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Appendix D-5
The Prospects for Immunizing Against Hepatitis B Virus

Effective, plasma-derived hepatitis B virus (HBV) vaccines have been marketed internationally by at least three companies. Licensees of these companies, plus new independent producers of similar vaccines, are working to broaden the distribution of these products. In addition, recombinant HBV vaccines are nearing licensure and their prospects appear favorable. Officials of most endemic countries are eager to incorporate an HBV vaccine into their immunization programs. Suitable candidates should be safe, immunogenic, low cost, and easy to deliver.

DISEASE DESCRIPTION

The diseases associated with HBV occur at two intervals after infection: acute hepatitis appears within several weeks; the manifestations of chronic hepatitis B infection may not appear until many years later.

Symptoms of acute hepatitis B virus infection include nausea, vomiting, abdominal pain, generalized myalgia with occasional joint pain, urticarial rash, and jaundice. HBV infection also is associated with certain immune complex diseases (polyarteritis nodosa and glomerulonephritis) and with acrodermatitis in young children. Severe cases of hepatitis B may require hospitalization, and death usually follows fulminant hepatitis. Infection is subclinical in one-third of all cases (Francis and Maynard, 1979). Of symptomatic cases in otherwise healthy adults, about half involve jaundice, and the other half involve more generalized symptoms. Children infected with HBV are much less likely to have symptoms of hepatitis; probably less than 1 in 100 HBV infections in newborns is symptomatic (Schweitzer et al., 1973; Stevens et al., 1975).

The late manifestations of HBV occur almost exclusively among chronic carriers of the virus. The proportion of infected people who

The committee gratefully acknowledges the efforts of D.P.Francis, who prepared major portions of this appendix. The committee assumes full responsibility for all judgments and assumptions.



