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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Appendix D-4 The Prospects for Immunizing Against Hepatitis A Virus DISEASE DESCRIPTION Hepatitis A virus (HAV) infection is a more prevalent but less serious disease than that caused by hepatitis B virus. It has a worldwide distribution, but the age of infection varies depending on socioeconomic and hygienic conditions. In the least developed areas, it is a disease of early childhood, with essentially all children except those of the highest socioeconomic classes experiencing asymptomatic or mild infection during the first years of life. As socioeconomic conditions improve, the usual age of infection shifts upward and the clinical manifestations of the disease become more severe; infection in adulthood normally results in frank icteric hepatitis. Hepatitis A is spread primarily by the fecal-oral route, directly from person to person. While in the poorest areas the disease remains uniformly endemic and rarely causes epidemics (due to low numbers of susceptible persons), in areas of moderate or better socioeconomic conditions the infection may cause cyclical communitywide or nationwide epidemics, with interepidemic intervals of 7 or more years. In the highest socioeconomic areas, epidemic cycles disappear and endemic foci of the disease may become uncommon; in these areas, the majority of cases occur among travelers to more highly endemic areas. The virus also may be spread by contaminated food or water, causing large common-source outbreaks in areas where a substantial proportion of the population remains susceptible. Some researchers suspect that HAV also may spread by the respiratory route, but there is no conclusive evidence to support this theory. In children under age 5, HAV illness is usually anicteric and may be entirely subclinical. When symptoms do occur, they may include fever, malaise, fatigue, headache, anorexia, nausea, vomiting, The committee gratefully acknowledges the efforts of S.C.Hadler, who prepared major portions of this appendix, and the advice and assistance of R.H.Purcell. 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 abdominal pain, and jaundice. Adults with HAV illness may be sick enough to require hospitalization. The disease has no known sequelae and is rarely fatal. Apart from the transient viremia that occurs during early HAV infection, there has been no identification of viremic carriers (Mosley, 1975). Socioeconomic status and general hygienic standards are the major risk factors for acquiring disease in most areas of the world. Specific risk factors for hepatitis A infection in developed areas include involvement in day care, homosexuality, personal contact with infected individuals, and foreign travel to endemic areas. PATHOGEN DESCRIPTION The HAV is an enterovirus about 28 nm in diameter (McCollum, 1982). It contains a single-stranded RNA and four polypeptides. Comparative studies of HAV from different geographic areas have been limited, but it appears that only one serotype exists. This simplifies potential vaccine development. Fecal excretion of the virus begins about 25 days after oral infection with HAV. Peak infectivity probably occurs before the onset of symptoms in the fourth week after exposure. HOST IMMUNE RESPONSE The host immune response to HAV infection involves both IgM and IgG (McCollum, 1982). Anti-HAV IgM appears as virus excretion begins to subside. Shortly thereafter, IgG levels begin to rise. IgG persists while IgM levels fall over the next 3 to 6 months. Cell-mediated immunity to HAV infection has not been reported. DISTRIBUTION OF DISEASE Geographic Distribution Hepatitis A virus infection and illness occur worldwide. As noted above, the severity of symptoms is related to the age at infection, which is dependent on the socioeconomic development of the region or country. Hence, the proportion of cases with moderate or severe symptoms is likely to be greater in the developed and more advanced developing countries, but the number of cases may be greater in the poorer countries. The rates of disease in different countries are discussed further below. Disease Burden Estimates Estimates of the numbers of cases of clinical hepatitis A illness worldwide are based on limited information and are therefore uncertain. Seroprevalence data show that hepatitis A is an infection of early
