First Posted 11/11/99

Miracle or Murder?

The Hepatitis B Vaccine Controversy

Few US public health initiative seem as successful as our mandatory vaccination programs. But a growing number of people believe that one vaccine--that for the hepatitis B virus--is both dangerous and largely unnecessary. Emotions run high in a debate that involves pharmaceutical and biotech companies, US health agencies, Congress, and the parents of children now dead or disabled from what they believe is a vaccine about which too little is known.

By B.J. Spalding

About a year ago, Michael Belkin's five-week-old daughter, Lyla Rose, got her third and final shot of the hepatitis B vaccine. She'd never been sick before getting that shot, but she was agitated and fussy at her final feeding that evening,. "And then she fell asleep and didn't wake up," says Belkin, president of Belkin Limited (New York), which provides statistical economic forecasts and financial forecasts to international mutual funds and investment banks.

About five years ago, Bohn Dunbar, who at the time was healthy and athletic, got his first shot of the hepatitis B vaccine. Within 24 hours, he came down with a fever and severe fatigue, symptoms that lasted around a week, and roughly two weeks after that, he developed chronic joint pain and muscle pain, as well as fatigue and symptoms similar to multiple sclerosis. Today, Dunbar is rated permanently and totally impaired at greater than 90%. His health care has already cost Texas--where he got the vaccination--over $500,000 through its worker's compensation program, a figure that will only grow given the severity of his illness. "His problems have been attributed to the hepatitis B vaccine by over a dozen different specialists of unquestionable medical expertise," states his sister, Bonnie Dunbar, a professor of molecular biology and cell biology in the department of cell biology--the largest such department in the US--at Baylor College of Medicine (Houston, TX).

Indeed, Lyla Rose Belkin's death and Bohn Dunbar's debilitating injuries are just two of the tens of thousands of adverse reactions attributed to the hepatitis B vaccine, which debuted in 1986 as the first recombinant vaccine to reach the US market. The safety of the controversial vaccine--as well as numerous other aspects of its commercialization--has come up at four recent Congressional hearings, though no legislation has yet been drafted regarding the product. Two of the hearings were held by the House subcommittee on Criminal Justice, Drug Policy, and Human Resources of the Committee on Government Reform, which is chaired by Congressman John Mica (R-FL). One of those hearings was devoted solely to investigating reports of hepatitis B vaccine injuries and deaths. The other two hearings were held by the Committee on Government Reform, which is chaired by Congressman Dan Burton (R-IN).

Burton, who has two grandchildren, said at the hearings that his granddaughter was hospitalized within hours of receiving the hepatitis B vaccine, while his grandson became autistic after getting shots of the vaccine. "You can call that a coincidence, but I think it's more," says Burton, adding that "we're going to be beating on this issue as long as I'm chairman of this committee." States Baylor's Dunbar, "Just about every time I talk to someone, they know someone who got sick after getting the vaccine. A lot of times, though, that person just didn't put the two together, the getting sick and the taking of the vaccine."

Developed by Chiron (Emeryville, CA), the hepatitis B vaccine--which racked up over $2 billion in worldwide sales last year--was licensed to Merck (Whitehouse Station, NJ), which subsequently licensed it to SmithKline Beecham (SKB, Philadelphia, PA). Biogen (Cambridge, MA) also played a role in developing the product and still receives royalties on its sales from both Merck and SKB, as does Chiron.

"One of the main reasons we formed Chiron was to continue development of the hepatitis B vaccine," explains Bill Rutter, chairman emeritus of the firm. Along with his colleagues, Rutter began working on the vaccine in the late 1970s at the University of California at San Francisco. When his team moved to Chiron in 1981, the work continued under contract to Merck, with Chiron responsible for developing the vaccine and Merck responsible for manufacturing and marketing it. "It was beautiful and mysterious and complex. It turned out that in yeast over 100 different peptides self-aggregated to form a true mimic of the hepatitis B surface antigen. It was the first time such a major structure had been formed in such a novel system," exclaims Rutter. "Forming the particle was both a major milestone in molecular biology and vaccinology, as well as one of the major success stories of the 20th century in disease prevention."

Naturally, the merits of any achievement depend on a person's point of view. Says Michael Belkin, "It will only be just when, in their afterlives, all of the people responsible for that vaccine meet my daughter, Lyla Rose. When they meet all those babies whose lives were stolen, who never got a chance."

Therein--in the irreconcilable and unresolvable contentions of the vaccine's detractors and supporters--lies the story of the hepatitis B vaccine, a story of contradiction and conflict, some of which is well-intended and some of which isn't.


