Kenneth M. Petersen

Antibody Levels and Protection after Hepatitis B Vaccination: Results of a 15-Year Follow-up

Context Although administration of hepatitis B vaccine for infants is routine practice in many countries, we do not know whether the protection that this vaccine offers lasts beyond 10 years. Such information is essential to develop policies about booster vaccination. Contribution Of 841 Alaska Natives who received 3 doses of hepatitis B vaccination during 19811982 and were followed for 15 years, 84% had protective levels of antibody to hepatitis B surface antigen that indicated continued protection. The greatest decline in antibody levels occurred in people who received vaccine before 4 years of age. Definite asymptomatic breakthrough infections occurred in 16 participants. Cautions Only about half of the initial cohort of 1578 was available for testing at 15 years. The Editors Universal vaccination of infants with hepatitis B vaccine is included in the immunization programs of most countries and has been shown to be effective in reducing the rate of chronic hepatitis B virus (HBV) infection (1, 2). Protection has been demonstrated in persons and populations vaccinated for 5 to 10 years, and rates of asymptomatic breakthrough HBV infection have been extremely low (3-9). However, the duration of protection afforded by hepatitis B vaccination beyond 10 years and the possible need for booster doses of this vaccine are unknown. Alaska Natives have a high prevalence of chronic HBV infection, primarily acquired during early childhood (10). Between November 1981 and May 1982, Alaska Natives residing in 15 villages in southwest Alaska were enrolled in a cohort study to ascertain the immunogenicity and long-term effectiveness of hepatitis B vaccination (11-14). We report data on the persistence of antibodies to hepatitis B surface antigen (anti-HBs), incidence of HBV infection, and the genetic characteristics of the HBV isolates in persons with breakthrough infections 15 years after initial vaccination of this cohort. Methods Participants and Data Collection A total of 1578 Alaska Natives who were serologically negative for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc) were vaccinated on a 0-, 1-, and 6-month schedule with 3 doses of plasma-derived hepatitis B vaccine (Heptavax, Merck & Co., Inc., West Point, Pennsylvania) beginning in 1981 (11). Persons younger than 20 years of age received the 10-g dose, and adults received the 20-g dose. Of the 1578 persons vaccinated, 1436 (91%) were tested for an anti-HBs response 6 months after the last vaccine dose. From 1982 to 1992, serum specimens were obtained annually and once again during 1996 from as many of the 1578 consenting participants as possible. The Institutional Review Boards of the Alaska Area Native Health Service, the Indian Health Service, the Centers for Disease Control and Prevention, and the Yukon-Kuskokwim Health Corporation and the Norton Sound Regional Alaska Native health boards approved this study. All participants 18 years of age and older and parents of children younger than 18 years of age had provided signed informed consent to participate in the study; children older than 7 years of age gave verbal assent. The number of HBsAg-positive persons in each village was obtained from a registry used to follow patients with chronic HBV infection (15). Serologic Testing All serum specimens were tested for HBsAg, anti-HBs, and anti-HBc by radioimmunoassay using commercial test kits (Abbott Laboratories, Abbott Park, Illinois). At the initial testing of the cohort for anti-HBs, results were reported in sample ratio units. However, subsequent anti-HBs results were reported in milli international units (mIU) per mL using a World Health Organization reference standard (12-14). To ensure comparability of results over time, all serum specimens from each participant with sufficient volume (99.9% of all specimens collected during the study) were retested to determine anti-HBs levels in mIU/mL. Detection of HBV DNA and Nucleic Acid Sequencing Hepatitis B virus DNA was extracted from serum specimens (50 L) of participants with serologic markers of HBV infection by using commercially available reagents (MasterPure Complete DNA and RNA Purification Kit, Epicentre Technologies, Madison, Wisconsin), as described previously (16, 17). The HBsAg genomic region was then amplified by dilution cloning polymerase chain reaction by using previously described primers and methods to identify circulating variants of HBsAg (16, 17). The polymerase chain reaction products were purified and the nucleic acid sequence of the amplified region were determined by using prism dye or dRhodamine terminator cycle reactions (Applied Biosystems, Foster City, California) and automated sequencing (ABI Model 373 or 377, Applied Biosystems) (18). Sequence data were further analyzed by Sequence Navigator (ABI) and GCG software (19). Definitions The initial anti-HBs level was measured 6 months after the third dose of