Hepatitis A Vaccine, Inactivated from SmithKline Beecham Biologicals (SKB; Rixensart, Belgium), a subsidiary of SmithKline Beecham PLC, has been approved by the FDA for prevention of hepatitis A virus infections. The vaccine, marketed under the trade name Havrix, is the world's first hepatitis A vaccine and is indicated for active immunization of persons at risk for hepatitis A exposure. There are an estimated 10 million cases of hepatitis A infection worldwide each year with most infections occurring in lesser developed countries. The vaccine's major market is among more affluent travelers from developed countries and military personnel. Havrix is currently available in over 40 countries worldwide including major markets in Europe and millions of vaccine doses have been administered to date. Another inactivated, alum-adjuvanted hepatitis A vaccine, Vaqta from Merck & Co., is available in some countries and is approaching approval in the U.S.

Havrix is prepared from formalin-inactivated hepatitis A virus strain HM-175 grown in continuous culture in primary African green monkey kidney (AGMK) cells. The vaccine uses a conventional alum adjuvant. Strain HM-175 contains mutations involved in culture adaptation which enable it to grow well in culture and which attenuate its human pathogenicity. The hepatitis A virus is a small, single-stranded RNA virus infection which commonly causes hepatitis. For further information, see publications including "Production, Quality Control and Characterization of an Inactivated Hepatitis A Vaccine," Vaccine, vol. 10, sup. 1, p. S99-101, 1992. Official U.S. labeling information is not yet available from FDA or SKB.

SKB reports cumulative worldwide Havrix sales of $82 million through the third quarter of 1994. The vaccine is administered to adults as an initial injection (1,440 units; about $44) followed by a booster 6-12 months later. The primary injection provides protection for up to one year and the booster further extends protection. Children receive an initial injection (360 units; about $15) followed by two booster doses. Thus, adult vaccination costs about $88 and pediatric vaccination costs about $45. The vaccine is supplied in prefilled disposable syringes.

As discussed in the February 1994 Bulletin (p. 35), the Vaccines and Related Biological Products Advisory Committee, FDA, reviewed Havrix and recommended its approval over a year ago. It has taken over a full year for FDA to resolve remaining issues and approve Havrix. Varivax (discussed in a story above) similarly has been available in many other countries and was similarly delayed by FDA. Both of these vaccines are commonly cited by FDA critics who view the agency as needlessly delaying approvable products.

Havrix is based on NIAID inventions, and both NIAID and the U.S. Army have played a major role in its development. Strain HM-175 and the inactivated vaccine were originally developed by NIAID researchers (including Purcell, R.H.; Gust, I.D.; Daemer, R.J.; and Feinstone, S.M.) and covered by U.S. patents assigned to NIH (including numbers 4,894,228; 4,532,215; 4,636,469; and 4,620,978). SKB already holds a nonexclusive license for these inventions from NIH which reports that this technology is still available for nonexclusive licensing. Even with SKB and Merck marketing hepatitis A vaccines in most countries, there may still be opportunities for other companies to develop markets in various countries and niches for Havrix-equivalent vaccines. Because SKB has a nonexclusive license, it is exempt from NIH requirements (expected to be changed soon) concerning "reasonable pricing" of inventions exclusively licensed from NIH. Preclinical studies and Phase I trials were conducted by NIAID. Both NIAID and the Centers for Disease Control and Prevention (CDC) assisted with Havrix development through formal Collaborative Research and Development Agreements (CRADAs) with SKB that began in November 1988.

The Walter Reed Army Institute of Research (WRAIR; Washington, DC) entered into a CRADA with SKB in 1991 that supported the U.S. Army (with assistance from CDC) conducting large-scale efficacy trials in Thailand. This included a controlled trial in 40,000 children administered either Havrix or Engerix-B (hepatitis B vaccine also from SKB). Havrix provided over 94% protection among the children in this study. About 3,000 episodes of illness were reported with only 60 acute cases of hepatitis A reported among Havrix vaccine recipients. In three other clinical trials in nearly 500 adult volunteers administered a single dose of Havrix, hepatitis A neutralizing antibodies were elicited in over 96% of the subjects after one month. The vaccine is generally well tolerated. The most common adverse effects noted in clinical trials have been soreness at the injection site (56% of adults, 15% of children) and headache (14% of adults, 5% of children). For a discussion of the Army's involvement in the development of Havrix and hepatitis A vaccines, see "Hepatitis A in the U.S. Army: Epidemiology and Vaccine Development," Vaccine, vol. 10, sup. 1, p S75-9, 1992.

Most persons in poorer, lesser developed countries where the disease is endemic become infected with hepatitis A and develop protective immunity during childhood and have no need to receive the vaccine. For example, 95% of the population in Mexico has been infected with hepatitis A by the age of 10. Most persons in the U.S. and other developed countries with high standards and infrastructure for public sanitation are not exposed during childhood and lack immunity. Hepatitis A virus is highly transmissible and a single infected person can lead to a community-wide epidemic. The disease is typically spread by the fecal-oral route, through close person-to-person contact or by ingestion of fecal contaminated food or water. Contamination sources include drinking water and ice; fruits, salads and foods handled by infected persons; and ingestion of shellfish (e.g., oysters, clams, mussels) from hepatitis A-infected waters. Many outbreaks are attributed to infected food handlers. Breakdown in sanitation facilities, such as after floods and natural disasters, can also cause outbreaks. Transmission rates are high within families with transmission rates up to 45% reported among children and 20% among susceptible adults in developed countries. Infected persons shed virus for about two weeks before the onset of symptoms, further complicating control of the disease.

