Gamma Globulin (Passive Immunoprophylaxis)
Almost 25 years before the successful transmission of hepatitis A to animals and nearly 30 years before visualization of the virus and development of assays for detection, prevention of clinical hepatitis A was achieved 233 as the result of a series of events. First, the recognition that human serum could attenuate or prevent clinical measles in susceptible individuals was reported in 1937 167. Convalescent-phase serum (enriched in specific antibody) was superior to pooled adult serum, and placental extract (containing passively transferred maternal antibody only) was ineffective. Second, methods were developed in the early 1940s to separate serum into component fractions 48. An average 25-fold concentration in antibody was achieved in fraction III, containing the immune globulins. Large-scale plasma fractionation programs were then undertaken by the Red Cross during World War II to provide plasma expanders. Gamma globulin was another product of the separation procedure. Finally, the demonstration of the effectiveness of the gamma globulin fraction in attenuation and prevention of measles in susceptible individuals exposed by household contact was made in 1944 187, 232.
During the summer of 1944, an outbreak of hepatitis occurred at a children's camp near Philadelphia 177. Joseph Stokes, Jr., a pediatrician on the faculty of the University of Pennsylvania School of Medicine, who knew that gamma globulin prevented or attenuated measles in susceptible, exposed individuals 232, was consulted regarding the epidemic. With knowledge of the effectiveness of gamma globulin in measles epidemics, Stokes took the next step, using gamma globulin to prevent the further transmission of epidemic hepatitis (hepatitis A) 233.
In the children's camp, icteric hepatitis developed in 125 of 278 (45%) putatively exposed individuals who did not receive gamma globulin and in 3 of 53 (6%) randomly selected individuals who were given gamma globulin (0.15 ml/lb of body weight). At this dose, they used all the available gamma globulin, hence the difference in numbers in the two groups 233. Confirmation of similar efficacy quickly followed in both military 89 and civilian 103 populations. Immune serum (gamma) globulin (ISG) was protective for up to 9 months, and doses as small as 0.01 ml/lb were effective 231, 257.
More recently, immune globulin was used to arrest an ongoing outbreak of hepatitis A in a religious community in 1989 191. Preliminary data indicated that persons under age 20 were uniformly susceptible, whereas the majority of older individuals were predicted to be immune (16 of 18 [89%] tested were anti-HAV positive and IgM anti-HAV negative). After administration of gamma globulin (0.02 ml/kg) to 2,287 individuals (total cost for vaccine and syringes, $3,620), there were only seven further cases of hepatitis A diagnosed between 2 weeks and 7 months after injection. The effectiveness of gamma globulin was calculated at 89% 191. Low levels of neutralizing antibody can be detected in recipients after ISG administration, although commercial tests for antibody are negative 265.
The current question is whether ISG preparations will continue to provide protection. The decrease in anti-HAV seropositivity in the general population may result in failure of protection from standard doses. The report of clinical hepatitis A in two recipients of standard doses of ISG in the United Kingdom is of great concern 26. In one individual who developed acute hepatitis A, transmission of infection was calculated to have occurred 2 months after the individual received 2.5 ml of ISG. In a second individual in whom fatal hepatitis A developed, symptoms commenced 10.5 weeks after inoculation. The titers of anti-HAV in the immune globulin preparations were 103 and 120 IU/ml 26, lower than those previously reported for similar preparations. The minimum protective level in recipients of ISG is unknown 265, but estimates of 10 mIU/ml are used. Simple mathematics indicate that 2.5 ml would administer 300 IU (120 IU/ml) initially. If the volume of distribution was 3 liters, then the level immediately after injection would be 100 mIU/ml. In one study, anti-HAV titers were measured 5 days after injection of ISG and again at 1, 2, 5, and 6 months 270. The half-life for the first interval (day 5 to 1 month) was 35 days, and for the remaining two intervals it was 21 days. Using these half-lives, an initial level of 100 mIU/ml would reach 6.25 mIU/ml in 98 days (14 weeks). With a larger volume of distribution, such as 4 liters, then the level falls below 10 mIU/ml before 11 weeks. These calculations are consistent with failure of protection for more than 2 to 2.5 months, as observed 26.
Since there may be a continued need for ISG unless universal vaccination is carried out, one solution may be to prepare ISG from donors with a history of jaundice, as suggested by Hopkins (118). He demonstrated a 10-fold-higher titer of anti-HAV activity in immunoglobulin preparations from HBV surface antigen-negative donors with a history of jaundice 118. Persons with a history of jaundice are usually dissuaded from donating blood because of the risk of transmitting disease. Despite sensitive assays for antigens and antibodies to detect evidence of various hepatitis viruses, there will be a small risk of transmission unless an assay for viral nucleic acids is introduced. Inevitably, some donated blood will be obtained during the "window" period, when the blood may be negative for antigen and antibody and yet contain virus.