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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Appendix D-5 The Prospects for Immunizing Against Hepatitis B Virus Effective, plasma-derived hepatitis B virus (HBV) vaccines have been marketed internationally by at least three companies. Licensees of these companies, plus new independent producers of similar vaccines, are working to broaden the distribution of these products. In addition, recombinant HBV vaccines are nearing licensure and their prospects appear favorable. Officials of most endemic countries are eager to incorporate an HBV vaccine into their immunization programs. Suitable candidates should be safe, immunogenic, low cost, and easy to deliver. DISEASE DESCRIPTION The diseases associated with HBV occur at two intervals after infection: acute hepatitis appears within several weeks; the manifestations of chronic hepatitis B infection may not appear until many years later. Symptoms of acute hepatitis B virus infection include nausea, vomiting, abdominal pain, generalized myalgia with occasional joint pain, urticarial rash, and jaundice. HBV infection also is associated with certain immune complex diseases (polyarteritis nodosa and glomerulonephritis) and with acrodermatitis in young children. Severe cases of hepatitis B may require hospitalization, and death usually follows fulminant hepatitis. Infection is subclinical in one-third of all cases (Francis and Maynard, 1979). Of symptomatic cases in otherwise healthy adults, about half involve jaundice, and the other half involve more generalized symptoms. Children infected with HBV are much less likely to have symptoms of hepatitis; probably less than 1 in 100 HBV infections in newborns is symptomatic (Schweitzer et al., 1973; Stevens et al., 1975). The late manifestations of HBV occur almost exclusively among chronic carriers of the virus. The proportion of infected people who The committee gratefully acknowledges the efforts of D.P.Francis, who prepared major portions of this appendix. The committee assumes full responsibility for all judgments and assumptions.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries become chronic carriers is highly age-dependent. It ranges from about 80 to 90 percent for offspring of e-antigen positive mothers to 5 to 10 percent for adults (Francis and Maynard, 1979; Stevens et al., 1975). Chronic infection may result (usually after a period of many years) in cirrhosis or primary hepatocellular carcinoma, either of which can lead to death. PATHOGEN DESCRIPTION HBV is a small (42 nm) virus particle consisting of an outer coat and a central core with an unusual circular, partially double-stranded DNA (Dane et al., 1970; Gerin and Wai-Kuo Shih, 1978; Robinson, 1978). The central core of the virus contains the core antigen (HBcAg) which, in solution, has a conformational variant, the so-called e antigen (HBeAg). The coat protein is designated the surface antigen (HBsAg) of the virus. In addition to the whole virus particle, the blood of infected individuals contains smaller (20 to 22 nm) spherical and tubular forms that consist entirely of HBsAg. HBsAg has several major antigenic determinants. The a antigen is shared by all known strains of HBV. In addition, there are two sets of mutually exclusive antigenic determinants (d/y and w/r) that, in combination, produce the four major viral subtypes, adw, adr, ayw, and ayr. Additional subtype classifications and variants of each of the above major determinants have been described, but their importance for HBV infection or for immunity to infection is unclear (Gerin et al., 1982). HOST IMMUNE RESPONSE The immune response to HBV infection involves antibody production to all the HBV antigens: anti-HBc, anti-HBe, and anti-HBs. Anti-HBs usually appears only after resolution of HBV infection and is the antibody that is considered protective (Francis and Maynard, 1979). Anti-HBc and anti-HBe may be present during acute or chronic HBV infection, as well as following resolution. Their contribution to protection against HBV, if any, has not been fully elucidated. Individuals who recover from HBV infection usually develop substantial anti-HBs levels, which probably persist for life. The major humoral immune response following infection is to the common a antigenic component (anti-HBs/a) (McAuliffe et al., 1982). Thus, most individuals who have recovered from infection with one subtype of HBV will have subtype cross-protection. Rarely, anti-HBs/a fails to develop; when this occurs, the patient may remain susceptible to the other subtypes. Investigations are under way to elucidate the role of the so-called preS region of the surface antigen protein(s). The preS region is removed in the processing of plasma derived vaccines and appears to enhance the protection provided by the s protein (National Institute of Allergy and Infectious Diseases, 1985).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries DISTRIBUTION OF DISEASE Geographic Distribution The disease burden of hepatitis B varies significantly in different parts of the world. The combined total of chronic carriers and healthy immune individuals provides a good measure of the rate of infection. Using this measure, the world can be divided into areas of high infection rate (sub-Saharan Africa, east Asia, and the Pacific Islands), moderate infection rate (Middle East, central Asia, South America, eastern Europe, and Arctic), and low infection rate (North America, western Europe, and Australia) (Francis, 1983). Lack of surveillance and lack of serologic testing hamper quantitation of disease incidence in many of the high-rate areas. Nevertheless, available estimates demonstrate the enormity of the problem. Acute HBV manifestations are relatively less common in endemic countries than in other areas because much of the disease burden occurs during childhood, when symptoms are less frequent. However, the total burden of acute disease is large in these countries because the disease is so widespread. The total disease burden resulting from HBV in endemic areas is large because of the high infection rates at early ages, with the late sequelae that result from persistent infection. For example, the incidence of primary hepatocellular carcinoma in many areas of the world exceeds the incidence of acute hepatitis B in the United States (Maupas and Melnick, 1981). The largest number of HBV infections occurs in China (60 million HBV carriers). Actual mortality rates in China have been reported for primary hepatocellular carcinoma (PHC) (Armstrong, 1980). The rate is extremely high in southeast China (50 to 60 per 100,000 per year). Throughout China, the rate is reported to be about 20 per 100,000 per year (Francis, personal communication, 1984). Less information is available on cirrhosis deaths, but a Taiwanese study found that there were 0.43 deaths from HBsAg-positive cirrhosis for every PHC death (Beasley et al., 1981). Complete data are not available for acute hepatitis B in China, but the annual incidence is estimated to be about 700,000 cases, and half of the infectious disease beds are occupied by hepatitis patients (over half of which are HBV-related). Disease Burden Estimates The disease burden estimates include three major disease states: acute hepatitis B, primary hepatocellular carcinoma, and cirrhosis. Acute Hepatitis B Cases and deaths due to acute hepatitis B were calculated as shown in Table D-5.1.