Irreconcilable Differences

One contention, one that would seem simple to solve, is the number of people in the US infected with the hepatitis B virus. Generally transmitted through infected body fluids, mainly through infected blood, the virus is most prevalent in such high-risk populations as intravenous drug users and sexually promiscuous adults, and in lower-risk populations such as babies born to virus-infected mothers. Symptoms of the disease include fatigue, fever, and yellowing of the skin. About 95% of patients suffer an acute form of the disease, in which they clear the virus from their blood within six months. Approximately 5% of patients suffer from chronic infections, meaning that they never clear the virus and that they always remain infectious.

Up until the latter half of 1991, the Centers for Disease Control and Prevention (CDC, Atlanta, GA), along with most other medical authorities, stated that the US had one of the lowest rates of hepatitis B in the world, with only 0.1% to 0.5% of the population infected. This compares to countries in the Far East and Africa, where the disease affects 5% to 20% or more of the population. Indeed, early in 1991, the CDC reported only 18,003 cases of hepatitis B in a total US population of 248 million.

Yet late in 1991, the CDC did an about face. It was then that its Advisory Committee on Immunization Practices (ACIP) recommended that all infants be injected with the first of three doses of hepatitis B vaccine at birth, before being sent home from the hospital. And almost immediately, the CDC generated disease statistics to support this recommendation, stating that the US had an "estimated" 1 million to 1.25 million people with chronic hepatitis B infections and that each year about 4,000 to 5,000 of these people die from chronic liver diseases. It added that from 1980 to 1991, roughly 200,000 to 300,000 new hepatitis B infections occurred annually.

"I guess the drug companies wanted a big increase in US sales of the hepatitis B vaccine, because all of a sudden the CDC started hyping the disease as a huge health threat. And it generated disease statistics, which had no anchor in documented fact, to support this threat," says Barbara Loe Fisher, the president of the National Vaccine Information Center (NVIC, Vienna, VA). Fisher, in fact, has filed a request under the Freedom of Information Act (FOIA) with the CDC, asking the agency to release copies of the "medical and laboratory criteria used by the CDC to estimate the total number of American adults and children chronically infected with hepatitis B disease."

Furthermore, Michael Belkin, who earns his livelihood working with statistics, states that the CDC is passing off "estimated, hypothetical numbers as actual cases. This is statistical fraud. In the financial world, such misrepresentation would lead to criminal charges. The whole exercise is designed to increase public hysteria about the risk of a low-risk disease, so the CDC can extend its pervasive influence, and so Merck and SKB can increase their annual vaccine revenues."

For its part, the CDC defends its 1991 change of the number of hepatitis B cases in the US. The first set of numbers that it reported--18,003 cases--were "acute, symptomatic" cases of the disease that doctors were seeing and reporting to their state health departments, which then sent these numbers on to the CDC, says Rob Lyerla, an epidemiologist in the agency's hepatitis branch. "But the CDC wanted to get a better idea about what was really happening in the states, because we knew we were just seeing the tip of the iceberg, the numbers for the symptomatic cases."

So the agency came up with the second set of numbers, including the 1 million to 1.25 million chronic cases of the disease. These numbers are actually estimates derived from a blood survey that took place over a four-year cycle and that was made up of hundreds of thousands of tests on blood drawn from randomly selected people who comprised a cross sectional survey of the US population, according to Lyerla. The survey picked up both symptomatic and asymptomatic cases of the disease, both acute and chronic cases. It showed that there had been a vast underreporting of the disease, that doctors had only been reporting acute, symptomatic cases. "So we projected from the survey the number of, not only acute cases of hepatitis B, but acute and chronic cases of hepatitis B that we would expect to find in the entire US. We estimated from the survey, based on statistical science, the actual number of US disease cases," Lyerla explains.

Both Merck and SKB stand by the CDC estimates. In fact, the CDC estimates have become facts. Somehow, they have evolved into the gold standard, cited unquestioningly by just about every mainstream medical organization on the globe, including the World Health Organization (Geneva), the American Medical Association (Chicago), and the American Academy of Pediatrics (Chicago), to name just a few such organizations. "They're the primary numbers. The CDC only reports primary data," says a Merck spokesperson, Isabelle Claxton. Adds an SKB spokesperson, Brian Jones, "These numbers are the rationale for our vaccinating for hepatitis B. They tell us that hepatitis B is a serious and life-threatening disease."

Is it safe?