Vaccination (Active Immunoprophylaxis)
The advent of an efficacious vaccine to prevent hepatitis A solves some (but not all) of the problems, from waning titers of anti-HAV antibody to increasing numbers of susceptible persons in the population. In 1991, a preliminary study of a vaccine manufactured at the Biologics Research Department, Walter Reed Army Institute of Research (appropriate, since Reed was the first person to transmit a viral disease, yellow fever, in human experiments), was published 222. The authors demonstrated acquisition of neutralizing anti-HAV antibody in recipients of a formalin-inactivated viral vaccine preparation. A live attenuated HAV vaccine was also capable of eliciting neutralizing antibody 171. Unlike those administered the inactivated vaccine, recipients developed IgM anti-HAV positivity without clinical hepatitis or evidence of significant liver dysfunction, although 40% reported gastrointestinal side effects.
By 1992, the clinical efficacy of the formalin-inactivated hepatitis A vaccines HAVRIX (Smith-Kline Beecham) 3 and VAQTA (Merck, Sharpe and Dohme) was apparent 260. Both use laboratory-attenuated strains of hepatitis A (HM175 for HAVRIX and CR326F for VAQTA) for production of a formalin-inactivated vaccine. A large-scale, double-blind, randomized, controlled field trial in elementary school children in Thailand demonstrated the efficacy of HAVRIX 124, 125. Of 40 cases of clinical hepatitis A that occurred among 40,119 children in the year following a single dose of vaccine, only 2 occurred in vaccinated individuals 125. The adverse reactions reported for the vaccine were minimal, and seroconversion after two doses was 99.8% in healthy individuals 3.
In a double-blind, placebo-controlled trial, the VAQTA vaccine was administered to 519 seronegative children aged 2 to 16 years living in a religious community in New York State, where hepatitis A was highly endemic. From day 21 after a single-dose injection, there were no cases of hepatitis A in the vaccine group, whereas 34 cases occurred in the placebo group. The seven cases in the vaccine group that occurred before day 21 were almost certainly due to transmission before vaccination. Similarly, hepatitis A outbreaks in two villages in Slovakia 198 and in rural communities in Alaska 168 were controlled with vaccination programs. Combined passive-active immunoprophylaxis is also effective 3, 96, 270, although the titers achieved are generally lower than with vaccine only 96, 270.
The Food and Drug Administration (FDA) licensed HAVRIX in February 1995 for administration to children who were 
2 years old and adults. The CDC recommendations included use for travelers to areas other than western Europe, Scandinavia, Canada, Japan, Australia, and New Zealand 6. They indicated that screening for existing antibody should be considered for potential recipients aged >40 years and those who had resided in areas of high endemicity (see below). VAQTA has also been licensed in the United States by the FDA. In addition to travelers, the American College of Physicians recommends that other high-risk groups be vaccinated 87. These include homosexual men, injection drug users, persons with chronic liver disease, and workers with an occupational risk of infection. When HBV vaccination is also recommended, combined HAV and HBV vaccination can be undertaken 1, 3. The Advisory Committee on Immunization Practices issued guidelines for hepatitis A prevention in late 1996 9. They recommended routine vaccination of travelers to countries with high or intermediate endemicity of infection and of children who were >2 years of age and living in U.S. communities that have high rates of hepatitis A infection (700 to 1,000 cases per 100,000 population annually). Other populations at increased risk of HAV infection or at increased risk of adverse outcomes, i.e., the high-risk groups identified by the American College of Physicians, were also recommended for vaccination.
Trials of efficacy, safety, and reactogenicity are carried out in healthy persons. However, if those with chronic liver disease are to be vaccinated, it is important to determine the response to vaccination in this group. The anti-HAV titer achieved in those with chronic liver disease was lower in two separate studies 134, 145, although most patients (94% in reference 134) did achieve detectable antibody levels. Similarly, titers were lower in homosexual men with human immunodeficiency virus (HIV) infection than in those without HIV infection 111, 178, and overall, seroconversion rates were somewhat lower (88% in reference 178) compared with 100% in non-HIV-infected individuals. The vaccines were well tolerated in all studies. Vaccine-induced antibody is predicted to be long-lived and persist for >20 years 250.
The most recent recommendations for prevention of hepatitis A from the Advisory Committee on Immunization Practice 13 broaden the target groups for vaccination. Routine vaccination is now recommended for children in states, counties, and communities with rates of hepatitis A infection that are twice the 1987 to 1997 national average of 10 cases per 100,000 population (Table 7) 13. In order of incidence, the states are Arizona (48 cases per 100,000 population), Alaska (45 cases), Oregon (40 cases), New Mexico (40 cases), Utah (33 cases), Washington (30 cases), Oklahoma (24 cases), South Dakota (24 cases), Idaho (21 cases), Nevada (21 cases), and California (20 cases). In addition, states, counties, and communities with rates exceeding the national average should consider routine childhood vaccination. These states include Missouri (19 cases per 100,000 population), Texas (16 cases), Colorado (16 cases), Arkansas (14 cases), Montana (11 cases), and Wyoming (11 cases). The recommendations for protection of travelers, men who have sex with men, users of illegal drugs, persons who are at occupational risk for infection, persons who have clotting factor disorders, and persons with chronic liver disease were unchanged.
