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Elimination of New Chronic Hepatitis B Virus Infections: Results of the Alaska Immunization Program

  1. Rafael Harpaz1,
  2. Brian J. McMahon3,
  3. Harold S. Margolis2,
  4. Craig N. Shapiro2,
  5. Dean Havron4,a,
  6. Gina Carpenter4,
  7. Lisa R. Bulkow2 and
  8. Robert B. Wainwright2
  1. 1National Immunization Program, Centers for Disease Control and Prevention, Atlanta, Georgia
  2. 2National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
  3. 3Hepatitis Control Program, Alaska Area Native Health Service, Indian Health Service, Anchorage
  4. 4Bristol Bay Area Health Corporation, Alaska Area Native Health Service, Dillingham
  1. Reprints: Dr. Harold Margolis, Hepatitis Branch, Centers for Disease Control and Prevention, Mailstop G37, 1600 Clifton Rd., Atlanta, GA 30333. Correspondence: Dr. Rafael Harpaz, National Immunization Program, Centers for Disease Control and Prevention, Mailstop E61, 1600 Clifton Rd., Atlanta, GA 30333 (rzh6{at}cdc.gov).
 
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Abstract

An immunization assessment and a serologic survey were conducted to evaluate the effectiveness of a hepatitis B immunization program in eliminating hepatitis B virus (HBV) transmission among Alaska Natives in a region in which HBV infection is endemic. Hepatitis B vaccine coverage was 93% among 567 children ⩽10 years old residing in the study villages, and catch-up vaccine coverage among 582 susceptible persons 11–30 years old was 62%. None of 271 tested children ⩽10 years old were chronically infected with HBV, and just 4 (1.5%) had evidence of resolved infection. In contrast, 16% of 332 persons 11–30 years old (those born before implementation of routine infant hepatitis B vaccination) were chronically infected. A hepatitis B immunization program that includes prevention of perinatal HBV infection, routine infant vaccination, and catch-up vaccination of older children and adults can eliminate new chronic HBV infections in a population with a high rate of chronic infection.

Chronic infection with hepatitis B virus (HBV) is estimated to affect >350 million persons worldwide and to result in 1 million deaths annually from chronic liver disease and hepatocellular carcinoma (HCC) [1, 2]. Because pre- and postexposure hepatitis B immunization provide long-term protection against HBV infection [3–5], routine immunization of infants and prevention of perinatal HBV infection are recommended, to eliminate transmission of new HBV infection and to prevent HCC [6]. In populations with a high rate of HBV infection, vaccination of infants has significantly decreased both chronic infection [7–9] and early onset HCC [10, 11]. However, the effect of adding a new vaccine to the childhood immunization schedule is not known, nor is it known whether the transmission of new HBV infections can be eliminated through integration of hepatitis B immunization into routine immunization programs. We report the effects of hepatitis B immunization on HBV infection and childhood immunization rates when conducted as part of routine public health services.

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Background

Alaska Natives have very high rates of chronic HBV infection and HBV-related HCC [12–15]. In April 1983, a program to eliminate HBV transmission was initiated under cooperative agreements between the Alaska Area Native Health Service (AANHS), the Alaska Department of Health and Social Services, and regional Alaska Native health corporations [16]. The program included routine screening of pregnant women to identify and immunize infants born to mothers infected with HBV; routine vaccination of infants as part of the childhood immunization schedule, with the first dose administered soon after birth; and catch-up vaccination of persons susceptible to HBV infection [16, 17]. Plasma-derived hepatitis B vaccine was initially used for all 3 components of the program, with recombinant hepatitis B vaccine introduced beginning in 1989.

Pregnant women are tested for hepatitis B surface antigen (HBsAg) during a prenatal visit, and infants of HBsAg-positive women receive postexposure immunization with hepatitis B immune globulin and hepatitis B vaccine within 12 h of birth. The second vaccine dose is given at age 1–2 months and the third dose at age 6 months; postvaccination serologic testing is done at age 12–15 months [6]. Term infants born to HBsAg-negative women are routinely given 3 doses of hepatitis B vaccine before hospital discharge, at age 6–8 weeks along with diphtheria-tetanus toxoids-pertussis (DTP) vaccine and oral polio vaccine (OPV), and at age 6 months along with DTP vaccine and OPV. In 1991, Haemophilus influenzae type B (Hib) conjugate vaccine (PRP-OMP [polyribosylribitol phosphate outer membrane protein]) was added to the routine childhood immunization schedule: It is administered at ages 2, 4, and 15 months.

Beginning in 1983, testing for susceptibility to HBV infection was offered to Alaska Natives, and susceptible persons were given hepatitis B vaccine as part of an ongoing catch-up vaccination program. By 1987, ∼53,000 Alaska Natives were tested: Statewide prevalence of HBsAg was 3.1%, with the highest prevalence (8.2%) in the Bristol Bay region of southwestern Alaska and the lowest (0.5%) in the North Slope and southeastern regions [18].

