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Effect of maternal antibody on immunogenicity of hepatitis A vaccine in infants
EFFECT OF MATERNAL ANTIBODY ON IMMUNOGENICITY OF HEPATITIS A VACCINE IN INFANTS G. WILLIAM LETSON, MD, CRAIG N. SHAPIRO, MD, DEBORAH KUEHN, RN/CNP, MSN, CHARLOTTE GARDEA, RN, THOMAS K. WELTY, MD, DAVID S. KRAUSE, MD, STEPHEN B. LAMBERT, MS, AND HAROLD S. MARGOLIS, MD
Objective To determine the effect of maternal antibody on hepatitis A vaccine immunogenicity in infants. Study design Infants of mothers negative for antibody to hepatitis A virus (anti-HAV; group 1) were administered hepatitis A vaccine at 2, 4, and 6 months of age, and infants of anti-HAV–positive mothers were randomized to receive either hepatitis A vaccine (group 2) or hepatitis B vaccine (group 3) on the same schedule. Group 3 infants subsequently received hepatitis A vaccine at 8 and 10 months of age.
Results At 15 months of age, 100% of infants in group 1, 93% in group 2, and 92% in group 3 had protective levels of antibody. However, there were significant differences in the geometric mean concentration (GMC) of anti-HAV between groups. Group 1 GMC was 231 mIU/mL, compared with 85 mIU/mL for group 2 and 84 mIU/mL for group 3 (P < .001, group 1 vs group 3). Conclusions Passively acquired maternal anti-HAV resulted in a significantly lower final antibody response when infants were administered hepatitis A vaccine at 2, 4, and 6 months of age or at 8 and 10 months of age. (J Pediatr 2004;144:327-32)
epatitis A is one of the most frequently reported vaccine-preventable diseases of children and adults in the United States.1,2 Historically, the highest rates of hepatitis A have been among American Indians/Alaska Natives and Hispanics, and American Indian reservations and some Hispanic communities have regularly had epidemics persisting for several years.1,3 In these communities, the highest disease rates are observed among children, because most adults, including women of childbearing age, have antibody to hepatitis A virus (anti-HAV) from infection acquired during childhood.3 Hepatitis A vaccination has been shown to produce protective levels of anti-HAV rapidly,4-6 to protect >95% of vaccinated persons from disease,7,8 and to interrupt disease transmission.1,9,10 Recently, routine hepatitis A vaccination has been recommended for children older than 2 years living in states and communities with disease rates that have exceeded the national average over the period of the past decade.1 Although vaccination of infants would be an ideal prevention strategy, few data exist concerning the performance of hepatitis A vaccine in infants, specifically infants who may have passively acquired maternal antibody. Several studies indicate that passively acquired anti-HAV interferes with the immune response to hepatitis A vaccine. For example, adults simultaneously administered immune globulin (IG) and hepatitis A vaccine do not respond as well as adults who receive hepatitis A vaccine alone.11-13 Infants born to mothers who are anti-HAV-positive acquire passively transferred antibody, which can be detected for at least 1 year.14,15 Limited data indicate that the presence of anti-HAV interferes with the immune response to hepatitis A vaccine in infants and young children.16-18 To evaluate the effect of maternal antibody on vaccine response in infants, we conducted a clinical trial to determine the immunogenicity of hepatitis A vaccine administered to infants beginning at 2 months of age along with other routinely administered vaccines.
H
Anti-HAV ELU GMC
Antibody to hepatitis A virus Enzyme-linked immunosorbent assay units Geometric mean concentration
HAV IG MEIA
Hepatitis A virus Immune globulin Microparticle enzyme immunoassay
From the Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia; Aberdeen Area Indian Health Service, Office of Epidemiology, Rapid City, South Dakota; and GlaxoSmithKline Biologicals, Collegeville, and Vicuron Pharmaceuticals, King of Prussia, Pennsylvania. Current affiliations are available from the journal. Supported by a Cooperative Research and Development Agreement between the Centers for Disease Control and GlaxoSmithKline Biologicals, No. CID-91-026-00. The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the Indian Health Service. Presented in part at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, September 1995 (abstract no. H61). Submitted for publication Apr 11, 2003; last revision received Aug 27, 2003; accepted Nov 25, 2003. Address correspondence to the first author at [email protected]. Reprint requests: Harold Margolis, MD, Division of Viral Hepatitis (Mailstop G37), National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA 30333. 0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2003.11.030
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Table I. Seroprotection rates and geometric mean concentrations of anti-HAV for infants receiving hepatitis A vaccine, by group and month of age Maternal Hepatitis Percent anti-HAV $20 mIU/mL (n/total tested) / GMC mIU/mL, by age (mo) anti-HAV A vaccine 2 4 6 8 15 Group status schedule (mo) 1
Negative
2, 4, 6
2
Positive
2, 4, 6
3
Positive
8, 10
0 (0/45) — 93 (26/28) 2631 100 (22/22) 1702
56 (31/55) 32 93 (25/27) 583 96 (22/23) 305
98 (51/52) 233 100 (23/23) 197 84 (16/19) 146
98 (52/53) 794 100 (25/25) 250* 63 (12/19) 97
100 (38/38) 231* 93 (14/15) 85 92 (11/12) 84
*Statistically significant (see text in RESULTS, Vaccine Immunogenicity).