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries childhood in the poorest areas, and therefore almost entirely limited to mild or asymptomatic infection. As socioeconomic conditions improve, infection is successively delayed to later childhood, to adulthood with a high proportion of the population infected, and finally, to adulthood with smaller proportions of the population infected. As infection is delayed, an increasing proportion of cases are symptomatic; paradoxically, the clinical disease burden may increase as socioeconomic standards rise. Actual data on disease incidence are limited; the most comprehensive source is the World Health Organization Annual Statistical Reports. This presents data on rates of reported clinical infectious hepatitis for many countries, with breakdowns by age of infection for some countries. These data do not distinguish hepatitis cases by type (A, B, or non-A, non-B), because such data are available only in the most highly developed areas. Furthermore, they provide no information about case-reporting efficiency; presumably, reporting is best in most developed areas and poorest in the least developed areas. Disease burdens were estimated from the most recent available data for both different regions and different socioeconomic development levels within certain regions, as follows (Hadler, personal communication, 1985). Reported age-specific incidences of “infectious” hepatitis were compiled for individual countries from World Health Organization (WHO) annual statistics (1975–1981) as available. Data from serologic studies of acute hepatitis cases from the United States, western Europe, South America, and other selected areas were used to estimate the proportion of reported hepatitis cases that are due to hepatitis A. Generally, such studies have shown that a high proportion (80 percent) of hepatitis in childhood is due to HAV in all areas of the world and that a variable proportion, with a median of about 30 percent, of hepatitis cases in adults is due to hepatitis A virus. Although the latter figure varies widely and may be higher in more developed than in less developed areas, for simplicity the 30 percent figure was used throughout. These proportions were applied to available age-specific hepatitis rates for different countries. Representative rates of hepatitis A were then selected for each subregion, to be applied throughout that region. Because reporting is highly variable and underreporting is the rule, higher estimates were used where data were available from several countries in a given area. Rates for each region estimated in this manner are shown in Table D-4.1, along with the estimate of the number of cases that would result (based on 1979 population data—the last reliable data available to the author). Table D-4.2 shows the estimated numbers of cases adjusted for the 1984 population numbers. Assuming only 20 percent of cases are likely to be reported, the probable true number of cases in the developing world is estimated to be 4.765 million. In general, developed areas in the United States, western Europe, Asia, and Oceania have modest estimated rates of hepatitis A, from 0 to 15 cases per 100,000 per year. Areas with moderate development consistently show the highest disease rates, ranging from 20 to 100 cases per 100,000 per year, and occasionally higher in parts of South and Central America, eastern Europe, the Middle East, and China. Finally,
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-4.1 Estimated Rates of Hepatitis A Worldwide by Continental Regions Estimated Hepatitis A Region Socioeconomic Status 1979 Population (millions) Rate/100,000/Year Cases/Year (thousands) North America United States, Canada High 247.6 10 25 Central and South America Argentina, Brazil, Chile, Uraguay, Colombia, Venezuela, Costa Rica, Mexico Cuba Moderate 280.4 40 112 Others Low 70.2 20 14 Europe North High 82.0 5 4 West, central, south High 284.3 10 28 East (including USSR) Moderate 381.3 60 229 Africa North Low-Moderate 88.6 40 35 Sub-Sahara Low 353.8 30 106 Middle East High 15.3 60 9 Low-Moderate 116.7 20 23 Asia India, Nepal, Ceylon, etc. Low 862.2 20 173 Southeast Asia, Korea Low 406.9 20 82 China Low-Moderate 946.6 30 284 Japan, Singapore, Hong Kong, Taiwan High 123.4 10 12 Oceania New Zealand, Australia High 17.5 15 3 Others Low-Moderate 5.0 30 2 Total 1,141 SOURCE: Hadler, personal communication, 1985.