Human T-cell lymphotropic virus type III infection in a cohort of homosexual men in New York City.

Using blood samples collected since 1978, we investigated the epidemiology of human T-cell lymphotropic virus type III (HTLV-III), the etiologic agent of the acquired immunodeficiency syndrome, in a group of 378 homosexually active men who have resided in New York City since the acquired immunodeficiency syndrome epidemic began. The anti-HTLV-III prevalence was 6.6% in sera from 1978 or 1979, and the subsequent annual incidence of seroconversion among susceptible men ranged between 5.5% and 10.6%. The highest incidences were in recent years, even though these men reported a decrease in their sexual activity during this time. These data demonstrate the continuing risk of HTLV-III infections in the homosexual population studied and emphasize the need for more effective prevention of transmission. The year during which antibody was first present was the only factor identified that was associated with altered cell-mediated immunity in antibody-positive men. Men who became antibody positive in 1981 or earlier currently had significantly lower OKT4/OKT8 ratios than did those who seroconverted more recently. Further follow-up will be necessary to establish the reasons for this association.

Hepatitis B vaccine in patients receiving hemodialysis. Immunogenicity and efficacy.

We evaluated the immunogenicity and efficacy of hepatitis B vaccine (Heptavax-B) in a randomized, double-blind, placebo-controlled trial involving 1311 patients receiving hemodialysis in the United States. After three doses of vaccine (40 micrograms each) had been administered, 63 per cent of the patients were antibody-positive. After correction for possible passive transfer of antibodies by blood transfusion, only 50 per cent of vaccine recipients were considered vaccine responders. The incidence of hepatitis B viral infection during the 25 months of the trial was much lower than had been anticipated and was virtually the same in the vaccine and placebo recipients (6.4 and 5.4 per cent, respectively). Four cases of hepatitis B occurred in patients who had an apparent antibody response to the vaccine, but in each case either antibody had reached low or undetectable levels before hepatitis B surface antigen was detected or the patient had been receiving immunosuppressive therapy. This study did not demonstrate the efficacy of the vaccine in a population of patients receiving dialysis in whom both the rate of antibody response to hepatitis B vaccine and the viral attack rate were low. Other measures to control transmission of hepatitis B virus in dialysis units, including surveillance for hepatitis B surface antigen and isolation of patients who are positive for the antigen, must be continued.

Baseline epidemiological studies for a hepatitis B vaccine trial in Kangwane.

Hepatitis B markers were determined by radioimmunoassay of serum samples from 1 495 Black subjects representative of the resident population of Kangwane, a rural area with a high incidence of chronic liver disease and hepatocellular carcinoma. Pregnant women formed an important part of the study group, since it was intended to assess the frequency of perinatal transmission and the passive immunity of their infants, two factors which would markedly influence an infant immunization programme. A high overall marker positivity rate was found, indicating that hepatitis B is endemic. The hepatitis B surface antigen (HBsAg) carrier rate was 14,6% in adult males and 4,6% in adult females, while 82.6% of adult males and 69,4% of adult females were positive for at least one marker, indicating that infection had been present at some stage. Of infants under 1 year of age 34,5% were positive for antibodies to HBsAg (anti-HBs), compared with 9,3% at 13-24 months, which indicates that transplacental transfer of anti-HBs is frequent. Other markers were acquired even in the 1st year of life, with the sharpest increase at 3-11 years. Perinatal transmission was not common, however, and horizontal transmission during early childhood seemed to play an important role. It was concluded that the risk and frequency of infection justified a vaccine trial in this population and that the target group for vaccination should be infants under 1 year of age.

Immune response to hepatitis B vaccine in newborns.

Three injections of 10 microgram/ml hepatitis B vaccine (Merck) given in the first week after birth, a month later and again at the age of six months to 63 neonates in a rural African population, elicited an antibody response in 93 per cent. The initial hepatitis B marker status of the babies and mothers did not influence the results at nine months. Side-effects were minor and we conclude that the vaccine can effectively and safely be used from birth in endemic situations.

Hepatitis B vaccine in medical staff of hemodialysis units: efficacy and subtype cross-protection.

We evaluated the efficacy of hepatitis B vaccine (Heptavax-B) containing only the ad subtype in a randomized, placebo-controlled, double-blind trial among 865 staff members of 43 hemodialysis units in the United States. Surface antibody developed in 92.6 per cent of the subjects after two doses of vaccine and in 96 per cent after the six-month booster. The incidence of infections with hepatitis B virus (with or without hepatitis) was 9.9 per cent in placebo recipients and 2.2 per cent in vaccine recipients (P less than 0.01). The two cases of hepatitis B among vaccine recipients did not occur in subjects in whom antibody had developed. In 81 per cent of the hepatitis events, the virus was of the ay subtype. The indicence of ay virus was 8.2 per cent among placebo recipients and 1.2 per cent among vaccine recipients (P less than 0.005). We conclude that these data confirm the efficacy of the vaccine and demonstrate subtype cross-protection.