MATERIALS AND METHODS Study Design and Population A prospective, randomized, single-blinded clinical study was conducted among American Indian infants in Rapid City, South Dakota, from July 1990 through March 1994. Serologic studies in this and neighboring populations showed a high prevalence of hepatitis A virus (HAV) infection among adults.3 Eligible participants were infants born to mothers who received well-child care at the Rapid City Indian Health Service (Sioux San) Hospital. Infants were excluded if they received IG, immunosuppressive therapy, blood, or blood products; were immune-compromised; were born to hepatitis B surface antigen-positive mothers; or were diagnosed with a severe developmental disability or progressive or unstable neurologic disorder. Infants of mothers who consented to participate in the study were assigned to vaccination groups based on their mother’s anti-HAV status (generally determined at the time of prenatal care). Infants of anti-HAV-negative mothers were assigned to group 1 and received hepatitis A vaccine at 2, 4, and 6 months of age. Infants of anti-HAV-positive mothers were randomly assigned to either group 2 or group 3 and received hepatitis A vaccine at 2, 4, and 6 months of age, or hepatitis B vaccine at 2, 4, and 6 months of age and hepatitis A vaccine at 8 and 10 months of age, respectively. Infants in groups 1 and 2 received hepatitis B vaccine at 8, 10, and 15 months of age. Study enrollment began before recommendations for universal infant hepatitis B immunization. Crossover immunization with either hepatitis A or B vaccine was added as an amendment to the protocol in February of 1992 after recommendations for universal infant immunization.19 Only two doses of hepatitis A vaccine were given to infants at 8 months of age based on preliminary study data indicating >90% seroconversion in infants administered doses at 2 and 4 months of age. Mothers were blinded to the vaccination group assignment of their infant. Infants in all three groups received routinely scheduled infant immunizations against polio, diphtheria-tetanus-pertussis, and Haemophilus influenzae type b at 2, 4, and 6 months of age. Serum specimens were obtained from infants at 2, 4, 6, 8, and 15 months of age. 328
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Because the hepatitis A vaccine was not licensed in the United States at the time of the study, the clinical trial was performed under an investigational new drug application. Informed consent for infant participation was obtained from the mothers. Study approval was obtained from the Rapid City Indian Health Board and the Institutional Review Boards of the Aberdeen Area Indian Health Service, the National Indian Health Service, and the Centers for Disease Control and Prevention.
Monitoring of Adverse Events Infants enrolled in the study received well-child and acute care in a special clinic to increase compliance with vaccination schedules and to monitor potential adverse reactions to vaccination. Adverse reactions were determined through prestamped postcards given to parents after administration of each vaccine dose. If the card was not received by the clinic within 2 weeks, the parent was contacted by telephone. If telephone contact was unsuccessful, the parent was questioned at the next clinic visit.
Vaccines The inactivated hepatitis A vaccine (HAVRIX; GlaxoSmithKline Biologicals, Rixensart, Belgium) was formulated to contain 360 enzyme-linked immunosorbent assay units (ELU) of HAV in a 0.5 mL volume and had been evaluated for safety and immunogenicity in adults, adolescents, and older children.4,6 The licensed hepatitis B vaccine (Engerix B; GlaxoSmithKline Biologicals) contained 10 lg antigen and was recommended for use in infants shortly after study approval and enrollment.19 Both vaccines were administered by intramuscular injection in the anterolateral thigh; other intramuscular vaccines given at the same visit were administered in the opposite thigh.
Laboratory Studies Maternal serum specimens were tested by microparticle enzyme immunoassay (MEIA) to detect total anti-HAV (HAVAB IMx; Abbott Laboratories, North Chicago, Ill). Anti-HAV concentrations in infants were determined by MEIA (HAVAB IMx) with a reference curve prepared by The Journal of Pediatrics March 2004
Figure. Concentrations of anti-HAV (mIU/mL) in infants receiving hepatitis A vaccine, by month and anti-HAV status of mother.
using the World Health Organization reference standard at the time of the study and expressed as milli-international units per milliliter. A protective level of anti-HAV (ie, seroprotection) was defined as $20 mIU/mL.
Statistical Analysis Data were entered in Epi Info Version 6.20 Geometric mean concentration (GMC) of anti-HAV was calculated for infants with detectable anti-HAV (anti-HAV >0 mIU/mL). The Kruskall-Wallis rank-sum test was used for comparisons of GMCs between groups. The v2 or Fisher exact tests were used for comparison of proportions. The initial target enrollment was 105 infants, randomized to achieve 35 infants in each group. This sample size would provide 80% power to detect a 35% difference in anti-HAV seroconversion between groups and would detect a threefold and fourfold GMC difference between groups at powers of 73% and 89%, respectively. The randomization assumed 60% to 80% antiHAV seropositivity among mothers.