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-5.1 Morbidity and Mortality due to Acute Hepatitis B Region Population at Risk (millions) Annual Incidence Rate (per 100,000) Number of Cases Deathsa High Risk Regions         South and east Asia 1,516 68b 1,030,880 1,546 Sub-Saharan Africa 407 68b 276,760 415 Oceania 5 68b 3,400 5 Moderate Risk Regions         Central Asia 1,146 60c 687,600 1,031 North Africa 124 60c 74,400 112 South America 397 40d 158,800 238 Total     2,231,840 3,347, aAssuming a case fatality rate of 1.5 per 1,000 cases. bIncidence rate in China assumed applicable to all high-risk regions. cAssumed to be close to Israel’s rate of 50 to 80 per 100,000. dAssumed to be between rates in Israel and the United States. SOURCE: Francis, personal communication, 1985. Cases and deaths were divided proportionally by population size into the 5 to 14 and 15 to 59 years age groups. It was assumed that all cases in the under 5 years age group are asymptomatic, and that the number of cases in people 60 years of age and over is insignificant. Cases were distributed into the acute categories as follows: 5 to 14 years age group, 25 percent in category A, 50 percent in category B, and 25 percent in category C; 15 to 59 years age group, 25 percent in category A, 25 percent in category B, and 50 percent in category C. An additional 3 percent of cases in each age group were assigned to category E, representing cases of chronic acute hepatitis (Berlin, 1980). Table D-5.2 shows the disease burden resulting from acute hepatitis B. Primary Hepatocellular Carcinoma PHC may occur in chronic hepatitis B carriers 20 years or more after an acute infection. The average survival rate of PHC is 6 months, so the numbers of cases and deaths are equal. The incidence rates in different populations are shown in Table D-5.3. Because of the time lag between acute hepatitis infection and PHC onset, it was assumed that the disease affects only two age groups. Cases and deaths were distributed proportionally according to the size of the population in each age group, and all cases were assigned to category E. Table D-5.4 shows the disease burden estimates for PHC.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-5.2 Disease Burden: Hepatitis B—Acute Illness     Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity     178,547 7 379,413 7     B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work     357,095 14 379,413 14     C Severe pain, severe short-term impairment, or hospitalization     178,547 28 758,826 28     D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)   n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)   n.a. 21,426 n.a. 45,530 n.a.   n.a. F Total impairment   n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility   n.a.   n.a.   n.a.   n.a. H Death   n.a. 1,071 n.a. 2,276 n.a.   n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-5.3 Morbidity and Mortality due to Primary Hepatocellular Carcinoma   Population at Risk (millions) Incidence Rate (per 100,000) Number of Cases=Number of Deaths High HBV Risk       South and east Asia 1,516 20 303,200 Sub-Saharan Africa 407 30 122,100 Oceania 5 10 500 Moderate HBV Risk       Central Asia 1,146 10 114,600 North Africa 124 10 12,400 South America 397 5 19,850 Total     572,650   SOURCE: Francis, personal communication, 1985. Cirrhosis Incidence rates of cirrhosis as a complication of hepatitis B have not been well documented. Beasley et al. (1981) found in Taiwan that for every death due to PHC there were 0.43 deaths from HBsAg-positive cirrhosis. This rate was applied to all PHC deaths. Cirrhosis deaths were assumed to equal 25 percent of cirrhosis cases. Cirrhosis cases were assigned to category E. Table D-5.5 shows the disease burden estimates for cirrhosis resulting from hepatitis B. Table D-5.6 shows the total disease burden estimates for hepatitis B. PROBABLE VACCINE TARGET POPULATION In highly endemic areas, the goal of HBV vaccination is to prevent both infection and the chronic carrier state. Because most population members of these areas are at risk of infection, universal vaccination is required. Furthermore, infection in these areas often occurs early in life, so the age of immunization must be adjusted accordingly. For areas of the world where perinatal infection is common, the first dose of vaccine should be given at birth (with the addition of hepatitis B immunoglobulin [HBIG] if vaccine alone is not effective in preventing perinatal infection) and subsequent doses delivered later. This approach is practical in many Asian countries because a substantial proportion of mothers deliver their infants in medical facilities. For areas of the world where perinatal infection is not a major problem, vaccination could be given simultaneously with other infant vaccinations. Thus, HBV vaccination could be incorporated into the World Health Organization Expanded Program on Immunization (WHO-EPI), with administration at the earliest current time of vaccine delivery.