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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

Persistence of seropositivity conferred by hepatitis A vaccine administered to children <2 years of age is unknown and passively transferred maternal antibodies to hepatitis A virus (maternal anti-HAV) may lower the infant's immune response to the vaccine. One hundred ninety-seven infants and young children were randomized into three groups to receive a two-dose hepatitis A vaccine: group 1 at 6 and 12 months, group 2 at 12 and 18 months, and group 3 at 15 and 21 months of age. Within each group, infants were randomized by maternal anti-HAV status. Anti-HAV levels were measured at 1 and 6 months and at 3, 5, 7, and 10 years after the second dose of hepatitis A vaccination. Children in all groups had evidence of seroprotection (>10 mIU/mL) at 1 month after the second dose. At 10 years, all children retained seroprotective anti-HAV levels except for only 7% and 11% of children in group 1 born to anti-HAV–negative and anti-HAV–positive mothers, respectively, and 4% of group 3 children born to anti-HAV–negative mothers. At 10 years, children born to anti-HAV–negative mothers in group 3 had the highest geometric mean concentration (GMC) (97 mIU/mL; 95% confidence interval, 71-133 mIU/mL) and children born to anti-HAV–positive mothers in group 1 had the lowest GMC (29 mIU/mL; 95% confidence interval, 20-40 mIU/mL). Anti-HAV levels through 10 years of age correlated with initial peak anti-HAV levels (tested at 1 month after the second dose). Conclusion: The seropositivity induced by hepatitis A vaccine given to children <2 years of age persists for at least 10 years regardless of presence of maternal anti-HAV. (HEPATOLOGY 2012)

Prior to the implementation of hepatitis A vaccination, an average of 26,000 cases of acute hepatitis A virus (HAV) infection were reported each year,1 and HAV was particularly hyperendemic among Alaska Natives and American Indians.1-4 Between 1996 and 2006, the Advisory Committee on Immunization Practices (ACIP) had incrementally expanded hepatitis A vaccine recommendations from groups at increased risk of infection to routine, universal vaccination of children ≥12 months of age.1 By 2000, the incidence of hepatitis A among Alaska Natives and American Indians had declined by >95% from 1990 rates4 and the low rates have been sustained to the present time.2, 5

Hepatitis A vaccine was initially recommended for children >2 years of age.6, 7 Although hepatitis A vaccine is generally very immunogenic and effective in children and adults, several studies among infants showed that the presence of passively acquired maternal antibodies to HAV (anti-HAV) at the time of vaccination reduces the immune response to the vaccine.8-10 In addition to decreased relative ability of the infant immune system to mount a strong response,11 a number of studies have indicated that passively acquired maternal anti-HAV persists for at least 6 months after birth and may interfere with the immune response to vaccination manifested primarily by lower anti-HAV levels rather than failure to respond to vaccination.12 We demonstrated that hepatitis A vaccine, when given to children <2 years of age, was highly immunogenic, though 6% of children of anti-HAV–positive mothers who were vaccinated starting at 6 months did not respond.12 As a result, the ACIP recommended changing the minimum age for initiating hepatitis A vaccine from 2 years to 12 months. However, the long-term duration of antibody when this vaccine is given at such a young age is unknown. If the long-term diminution of the initial lower anti-HAV levels over time was significant, children receiving early hepatitis A vaccination, especially in the presence of maternal anti-HAV, could potentially be susceptible again in adulthood when, if infected, clinical symptoms from HAV infection are more severe.13 The primary objective of this study was to determine the long-term duration of seropositivity induced by two doses of hepatitis A vaccine given to infants starting at three different ages (6, 12, and 15 months). In addition, we examined the persistence of anti-HAV in children who were born either to anti-HAV–positive or anti-HAV–negative mothers.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

Study Population and Procedures.