Screening Prior to Vaccination
Considerable differences exist in recommendations for serologic screening before vaccination 40, 230, 251. The aim is to reduce the cost of vaccination by eliminating those with previous natural infection. The economics are determined by the rate of seropositivity, the cost of screening, and the cost of vaccination. If two doses of vaccine are administered, then cost neutrality occurs when the fractional rate of seropositivity is equal to the screening cost divided by the vaccination cost. For example, anti-HAV seropositivity was 33% (or 1 in 3) in the National Health and Nutrition Examination Survey III (NHANES III), and therefore, the costs of screening before vaccination and of vaccinating all persons are identical if the screening cost (total anti-HAV testing) is one third the vaccination cost, e.g., $20 for screening tests and $60 for two vaccinations. If screening is cheaper, e.g., $10, or vaccination is more expensive, e.g., $80, then screening first generates cost savings on a population basis. Similarly, if the seropositive rate is higher in a given population, screening will be cost beneficial. Alternatively, if vaccination is cheaper, e.g., $40, then it is economically better to vaccinate without screening.
There are some disadvantages to screening before vaccination of high-risk groups other than the potential cost and the need to obtain samples for testing. Because the test results are not available immediately, screened persons must return for vaccinations. Consequently, there is a possible loss of vaccinees who do not follow up after screening. Another difficulty in deciding between screening first and universal vaccination is the lack of valid seroprevalence data for many populations. We have analyzed seropositivity in the Parkland Memorial Hospital Liver Clinic population with chronic HCV infection (J. A. Cuthbert, G. Vinson, J. S. Reisch, and M. Q. Ansari, submitted for publication). There were ethnic differences in seroprevalence. In Hispanics, 42 of 47 (89%) were anti-HAV positive, whereas 51 of 74 (69%) African-Americans and 49 of 102 (48%) non-Hispanic Caucasians were anti-HAV positive. There was no difference with age of The estimated screening cost is $17.50, and the vaccine cost (without supplies or labor charges) is currently $16.17 per dose (government contract rate). For the Dallas County Hospital District, screening will be cost-beneficial in Hispanics and African-Americans, but vaccination without screening appears to be rational for non-Hispanic Caucasians. Similarly, in Ireland, universal vaccination without screening is considered the best strategy if the seroprevalence rate is 205
Why Prevent Hepatitis A?
Different populations have different goals. Governments want to save money, armies want to have healthy troops, and travelers want to enjoy their vacations. For prospective travelers, an estimate of the risk of hepatitis A infection can be obtained by examining seroprevalence data. The rates are lowest in Scandinavia. Thus, the anti-HAV positive rate was 2% in Swedes born after 1950 35. In heterogeneous populations, particularly those with immigrants, the overall prevalence of anti-HAV is predictably higher and differs with birthplace. For example, 45% of U.K.-born Londoners are anti-HAV positive but 70% of those born in a foreign country are positive 30. Intermediate rates of seropositivity are found in the Mediterranean. In Spain, the effect of socioeconomic level is shown by the 63% anti-HAV positive rate among gypsy children aged 1 to 14 years, compared with 46% for children in an orphanage and 23% for nongypsy families 174. In Italy, seropositive rates are higher in the southern part of the country, e.g., 27% anti-HAV positivity in persons aged 3 to 19 years, compared with 5% in northern Italy 235. Among U.S. military personnel, deployment in the Carribean was associated with an increased seroprevalence rate 107. Consistent with endemicity in the Carribean, 73% of children 2 to 4 years of age in Nicaragua were seropositive 194. At the far end of the spectrum, 97% of elementary school children in Sierra Leone were anti-HAV positive 114, as were 100% of Australian aboriginals 11 to 15 years of age living at the "top end" of the Northern Territory 36; 100% of Egyptian village children aged 1 to 3 years were seropositive 58; and 100% of Indian children in Pune were anti-HAV positive by late childhood 17. From these data, it is apparent that there is a considerable risk of hepatitis A infection with travel to Africa, the Indian subcontinent, and the Carribean, lower risk in the Mediterranean area, and negligible risk in Scandinavia.
From the economic perspective, hepatitis A is a costly burden to society that could be mitigated by universal childhood vaccination. The cost of HAV infection was recently calculated to be $332 million to $580 million annually in the United States 29. A food-borne outbreak of hepatitis A in Denver, for example, was calculated to cost $689,314 for disease control, including $450,397 for 16,293 ISG injections 56. The medical costs for hepatitis A cases requiring hospitalization are estimated to be $1,070 to $2,460 each 56, 149. One economic analysis indicated that either universal vaccination or screening and vaccination of 2-year-old children should be considered cost-effective in developed countries 59. In another analysis, neither universal vaccination nor screening and vaccination of adults who were >50 years old were cost-effective 183. These data support the most recent recommendation of universal vaccination of children in U.S. areas of high endemicity as a method of disease control.
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