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-4.2 Cases of Hepatitis A Likely to be Reported in the Developing World in 1984 Region Number of Cases per Year Africa 172,000 Asia 637,000 Latin America 142,000 Oceania 2,000 Total 953,000 NOTE: Numbers are based on estimates derived in Table D-4.1 and are adjusted for the increase in population between 1979 and 1984 (see Chapter 4) . the lowest socioeconomic areas in all parts of the world show the most variation in rates, from less than 1 to 90 cases per 100,000 per year. In these areas it is least certain whether low rates are due to asymptomatic infection during early childhood, or simply to poor reporting. For these areas, modest rates of 20 to 30 cases per 100,000 per year have been used. It should be noted, however, that the incidences of clinical illness in such areas may be expected to increase as socioeconomic conditions improve. Finally, the estimates used here have minimal correction for reporting efficiency; incorporating a correction factor to adjust for this probably would increase frequency of disease by 2- to 10-fold. A 5-fold underreporting is assumed in the calculation for this report to reflect the probable number of cases. Because of the scarcity of worldwide data on frequency of hospitalization or death rates due to hepatitis A, further refinement of the “clinical” or icteric disease load is difficult. The estimated mortality rate from the United States (3 per 1,000 clinical cases) has been applied throughout the world for the committee’s calculations. The proportion of severe cases, for which hospitalization would be desirable, has been estimated from U.S. data (i.e., one-third); however, actual rates of hospitalization in different areas may vary much more than mortality rates. The number and distribution of cases resulting from these assumptions is shown in Table D-4.3. There is little data from the developing world on which to base the distribution of cases among the age groups used in this disease comparison. For the purposes of this effort, the age distribution is assumed to be similar to that estimated for the United States and is shown in Table D-4.4 (Institute of Medicine, 1985). Application of these proportions to the estimated number of cases in Table D-4.3 yields the disease burden estimates shown in Table D-4.5.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-4.3 Estimated Morbidity and Mortality from Hepatitis A in the Developing World Category Number of Cases Typical cases of illness (morbidity category B) 3,178,255 Severe cases of illness (morbidity category C) 1,586,745 Fatalities (morbidity category H, 3/1,000 clinical cases) 14,295 TABLE D-4.4 Clinically Symptomatic Illness Caused by Hepatitis A Virus in Specific Age Groups Age Group (years) Typical Cases (morbidity category B) (percent) Severe Cases (morbidity category C) (percent) Deaths (percent) Under 5 4.4 2.0 0 5–14 20.0 10.0 8.0 15–59 71.0 77.0 36.0 60 and over 4.7 13.0 56.0 All ages 100 100 100 NOTE: Age distributions are based on reporting in the United States and are assumed to have a distribution the same as that for all reported cases. Cases of unknown age are assumed, for the purposes of this report, to occur proportionally in the three largest groups. PROBABLE VACCINE TARGET POPULATION The target population for an HAV vaccine would be young (preschool) children in all parts of the world and, ultimately, the cohort of babies born each year. The accessibility of this population has been demonstrated by the success of childhood immunization programs in all parts of the world. Childhood vaccination would directly benefit the most commonly affected group in the least developed areas. In more developed areas, it also would benefit adults because herd immunity plays a significant role in this disease, and because children are usually responsible for introducing infection into the household. In areas of moderate to good hygienic/socioeconomic conditions, where the major proportion of cases occur in older children or adults, initial vaccine programs also might focus on the specific highest risk groups, such as children in day-care centers or adults (travelers to highly endemic areas, military, homosexual men). The accessibility of
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-4.5 Disease Burden: Hepatitis A Virus 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 139,843 7 635,651 7 2,256,561 7 149,378 7 C Severe pain, severe short-term impairment, or hospitalization 31,735 14 158,675 14 1,221,794 14 206,277 14 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. 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 0 n.a. 1,144 n.a. 5,146 n.a. 8,005 n.a.