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Methods

Study population

In 1993, the Alaska Native population was ∼94,200, of which 4900 (5%) resided in the Bristol Bay region [19]. A seroprevalence study was done from December 1993 to January 1994 among Alaska Natives 2–30 years old, who lived in 7 villages in the Bristol Bay region, including Iliamna, Kokhanok, Newhalen, Koliganek, New Stuyahok, Goodnews Bay, and Togiak. These villages had a combined population of 1847, representing ∼38% of the Alaska Native population in the region [19]. Villages were selected because of accessibility, a predominately (∼90%) Yupik population, population stability, and a wide range in prevalence of chronic HBV infection as determined in the 1983–1987 statewide susceptibility testing program. From AANHS records and census projections, it was estimated that 500 Alaska Native children were born in the study villages after initiation of the hepatitis B immunization program. Results of this serosurvey were compared with those of a prior serosurvey conducted from 1983 to 1987, the methods of which have been described elsewhere [16, 18, 20].

Specimen and data collection

In each village the community health aide publicized the study, and an updated village census was used to identify and contact eligible study participants. Phlebotomy was conducted in the village by a study team that also obtained the informed consent. Whole blood was separated in the field, and serum was stored frozen at −20°C until tested for markers of HBV infection. Vaccination records and the AANHS computerized Record Patient Management system were audited for all villagers 2–30 years old, to determine the number and timing of doses of hepatitis B and other childhood vaccines administered since 1980.

Serologic testing

RIAs and EIAs for hepatitis B serologic markers were obtained from Abbott Laboratories (Abbott Park, IL). Each serum specimen was tested by RIA for antibody to hepatitis B core antigen (anti-HBc). Antibody to HBsAg (anti-HBs) was measured qualitatively and quantitatively by RIA and EIA, respectively. Specimens positive for anti-HBc and negative for anti-HBs were tested by RIA for HBsAg. Specimens positive for HBsAg were tested by EIA for hepatitis B e antigen (HBeAg), antibody to HBeAg (anti-HBe), and antibody to hepatitis D virus (HDV). Anti-HBs was quantified in milli-international units (mIUs) per milliliter, with reference to the World Health Organization standard preparation obtained from the Netherlands Red Cross, Amsteam; for analytic purposes, specimens with undetectable anti-HBs were assigned a value of 0.5 mIU/mL.

Definitions

Persons born before 1983 (i.e., ⩾11 years old) who received any doses of hepatitis B vaccine were defined as receiving catch-up vaccination, and those born in 1983 or later were defined as receiving hepatitis B vaccine through routine childhood vaccination. Persons were considered fully vaccinated at the time of the study if they had received (1) ⩾3 doses of hepatitis B vaccine, (2) ⩾3 doses of OPV, (3) ⩾4 doses of DTP vaccine, and (4) ⩾3 doses of Hib conjugate vaccine.

The presence of anti-HBc plus detectable anti-HBs was considered to be evidence of resolved HBV infection. Anti-HBs was considered to be protective if the concentration was ⩾10 mIU/mL, and the presence of anti-HBs alone in a vaccinated person was considered to be vaccine induced. Only 8 persons had anti-HBc alone. This serologic pattern was not considered indicative of current or past infection [21–23]. Chronic HBV infection was defined as the presence of HBsAg and anti-HBc.

Data analysis

All statistical calculations were done with EPI INFO version 6.0 software [24]. Proportions were compared by the Mantel-Haenszel χ2 or Fisher's exact test. A lower 95% confidence interval was considered significant if the value was >1. All P values were 2-tailed; P < .05 was judged significant. Statistical analysis was not conducted for geometric mean concentrations, and comparisons are descriptive.

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Results

Hepatitis B vaccine coverage

Of the 567 children ⩽10 years of age residing in the study villages, 93% had received ⩾3 doses of hepatitis B vaccine through routine childhood vaccination programs. Rates of complete hepatitis B vaccination did not differ from those for OPV or DTP vaccine but were higher than those for Hib conjugate vaccine after its introduction (P < .001) (table 1).

Table 1
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Table 1

Coverage rates for routine childhood vaccines in study villages, Bristol Bay, Alaska, 1993.