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-5.4 Disease Burden: Hepatitis B—Primary Hepatocellular Carcinoma     Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity                 B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work                 C Severe pain, severe short-term impairment, or hospitalization                 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)   n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)   n.a.   n.a. 509,659 n.a. 62,991 n.a. F Total impairment   n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility   n.a.   n.a.   n.a.   n.a. H Death   n.a.   n.a. 509,659 n.a. 62,991 n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-5.5 Disease Burden: Hepatitis B—Cirrhosis     Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity                 B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work                 C Severe pain, severe short-term impairment, or hospitalization                 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability   n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)   n.a.   n.a. 876,612 n.a. 108,344 n.a. F Total impairment   n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility   n.a.   n.a.   n.a.   n.a. H Death   n.a.   n.a. 219,153 n.a. 27,086 n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-5.6 Disease Burden: Hepatitis B—All     Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity     178,547 7 379,413 7     B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work     357,095 14 379,413 14     C Severe pain, severe short-term impairment, or hospitalization     178,547 28 758,826 28     D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)   n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)   n.a. 21,426 n.a. 1,431,801 n.a. 171,335 n.a. F Total impairment   n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility   n.a.   n.a.   n.a.   n.a. H Death   n.a. 1,071 n.a. 731,088 n.a. 90,077 n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Assumptions about the proportion of the disease burden this would prevent are discussed below. The need for booster doses requires further evaluation. Vaccine Preventable Illness* Assuming that the entire target population could be vaccinated at birth, nearly all illness theoretically could be prevented (some infections occur in utero). Because early infection in infancy is common in highly endemic areas, and because incorporation into the current WHO-EPI probably would result in delivery of the first dose at a few weeks to a few months of age, the proportion of the total disease burden that would be vaccine preventable under these circumstances is judged to be about 60 percent. If vaccination at birth is adopted, as might be the case in some regions (e.g., some Asian countries) this estimate may underestimate the potential benefits of the vaccine in the calculations in Chapter 7. SUITABILITY FOR VACCINE CONTROL Plasma-derived HBV vaccines have been shown to be safe and effective for adults (Coutinho et al., 1983; Francis et al., 1982; Szmuness et al., 1980) and children (Maupas and Melnick, 1981). Recent studies of perinatal infection have reported efficacies of more than 90 percent for vaccine and HBIG together (Beasley et al., 1983), and ongoing studies of vaccine alone indicate efficacies of between 75 and 95 percent (Xu et al., 1985). Alternative Control Measures and Treatment No effective treatment for acute or chronic hepatitis B exists. Although some researchers have shown that the combination of alphafetoprotein screening and surgery can effectively treat primary hepatocellular carcinoma, the logistics and expense of this combination make widespread application impractical for the developing world. PROSPECTS FOR VACCINE DEVELOPMENT Plasma-derived HBV vaccines are now being produced in some of the more technically advanced developing countries. The technical problems *   Vaccine preventable illness is defined as that portion of the disease burden that could be prevented by immunization of the entire target population (at the anticipated age of administration) with a hypothetical vaccine that is 100 percent effective (see Chapter 7).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries involved in establishing production facilities and procedures and developing quality and safety controls are substantial; these ventures generally have involved collaboration with the United States, Europe, or Japan. Efforts to produce HBV vaccines using recombinant DNA technology (Burrell et al., 1979; McAleer et al., 1984; Miyanohara et al., 1983; Valenzuela et al., 1979) and synthetic polypeptides (Dreesman et al., 1982a; Gerin et al., 1983a,b; Hopp, 1981; Lerner et al., 1981) are under way in numerous laboratories. Several groups have introduced the HBsAg genome of HBV into bacteria, yeast, and mammalian cells. These laboratories include Merck Sharp & Dohme, Am Gen, Wellcome Biotechnology, and Smith-Klein-RIT in yeast cells; Genentech, Inc., Connaught Laboratories Ltd., and Institut Pasteur in mammalian cells (National Institute of Allergy and Infectious Diseases, 1985). Thus far, the most successful have been those that express HBsAg in yeast (McAleer et al., 1984) and mammalian cells (Patzer et al., 1984). At least two of these recombinant vaccines are permitted for investigational use in humans by the U.S. Food and Drug Administration. Safety and immunogenicity studies for yeast-derived vaccines began in late 1983 and for mammalian cell-derived vaccines shortly thereafter. For the yeast vaccine, Scolnick et al. (1984) report that in two groups of healthy, low-risk volunteer adults the vaccine was highly immunogenic. The 37 subjects each received a 10 µg dose of HBsAg at 0, 1, and 6 months. By 3 months, 80 to 100 percent of vaccinees were antibody positive. Large boosts in titer followed the third dose. Phase 1 clinical trials with the Genentech mammalian cell derived vaccine suggest that it is at least as immunogenic as the presently licensed vaccine (National Institute of Allergy and Infectious Diseases, 1985). There have been no serious reactions attributable to either candidate vaccine. Based on these results and other findings, it is estimated that a recombinant vaccine made in yeast or mammalian cells or both will be available in 1 to 2 years. Studies are under way with rDNA vaccines that contain the preS region (National Institute of Allergy and Infectious Diseases, 1985). The gene coding for HBsAg also has been incorporated into the vaccinia virus, which then expresses HBsAg on its surface (Smith et al., 1983). Studies in chimpanzees of the resulting vaccine, its safety and immunogenicity, and its ability to protect against challenge with wild HBV already have begun (Paoletti, 1984; Smith, 1984). The advantages of using vaccinia as a vehicle for immunization against hepatitis are presumed ease of production (no need for procedures to inactivate HBV or to remove extraneous immunogens), low cost (technologies already are in place for vaccine production), and the use of live replicating virus. Potential barriers to the use of this vaccine include: (1) the fact that vaccinia vaccine for smallpox prophylaxis has been abandoned worldwide—some countries might be reluctant to reintroduce it; (2) the inherent danger of potential side effects in individuals with dermatitis or unrecognized immune deficiencies; (3) uncertainty about successful “takes” following administration and the effectiveness of booster doses;