Participants included in this long-term follow-up study were recruited from children originally enrolled in an immunogenicity study reported by Bell et al.12 In that study, children were enrolled from pediatric clinics at the Southcentral Foundation Primary Care Center at the Alaska Native Medical Center (ANMC) in Anchorage, Alaska, and the Anchorage Neighborhood Health Center. However, the Anchorage Neighborhood Health Center was excluded from this long-term follow-up analysis because their participants were not eligible for care at the ANMC, where the long-term study was to be conducted. Recruitment of study participants at ANMC was conducted among mothers who presented for prenatal care at the time of delivery, and their infants, who were seen in pediatric clinics during well-child visits up to 4 months of age. Study investigators enrolled infants who had been delivered at term and were considered healthy at 6 months of age. Mothers provided informed consent and were tested for total antibody to HAV (anti-HAV) at the ANMC using a standard, commercially available assay (HAVAB; Abbott Laboratories, North Chicago, IL).

Using a computerized randomization scheme, infants and young children were randomized to receive hepatitis A vaccine on three different schedules: at ages 6 and 12 months (group 1), 12 and 18 months (group 2), and 15 and 21 months (group 3). Furthermore, within each group, subjects were stratified to achieve a relatively equal number of children born to anti-HAV–positive and anti-HAV–negative mothers.

The study was approved by the institutional review boards of the Alaska Area Indian Health Service and the Centers for Disease Control and Prevention (CDC); by the Alaska Native Health Board, The Alaska Native Tribal Health Consortium Board, Southcentral Foundation; and by the US Food and Drug Administration under an Investigational New Drug Application, Phase IV. A flow diagram of recruitment and retention of the patients in the original study is in the Supporting Information.

Two doses of the inactivated hepatitis A vaccine HAVRIX (GlaxoSmithKline Biologicals, Rixensart, Belgium) were given to each participant in the pediatric formulation of 720 enzyme-linked immunoassay units per dose which was only licensed at the time for children >2 years of age. Hepatitis A vaccine was administered as described by Bell et al.12 The Alaska State Health Department provided other routine vaccinations to participants as recommended during the study period.

Sampling Time Points and Measurement of Anti-HAV.

Serum samples were collected from study participants at 1 and 6 months after the second hepatitis A vaccine dose and during postvaccination follow-up at 3, 5, 7, and 10 years of age. All serum samples were tested for anti-HAV in 2010 by the Assay Development and Diagnostic Reference Laboratory of the Division of Viral Hepatitis, CDC, using the ETI-AB-HAVK-PLUS enzyme immunoassay diagnostic kit in accordance with the manufacturer's instructions (DiaSorin Inc., Stillwater, MN). The ETI-AB-HAVK-PLUS High Positive Control, containing 1,200-2,000 mIU/mL anti-HAV (World Health Organization 2nd International Standard, 1998) was serially diluted and dilutions were used as calibrators in the assay to quantify total anti-HAV in the measuring range between 10 and 80 mIU/mL. Serum samples with total anti-HAV levels ≥80 mIU/mL were further diluted as necessary to determine the actual anti-HAV levels.

Data Analysis.

The original study was designed with a sample size of at least 30 subjects per subgroup (60 subjects per group), which resulted in 80% power to detect at least a two-fold difference in anti-HAV GMC between subgroups in each group (alpha = 0.05, two-sided). However, not all subjects who consented were included in the long-term follow-up. One of the facilities included in the original study did not participate in the follow-up study, and those children were not included in the present study. Furthermore, children who inadvertently received additional doses of hepatitis A vaccine were not recruited for long-term follow-up, nor were the two children in group 1 whose mothers were anti-HAV–positive and failed to respond to the vaccine series, because these children also received an extra dose of vaccine.

Complete follow-up of all study participants was not available; in addition to children who were not available for follow-up, some children received extra doses of hepatitis A vaccine, and their results were censored at that time. Hence an analysis using multiple imputation was performed to enable an examination of the effects of maternal status and vaccine group on anti-HAV status at follow-up. Values for the missing anti-HAV levels were imputed using a combination of methods: Markov chain Monte Carlo method to achieve a monotone dataset, and subsequent regression fitting of the missing values.14 The imputation model included separate effects for each combination of maternal anti-HAV status and vaccine group. The subsequent regression step included a separate regression on the previous anti-HAV level for each subset. The multiply imputed data (M = 5) were combined for analysis using Rubin's rules to incorporate the between-imputation variability.