RESULTS Vaccine Immunogenicity A total of 123 infants were enrolled in the trial and received at least one dose of vaccine. Maternal anti-HAV seropositivity was lower than expected (51.2%), which led to the following distribution of infants between groups: 60 in group 1, 32 in group 2, and 31 in group 3. Of these, 53 (88%) of group 1 infants and 25 (78%) of group 2 infants received Effect of Maternal Antibody on Immunogenicity of Hepatitis A Vaccine in Infants
three doses of hepatitis A vaccine and had serum specimens available at 8 months. Nineteen (61%) of group 3 infants received three doses of hepatitis B vaccine and had adequate serum for testing at 8 months of age. Table I shows seroresponse data for the number of infants vaccinated in each group who had adequate sera for testing at each time point in the immunization schedule. For groups 1 and 2, hepatitis A vaccine doses were administered at 60 ± 10 days (mean ± SD), 120 ± 31 days, and 176 ± 14 days of age, and there were no statistically significant differences between the groups in timing of vaccine doses. For group 3, hepatitis A vaccine was administered at 294 ± 60 and 374 ± 56 days of age. All infants in group 1 were anti-HAV-negative before vaccine administration at 2 months of age, and 98% had protective levels of antibody after the second dose of vaccine (Table I). Among infants in group 2, 93% had protective antibody levels before vaccination and all infants had protective antibody levels after the second vaccine dose. In contrast, only 63% of infants who were born to anti-HAVpositive mothers and who initially received hepatitis B vaccine (group 3) had protective levels of antibody at 8 months of age (P = .005; Table I). Among infants born to anti-HAV-negative mothers (group 1), antibody concentrations increased after each vaccine dose, with highest levels 2 months after the third dose. Infants born to anti-HAV-positive mothers (groups 2 and 3) had high anti-HAV levels at 2 months of age, but infants who received hepatitis A vaccine (group 2) had higher antibody levels at 8 months of age (P = .005; Table I). However, infants in group 2 329
Table II. Frequency of adverse events after hepatitis A and hepatitis B vaccination at 2, 4, and 6 months of age
Adverse event Injection site Redness Hardness Swelling Soreness Heat General Loss of appetite Fussiness Fever >388C Drowsiness
Hepatitis A vaccine (total doses = 273) n (%) 5 14 6 22 28
(1.8) (5.1) (2.2) (8.1) (10.3)
17 42 6 39
(6.0) (16.4) (2.2) (11.9)
Hepatitis B vaccine (total doses = 74) n (%) 1 1 0 2 2
(1.4) (1.4) (2.7) (2.7)
3 (4.1) 10 (13.5) 0 5 (6.8)
P value NS* NS NS NS .04 NS NS NS NS
*Nonsignificant (P > .05) by v2 test.
had lower peak antibody levels at 8 months of age than infants born to antibody-negative mothers (group 1) P < .00001; (Table I and Figure). At 15 months or age, the anti-HAV concentrations in vaccinated infants (groups 1 and 2) had declined from their peak at 8 months of age. However, antibody levels for group 1 infants were higher than for group 2 infants (Table I; P < .001). At 15 months of age, antibody levels for infants in group 3 no longer represented the natural decline of maternally acquired anti-HAV, but represented antibody levels after two doses of hepatitis A vaccine at 8 and 10 months of age. However, there was no significant difference in GMC between groups 2 and 3 at the 15-month follow-up. Among the 12 infants in group 3 who had follow-up testing at 15 months of age, three (25%) had anti-HAV levels < 20 mIU/mL before administration of their first hepatitis A vaccine dose at 8 months of age. At the 15-month follow-up, the antibody levels in the three infants with prevaccination anti-HAV < 20 mIU/mL were higher, but not statistically different, compared with the nine infants whose prevaccination anti-HAV was $20 mIU/mL (128 mIU/mL vs 72 mIU/ mL, P = .41). In addition, antibody concentrations at age 15 months among group 3 infants with prevaccination antibody < 20mIU/mL were lower than antibody concentrations among group 1 infants (128 mIU/mL vs 231 mIU/mL, P = .29). There was no significant difference in antibody levels at 15 months of age between group 2 and 3 infants with anti-HAV levels $20 mIU/mL at 8 months of age (84 mIU/mL vs 72 mIU/mL, P = .49).
Vaccine Reactogenicity The frequency of adverse reactions within 72 hours after vaccination among infants who received hepatitis A vaccine (groups 1 and 2) was compared with the frequency of such 330
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events among infants who received hepatitis B vaccine at the same ages (group 3). To minimize potential recall bias, this analysis was based on data from the cards given to parents at the time of vaccination and mailed back to the study site. Cards were received from parents after the administration of 61% of the hepatitis A vaccine doses and 68% of the hepatitis B vaccine doses. After vaccination at 2, 4, and 6 months of age, hepatitis A vaccine had a significantly greater frequency of warmth at the injection site (Table II). The frequency of adverse events after vaccination at 8 and 10 months with either vaccine was exceedingly rare (< 1%; data not shown). There were no serious adverse events associated with any of the vaccines used during the study.