A controlled clinical trial of the efficacy of the hepatitis B vaccine (Heptavax B): a final report.

A controlled, randomized, double-blind trial in 1,083 homosexual men from New York confirmed that a highly purified, formalin-inactivated vaccine against hepatitis B prepared from HBsAg positive plasma, is safe immunogenic, and highly efficacious. Over 95% of vaccinated subjects developed antibody against the surface antigen. Vaccine-induced antibody persisted for the entire 24-month follow-up period. The attack rate of all hepatitis B virus infections (excluding conversions of anti-HBc alone) was 3.2% in vaccine recipients compared with 25.6% in placebo recipients (p less than 0.0001). In those who received all three doses of vaccine, of 40 micrograms each, the protective efficacy rate was close to 100%. The vaccine protects against acute hepatitis B, asymptomatic infection, and chronic antigenemia. There is reason to assume that the vaccine is also partially effective when given postexposure.

Prevalence of hepatitis B "e" antigen and its antibody in various HBsAg carrier populations.

A total of 749 persistent carriers of hepatitis B surface antigen (HBsAg) were tested for hepatitis B e antigen/antibody to e antigen (HBeAg/anti-HBe) by a radioimmunoassay method. The prevalence of HBeAg was found to be: 9.1% in carrier-blood donors, 10.3% in mentally retarded patients without Down's syndrome, 23.6% in Chinese-Americans, 35.3% in drug addicts, 39.2% in mentally retarded patients with Down's syndrome, 61.4% in homosexual men, and 71.2% in dialysis patients. The prevalence of HBeAg appears to be independent of sex, race, and HBsAg antigenic subtype. Younger carries tend to be more frequently HBeAg positive than older ones. All individuals acutely infected with hepatitis B virus become at least transiently positive for HBeAg. Appearance or clearance of HBsAg, HBeAg and their corresponding antibodies seem to be interrelated.

The immune response of healthy adults to a reduced dose of hepatitis B vaccine.

Three hundred thirty-six medical personnel from hemodialysis centers were treated with three doses, 20 microgram each, of the Merck hepatitis B vaccine (at 0, 1, and 6 months). Within 1 month after the first injection, 41% converted to anti-HBs positivity; after the second injection the conversion rate rose to 80-90%; and after the booster, to 96-98%. The later rate remained unchanged during the 18-month follow-up period. Only 2.8% of those vaccinated did not respond to the vaccine. The patterns of immune responses to 20-microgram doses were found to be exactly the same as to 40-microgram doses. It is suggested that reduced doses of vaccine should be as efficacious as the larger ones.

Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States.

We assessed the efficacy of an inactivated hepatitis B vaccine in a placebo-controlled, randomized, double-blind trial in 1083 homosexual men known to be at high risk for hepatitis B virus infection. The vaccine was found to be safe and the incidence of side effects was low. Within two months, 77% of the vaccinated persons had high levels of antibody against the hepatitis B surface antigen. This rate increased to 96% after the booster dose and remained essentially unchanged for the duration of the trial. For the first 18 months of follow-up, hepatitis B or subclinical infection developed in only 1.4 to 3.4% of the vaccine recipients as compared with 18 to 27% of placebo recipients (P < 0.0001). The reduction of incidence in the vaccinees was as high as 92.3%; none of the vaccinees with a detectable immune response to the vaccine had clinical hepatitis B or asymptomatic antigenemia. A significant reduction of incidence was already seen within 75 days after randomization; this observation suggests that the vaccine may be efficacious even when given after exposure.

An antigen detected frequently in human sera with elevated levels of alanine aminotransferase: a potential marker for non-A, non-B hepatitis.

In a search for additional antigens associated with virus-induced human liver disease a radioimmunoassay (RIA) was developed using IgG from sera of a multiply transfused person. Polystyrene beads coated with IgG F(ab)'2 fragments, dinitrophenylated F(ab)'2 fragments and 125I-labelled anti-2,4-dinitrophenyl antibodies (Neurath & Strick, 1979) were used in the RIA. An apparently new antigen or the corresponding antibodies were detected in 155 serum specimens from 35/37 (94%)individuals who developed non-A, non-B hepatitis. The antigen was also present in hepatitis B surface antigen-negative sera of blood donors with normal (13.2%) and elevated levels of alanine aminotransferase (34%). The antigen has an approximate mol. wt. of 45,000, a buoyant density of 1.23 g/ml and an isoelectric point of 7.

Radioimmunoassay of hepatitis B e-antigen (HBeAg): identification of HBeAg not associated with immunoglobulins.