Susceptible Alaska Natives identified through testing in 1983–1987 were offered the 3-dose series of plasma-derived hepatitis B vaccine through catch-up vaccination. On the basis of data collected from this program, among the 686 persons in the study villages 10–30 years of age, 104 were immune, 122 were susceptible, and 460 were not tested; of 582 susceptible or untested persons, 362 (62%) received catch-up vaccination with ⩾3 doses of hepatitis B vaccine. This compares with 41% of susceptible or untested persons 10–30 years of age who were vaccinated with ⩾2 doses of vaccine statewide [20]. In all, 466 (68%) of the 686 villagers were covered by the hepatitis program by being identified as immune to HBV or by receiving catchup hepatitis B vaccine.

Prevalence of HBV infection

Between 1983 and 1987, Alaska Natives in all 32 villages of the Bristol Bay region were tested for markers of HBV infection. In the 7 villages included in the present study, 668 (45%) of 1479 Alaska Natives of all ages were anti-HBc positive, and 189 (13%) were HBsAg positive. The rates of chronic infection in the villages were l%–35%.

Of the ∼1847 Alaska Natives residing in the 7 villages at the time of the present study [19], ∼1238 were in the target age group (2–30 years), and 603 (49%) consented to study participation or participation by their children. No children ⩾10 years of age (n = 271) were HBsAg positive, and only 4 children (1%) had serologic evidence of resolved HBV infection (table 2). Of the 603 participants of all ages, 53 (9%) tested HBsAg positive, including 44 (21%) of 214 persons 16–30 years of age (table 2). None of these persons had evidence of HDV infection. Of the 53 HBsAg-positive participants, 45 were first identified during testing in 1983–1986; an additional 8 persons had never undergone screening or hepatitis B vaccination and could have been infected at any time in the past. An additional 95 participants (16%) had serologic evidence of resolved HBV infection. Therefore, evidence of chronic or resolved infections was present in 148 persons (25%; range, 2%–56% among the villages). Similar variations in infection rates among the villages were found in 1983–1986 (data not shown).

Table 2
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Table 2

Prevalence of hepatitis B virus infection and immunity among Alaska Natives in study villages, Bristol Bay, Alaska, 1993.

Among the 603 participants, 425 had documentation of ⩾3 doses of hepatitis B vaccine. Serologie evidence of HBV infection was detected in 10 (2%) of the 425 vaccinated persons, only 2 (0.8%) of whom were ⩾10 years old. No vaccinated person was HBsAg positive. In addition, of the 8 people with anti-HBc alone and the 10 people with anti-HBc plus anti-HBs of <10 mIU/mL, none had been vaccinated, and none were ⩽10 years of age.

Of the 51 study participants who had been tested in 1983–1987 and found to be HBsAg positive, 45 (88%) were HBsAg positive in 1993. In contrast, of 22 study participants who were also HBeAg positive in 1983–1987, only 8 (36%) were positive in 1993. Among HBsAg-positive persons in this study, the proportion who were HBeAg positive tended to be inversely related to age (P = .11; table 2). The prevalence of HBeAg positivity among all tested persons 2–30 years of age in the 7 villages declined by 77% during the 10-year period, from 54 (7.2%) of 751 persons in 1983–1987 to only 10 (1.7%) of 603 persons by 1993.

Vaccine-induced antibody

Among vaccinated persons with no serologic evidence of HBV infection, the proportion of persons with anti-HBs concentrations ⩾10 mIU/mL was highest among older age groups (table 3). Among children 2–10 years of age (n = 271), 266 had received ⩾3 doses of vaccine as part of the routine childhood vaccination or the perinatal HBV prevention programs. The geometric mean concentration of anti-HBs for this group was <4 mIU/mL, and 86 (32%) had levels ⩾10 mIU/mL (table 3). Geometric mean anti-HBs concentrations varied directly by age at the time of the study and by age at receipt of the vaccine; children vaccinated beginning at birth had lower antibody levels at the time of the study than did children vaccinated at older ages. Antibody concentrations did not vary by gender or village; they also did not vary by receipt of vaccine before or after 1989, when the villages changed from plasma-derived to recombinant vaccine (data not shown).

Table 3
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Table 3

Antibody to hepatitis B surface antigen (anti-HBs) among vaccinated persons in study villages, Bristol Bay, Alaska, 1993.

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Discussion

This study found that transmission of chronic HBV infection was eliminated among children born since the introduction of a comprehensive hepatitis B immunization program in a population with a very high prevalence of infection. Among children born after the introduction of the vaccination program, we found only 2 infections, both of which resolved. In 1983–1987, the statewide prevalence of HBsAg among Alaska Natives was 3.1% [18]. On the basis of the demonstrated effectiveness of the hepatitis program in eliminating new chronic infections, one can estimate that ∼756 (i.e., 3.1%) chronic infections were averted among the 24,391 Alaska Native children <10 years old throughout Alaska who were born after the program was implemented [19].