DISCUSSION This study showed that infants born to anti-HAVnegative mothers respond well to hepatitis A vaccine. Nearly all study infants developed protective levels of antibody after two doses of the 360 ELU vaccine, and all had protective levels of antibody 9 months after the third dose (at 15 months of age). However, infants born to mothers who were anti-HAVpositive had a poorer response to the vaccine series; antibody concentrations were 66% lower compared with infants of antiHAV-negative mothers vaccinated on the same schedule. In addition, infants with pre-existing maternal antibody when vaccinated at an older age (group 3) demonstrated a steady antibody decline and had lower final antibody concentrations than infants without pre-existing antibody. Of interest were the three infants born to anti-HAVpositive mothers whose prevaccination anti-HAV levels were < 20 mIU/mL at 8 months of age. Although their final antibody concentrations at 15 months showed a trend toward being higher in comparison with infants with prevaccination antibody at 8 months of age, their final antibody levels trended lower in comparison with infants born to anti-HAV-negative mothers. These nonsignificant trend data suggest that very low levels of pre-existing anti-HAV, undetectable in current immunoassays, continued to exist and inhibited the response to hepatitis A vaccine given at 8 and 10 months. Interference by maternal antibodies has been generally thought to be of more concern for live virus vaccines, such as measles vaccine, than for inactivated vaccines.21-23 However, interference by pre-existing antibody has been seen with some inactivated vaccines, including diptheria-tetanus-pertussis, and hepatitis B.24-27 Studies in adults have shown that simultaneous administration of IG and hepatitis A vaccine results in antibody levels at least 50% lower than when vaccine is administered alone.11,12 Anti-HAV levels after IG administration are generally < 100 mIU/mL and are not detectable by commercially available immunoassays that have not been modified.28 Anti-HAV levels at 2 months of age from passively acquired maternal antibody are substantially higher than those observed after IG administration and would be expected to have a similar or greater effect on the response to vaccine.29 All vaccinated infants of anti-HAV-positive mothers had protective levels of anti-HAV at 15 months of age that were lower than levels of infants born to anti-HAV–negative The Journal of Pediatrics March 2004
mothers. However, the clinical implications of these lower anti-HAV levels are unclear. Among infants in Israel vaccinated at 2, 4, and 6 months of age with hepatitis A vaccine containing 720 ELU, lower postvaccination anti-HAV levels were observed among infants born to anti-HAV–positive mothers compared with infants born to anti-HAV–negative mothers.18 Even though the anti-HAV concentrations of vaccinated infants born to anti-HAV–positive mothers continued to decline steadily until 12 months of age, all infants demonstrated an anamnestic anti-HAV response to a 720-ELU booster dose of vaccine administered at that time, suggesting that the initial vaccine series had induced priming and immune memory. In a long-term follow-up study of 11 infants from groups 1 and 2 of our study who had no detectable anti-HAV at age 6 years, all demonstrated an anamnestic anti-HAV response with a 360 ELU booster dose of vaccine. However, those infants with prevaccination antiHAV had a lower anti-HAV response compared with infants without prevaccination anti-HAV.30 Hepatitis A vaccine was well tolerated by infants born to anti-HAV-negative and to anti-HAV-positive mothers. Adverse reactions were mild, and although there was a proportionally greater frequency of adverse reactions in the hepatitis A compared with hepatitis B vaccine recipients, only heat at the injection site reached statistical significance. Hepatitis A vaccination has its greatest benefit in populations with high disease rates. In such populations, a greater proportion of women of childbearing age are likely to be anti-HAV-positive; therefore, their infants would have antibody that would interfere with a vaccine administered early in life. Vaccination of older children has been shown to reduce significantly the incidence of hepatitis A in such communities.7-10 Toddlers often have asymptomatic infection and are the source of silent transmission to susceptible persons and maintenance of the virus in a community over time.3 Therefore, sustained vaccination of children, preferably as part of the early childhood immunization schedule, will be required to prevent HAV transmission and the reintroduction of disease into communities. Our study is limited in its size, and this limitation may have been magnified by the difficulty of follow-up in a population that is highly mobile, which led to rather high dropout rates by age 15 months and wide variation in times of vaccine receipt. Further studies are needed to determine the appropriate dose and timing of immunization that would achieve a balance between optimal short-term and long-term immunogenicity and integration of hepatitis A vaccine into the childhood immunization schedule. Childhood hepatitis A vaccination has the potential to eliminate the high rates of transmission previously observed in susceptible populations that often have a high prevalence of anti-HAV-positive women of child-bearing age. We acknowledge the support and assistance of the Rapid City Indian Health Board; the laboratory and staff at Sioux San Hospital, Rapid City, South Dakota; Indian Health Service and Centers for Disease Control and Prevention employees Jeri Archer, Tom Bad Heart Bull, Marcia Beshara, MD, Sue Girga, Laurie Hrachavec, Joni Kaluba,
Effect of Maternal Antibody on Immunogenicity of Hepatitis A Vaccine in Infants
Jana Pfister, Sheila Romero, Randy Ross, Mar Than, and Deonne Warwick; the Rapid City Indian community; and parents and children who participated in the study. We also acknowledge Dr. Everett Rhoades, Director of the Indian Health Service at the time of the study, for his support and assistance in educating the Indian community on its importance.