A radioimmunoassay for hepatitis B e-antigen (HBeAg) is described. Polystyrene beads coated with IgG prepared from a human serum containing antibodies to HBeAg (anti-HBe) and anti-HBe IgG labelled with 125I-p-hydroxyphenylpropionic acid N-hydroxysuccinimide ester were used in the test. The radioimmunoassay was approximately 1,000-fold more sensitive than immunodiffusion. At least a transient presence of HBeAg in serum appears to be a common feature of infections by hepatitis B virus. The radioimmunoassay was instrumental in establishing conditions for identification of apparently free monomeric HBeAg. The HBeAg has an approximate mol. wt.of 35,000 and was recovered after isoelectric focusing in fractions with a pH between 4.25 and 4.8. Polyacrylamide gel electrophoresis revealed the presence in HBeAg of a polypeptide with an apparent mol. wt. of 17,000.

Radioimmunoassay and some properties of human antibodies to hepatitis B core antigen.

A solid-phase radioimmunoassay for antibodies to hepatitis B core antigen (anti-HBc) is described. Polystyrene beads coated with anti-HBc, hepatitis B core antigen prepared from pooled sera of humans infected with hepatitis B virus (HBV) and 125I-labelled anti-HBc were used for the test. Distinct patterns of development and changes of anti-HBc and their immunologic properties are all related to variations of other markers specific for HBV infections. Knowledge concerning the detailed features of the immune response to hepatitis B core antigen may provide deeper insight into the pathogenesis of HBV infections.

Distribution of antibody to hepatitis a antigen in urban adult populations.

To investigate the prevalence and distribution of antibody to hepatitis A antigen we tested 947 randomly selected people in the Greater New York City area; 45 per cent were antigen positive, as determined by the immune adherence method. Antibody was detected two to three times more frequently in lower social classes (72 to 80 per cent) than in middle and upper-middle classes (18 to 30 per cent). The rate of antibody detection was strongly correlated with age; the prevalence gradually increased throughout adulthood and reached its peak level in people 50 years of age and older. Those with serologic evidence of past exposure to hepatitis B virus were significantly more often antibody positive than those without such evidence (61 vs. 40 per cent; P less than 0.001). Very few of the positive subjects had had hepatitis. The prevalence of this antibody varies among different population groups, increases with age, decreases with rise in socioeconomic status, is independent on sex and race, and correlates with serologic evidence of hepatitis B virus infections.

On the role of sexual behavior in the spread of hepatitis B infection.

There is a significant excess of serologic evidence of hepatitis type B infection in two high-promiscuity populations: patients with venereal diseases and their unrelated sexual contacts (15% to 18%) and male, but not female, homosexuals (37% to 51%). Spouses of asymptomatic chronic carriers of antigen had a higher prevalence (26% to 28%) than spouses of noncarriers (10% to 11%); however, the prevalence in the former is relatively low when compared with rates seen in other relatives of carriers. Persons who had a higher-than-average probability of exposure to potentially infective partners or whose patterns of sexual behavior made such exposure more likely (large numbers of sexual partners, long duration of homosexuality, involvement in predominantly anal intercourse) were found to have serologic evidence of hepatitis B more frequently than those with other patterns of sexual behavior. This study showed a strong association between serologic evidence of type B hepatitis and patterns of sexual behavior. However, whether or not transmission of hepatitis type B virus occurs through vaginal intercourse could not be ascertained.

Intrafamilial spread of asymptomatic hepatitis B.

A survey of 751 families with a total number of more than 3,200 individuals was carried out. The sex-age standardized prevalence of serologic evidence of hepatitis B (HB) was, in familes with an index-donor antigen positive, ten times as high, and in those with an index-donor antibody positive, two of three times as high as in control families of the same ethnic background. The frequency of familial aggregation (two or more cases) was also unusually high (39-48 per cent). Familial prevalence and aggregation were found to be associated with family size. The highest prevalence of antigenemia was observed among sibs and patients (11 to 34 per cent) and the lowest among spouses (0 to 5 per cent). Sibs matched to the index-carriers by age showed a four to sixfold higher antigen prevalence than unmatched sibs. An excellent fit with the recessive inheritance hypothesis was obtained in genetic segregation analyses. In two of three matings with both members antigen positive, all progeny were found to be antigen positive. This study provided evidence indicating that familial aggregation and segregation of HB are influenced by both environmental and genetic factors.

Hepatitis B surface antigen in blood donors: further observations.

A survey of 128,000 volunteer blood donors from the Greater New York metropolitan area revealed that first-time male donors were positive for hepatitis B surface antigen (HBsAg) 2.5 times more frequently than were first-time female donors; Negroes and Mongols were positive four to 20 times more frequently than Caucasians. The ratio of ad to ay seemed to be higher in non-Caucasian antigen carriers than in Caucasian carriers. Among both Caucasians and non-Caucasians the rate of positivity declined after the age of 50. An excess prevalence of HBsAg was observed in donors with the lowest level of education and in those with the highest level. HBsAg was detectable nine times less frequently among repeat donors than among first-time donors (0.2 vs.1.90 per 1,000). Detection of HBsAg was unrelated to ABO-Rh blood groups. Several mechanisms for these wide variations of antigen detection are possible.