Hepatitis B Vaccine Safety

Hepatitis B vaccine is among the safest vaccines available and is highly effective for protection against this killer liver disease.

As with all medical and public health interventions, the potential risks, as rare as they may be, need to be weighed against the benefits to the individual and to the society. The following information about possible side effects, in question and answer format, has been developed by leading public health physicians in the National Immunization Program at the Centers for Disease Control and Prevention in Atlanta Georgia:

Q & A

Q. Is hepatitis B vaccine safe?

Hepatitis B vaccines have been shown to be very safe when given to infants, children or adults (CDC, 1991 a; Greenberg, 1993). More than 20 million persons have received hepatitis B vaccine in the United States and more than 500 million persons have received the vaccine worldwide. The most common side effects from hepatitis B vaccination are pain at the injection site and mild to moderate fever (Szmuness, 1980; Francis, 1982; Zajac, 1986; Stevens, 1985; Andre, 1989; Greenberg, 1993). Studies show that these side effects are reported no more frequently among those vaccinated than among persons not receiving vaccine (Szmuness, 1980; Francis, 1982). Among children receiving both hepatitis B vaccine and diphtheria-tetanus-pertussis (DTP) vaccine, these mild side effects have been observed no more frequently than among children receiving DTP vaccine alone (CDC, 1991 a; Greenberg, 1993).

Whenever large numbers of individuals are vaccinated, rare reports of subsequent adverse events occur. Whether they are caused by or coincidental to the vaccination requires further study. Such reports do not mean that the vaccine is unsafe for the population, however, since millions of persons have received the vaccine without problem.

Q. Is there an association between hepatitis B vaccine and serious side effects?

Serious side effects reported after receiving hepatitis B vaccine are very uncommon (Andre, 1989; CDC, 1991 a; Greenberg, 1993; Niu, 1996). While reported, there is no confirmed scientific evidence that hepatitis B vaccine causes chronic illness, including multiple sclerosis, chronic fatigue syndrome, rheumatoid arthritis, or autoimmune disorders. There is no risk of HBV infection from the vaccine.

Large-scale hepatitis B immunization programs in Taiwan, Alaska, and New Zealand have observed no association between vaccination and the occurrence of serious adverse events. Furthermore, surveillance of adverse events in the United States after hepatitis B vaccination have not shown a clear association between hepatitis B vaccine and the occurrence of serious adverse events including Guillain-Barre' syndrome, transverse myelitis, optic neuritis, and seizures (Shaw, 1988; CDC, 1991 a; Niu, 1996; Niu 1998 CDC, unpublished data). Additional evaluations are ongoing. A recent study suggested persons developing rheumatoid arthritis after hepatitis b vaccination were genetically at-risk for rheumatoid arthritis (Pope, 1998).

A low rate of anaphylaxis (hives, difficulty breathing, shock) has been observed in vaccine recipients based on reports to the Vaccine Adverse Event Reporting System (VAERS), with an estimated incidence of 1 in 600,000 vaccine doses distributed. One case has been reported in 100,763 children (10-11 years old) vaccinated with recombinant vaccine in British Columbia and no cases were observed in 166,757 children vaccinated in New Zealand. Although none of the persons who developed anaphylaxis died, anaphylactic reactions can be life-threatening, and therefore further vaccination with hepatitis B vaccine is contraindicated in persons with a history of anaphylaxis after a previous dose of vaccine. There have been rare reports of hair loss after hepatitis B vaccination, with the majority of individuals regrowing their hair (Wise, 1997). Studies are in progress to better quantify the possible slight risk of hair loss.

Any presumed risk of adverse events associated with hepatitis B vaccination must be balanced with the expected 4,000 to 5,000 HBV-related liver disease deaths that would occur without immunization, assuming a 5 percent lifetime risk of HBV infection.

Q. Does hepatitis B vaccination cause demyelinating diseases such as multiple sclerosis (MS)?

The scientific evidence to date does not support hepatitis B vaccination causing MS or other demyelinating diseases.

Multiple sclerosis is a disease of the central nervous system characterized by the destruction of the myelin sheath surrounding neurons, resulting in the formation of "plaques." MS is a progressive and usually fluctuating disease with exacerbations (patients feeling worse) and remissions (patients feeling better) over many decades. Eventually, in most patients, remissions do not reach baseline levels and permanent disability and sometimes death occurs. The cause of MS is unknown. The most widely held hypothesis is that MS occurs in patients with a genetic susceptibility and that some environmental factors "trigger" exacerbations. MS is 3 times more common in women than men, with diagnosis usually made as young adults.

The concern that hepatitis B vaccination may cause MS or exacerbate it derives from case reports and media attention in France and, more recently, televised news reports in the United States. However, it is possible that these MS case reports are purely coincidental to hepatitis B vaccination. Carefully controlled studies (currently underway) are needed to determine the nature of these reports.

Other than these case reports, what then is the current scientific evidence that hepatitis B vaccination causes MS or other demyelinating diseases? First, extensive pre-licensure clinical trials did not document such an effect. Second, hundreds of millions of persons worldwide have been immunized without developing MS (or any other autoimmune disease). This finding provides important negative evidence as well as an appropriate framework for assessing this possible association-namely, that if vaccination causes MS, it does so extremely rarely.