REFERENCES 1. Centers for Disease Control Prevention. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999;48(RR-12): 1-38. 2. Centers for Disease Control Prevention. Hepatitis surveillance report no. 57. Atlanta (GA): Centers for Disease Control and Prevention; 2000. p. 38. 3. Shaw FE, Shapiro CN, Welty TK, Dill W, Reddington J, Hadler SC. Hepatitis transmission among the Sioux Indians of South Dakota. Am J Public Health 1990;80:1091-4. 4. Horng YC, Chang MH, Lee CY, Safary A, Andre FE, Chen DS. Safety and immunogenicity of hepatitis A vaccine in healthy children. Pediatr Infect Dis J 1993;12:359-62. 5. McMahon BJ, Williams J, Bulkow L, Snowball M, Wainwright R, Kennedy M, et al. Immunogenicity of an inactivated hepatitis A vaccine in Alaska Native children and Native and non-Native adults. J Infect Dis 1995;171:676-9. 6. Balcarek KB, Bagley MR, Pass RF, Schiff ER, Krause DS. Safety and immunogenicity of an inactivated hepatitis A vaccine in preschool children. J Infect Dis 1995;171:S70-2. 7. Werzberger A, Mensch B, Kuter B, Brown L, Lewis J, Sitrin R, et al. A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children. N Engl J Med 1992;327:453-73. 8. Innis BL, Snitbhan R, Kunasol P, Laorakpongse T, Poopatanakool W, Kozik CA, et al. Protection against hepatitis A by an inactivated vaccine. JAMA 1994;271:1328-34. 9. McMahon BJ, Beller M, Williams J, Schloss M, Tanttila H, Bulkow L. A program to control and outbreak of hepatitis A in Alaska by using an inactivated hepatitis A vaccine. Arch Pediatr Adolesc Med 1996;150:733-9. 10. Averhoff F, Shapiro CN, Bell BP, Hyams I, Burd L, Deladisma A, et al. Control of hepatitis A through routine vaccination of children. JAMA 2001;286:2968-73. 11. Leentvaar-Kuijpers A, Coutinho RA, Brulein V, Safary A. Simultaneous passive and active immunization against hepatitis A. Vaccine 1992;10:S138. 12. Wagner G, Lavanchy D, Darioli R, Pecoud A, Brulein V, Safary A, Frei PC. Simultaneous active and passive immunization against hepatitis A studied in a population of travelers. Vaccine 1993;11:1027-32. 13. Green MS, Cohen D, Lerman Y, Sjogren M, Binn LN, Zur S, et al. Depression of the immune response to an inactivated hepatitis A vaccine administered concomitantly with immune globulin. J Infect Dis 1993; 168:740-3. 14. Burke DS, Nimmannitya S. Passively acquired antibody to hepatitis A virus in Thai infants. Southeast Asian J Trop Med Public Health 1980;11:415-6. 15. Vargas V, Pedreira JD, Esteban R, Hernandez JM, Guardia J, Bacardi R. Materno-fetal transmission of hepatitis A antibody. Acta Paediatr Scand 1980;69:533. 16. Troisi CL, Hollinger FB, Krause DS, Pickering LK. Immunization of seronegative infants with hepatitis A vaccine (HAVRIX; SKB): a comparative study of two dosing schedules. Vaccine 1997;15:1613-7. 17. Piazza M, Safary A, Vegnente A, Soncini R, Pensati P, Sardo M, et al. Safety and immunogenicity of hepatitis A vaccine in infants: a candidate for inclusion in the childhood vaccination programme. Vaccine 1999;17:585-8. 18. Dagan R, Amir J, Mijalovsky A, Kalmanovitch I, Bar-Yochai A, Thoelen S, et al. Immunization against hepatitis A in the first year of life: priming despite the presence of maternal antibody. Pediatr Infect Dis J 2000;19:1045-52.
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19. Centers for Disease Control Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40(RR-13):1-25. 20. Dean AG, Dean JA, Coulombier D, Burton AH, Brendel KA, Smith DC, et al. Epi Info, version 6: a word-processing, database, and statistics program for public health on IBM-compatible microcomputers. Atlanta (GA): Centers for Disease Control and Prevention; 1994. 21. Schluederberg A, Lamm SH, Landrigan PJ, Black FL. Measles immunity in children vaccinated before one year of age. Am J Epidemiol 1973;97:402-9. 22. Shelton JD, Jacobsen JE, Orenstein WA, Schulz KF, Donnell HD Jr. Measles vaccine efficacy: influence of age at vaccination vs. duration of time since vaccination. Pediatrics 1978;62:961-4. 23. Wilkins J, Wehrle PF. Additional evidence against measles vaccine administration to infants less than 12 months of age: altered immune response following active/passive immunization. J Pediatr 1979;94:865-9. 24. Sarvas H, Kurikka S, Seppala IJ, Makela PH, Makela O. Maternal antibodies partly inhibit an active antibody response to routine tetanus toxoid immunization in infants. J Infect Dis 1992;165:977-9.
25. Englund JA, Anderson EL, Reed G, Decker MD, Edwards KM, Pichichero ME, et al. The effect of maternal antibody on the serologic response and the incidence of adverse reactions after primary immunization with acellular and whole cell-pertussis vaccines combined with diphtheria and tetanus toxoids. Pediatrics 1995;96:580-4. 26. Siegrist C-A, Cordova M, Brandt C, Barrios C, Berney M, Tougne C, et al. Determinants of infant responses to vaccines in presence of maternal antibodies. Vaccine 1998;16:1409-14. 27. Xu Z-Y, Duan S-C, Margolis HS, Purcell RH, Ou-yang P-Y, Coleman PJ, et al. Long-term efficacy of active postexposure immunization of infants for prevention of hepatitis B virus infection. J Infect Dis 1995;171:54-60. 28. Lemon SM. Immunologic approaches to assessing the response to inactivated hepatitis A vaccine. J Hepatol 1993;18(Suppl 2):S15-9. 29. Linder N, Karetnyi Y, Gidony Y, Ohel G, Levin E, Kuint J, et al. Placental transfer of hepatitis A antibodies in full term and preterm infants. Ped Infect Dis J 1997;162:245-7. 30. Fiore AE, Shapiro CN, Sabin K, Labonte K, Darling K, Culver D, et al. Hepatitis A vaccination of infants: effect of maternal antibody status on antibody persistence and response to a booster dose. Pediatr Infect Dis J 2003;22:354-9.