vaccine and 1 year after the first dose of vaccine. Participants with an initial anti-HBs level of at least 10 mIU/mL were considered vaccine responders. An anti-HBs level of 2 mIU/mL or greater was considered a positive result on subsequent specimens. A booster response was defined as a 2-fold or greater increase in anti-HBs levels between serologic test results. A definite HBV infection in a participant was defined as 1) 2 or more consecutive serum specimens positive for anti-HBc more than 1 year after the initial vaccine dose, 2) a single positive anti-HBc result with a positive HBV DNA result, or 3) any HBsAg-positive test result. A possible HBV infection was defined as a single positive or 2 nonconsecutive positive anti-HBc results. Participants who developed anti-HBc were interviewed for history of icterus or other clinical signs or symptoms compatible with acute hepatitis, and village and hospital medical records were reviewed for evidence of an illness compatible with viral hepatitis. Statistical Analysis Among persons who inadvertently received additional doses of hepatitis B vaccine during the follow-up period, anti-HBs results after the additional vaccine dose or doses were excluded from the analyses. Results for anti-HBs among persons with definite HBV infections were excluded from analyses after anti-HBc appeared. The primary outcomes in this study were the cumulative number of persons with a definite HBV infection during all follow-up years and the anti-HBs levels at the 15-year follow-up. The definitions of age classes (0 to 4 years, 5 to 19 years, 20 to 49 years, 50 years) were similar to those in a previously published analysis of this cohort (14). Although these data have been presented previously (11-14), we have provided the proportion of persons initially responding to vaccination. Quantitative anti-HBs levels are presented as geometric mean concentrations (GMCs). In bivariate analyses, analysis of variance was used to test the 15-year anti-HBs concentrations (log-transformed). Incidence rates of definite HBV infection were compared by using the Fisher exact test. We analyzed factors associated with anti-HBs levels over the 15 years after the first vaccine dose by using a linear mixed model (PROC MIXED in SAS version 9.1, SAS Institute, Inc., Cary, North Carolina) (19). We chose a longitudinal mixed linear model because it makes inferences by using information from the entire cohort collected at all follow-up time points. Levels of anti-HBs were log-transformed before analysis, and concentrations of 0 mIU/mL were assigned a value of 1.0 mIU/mL. Factors considered in the model were time (entered as a continuous covariate; linear and quadratic term were considered), age class at initial vaccination, sex, the log of the initial anti-HBs level, presence of an HBsAg-infected person in the household at the start of the study, and the proportion of village residents with chronic HBV infection at the end of follow-up, along with interaction terms involving time. Significance of 1 factor alone, such as age or sex, is called a main effect and is not of primary interest for this presentation. Of primary interest are the interaction terms between time and other factors. A significant interaction of time with another variable, such as sex, indicates that the decline in anti-HBs level differed between males and females. We obtained parameter estimates by using restricted maximum likelihood. We used an unstructured covariance matrix to account for dependence of observations across time within individuals. Backward elimination of statistically nonsignificant terms yielded a final model of main effects and time interaction terms. If the time interaction term was statistically significant, the main effect term remained in the model regardless of statistical significance. We used the Wald chi-square statistic to test covariates. Contrast tests were 2-sided, and an level of 0.05 was required. We used residual plots to evaluate model fit. A secondary outcome was a boost in anti-HBs level at the 11- or 15-year follow-up among persons without additional doses of vaccine. We used the chi-square test or the CochranMantelHaenszel test to compare age and sex of persons with a booster response to those of persons without a booster response at both follow-up years. All P values were exact where appropriate and were 2-sided; results were considered statistically significant at the 0.05 level. We conducted analyses by using StatXact4 (Cytel Software Corp., Cambridge, Massachusetts) and SAS software, version 9.1 (SAS Institute, Inc.). Missing Data Throughout the entire study, anti-HBs determinations were observed for 68% of all potential observational time points (Appendix Table 1). The 15 remote rural Alaskan study villages are accessible only by airplane. During each year, study personnel flew into each village for 1 to 2 days and attempted to recruit all available participants. Persons not available or out of the village for the day were considered miss