Anti-HAV levels were log-transformed before the statistical analysis. Antibody levels below the lower limit of detection of the assay were assigned a value of 10 mIU/ML. Comparisons of log anti-HAV levels by vaccination schedules and by maternal anti-HAV status at each time point were made using linear regression analysis of the multiply imputed data sets. In addition to accounting for differences by vaccination schedule and maternal anti-HAV status, we analyzed the data for differences by sex, and among group 1 infants by source of maternal anti-HAV (naturally infected versus vaccine-induced). GMCs were calculated by taking the log transformation of the estimated anti-HAV levels.

Subjects with anti-HAV levels above 10 mIU/mL were considered seropositive. The proportion of study subjects who were seropositive was compared within and between groups at various times using logistic regression of the multiply imputed data (dichotomized after imputation). Correlation between log anti-HAV levels at each time point and peak log anti-HAV levels (i.e., 1 month after the second dose) through 10 years of age was measured with Pearson correlation of the multiply imputed data. Analyses were performed using SAS version 9.2.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

Study Population and Follow-up.

Among 197 children available for long-term study following receipt of two doses of hepatitis A vaccine, 99 (50%) were male and 189 (96%) were Alaska Native/American Indian; these characteristics differed neither by study group nor maternal anti-HAV status (P > 0.05). During follow-up, 103 (52%) children had anti-HAV results available at all six time points, 150 (76%) had results at five or more time points, and 179 (91%) had results at four or more time points. The proportion of time points sampled did not differ significantly by vaccine group or maternal anti-HAV status (P > 0.05). The 122 (62%) children who remained in the study through the age of 10 years comprised the following: 53 of 82 (65%) children initially enrolled in group 1, 30 of 83 (36%) in group 2, and 39 of 83 (50%) in group 3; 79 (56%) of 140 initially enrolled children born to mothers with anti-HAV–negative status and 43 (40%) of 108 initially enrolled children born to mothers with anti-HAV–positive status.12 Participants who were not available at 10 years did not differ significantly from those who remained in the study by vaccine groups or maternal anti-HAV status. Ten children who were enrolled in the long-term study received one or more booster doses of hepatitis A vaccine. These children had an average of 3.3 (minimum 1, maximum 5) specimens tested before the receipt of a booster dose.

Persistence of Seropositivity After Hepatitis A Vaccination.

The persistence of immune response after two doses of hepatitis A vaccine (percentage of vaccine recipients with anti-HAV >10 mIU/mL) and anti-HAV GMC by study group and maternal anti-HAV status is shown in Table 1. All children in group 2 and group 3 with anti-HAV–negative mothers remained seropositive at all time points during 10 years of follow-up. In group 1, all children were seropositive through 3 years, but 3%, 5%, and 7% of children whose mothers were anti-HAV–negative lost seroprotection at 5, 7, and 10 years, respectively; 1%, 2%, and 11% of children born to mothers with anti-HAV–positive status, lost seroprotection at 5, 7, and 10 years; 2%, 3%, and 4% of group 3 children whose mothers were anti-HAV–positive lost seroprotection at 5, 7, and 10 years.

Table 1. Anti-HAV Levels After Two Doses of Hepatitis A Vaccine by Group (Initial Vaccination Schedule), Maternal Anti-HAV Status and Follow-up Period
Group*Maternal Anti-HAV Status1 Month After Dose 26 Months After Dose 23 Years of Age5 Years of Age7 Years of Age10 Years of Age
nAnti-HAV+GMCnAnti-HAV+GMCnAnti-HAV+GMCnAnti-HAV+GMCnAnti-HAV+GMCnAnti-HAV+GMC
  • Abbreviations: Anti-HAV+, anti-HAV–positive.

  • *

    Hepatitis A vaccine was administered at ages 6 and 12 months in group 1, at ages 12 and 18 months in group 2, and at ages 15 and 21 months in group 3.

  • GMC data are presented as the mean mIU/mL (95% confidence interval).

  • Data points with no imputed values.