50 Years Ago in The Journal of Pediatrics THE TONSIL PENDULUM Editor’s column. J Pediatr 1954;44:235-6 The Editor congratulates the end of an era of unnecessary excess of tonsillectomies, recommending that the process of decision-making to perform this procedure should be based on the same rigor used for a more complex surgery such as an appendectomy. Fifty years later, although the frequency of amigdalectomies has decreased and indications have been clearly defined, it continues to be one of the most common surgical interventions in pediatrics. This indicates that the enormous progress in medical knowledge that has occurred during the last half century has not been accompanied at a same pace by an advance in medical judgment and critical medical assessment. The Editor supports the conservation of the tonsils with the argument, accepted in those days, that the more severe form of polio, bulbar polio, was commonly preceded within a few weeks by the surgical extraction of them. The Editor cites three studies reporting an excess of fatal cases in patients without tonsils and adenoids, even if the extraction had been performed years before, proposing the hypothesis that this severe complication may have been not so much a consequence of the surgical trauma but, ‘‘perhaps the loss of a filter, so to speak.’’ Advances in the field of immunology have showed that this ‘‘perhaps’’ was in the right track because adenoids and tonsils are currently considered highly relevant in protecting against pathogen invasion of the upper respiratory tract, reacting through stimulation of both the humoral and cellular components of the immune response. Medicine in the 1950s was based largely on observation, not always supported by the more complete laboratory research of today, and thus for not uncommonly reaching erroneous conclusions. Appropriately used though, observation will remain to be a much needed scientific tool for the generation of new ideas, maintaining in a way, a healthy oscillation of the pendulum. Perhaps. . . Walter Ledermann, MD Service and Department of Pediatrics Hospital Luis Calvo Mackenna, Universidad de Chile Antonio Varas 360, Santiago, Chile YMPD627 10.1016/j.jpeds.2003.11.003
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The Journal of Pediatrics March 2004
Objective To determine the effect of maternal antibody on hepatitis A vaccine immunogenicity in infants. Study design Infants of mothers negative for antibody to hepatitis A virus (anti-HAV; group 1) were administered hepatitis A vaccine at 2, 4, and 6 months of age, and infants of anti-HAV–positive mothers were randomized to receive either hepatitis A vaccine (group 2) or hepatitis B vaccine (group 3) on the same schedule. Group 3 infants subsequently received hepatitis A vaccine at 8 and 10 months of age.
Results At 15 months of age, 100% of infants in group 1, 93% in group 2, and 92% in group 3 had protective levels of antibody. However, there were significant differences in the geometric mean concentration (GMC) of anti-HAV between groups. Group 1 GMC was 231 mIU/mL, compared with 85 mIU/mL for group 2 and 84 mIU/mL for group 3 (P < .001, group 1 vs group 3). Conclusions Passively acquired maternal anti-HAV resulted in a significantly lower final antibody response when infants were administered hepatitis A vaccine at 2, 4, and 6 months of age or at 8 and 10 months of age. (J Pediatr 2004;144:327-32)
epatitis A is one of the most frequently reported vaccine-preventable diseases of children and adults in the United States.1,2 Historically, the highest rates of hepatitis A have been among American Indians/Alaska Natives and Hispanics, and American Indian reservations and some Hispanic communities have regularly had epidemics persisting for several years.1,3 In these communities, the highest disease rates are observed among children, because most adults, including women of childbearing age, have antibody to hepatitis A virus (anti-HAV) from infection acquired during childhood.3 Hepatitis A vaccination has been shown to produce protective levels of anti-HAV rapidly,4-6 to protect >95% of vaccinated persons from disease,7,8 and to interrupt disease transmission.1,9,10 Recently, routine hepatitis A vaccination has been recommended for children older than 2 years living in states and communities with disease rates that have exceeded the national average over the period of the past decade.1 Although vaccination of infants would be an ideal prevention strategy, few data exist concerning the performance of hepatitis A vaccine in infants, specifically infants who may have passively acquired maternal antibody. Several studies indicate that passively acquired anti-HAV interferes with the immune response to hepatitis A vaccine. For example, adults simultaneously administered immune globulin (IG) and hepatitis A vaccine do not respond as well as adults who receive hepatitis A vaccine alone.11-13 Infants born to mothers who are anti-HAV-positive acquire passively transferred antibody, which can be detected for at least 1 year.14,15 Limited data indicate that the presence of anti-HAV interferes with the immune response to hepatitis A vaccine in infants and young children.16-18 To evaluate the effect of maternal antibody on vaccine response in infants, we conducted a clinical trial to determine the immunogenicity of hepatitis A vaccine administered to infants beginning at 2 months of age along with other routinely administered vaccines.
