organizing a collaborative research group on children's cancers with the assistance of the Children's Hospital of Columbus, Ohio. Collaborative groups, such as those in the United States, allow clinical trials and exchange of information within the group--frequently among individuals and research centers in different parts of the country. Welsch points out that in some cases, children's cancers can be cured, "but the success rate in China is low."

The problem, as Wolf notes, is that China's previously well-funded health care system is now suffering from lack of money, which may make research and screening more difficult to accomplish.

  1. S.L. Lu et al., "The genetic basis for nasopharyngeal carcinoma of linkage to HLA region," Nature, 346:470-1, 1990.