Third, prospective studies of MS patients have shown that exacerbations appeared to be more frequent after nonspecific viral illnesses (Sibley, 1985). This is presumably due to generalized stimulation of the immune system that occurs with such infections (Owen, 1980). There have been reports of exacerbations of MS following immunization of persons who already had MS but no evidence that vaccination increases the rate of MS in otherwise healthy persons. Given the large number of vaccinations administered worldwide, it is not surprising that surveillance systems in the U.S., France, and elsewhere (Quast, 1991), have received some reports of MS temporally (coincidentally) associated with vaccinations. As with all such case reports, however, they only constitute signals of possible causal associations. Further controlled studies are necessary to establish causation.

A recent (and largest to date) multi-center randomized double-blind placebo controlled trial of influenza immunization in 104 MS patients failed to show any difference in attack rate or disease progression over 6 months between vaccines and placebo recipients (Miller, 1997). This study suggests that even if a vaccine can exacerbate MS, it must do so only among a small minority of MS patients.

Fourth, whether vaccinations actually cause an overall excess of MS in the population (vs. being just one of multiple possible triggers for MS in genetically susceptible individuals, without causing an excess of MS) can only be evaluated in a population-based study.

Finally, MS is an autoimmune disorder in which a person's antibodies attack the body's own myelin (a sheath that covers the nerves). According to the "molecular mimicry" hypothesis, the hepatitis b vaccine must somehow be similar to the myelin in three dimensional structure thus provoking anti-myelin antibodies to form. However, recent research (as yet unpublished) using genetic sequencing has not shown a similarity between hepatitis B vaccine and myelin basic protein. This research raises doubts about the validity of the "molecular mimicry" hypothesis.

Although scientific evidence to date does not support hepatitis B vaccination causing multiple sclerosis (MS) or other demyelinating diseases, studies are currently being organized in the Vaccine Safety Datalink project at CDC and elsewhere because of public concern about this issue in France and other places and because there is little available research on this specific topic (Chen, 1997). Computerized medical records on approximately 5 million or 2 percent of the U.S. population are available in this study. It will probably be at least one year, however, before any results are available.

In the meantime, the concern regarding a suggested association between vaccination and MS or any other chronic illness must be weighed against the very strong evidence that vaccines have in protecting against disease and death.

Q. Are there any studies being conducted to examine what relationship, if any, exists between the hepatitis B vaccine and multiple sclerosis (MS)?

YES, there are at least six research projects underway. In recent years, several unproven theories have caused concern in the general public by suggesting there is an association between the hepatitis B vaccine and demyelinating disorders, including MS. As a result, the research studies described below were developed to investigate these hypotheses further.

The first two research projects were sponsored by the French Medications Agency, an organization similar to the United States Food and Drug Administration (FDA). One was a case-control study based on clinical reports of demyelinating disorders that were seen in 11 neurology centers across France. The second was also a case-control study. This research project was based on approximately 4 million patients receiving care through general practices in the United Kingdom. A third project was done by one of the vaccine manufacturers. Preliminary results from all three studies were shared with the French Medications Agency and the Viral Hepatitis Prevention Board in September 1998. These results are not yet available to others. If determined to be scientifically sound, these papers will be published in peer-reviewed medical journals in the near future.

The CDC's National Immunization Program (NIP) is using the Vaccine Safety Datalink (VSD) Project to examine whether there is an increased risk of MS following hepatitis B vaccination. The VSD contains data on more than 6 million people which is collected from four health maintenance organizations on the west coast. All vaccines administered within the study population are recorded. Available data include vaccine type, date of vaccination, concurrent vaccinations, the manufacturer, lot number and injection site. After vaccine administration, the medical records are monitored for potential health effects occur around the time of immunization. In this project, a case-control research design is being used to study patients 18 to 49 years of age without a prior diagnosis of MS or optic neuritis. NIP anticipates that within the study population, about 500 patients will be diagnosed with MS by a physician using specific criteria. This study is being funded and organized by CDC in collaboration with Kaiser Permanente HMO's in Portland, Oregon, Northern California, and Southern California, and Group Health Cooperative of Puget Sound in Seattle, Washington. Research results will be available within the next few years.

Data from the Harvard Nurses Health Study (NHS) are being used to examine whether a possible relationship between hepatitis B vaccine and MS exists. NHS data collection began in 1976 and longitudinal follow-up is on-going. The study population includes a randomly selected cohort of nurses age 25-55. Researchers are using a nested case-control design with approximately 200 MS cases having been identified. Cases are being verified by follow-up questionnaires to the patient's physician as well as classification by a blinded panel of neurologists. Two control groups are being used. Every MS patient will be matched with five healthy controls and one control with a diagnosis of breast cancer (to control for recall bias). This study is being supported by Merck and results are expected during the fall of 1999.