1Negative40100%1,177 (843-1,642)38100%421 (314-566)36100%214 (141-325)3597%103 (68-156)3395%63 (42-95)3193%51 (35-74)
Positive33100%646 (370-1,127)36100%233 (144-376)35100%115 (63-178)3399%65 (46-91)3198%46 (32-64)2289%29 (20-40)
2Negative37100%1,558 (1,107-2,193)41100%547 (405-739)35100%585 (428-801)38100%262 (185-372)30100%154 (107-221)21100%107 (79-143)
Positive17100%988 (528-1,849)17100%399 (229-696)16100%422 (207-886)16100%156 (73-331)14100%105 (52-210)9100%79 (42-150)
3Negative36100%1,568 (1,175-2,092)38100%599 (468-766)35100%514 (363-730)36100%190 (137-263)34100%137 (102-184)27100%97 (71-133)
Positive20100%1,690 (1,093-2,611)23100%504 (291-873)20100%400 (220-730)1898%157 (91-271)1997%96 (60-155)1296%73 (38-138)

Within each group and maternal anti-HAV status category, there was a decrease in GMCs over time for all time points, ranging from a high of 1,690 mIU/mL (95% confidence interval, 1,093-2,611 mIU/mL) among maternal anti-HAV–positive children in group 3 at 1 month after the second dose to a low of 29 mIU/mL (95% confidence interval, 20-40 mIU/mL) among maternal anti-HAV–positive children in group 1 at age 10 years (Table 1). Over all time points, children in group 3 had consistently the highest and children in group 1 the lowest GMCs, as did children of mothers who were anti-HAV–negative compared with those anti-HAV–positive. Among children of anti-HAV–positive mothers, there was a statistically significant difference in GMCs between the three groups at 3, 5, and 7 years of age (P < 0.001, P = 0.008, P = 0.015, respectively). Among children of anti-HAV–negative mothers, there was a statistically significant difference in GMCs between the three groups at 3, 5, 7, and 10 years of age (P < 0.001, P < 0.001, P < 0.001, P = 0.002, respectively). Children of anti-HAV–positive mothers had consistently lower anti-HAV GMC than those of anti-HAV–negative mothers, but this difference was significant only for group 1 at 6 months after the second dose (P = 0.032), at 3 years of age (P = 0.042), and 10 years of age (P = 0.025). All tests of interaction were negative.

To determine whether there were any differences in antibody persistence among groups who started the vaccination before or after 1 year of age, we compared GMC of anti-HAV over time between those in group 1 to those in group 2 and 3 (Table 1). Group 1 children had consistently lower GMCs of anti-HAV compared with groups 2 or 3 at all follow-up time points. Among children of anti-HAV–positive mothers, GMCs were significantly lower in group 1 than groups 2 or 3 at all time points (P = 0.024, P < 0.001, P = 0.002, P = 0.003, P < 0.001, respectively). Within each group, children of anti-HAV–positive mothers had consistently lower anti-HAV GMCs than children of anti-HAV–negative mothers, but the differences were significant only for those in group 1 children mentioned previously. Of the 36 GMCs presented in Table 1, 27 (75%) were within <1% of the GMC calculated from the raw data. An additional 5 (14%) are within 1%-3% of the raw data. The greatest difference was 8%.

To determine whether there was a differential impairment in the persistence of anti-HAV among children in group 1 whose mothers were anti-HAV–positive as a result of natural infection versus from vaccination, the GMC levels at all time points after the second vaccine dose were compared for children in the following categories: (1) children of anti-HAV–negative mothers, (2) children whose mothers were anti-HAV–positive due to previous HAV infection (i.e., postnatural immunity), or (3) children born to mothers who were anti-HAV–positive as a result of vaccination received prior to pregnancy (Table 2). There were significant differences (P < 0.05) between the GMCs of the three categories for the first three time periods, but not for the last three. For the first three, the difference was noted between the postnatural and the other two categories; the children of anti-HAV–negative and anti-HAV–positive mothers due to vaccination did not differ significantly from each other.

Table 2. Anti-HAV Levels After Two Doses of Hepatitis A Vaccine Among Group 1 Infants, by Maternal HAV Status and Follow-up Period
Maternal Anti-HAV Status1 Month After Dose 26 Months After Dose 23 Years of Age5 Years of Age7 Years of Age10 Years of Age
NGMC*NGMCNGMCNGMCNGMCNGMC
  • Group 1 received the hepatitis A vaccine at ages 6 and 12 months.

  • Abbreviations: Pos-Natural, children whose mothers were anti-HAV–positive as a result of natural infection; Pos-Vaccine, children whose mothers were anti-HAV–positive as a result of vaccination.