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries and (4) possible alteration of the tissue tropism of vaccinia virus by modification. Several laboratories have identified the major antigenic site of HBsAg, a hydrophilic sequence of 8 to 12 amino acids (Dreesman et al., 1982b; Gerin et al., 1983a,b; Hopp, 1981; Lerner et al., 1981). Polypeptides of various sequences have been synthesized, and studies of immunogenicity in animals have begun. The major barrier to successful development of synthetic vaccines is the poor immune response to small polypeptides. Current investigations are directed at enhancing immunogenicity, either through structural modifications (e.g., the circular polypeptide developed by investigators at Baylor) or by attaching the peptide to larger carrier molecules and adjuvants. Whether or not these efforts will succeed and how long they will take remain uncertain. A further approach to vaccination against hepatitis B has been investigated, namely the use of anti-idiotype vaccines. This approach has been reported to provide protection in chimpanzees against challenge with HBV (Kennedy et al., 1985). Further investigations of this approach are required to evaluate its safety and suitability for use in humans and for HBV. Yet other possibilities include the development of hepatitis B polypeptide micelle vaccines (Howard et al., 1984). REFERENCES Armstrong, B. 1980. The epidemiology of cancer in the People’s Republic of China. Int. J.Epidemiol. 9:305–315. Beasley, R.P., L.-Y.Hwang, G.C.Y.Lee, C.-H.Roan, L.-Y.H.Wang, C.-C.Lan, F.Y.Huang, and C.-C.Chen. 1983. Prevention of perinatally transmitted hepatitis B virus infection with hepatitis B immunoglobulin and hepatitis B vaccine. Lancet II:1099–1102. Beasley, R.P., L.-Y.Hwang, C.-C.Lin, and C.-S.Chien. 1981. Hepatocellular carcinoma and hepatitis B virus: A prospective study of 22,707 men in Taiwan. Lancet II:1129–1132. Berlin, B.S. 1980. Viral hepatitis. Pp. 567–579 in The Biological and Clinical Basis of Infectious Diseases, 2d ed., G.P.Youmans, P.Y.Paterson, and H.M.Somers, eds. Philadelphia: W.B.Saunders. Burrell, C.J., P.Mackay, P.J.Greenaway, P.H.Hofschneider, and K. Murray. 1979. Expression in Escherichia coli of hepatitis B virus DNA sequences cloned in plasmid pBR322. Nature 279(5608): 43–47. Coutinho, R.A., N.Lelie, P.A. Van Lent, E.E.Reerink-Brongers, L. Stoutjesdijk, P.Dees, J.Nivard, J.Huisman, and H.W.Reesink. 1983. Efficacy of a heat inactivated hepatitis B vaccine in male homosexuals: Outcome of a placebo controlled double blind trial. Brit. Med. J. 286:1305–1308. Dane, D.S., C.H.Cameron, and M.Briggs. 1970. Virus-like particles in serum of patients with Australia-antigen-associated hepatitis. Lancet I:695–698. Dreesman, G.R., I.Ionescu-Matiu, Y.Sanchez, F.B.Hollinger, and J.L. Melnick. 1982a. Immunochemical studies with HBsAg polypeptide vaccines. P. 760 in Viral Hepatitis: 1981 International Sympos-

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