Another contention between the victims and the supporters of the hepatitis B vaccine--aside from the true number of virus-infected Americans--is the safety of the vaccine, particularly its safety in babies and children. Following the 1991 ACIP recommendation to begin vaccinating babies for hepatitis B at birth, roughly 40 states mandate that children show proof that they have received three doses of the hepatitis B vaccine before entering daycare or school, with many states beginning the vaccination process near birth. "This, despite the fact that almost nothing is known about the health and integrity of an individual baby's immune system and neurological system at birth," states NVIC's Fisher. Her FOIA to the CDC, in fact, also requests copies of the "peer-reviewed, scientific studies" used to support the safety of the ACIP's 1991 recommendation.

"I would challenge any clinician or researcher to claim that we have a basic understanding of the human newborn immune system," says Baylor's Dunbar. "It's well-established in studies in animal models that the newborn immune system is very distinct from the adolescent or adult. In view of this lack of scientific and medical information of neonatal immunology, it's remarkable to me that newborn infants are being administered multiple injections of this vaccine, especially since there have been few, if any, clinical trials to adequately evaluate the potential long-term effects of neonatal immunization."

Michael Belkin has generated numbers that support these safety concerns for infants. He states that in 1996 doctors reported only 54 cases of hepatitis B to the CDC in babies between the ages of hours and one year. Yet that same year, the Vaccine Adverse Event Reporting System (VAERS)--a system jointly managed by the CDC and the Food and Drug Administration (FDA, Rockville, MD)--received a total of 1,080 reports of adverse reactions to the hepatitis B vaccine in babies from hours to one-year old, including 47 deaths. Exclaims Belkin, "So total VAERS hepatitis B reports for the 0 to 1 age group outnumber reported cases of hepatitis B by 20 to 1."

Overall, VAERS has received a total of 17,497 reports of adverse reactions to the hepatitis B vaccine, reactions that occurred after people received the vaccine alone, rather than in combination with other vaccines, during the period between July 1, 1990 and October 21, 1998. Moreover, fully 5,983 of these reports chronicled such serious events as hospitalizations, while 146 of them told of deaths. VAERS, furthermore, is a passive system, not a mandatory one. This suggests that only a fraction of adverse events are actually reported, a fraction estimated by FDA officials to be as low as 1% to 10%.

The CDC puts little stock in VAERS, since "case reports of adverse events following vaccination rarely provide a convincing link between the event and vaccination," claims Harold Margolis, chief of the CDC's hepatitis branch. VAERS case reports of adverse events may be "temporally linked, but causally unrelated. By chance alone, some patients who develop symptoms of illness will do so within several days of receiving a vaccine. Or a vaccine may lead to the earlier recognition of an illness, without increasing the overall risk of that illness occurring," Margolis states.

Interestingly, Merck, like the CDC before it, has come up with its own hepatitis B numbers, though Merck's figures deal with vaccine-related adverse reactions. These numbers, according to spokesperson Claxton, focus on Indiana, the home state of Congressman Burton, who chaired two of the hearings in which the safety and other aspects of the hepatitis B vaccine was raised. "If you immunized all of the people in the three biggest cities in Indiana with our hepatitis B vaccine, only one person would be at risk of suffering an adverse reaction. The risk of a serious adverse event would be over 1 in 10 million," says Claxton, though she didn't say how Merck generated these numbers.

Baylor's Dunbar, for her part, found the VAERS reports at least partially useful. "What was obvious from the information I obtained from the VAERS reports was that there are thousands of reports listing such conditions as neurological damage, arthritis symptoms, and other serious immunological disorders. These are the same types of medical conditions that, in my extensively detailed investigation of the literature, have been published in dozens of medical journals that cite the correlation of this vaccine and severe immunological reactions."

Dunbar, in fact, has put together a table entitled "Reports of adverse reactions to hepatitis B vaccine" that lists 110 references from medical journals including the New England Journal of Medicine, the Journal of the American Medical Association, and the Archives of Internal Medicine, as well as numerous overseas publications, including the Lancet and the British Journal of Rheumatology. All of these references detail the diagnosis of adverse reactions to the hepatitis B vaccine, including lupus, arthritis, vascular disorders, demyelinating disorders, and chronic fatigue, among other diseases. A minority of these references, however, report on the original plasma-derived hepatitis B vaccine, which predated the recombinant form of the vaccine. "Patients are reacting to a protein in the vaccine," says Dunbar. "The source of the protein doesn't matter. It's still the same protein, whether it's plasma-derived or recombinant."