Bronchiectasis in Alaska Native children: Causes and clinical courses†

Although bronchiectasis has become a rare condition in U.S. children, it is still commonly diagnosed in Alaska Native children in the Yukon Kuskokwim Delta. The prevalence of bronchiectasis has not decreased in persons born during the 1980s as compared with those born in the 1940s. We reviewed case histories of 46 children with bronchiectasis.

High Prevalence of Helicobacter pylori in the Alaska Native Population and Association with Low Serum Ferritin Levels in Young Adults

ABSTRACT Iron deficiency anemia is a common public health problem in the Alaska Native population. Yet, a clear etiology has eluded researchers for decades. Previous studies suggested a link betweenHelicobacter pylori infection, gastrointestinal blood loss due to hemorrhagic gastritis, and generalized iron deficiency anemia in adult Alaska Natives. Therefore, we examined the association between the prevalence of H. pylori-specific immunoglobulin G (IgG) and serum ferritin levels, a marker of iron deficiency. A random sample of 2,080 serum samples from Alaska Native residents drawn between 1980 and 1986 from residents in 13 regions was selected, and the samples were stratified by age, sex, and region. Overall, 75% were positive for H. pylori-specific IgG. The rate of H. pylori seropositivity increased with age; by age 14 years, 78% of the residents were positive. There were no gender differences inH. pylori seropositivity. However, marked regional differences were observed. Serum ferritin levels of <12 ng/ml were found most commonly among persons <20 years of age and among women of childbearing age. A significant association between low serum ferritin levels and prevalence of H. pylori-specific IgG was found, particularly for people aged less than 20 years. H. pylorimay be a factor contributing to the iron deficiency anemia in the Alaska Native population.

Severe Respiratory Syncytial Virus Disease in Alaska Native Children

Hospitalization rates for respiratory syncytial virus (RSV) infection range from 1 to 20/1000 infants. To determine the rate and severity of RSV infections requiring hospitalization for infants in the Yukon-Kuskokwim (YK) Delta of Alaska, a 3-year prospective surveillance study was conducted. The annual rate of RSV hospitalization for YK Delta infants <1 year of age was 53-249/1000. RSV infection was the most frequent cause of infant hospitalization. RSV disease severity did not differ among non-high-risk infants in the YK Delta and at Johns Hopkins Hospital (JHH). On average, 1/125 infants born in the YK Delta required mechanical ventilation for RSV infection. During the peak season, approximately

Duration of hepatitis B immunity in low risk children receiving hepatitis B vaccinations from birth

1034/child <3 years of age was spent on RSV hospitalization in the YK Delta. In YK Delta infants </=6 months old, RSV microneutralizing antibody titers <1200 were associated with severe disease (odds ratio=6.2, P=.03). In the YK Delta and at JHH, newborns may be at greater risk for severe RSV illness than previously thought.

Changes in Antibiotic-Prescribing Practices and Carriage of Penicillin-Resistant Streptococcus pneumoniae: A Controlled Intervention Trial in Rural Alaska

Background: The duration of protection after hepatitis B vaccination of infants is unknown. Methods: We determined antibody to hepatitis B surface antigen (anti-HBs) at 4–13 years of age in 363 low risk children who had been vaccinated starting at birth with hepatitis B vaccine. Those with nonprotective titers (<10 mIU/mL) received a booster dose. We similarly followed 16 children of hepatitis B surface antigen (HBsAg)-positive mothers. Results: Of low risk infants receiving a plasma-derived vaccine, 41% (42 of 102) of those whose primary response was unknown and 24% (4 of 17) who had initially responded retained protective titers (≥10 mIU/mL) of anti-HBs at 9 and 13 years, respectively. Of those who did not have protective antibody titers, 61% (33 of 54) and 67% (8 of 12), respectively, responded to a booster dose. In children of HBsAg-positive mothers, 31% retained protective anti-HBs at 12 years, and 90% (9 of 10) with nonprotective titers responded to a booster. In low risk children initially receiving a recombinant vaccine, 12.5% (26 of 208) and none (0 of 36) retained protective anti-HBs titers at 5 and 7 years of age, respectively. Of those who did not have protective titers, 90% (120 of 134) and 91% (32 of 35), respectively, responded to a booster. Conclusions: Anti-HBs disappeared by 5 years of age in most children who were vaccinated with hepatitis B vaccine from birth. Although most children showed immunologic memory, one-third failed to demonstrate an anamnestic response to a booster dose. Additional long term studies of low risk infants are needed to determine duration of protection and the necessity for or timing of booster doses.