H
Anti-HAV ELU GMC
Antibody to hepatitis A virus Enzyme-linked immunosorbent assay units Geometric mean concentration
HAV IG MEIA
Hepatitis A virus Immune globulin Microparticle enzyme immunoassay
From the Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia; Aberdeen Area Indian Health Service, Office of Epidemiology, Rapid City, South Dakota; and GlaxoSmithKline Biologicals, Collegeville, and Vicuron Pharmaceuticals, King of Prussia, Pennsylvania. Current affiliations are available from the journal. Supported by a Cooperative Research and Development Agreement between the Centers for Disease Control and GlaxoSmithKline Biologicals, No. CID-91-026-00. The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the Indian Health Service. Presented in part at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, September 1995 (abstract no. H61). Submitted for publication Apr 11, 2003; last revision received Aug 27, 2003; accepted Nov 25, 2003. Address correspondence to the first author at [email protected]. Reprint requests: Harold Margolis, MD, Division of Viral Hepatitis (Mailstop G37), National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA 30333. 0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2003.11.030
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Table I. Seroprotection rates and geometric mean concentrations of anti-HAV for infants receiving hepatitis A vaccine, by group and month of age Maternal Hepatitis Percent anti-HAV $20 mIU/mL (n/total tested) / GMC mIU/mL, by age (mo) anti-HAV A vaccine 2 4 6 8 15 Group status schedule (mo) 1
Negative
2, 4, 6
2
Positive
2, 4, 6
3
Positive
8, 10
0 (0/45) — 93 (26/28) 2631 100 (22/22) 1702
56 (31/55) 32 93 (25/27) 583 96 (22/23) 305
98 (51/52) 233 100 (23/23) 197 84 (16/19) 146
98 (52/53) 794 100 (25/25) 250* 63 (12/19) 97
100 (38/38) 231* 93 (14/15) 85 92 (11/12) 84
*Statistically significant (see text in RESULTS, Vaccine Immunogenicity).
MATERIALS AND METHODS Study Design and Population A prospective, randomized, single-blinded clinical study was conducted among American Indian infants in Rapid City, South Dakota, from July 1990 through March 1994. Serologic studies in this and neighboring populations showed a high prevalence of hepatitis A virus (HAV) infection among adults.3 Eligible participants were infants born to mothers who received well-child care at the Rapid City Indian Health Service (Sioux San) Hospital. Infants were excluded if they received IG, immunosuppressive therapy, blood, or blood products; were immune-compromised; were born to hepatitis B surface antigen-positive mothers; or were diagnosed with a severe developmental disability or progressive or unstable neurologic disorder. Infants of mothers who consented to participate in the study were assigned to vaccination groups based on their mother’s anti-HAV status (generally determined at the time of prenatal care). Infants of anti-HAV-negative mothers were assigned to group 1 and received hepatitis A vaccine at 2, 4, and 6 months of age. Infants of anti-HAV-positive mothers were randomly assigned to either group 2 or group 3 and received hepatitis A vaccine at 2, 4, and 6 months of age, or hepatitis B vaccine at 2, 4, and 6 months of age and hepatitis A vaccine at 8 and 10 months of age, respectively. Infants in groups 1 and 2 received hepatitis B vaccine at 8, 10, and 15 months of age. Study enrollment began before recommendations for universal infant hepatitis B immunization. Crossover immunization with either hepatitis A or B vaccine was added as an amendment to the protocol in February of 1992 after recommendations for universal infant immunization.19 Only two doses of hepatitis A vaccine were given to infants at 8 months of age based on preliminary study data indicating >90% seroconversion in infants administered doses at 2 and 4 months of age. Mothers were blinded to the vaccination group assignment of their infant. Infants in all three groups received routinely scheduled infant immunizations against polio, diphtheria-tetanus-pertussis, and Haemophilus influenzae type b at 2, 4, and 6 months of age. Serum specimens were obtained from infants at 2, 4, 6, 8, and 15 months of age. 328
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Because the hepatitis A vaccine was not licensed in the United States at the time of the study, the clinical trial was performed under an investigational new drug application. Informed consent for infant participation was obtained from the mothers. Study approval was obtained from the Rapid City Indian Health Board and the Institutional Review Boards of the Aberdeen Area Indian Health Service, the National Indian Health Service, and the Centers for Disease Control and Prevention.
Monitoring of Adverse Events Infants enrolled in the study received well-child and acute care in a special clinic to increase compliance with vaccination schedules and to monitor potential adverse reactions to vaccination. Adverse reactions were determined through prestamped postcards given to parents after administration of each vaccine dose. If the card was not received by the clinic within 2 weeks, the parent was contacted by telephone. If telephone contact was unsuccessful, the parent was questioned at the next clinic visit.
Vaccines The inactivated hepatitis A vaccine (HAVRIX; GlaxoSmithKline Biologicals, Rixensart, Belgium) was formulated to contain 360 enzyme-linked immunosorbent assay units (ELU) of HAV in a 0.5 mL volume and had been evaluated for safety and immunogenicity in adults, adolescents, and older children.4,6 The licensed hepatitis B vaccine (Engerix B; GlaxoSmithKline Biologicals) contained 10 lg antigen and was recommended for use in infants shortly after study approval and enrollment.19 Both vaccines were administered by intramuscular injection in the anterolateral thigh; other intramuscular vaccines given at the same visit were administered in the opposite thigh.