Hepatitis A causes acute liver disease and debilitating symptoms that can last for up to one year after the acute infection subsides. Respiratory symptoms, rash and joint pain occur in some patients. Severity can range from few and mild symptoms (as is common in young children) to more serious symptoms in 75-90% of infected adults. An estimated 67% of cases occur in children and young adults, while over 70% of hepatitis A-related mortality occurs in those over 49 years old. Hepatitis A infection is often asymptomatic in children under two years of age, and these children often transmit infection to others, especially in day care and other common child care facilities. While disease resolves itself in most patients within 6-12 months, relapse and extended illness has been reported in about 20% of cases. Mortality rates for hepatitis A infection are low, about 6/1,000 cases, but mortality rates are higher in older persons, about 27/1,000 cases in those over 49 years old.

Hepatitis A is the most common traveler-related disease now preventable by vaccine. Hepatitis A occurs about 100 times more often in unvaccinated travelers than does typhoid fever and about 1,000 times more often than cholera. The major U.S. market for Havrix will be the over 24 million U.S. citizens who annually visit regions where the disease is endemic with another sizeable market being U.S. military personnel stationed overseas. Unlike Varivax (discussed in a story above), for which universal vaccination is recommended, most use of Havrix in the U.S. and other countries will be in travelers to regions where hepatitis A is endemic, including parts of Mexico and Central America, the Caribbean, South America, Africa, Asia (except Japan), the Mediterranean basin, Eastern Europe and the Middle East. Havrix will also be used by persons in certain occupations at risk for hepatitis A infection, including military personnel, certain health care professionals, sewage workers and staff in day care, disabled care and other institutional settings.

No antiviral drugs are available for hepatitis A treatment. Hepatitis A immune globulin is available for passive immunization, both for pre-exposure prophylaxis and post-exposure prophylaxis during the incubation period. While hepatitis A immune globulin provides 80-90% protection against clinical illness, this is costly, requires repeated doses, carries risks due to its being derived from human blood, and is not practical for large-scale prophylactic use. Even high doses (e.g., 5 ml) provide 3-5 months of protection at most, requiring re-inoculation among frequent travelers and those residing in endemic areas. Also, as sanitation and use of Havrix and other hepatitis A vaccines increase, the availability of high titer hepatitis A plasma will decrease. In fact, last month, Armour Pharmaceutical Co., the sole U.S. manufacturer and marketer of hepatitis A immune globulin, reported that the product is in short supply. The Department of Defense (DOD), the largest purchaser of hepatitis A immune globulin, had essentially exhausted the available supplies for use in military personnel sent to Haiti and the Middle East. Several other U.S. companies that previously produced hepatitis A immune globulin have abandoned the product in recent years. Armour currently produces between 1.5-2 million doses annually. The company reports that the DOD has reduced its orders by 25% and the company is increasing production by 25% to meet demand. Supplies are expected to return to normal in several months.

Awareness of the need (and now the opportunity) for protection against hepatitis A among travelers in the U.S. and other developed countries is low, and the public and medical community will have to be educated about the availability and utility of Havrix. A 1994 Roper Starch survey found that most Americans are unaware of hepatitis A risks. The survey found that: over half of those persons having traveled outside the U.S. in the last 2-3 years visited areas where the disease is endemic; that only 2% of travelers sought available protection (hepatitis A immune globulin); nearly 75% of Americans have no knowledge of hepatitis A or its risks; 44% have no knowledge of risk factors for hepatitis A; only 2% recognized that travel is a risk factor for hepatitis A; and that only 4% recognized poor sanitation as a risk factor. When instructed about hepatitis A and related risk factors, 58% responded that they would be likely to seek vaccination if they expected to encounter potential risks. Presuming that 10% (2.4 million) of U.S. travelers to areas where the disease is endemic receive Havrix, this will provide SKB with additional sales of over $200 million. As the market for Havrix grows, it will become a major source of royalty income, providing millions of dollars annually, for NIAID and NIH.

The CDC reports 143,000 cases of hepatitis A in the U.S. each year costing the economy an estimated $200 million, but the disease is considered underreported. Direct medical care alone typically costs $2,800 for each case requiring hospitalization and $700 for other cases. Acute infection typically involves loss of an average of 30 work days (estimated $2,600 in lost wages) with symptoms including jaundice, fever, nausea, vomiting, diarrhea and appetite loss. The disease is a threat to travelers even if they stay in expensive Western-style resorts and hotels overseas.

Besides travelers to lesser developed parts of the world, hepatitis A is a threat to various persons (and those coming into contact with these persons) including: ethnic and geographic populations that experience cyclic epidemics, such as among native peoples in Alaska and North America; homosexuals; injectable drug users; military personnel and others housed in confined conditions with poor sanitation facilities; health care workers in contact with fecal material; child day care workers; primate handlers; and laboratory workers possibly handling hepatitis A samples.