Researchers at the University of Lyon in France are examining whether immunization (with any vaccine) increases the short-term risk of relapse in patients already diagnosed with MS. This project, known as the VACCIMUS study, employs a case-crossover design (where cases also serve as controls). The study includes 600 MS patients identified from neurology departments belonging to a network specializing in MS. Researchers will compare vaccination history in the three months prior to a relapse with a control period. This project is funded, in part, by Pasteur Merieux Connaught and results are expected in the fall of 1999.

References

Andre FE. Summary of safety and efficacy data on a yeast derived hepatitis B vaccine. Am J Med. 1989;87(Suppl 3A): 14s-20s.

Centers for Disease Control and Prevention. Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through Universal Childhood Vaccination. MMWR. 1991;40 (RR-13):1-17.

Chen RT, Glasser J, Rhodes P, et al. The Vaccine Safety Datalink Project: A New Tool for Improving Vaccine Safety Monitoring in the United States. Pediatrics 1997;99:765-73.

Francis DP, Hadler SC, Thompson SE, et al. Prevention of hepatitis B vaccine: report from the Centers for Disease Control multi-center efficacy trial among homosexual men. Ann Intern Med. 1982;97:362-6.

Greenberg DP. Pediatric experience with recombinant hepatitis B vaccines and relevant safety and immunization studies. Pediatr Infect Dis J. 1993;12:438-445.

Miller AE, Morgante LA, Buchwald LY et al. A multi center, randomized double-blind placebo controlled trial of influenza immunization in multiple sclerosis. Neurology 1997:48:312-314.

Niu MT, Davis DM, Ellenberg S. Recombinant hepatitis B vaccination of neonates and infants: emerging safety data from the Vaccine Adverse Event Reporting System. Pediatr Inf Dis J 1996;15:771-6.

Niu MT, Rhodes P, Salive M, Lively T, et. al. Comparative safety data of two recombinant hepatitis B vaccines in children: data from the Vaccine Adverse Event Reporting System (VAERS) and Vaccine Safety Datalink (VSD). J Clin Eidemiol 1998;51:503-10.

Owen RL, Dau PC, Johnson KP, Spitler LE. Immunologic mechanisms in multiple sclerosis: exacerbation by type A hepatitis and skin test antigen. JAMA 1980;244:2307-2309.

Pope JE, Adams S, Howson W, et al. The development of rheumatoid arthritis after recombinant hepatitis b vaccination. J Rheumatol 1998; 25: 1687-93.

Quast U, Herder C, Zwisler O. Vaccination of patients with encephaloymelitis disseminata. Vaccine 1991;9:228-230.

Shaw FE, Graham DJ, Guess HA, et al. Postmarketing surveillance for neurologic adverse events reported after hepatitis B vaccination. Am J Epidemiol. 1988;127:337-352.

Sibley WA et al. Clinical viral infections and multiple sclerosis. Lancet 1985;1:1313-1315.

Stevens CE, Toy PT, Tong MJ, et al. Perinatal hepatitis B virus transmission in the Unites States: prevention by passive-active immunization. JAMA. 1985; 253:1740-1745.

Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high risk population in the United States. N Engl J Med. 1980;303:833-841.

Wise RP, Kiminyo KP, Salive ME. Hair loss after routine immunizations. JAMA. 1997;278:1176-1178.

Zajac BA, West DJ, McAleer WJ, Scolnick EM. Overview of clinical studies with hepatitis B vaccine made by recombinant DNA. J Infect. 1986;13(Suppl A):39-45.

Additional Resources

General information on hepatitis B vaccine - http://www.cdc.gov/nip/news/messhepb.htm

Questions and answers on hepatitis B vaccine - http://www.cdc.gov/nip/vacsafe/fs/qhepb.htm

Questions and answers on vaccine safety - http://www.cdc.gov/nip/news/vacsafe.htm

Vaccine safety and injury compensation - http://www.cdc.gov/nip/news/keymess.htm

"What Would Happen If We Stopped Vaccination?" - http://www.cdc.gov/nip/vacsafe/fs/valuefs.htm

A recent statement on the importance of immunization by Donna Shalala, Secretary, U.S. Department of Health and Human Services - http://www.cdc.gov/nip/news/shalala.htm

A list of contact telephone numbers and Internet sites that can be accessed to provide more information - http://www.cdc.gov/nip/news/resources.htm

National Immunization Program website - http://www.cdc.gov/nip

Hepatitis Branch website - http://www.cdc.gov/ncidod/diseases/hepatitis/hepatitis.htm

National Multiple Sclerosis Society - http://www.nmss.org/newsframe.html

World Health Organization - http://www.who.org/gpv-safety (see "Hot Topics")

Scare of multiple sclerosis from hep B vaccine Aquite unfounded. Vaccine and Immunization News: The newsletter of the global programme for vaccines and immunization, World Health Organization. 1997; No. 4: p. 8.

No evidence that hepatitis B vaccine causes multiple sclerosis. Weekly Epidemiological Record, World Health Organization. 1997; No. 21: pp. 149-152.

National Immunization Information Hotline (1-800-232-2522)

Hepatitis Hotline (1-888-443-7232)