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries these groups will vary widely with the group (the military will be most accessible) and with the health care system of the area. Incorporation of the HAV vaccine into the WHO Expanded Program on Immunization (WHO-EPI) would be the key to implementing HAV control in the poorer areas of the world. The feasibility of this depends on the nature of the vaccine (live versus killed), the number and schedule of doses necessary, the vaccine potency under various handling conditions (necessity for cold chain), and other circumstances. A single-dose live vaccine would be more easily incorporated into the program than a multi-dose killed vaccine, but it also might require more rigorous handling conditions for preservation of potency. Vaccines that have good potency when given within the first year of life would be more easily incorporated into the schedule than a vaccine that must be given later to have maximal potency. Vaccine Preventable Illness* Because HAV infection in infants and young children is almost always subclinical, and because it probably will be practical to deliver an HAV vaccine (that has shown to be safe and effective) at an early age, it is reasonable to assume that, theoretically, all illness associated with HAV vaccine could be vaccine preventable. SUITABILITY FOR VACCINE CONTROL Both the human immune response to HAV infection and vaccine studies in experimental animals suggest that the virus is an ideal candidate for vaccine control. Natural infection with HAV appears to induce long-lasting immunity. In addition, small doses of pooled human immune globulin are highly effective in preventing or ameliorating HAV infection in contacts of cases and in persons regularly exposed to known endemic settings (McCollum, 1982). Studies in marmoset and chimpanzee models with both killed and live attenuated virus vaccines have been quite successful. Both vaccines induced neutralizing antibody against the virus; subsequently, the animals were totally protected against parenterally administered challenge virus (Provost et al., 1982, 1983). Alternative Control Measures and Treatments Improved hygiene and sanitation are effective techniques for reducing the transmission and incidence of HAV infection, and immune * 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 globulin administration can diminish or eliminate symptoms in exposed individuals. Improvements in hygiene and sanitation in the developing world will reduce many diseases. For HAV, however, the picture will shift from one of predominantly subclinical infections in infancy to clinical disease that occurs with infections in older children and young adults, because the average age of infection will increase due to lowered transmission. Thus, only a vaccination program will provide true control of the disease. PROSPECTS FOR VACCINE DEVELOPMENT During early research, the major stumbling block to HAV vaccine development was lack of a suitable animal model. This was overcome when Holmes et al. (1969) first unequivocally demonstrated the infection of marmosets with HAV. Subsequently, Provost et al. (1975) demonstrated that the virus derived from marmoset liver was readily inactivated by treatment with formaldehyde. This finding led to preparation of the first killed HAV vaccine. Tests of this vaccine in marmosets demonstrated that it could stimulate antibody and that the resulting antibody was protective (Provost and Hilleman, 1978). The next advance in hepatitis A vaccine research came in the late 1970s, when several laboratories reported reliable propagation of the virus in cell culture. Since then, it has become apparent that the virus grows in a variety of cells, including the WI-38 and MRC-5 human diploid strains (Provost and Hilleman, 1979; Provost et al., 1982; Purcell et al., 1984). Because until recently the yield of virus from cell cultures was relatively low and involved lengthy culture periods, most vaccine development efforts have focused on live attenuated vaccines or, more recently, on molecular cloning approaches. However, a formalin inactivated hepatitis A vaccine has been prepared by investigators at the Walter Reed Army Institute of Research. Preclinical testing in animals indicated that it was safe and immunogenic. Phase 1 clinical trials for humans are projected to begin in 1986 (National Institute of Allergy and Infectious Diseases, 1985). Sequential passage of the virus in cell culture attenuated it for chimpanzees, yet it retained the ability to elicit antibodies (Provost et al., 1983; Purcell et al., 1984). Studies are now under way to find the optimal level of attenuation for a human vaccine (Purcell et al., 1984). Recently, questions have been raised regarding whether a live attenuated vaccine will be feasible. Purcell et al. (1984) noted that some evidence exists to suggest that host cytopathic and immunologic components of HAV infection may be responsible for the observed damage to hepatocytes. If this is confirmed it may be difficult to develop a live virus sufficiently modified to avoid such reactions and provide the desired level of safety, information from a small clinical trial of attenuated live vaccine has not yet been published but is reported to suggest that the approach may be feasible (Emini, personal communication, 1985).