Molecular Mimicry: A Possible Culprit

Despite the weight of the evidence to the contrary, supporters of the hepatitis B vaccine deny that it causes any more adverse reactions than expected, as all vaccines cause at least some bad reactions. "No causal link has been scientifically proven between the vaccine and an unexpectedly high number of adverse events," says SKB's Jones. CDC's Margolis states, "Both pre-licensure and post-licensure reviews have shown that the hepatitis B vaccine is among the safest vaccines we have." And Chiron's Rutter adds, "The data show that the benefits of the vaccine far outweigh its risks, if it has any risks at all."

Dunbar, along with other researchers, believes that the risks of the hepatitis B vaccine are great, particularly to specific genetic populations. These researchers postulate that the hepatitis B protein used in the vaccine can cause autoimmune diseases in these subpopulations through several potential mechanisms. One is through a process called molecular mimicry. This process occurs when a person's immune system commits a colossal mistake, confusing a foreign protein for one of the body's own proteins. Consequently, when the immune system attacks the foreign protein, it also attacks its own protein, one of the very proteins that the immune system exists to protect. Such foreign proteins are contained by pathogens like viruses or, more specifically, viral antigens. The hepatitis B vaccine, for its part, is practically an exact replica of a protein antigen on the surface of the hepatitis B virus.

When the body encounters a virus, for instance, certain immune cells literally engulf the virus and chop it up into thousands of protein fragments, known as peptides, each of which is made up of 10 to 15 amino acids. A few of these peptides are carried to the immune-cell surface and placed in a sort of pocket atop what is called a major histocompatability complex (MHC). This signals the immune system to destroy all cells containing that peptide. Yet the immune system destroys not only virus-infected cells containing the peptide, but also cells in the body that contain similar peptides. "The process can set into motion a cascade of self destruction. And certain people end up developing autoimmune disorders," says Dunbar.

The reason for this is an individual's MHC genes, as well as potentially other genes involved in regulating the immune system. An individual's specific genetic makeup determines which of the thousands of peptides that the immune cell chops the virus into is eventually placed in the pocket of the MHC.

In the case of the association of the hepatitis B vaccine and demyelinating disorders, a number of phenomena appear to occur, Dunbar states. One involves a subpopulation of people, most probably of Caucasian origin, who share similar MHC genes or other genes regulating the immune system. A second involves the MHC genes, which seem to code for the selection of a peptide to be placed in the MHC pocket that is similar in structure to a peptide that is associated with myelin, a substance containing numerous peptides that insulate the nerves of the central nervous system. The third involves the hepatitis B vaccine, which must contain one or more similar peptides that have similar amino acid sequences or similar structures to the myelin-associated peptides.

"Molecular mimicry can then occur, as has been shown in numerous animal-model studies," states Dunbar. She adds that the National Institutes of Health (Bethesda, MD) has twice refused to fund a research proposal in which she and her colleagues would, among other aims, have attempted to "test our hypothesis that subsets of patients having adverse reactions to the hepatitis B vaccine have similar and predictable MHC gene sequences."

In near-absolute agreement with Dunbar is Burton Waisbren, a doctor in Milwaukee, WI, who presently is focusing on neurological disorders and who is a founding member of the Infectious Disease Society of America (Alexandria, VA). Says he, "The literally thousands of individuals who've been reported to VAERS and pharmaceutical companies, who claim to have suffered demyelination and autoimmunity from the hepatitis B vaccine, should be followed up to determine their MHC gene sequences to ascertain if host factors are partially causative of the complication." And he states that the hepatitis B vaccine should be "tested for the extent of its polypeptide homology with human tissue. If significant homology is shown, the offending polypeptides could be removed from the vaccine, or a synthetic vaccine could be produced without them.

Indeed, aside from hotly criticizing the CDC's recommendation to immunize all children with the hepatitis B vaccine, NVIC's Fisher cites a recent NVIC poll of 1,000 registered voters, in which 68% of Americans support a parent's right to choose whether or not their children should receive certain vaccines that could potentially hurt them. States Michael Belkin, "If the hepatitis B vaccine was recommended in 1991 without scientific proof that it was safe in a broad sample of racially and genetically diverse babies less than 48 hours old, then the CDC has been experimenting on babies like guinea pigs, and the universal immunization policy should be suspended."

Both Fisher and Belkin believe that the US should do what France has already done. Late last year, France became the first country to end its hepatitis B vaccination requirements for schoolchildren, after reports of adverse reactions associated with the vaccine simply overwhelmed the country's Health Minister.