  • *

    GMC data are presented as the mean mIU/mL (95% confidence interval).

  • Data points with no imputed values.

Negative401,177 (843-1,642)38421 (314-566)36214 (141-325)35103 (68-156)3363 (42-95)3151 (35-74)
Pos-Natural17300 (128-545)1994 (51-173)1872 (40-132)1851 (29-90)1537 (20-68)925 (14-46)
Pos-Vaccine161,523 (909-2,552)17639 (462-884)17194 (111-342)1584 (57-123)1657 (39-83)1333 (22-50)

Anti-HAV GMCs were consistently higher in female children. When included in a linear regression model of anti-HAV levels, group, maternal status (anti-HAV–negative), and female sex all remained statistically significantly associated with higher GMC at all time points. The two-way interactions of each of these variables were not statistically significant at any time point. Alaska Native/American Indian children did not have significantly different anti-HAV levels at any time point, compared with children who were not Alaska Native/American Indian (data not shown). Only two persons had a four-fold or higher anti-HAV increase between subsequent time points that might be attributed to the natural boosting at subsequent time points.

Anti-HAV levels remain highly correlated with peak anti-HAV levels (1 month after second dose) through 10 years of age (correlations with peak: 6 months after second dose [R = 0.75, P < 0.001], 3 years of age [R = 0.61, P < 0.001], 5 years of age [R = 0.55, P < 0.001], 7 years of age [R = 0.52, P < 0.001], and 10 years of age [R = 0.51, P < 0.001]).

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

This is the first report to describe 10 years of follow-up of serial anti-HAV levels after two doses of inactivated hepatitis A vaccine among three groups of children aged 6-21 months. All three groups were stratified by maternal anti-HAV status. Our findings provide strong evidence that two doses of inactivated hepatitis A vaccine provide excellent seroprotection that persists for at least 10 years when vaccination is initiated at ages of 12 months. More than 95% of infants vaccinated at age 12 and 18 months and at age 15 and 21 months remained seroprotected at all time points through 10 years of age. Furthermore, fewer than 12% of children vaccinated at age 6 and 12 months lost anti-HAV between 7 and 10 years after the second dose, although the initial antibody response to hepatitis A vaccination was the lowest in this group. Such persisting seroprotection among infants vaccinated at 6 months might warrant future studies examining practical uses of administering hepatitis A vaccine to children less than 12 months of age, for example in countries where HAV infection occurs early in life may benefit from earlier vaccination schedules. Hepatitis A vaccine might also be considered for pre- or postexposure prophylaxis for a child aged 6-12 months if immunoglobulin (currently recommended for this age group) is not available.

A lower peak antibody response in group 1 may be explained by the relative immaturity of the immune system in the first year of life in general.11 Maternal anti-HAV levels remain high through the first 6 months of an infant's life and then decay significantly by 12 months of age.15 This may explain the observed higher GMCs in children vaccinated at 12 and 18 (group 2) and 15 and 21 months (group 3) compared with GMCs in children vaccinated at ages 6 and 12 months (group 1) in our study. As reported elsewhere,12, 16 anti-HAV levels (measured at 1 month after the second dose) remained highly correlated with subsequent antibody levels through age 10 years.

Our study is the first to examine the effects of maternal anti-HAV status and administration of hepatitis A vaccine during infancy on long-term persistence of vaccine-induced seropositivity. Passively transferred maternal anti-HAV can interfere with the initial response to the hepatitis A vaccination series when given starting at 2 months of age.9, 15 Our finding that the GMCs of anti-HAV were higher in those infants starting the vaccination series after 12 months of age supports current CDC/ACIP guidelines for the routine administration of hepatitis A vaccine to all children in the United States beginning at the age of 12 months.1

We found that children of anti-HAV–positive mothers had consistently lower anti-HAV GMCs at all follow-up time periods than did children of anti-HAV–negative mothers, though the differences were significant only for the first three time periods. Nevertheless, anti-HAV GMCs in infants whose mothers seroconverted due to receipt of hepatitis A vaccine prior to pregnancy were similar to those whose mothers were anti-HAV–negative. As reported elsewhere hepatitis A infection results in higher levels of anti-HAV, compared to vaccine induced anti-HAV levels.10, 12 Infants are likely to acquire higher levels of transplacental anti-HAV from mothers with post-natural immunity (versus postvaccine seropositivity) which may result in more effective blunting of immunologic response to hepatitis A vaccine.17

We found anti-HAV levels to be consistently higher among female children. Rendi-Wagner et al.18 found that male sex was significantly associated with lower GMCs 10 years after receipt of three doses of inactivated hepatitis A vaccine among an unselected sample of adolescents and adults. However, in that study as well as ours, no sex differences were observed with regard to seroprotection through 10 years of follow-up.