Vitamin A therapy for children with respiratory syncytial virus infection : a multicenter trial in the United States

From 1998 to 2000, 13 rural Alaskan villages (population, 3326) were surveyed annually by nasopharyngeal cultures for Streptococcus pneumoniae carriage. Data regarding antibiotic use for the entire population was abstracted from clinic records. In 1999, education of medical providers and the community about appropriate antibiotic use began in 4 villages; this program was expanded to include all villages in 2000. Antibiotic courses per person decreased by 31% in the initial intervention villages and by 35% in the remaining villages after education (P<.01 for each). Samples were obtained for culture from a mean of 31% of the population each year; 31% carried pneumococcus. No sustained decrease in carriage of penicillin-nonsusceptible strains was observed. When linear regression was used, serotype accounted for 81% of the variance in pneumococcal minimum inhibitory concentrations after the intervention, compared with 7% for antibiotic use. This suggests that reducing the carriage of serotypes associated with antibiotic resistance by use of pneumococcal conjugate vaccines may have a greater short-term impact than does decreasing antibiotic use.

Hospitalizations for respiratory syncytial virus infection in Alaska Native children.

BACKGROUND High dose vitamin A therapy is effective in reducing morbidity and mortality associated with measles infection. Children with acute respiratory syncytial virus (RSV) infection have low serum vitamin A concentrations. METHODS We performed a multicenter, randomized, placebo-controlled trial of high dose vitamin A therapy among 239 children 1 month to 6 years of age to determine whether high dose vitamin A therapy would reduce morbidity associated with RSV infection. RESULTS There were no differences between the vitamin A and placebo recipients for most clinical outcomes; however, vitamin A recipients had-longer hospital stays than placebo recipients (5.0 days vs. 4.4 days, P = 0.01) after enrollment. This effect was significant for children who were older than 1 year (who also had received the highest doses of vitamin A), particularly among those at low risk for complications of RSV infection and those enrolled during the second study season. Serum retinol levels at enrollment were inversely correlated with severity of illness. CONCLUSIONS We found no evidence of a beneficial effect of vitamin A for the treatment of RSV infection in children in the United States. There may be groups of children for which vitamin A has an adverse effect, resulting in longer hospital stays.

Bronchiectasis in Alaska Native children: Causes and clinical coursesThis article is a US Government work and, as such, is in the public domain in the United States of America.

To characterize the epidemiology of Alaska Native children hospitalized for respiratory syncytial virus infections, we reviewed records of hospitalizations during the winter seasons of 1991 to 1992 and 1992 to 1993 at a hospital in Anchorage and a rural hospital in the Yukon Kuskokwim Delta (YKD) region of southwestern Alaska. The median age of hospitalization for respiratory syncytial virus infection was 2 months of age for YKD residents and 4.5 months for Anchorage residents. Sixteen percent of the hospitalized YKD children were less than 1 month of age, whereas the same was true for only 3% of the Anchorage children. Eight percent of the YKD patients required mechanical ventilation, whereas none of the Anchorage patients required ventilation. The median hospital stay was 4.8 days for YKD patients and 3.2 days for Anchorage patients. Hospitalization rates for infants less than 1 year of age were 33/1000 for Alaska Natives in Anchorage and 100/1000 for those in the YKD region. The extremely high hospitaliza

Pervasive occult gastrointestinal bleeding in an Alaska native population with prevalent iron deficiency: Role of Helicobacter pylori gastritis

Although bronchiectasis has become a rare condition in U.S. children, it is still commonly diagnosed in Alaska Native children in the Yukon Kuskokwim Delta. The prevalence of bronchiectasis has not decreased in persons born during the 1980s as compared with those born in the 1940s. We reviewed case histories of 46 children with bronchiectasis. We observed that recurrent pneumonia was the major preceding medical condition in 85% of patients. There was an association between the lobes affected by pneumonia and the lobes affected by bronchiectasis. Eight (17%) patients had surgical resection of involved lobes. We conclude that the continued high prevalence of bronchiectasis appears to be related to extremely high rates of infant and childhood pneumonia. Pediatr Pulmonol. 2000;29:182-187. Published 2000 Wiley-Liss, Inc.