This study also demonstrates that a comprehensive hepatitis B vaccination strategy can be effectively integrated into established health care and vaccine delivery programs, even in remote rural areas. Components of the Alaska hepatitis B control program include perinatal maternal HBsAg screening with postexposure prophylaxis of at-risk infants, routine infant vaccination, and catch-up vaccination for older children and adults; these have since been adopted throughout the United States [6], and each is cost-effective in a variety of settings [25, 26]. Although data were not collected for the program to prevent perinatal HBV infection, we determined that only the 2 children <10 years of age with resolved infection could have acquired their infection by perinatal transmission. It therefore appears that, in the face of continued risk of HBV infection from the large proportion of the population with existing chronic infection, a comprehensive program to eliminate HBV transmission among vaccinated persons [6] is very effective.

The primary objective of hepatitis B immunization is to prevent chronic infection in young children that can result in sequelae such as HCC [27, 28]. Although the incidence of HCC is high among Alaska Natives, the long latency period and small population do not yet allow demonstration of a reduction in HCC rates. However, such beneficial outcomes have been demonstrated in Taiwan after introduction of a hepatitis B vaccination program that achieved an even lesser reduction of HBV transmission than was observed in this study [10, 11].

A secondary objective of hepatitis B immunization is to reduce the pool of persons with chronic HBV infection that is highly infectious to others and, ultimately, to eliminate this source of HBV transmission to others. Children <5 years old have played a key role in keeping levels of HBV infection high among Alaska Natives and other populations [27, 29, 30]. Not only are new HBV infections among young children likely to become chronic [27], but chronically infected children are likely to be HBeAg positive and highly infectious to others, resulting in person-to-person (horizontal) transmission [13, 29]. Our study demonstrated that catch-up vaccination of children and adults born before introduction of routine infant vaccination rapidly eliminated horizontal HBV transmission and allowed the number of HBeAg-positive persons to decline rapidly owing to the inherent clearance of HBeAg over time [13]. Elimination of HBV transmission over a wide range of age groups appears to have been ensured by the expanding cohort of children immunized as infants and the declining population of HBeAg-positive persons. Together, these factors have greatly decreased the likelihood that an infectious person would come in contact with a susceptible individual.

This study also demonstrated the durability of protection provided by 3 doses of hepatitis B vaccine. Previous studies in a cohort of Alaska Natives showed that >95% of children and young adults responded to the 3-dose vaccine series and retained long-term protection from infection [3, 13]. Our study found that, although most vaccinated children had low or undetectable levels of anti-HBs, there was almost no HBV transmission for a full decade after vaccination. However, the marked differences between anti-HBs concentrations in persons ⩾10 years old and in those <10 years old cannot be readily explained. Although the former group received plasma-derived vaccine, this vaccine was also received by children who were 6–10 years old at the time of the study. The only differences between the 2 age groups was that the first dose was given to the younger age group at birth or soon after. In addition, there was no evidence of natural boosting of anti-HBs levels among study participants: Persons in villages with higher rates of HBsAg positivity did not have higher anti-HBs levels.

Elimination of chronic HBV infection worldwide has been proposed as an achievable public health strategy [31]. The epidemiology of HBV transmission in Alaska is similar to that in many developing countries with high endemicity of HBV infection. The results of the Alaska immunization program indicate that elimination of new chronic HBV infections can be achieved with a comprehensive immunization strategy in all settings, including challenging rural and underserved areas. In areas of high endemicity of infection, such programs must provide, at a minimum, routine vaccination for all infants, preferably at birth, in order to prevent perinatal infection. The addition of catch-up vaccination for those not vaccinated as infants may not be affordable in all settings but would more rapidly eliminate this vaccine-preventable cause of chronic liver disease and cancer.

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Acknowledgments

We thank Alan J. Parkinson, Annette Harpster, Carolyn Zanis, Helen V Peters, Fran Arseneau, Marilyn Getty, Ana K. Douglas, Debra J. Parks, David Goldstein, Stephen Lambert, William Brisbay, Donna J. Ing, and the respective village health aides and public health nurses from the Alaska Department of Health for contributions to the implementation of the study, data management, and laboratory testing of specimens.

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Footnotes

  • ↵a D.H. is in private practice in Winchester, VA.

  • Written informed consent was obtained from adults for themselves and/or their children; in addition, children >7 years old were included only if they verbally agreed to participate. This study was conducted in accordance with guidelines of the US Department of Health and Human Services, the Alaska Area Native Health Service (AANHS), and the Bristol Bay Area Health Corporation (BBAHC).

  • The study was approved by institutional review boards of the Centers for Disease Control and Prevention, AANHS, and BBAHC.

  • Financial support: Centers for Disease Control and Prevention.

  • Received July 6, 1999.
  • Revision received September 30, 1999.
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  1. J Infect Dis. (2000) 181 (2): 413-418. doi: 10.1086/315259
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