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries An alternative vaccine might employ one or a number of antigens of the virus prepared by recombinant DNA technology, probably in commercial yeast cells. Much progress on this approach has been made by a number of groups recently (National Institute of Allergy and Infectious Diseases, Chiron Corporation, Merck Sharp & Dohme [National Institute of Allergy and Infectious Diseases, 1985]) and has been reviewed by Purcell et al. (1984). One of these noninfective antigens might be ideal for inclusion in a complex vaccine against multiple agents. A possible combination would include an HAV subunit and agents of the herpesvirus family (e.g., herpes simplex, cytomegalovirus, and varicella-zoster). Other approaches to hepatitis A vaccines include the use of synthetic peptides mimicking portions of the viral coat proteins. These would be used with adjuvants or carriers. A single injection of live virus vaccine would be expected to induce lifetime immunity. The noninfective antigens might have to be administered intermittently. Predictions on the prospects of vaccine development are shown in Table 5.1. Clinical testing of an attenuated live virus vaccine prepared by the National Institute of Allergy and Infectious Diseases has been projected for 1986 (National Institute of Allergy and Infectious Diseases, 1985). REFERENCES Emini, E.A. 1985. Personal communication, Merck Sharp & Dohme, West Point, Penn. Hadler, S.C. 1985. Personal communication, Holmes, A.W., L.Wolfe, H.Rosenblate, and F.Deinhardt. 1969. Hepatitis in marmosets: Induction of disease with coded specimens from a human volunteer study. Science 165:816–817. Institute of Medicine. 1985. Establishing Priorities for New Vaccine Development: Establishing Priorities, Volume I. Diseases of Importance in the United States. Washington, D-C.: National Academy Press. McCollum, R.W. 1982. Viral hepatitis. Pp. 327–350 in Viral Infections of Humans, 2nd edition, A.S.Evans, ed. New York: Plenum. Mosley, J.W. 1975. The epidemiology of viral hepatitis: An overview. Am. J. Med. Sci. 270(2):253–270. National Institute of Allergy and Infectious Diseases. 1985. Program of Accelerated Development of New Vaccines. Progress Report. Bethesda, Md.: National Institutes of Health. Provost, P.J., and M.R.Hilleman. 1978. An inactivated hepatitis A virus vaccine prepared from infected marmoset liver. Proc. Soc. Exp. Biol. Med. 159(2):201–203. Provost, P.J., and M.R.Hilleman. 1979. Propagation of human hepatitis A virus in cell culture in vitro. Proc. Soc. Exp. Biol. Med. 160:213–221.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Provost, P.J., B.S.Wolanski, W.J.Miller, O.L.Ittensohn, W.J. McAleer, and M.R.Hilleman. 1975. Physical, chemical and morphologic dimensions of human hepatitis A virus strain CR326. Proc. Soc. Exp. Biol. Med. 148(2):532–539. Provost, P.J., F.S.Banker, P.A.Giesa, W.J.McAleer, E.B.Buynak, and M.R.Hilleman. 1982. Progress toward a live, attenuated human hepatitis A vaccine. Proc. Soc. Exp. Biol. Med. 170(1):8–14. Provost, P.J., P.A.Conti, P.A.Giesa, F.S.Banker, E.B.Buynak, W.J. McAleer, and M.R.Hilleman. 1983. Studies in chimpanzees of live, attenuated hepatitis A vaccine candidates. Proc. Soc. Exp. Biol. Med. 172(3):357–363. Purcell, R.H., S.M.Feinstone, J.R.Ticehurst, R.M.Daemer, and B.M. Baroudy. 1984. Hepatitis A virus. Pp. 9–22 in Viral Hepatitis and Liver Disease, G.N.Vyas, J.L.Dienstag, and J.H.Hoofnagle, eds. Orlando, Fla.: Grune and Stratton. World Health Organization. 1981. World Health Organization Annual Statistical Reports, Vol. 1 and 2. Geneva: World Health Organization.
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