Few reports have been published on the long-term immunogenicity of hepatitis A vaccine given to children aged >1 year with at least 10 years of follow up after initial immunization, and we found no reports with the long-term follow up of children that received hepatitis A vaccine at <1 year of age. A study conducted in Alaska Native children vaccinated at ages 3-6 years with a three-dose hepatitis A vaccine regimen showed that all children had anti-HAV at 15 years, and further modeling of antibody decline in this cohort showed that protection would last for at least 26-32 years after immunization.16 In addition, hepatitis A vaccine likely induces cellular immune memory, which would prolong seropositivity beyond detectable antibody levels.19

A study from China reported on long-term seropositivity 10 years after administration of two doses of inactivated hepatitis A vaccine in children approximately 2 years of age and found that 99% remained anti-HAV–positive.20 Another study from Argentina showed that 97.9% of children were anti-HAV–positive at 10 years,21 although in that study some participants' anti-HAV levels might have naturally boosted due to documented exposure to acute HAV infection.21 We found no evidence that natural boosting contributed to the persistence of seroprotective GMCs among study participants during the 10 years of follow-up. Moreover, the incidence of reported acute hepatitis A in Alaska in the past decade was <1 per 100,000, lower than seen in the continental United States.5 In addition, two separate studies using a formulation with a combination of hepatitis A and B vaccines given to children between 6 and 10 years of age and 12 and 15 years of age showed that all had anti-HAV at 10 years.22, 23

Long-term studies of the duration of protection afforded by hepatitis A vaccination when given in childhood are crucial for public health officials to craft immunization policy in the US and elsewhere. In the US, hepatitis A vaccination is recommended for all children because they played a key role in sustaining HAV transmission to older children and adults in the prevaccine era. However, for this policy to be effective, protection must last through adulthood, when infection is likely to lead to symptomatic disease. If protection is shown to disappear at some age, booster doses may be needed. Our study, which includes the youngest cohort of children reported to date, adds to the body of knowledge demonstrating long-term seropositivity induced by hepatitis A vaccine in children.

Our study has a few limitations. First, the loss of participants reduced the sample size over the 10-year study period and may have influenced our ability to detect statistically significant differences between subgroups; however, the proportion of time points sampled did not differ significantly by vaccine group or maternal anti-HAV status. Second, our cohort consisted mostly of Alaska Native children. Previous vaccination studies5 have shown no difference in response to vaccination between Alaska Native people and non-Native people.5 Third, the lowest anti-HAV titer needed to confer protection is unknown.1 In other studies, lower limit of detection of anti-HAV (as prescribed by the assays used) is used to define seroprotection which varied from >10 to >33 mIU/mL.24, 25 We used the assay with a lower limit of detection of 10 mIU/mL, which might have resulted in higher yield of seroprotected children in our study.

In conclusion, our study demonstrates that seropositivity to hepatitis A persists for at least 10 years after primary vaccination with two-dose inactivated HAV vaccine when administered to children at ages 12 months and older, regardless of their mothers' anti-HAV status; in addition, >90% of infants vaccinated at 6 months of age also maintained seroprotective levels of anti-HAV. These findings support current CDC/ACIP guidelines for the routine administration of two doses of inactivated hepatitis A vaccine to all children in the United States beginning at the age of 12 months.1 Despite a substantial decrease in hepatitis A incidence in Alaska and the rest of the United States,2 continued follow-up of hepatitis A vaccine cohorts is warranted to determine whether in the future a booster dose will be necessary to maintain seropositivity. Therefore, we plan to follow this cohort through at least 15 years after initial immunization and thereafter as long as it is feasible.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References
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