Laboratory Studies Maternal serum specimens were tested by microparticle enzyme immunoassay (MEIA) to detect total anti-HAV (HAVAB IMx; Abbott Laboratories, North Chicago, Ill). Anti-HAV concentrations in infants were determined by MEIA (HAVAB IMx) with a reference curve prepared by The Journal of Pediatrics March 2004
Figure. Concentrations of anti-HAV (mIU/mL) in infants receiving hepatitis A vaccine, by month and anti-HAV status of mother.
using the World Health Organization reference standard at the time of the study and expressed as milli-international units per milliliter. A protective level of anti-HAV (ie, seroprotection) was defined as $20 mIU/mL.
Statistical Analysis Data were entered in Epi Info Version 6.20 Geometric mean concentration (GMC) of anti-HAV was calculated for infants with detectable anti-HAV (anti-HAV >0 mIU/mL). The Kruskall-Wallis rank-sum test was used for comparisons of GMCs between groups. The v2 or Fisher exact tests were used for comparison of proportions. The initial target enrollment was 105 infants, randomized to achieve 35 infants in each group. This sample size would provide 80% power to detect a 35% difference in anti-HAV seroconversion between groups and would detect a threefold and fourfold GMC difference between groups at powers of 73% and 89%, respectively. The randomization assumed 60% to 80% antiHAV seropositivity among mothers.
RESULTS Vaccine Immunogenicity A total of 123 infants were enrolled in the trial and received at least one dose of vaccine. Maternal anti-HAV seropositivity was lower than expected (51.2%), which led to the following distribution of infants between groups: 60 in group 1, 32 in group 2, and 31 in group 3. Of these, 53 (88%) of group 1 infants and 25 (78%) of group 2 infants received Effect of Maternal Antibody on Immunogenicity of Hepatitis A Vaccine in Infants
three doses of hepatitis A vaccine and had serum specimens available at 8 months. Nineteen (61%) of group 3 infants received three doses of hepatitis B vaccine and had adequate serum for testing at 8 months of age. Table I shows seroresponse data for the number of infants vaccinated in each group who had adequate sera for testing at each time point in the immunization schedule. For groups 1 and 2, hepatitis A vaccine doses were administered at 60 ± 10 days (mean ± SD), 120 ± 31 days, and 176 ± 14 days of age, and there were no statistically significant differences between the groups in timing of vaccine doses. For group 3, hepatitis A vaccine was administered at 294 ± 60 and 374 ± 56 days of age. All infants in group 1 were anti-HAV-negative before vaccine administration at 2 months of age, and 98% had protective levels of antibody after the second dose of vaccine (Table I). Among infants in group 2, 93% had protective antibody levels before vaccination and all infants had protective antibody levels after the second vaccine dose. In contrast, only 63% of infants who were born to anti-HAVpositive mothers and who initially received hepatitis B vaccine (group 3) had protective levels of antibody at 8 months of age (P = .005; Table I). Among infants born to anti-HAV-negative mothers (group 1), antibody concentrations increased after each vaccine dose, with highest levels 2 months after the third dose. Infants born to anti-HAV-positive mothers (groups 2 and 3) had high anti-HAV levels at 2 months of age, but infants who received hepatitis A vaccine (group 2) had higher antibody levels at 8 months of age (P = .005; Table I). However, infants in group 2 329
Table II. Frequency of adverse events after hepatitis A and hepatitis B vaccination at 2, 4, and 6 months of age
Adverse event Injection site Redness Hardness Swelling Soreness Heat General Loss of appetite Fussiness Fever >388C Drowsiness
Hepatitis A vaccine (total doses = 273) n (%) 5 14 6 22 28
(1.8) (5.1) (2.2) (8.1) (10.3)
17 42 6 39
(6.0) (16.4) (2.2) (11.9)
Hepatitis B vaccine (total doses = 74) n (%) 1 1 0 2 2
(1.4) (1.4) (2.7) (2.7)
3 (4.1) 10 (13.5) 0 5 (6.8)
P value NS* NS NS NS .04 NS NS NS NS
*Nonsignificant (P > .05) by v2 test.
had lower peak antibody levels at 8 months of age than infants born to antibody-negative mothers (group 1) P < .00001; (Table I and Figure). At 15 months or age, the anti-HAV concentrations in vaccinated infants (groups 1 and 2) had declined from their peak at 8 months of age. However, antibody levels for group 1 infants were higher than for group 2 infants (Table I; P < .001). At 15 months of age, antibody levels for infants in group 3 no longer represented the natural decline of maternally acquired anti-HAV, but represented antibody levels after two doses of hepatitis A vaccine at 8 and 10 months of age. However, there was no significant difference in GMC between groups 2 and 3 at the 15-month follow-up. Among the 12 infants in group 3 who had follow-up testing at 15 months of age, three (25%) had anti-HAV levels < 20 mIU/mL before administration of their first hepatitis A vaccine dose at 8 months of age. At the 15-month follow-up, the antibody levels in the three infants with prevaccination anti-HAV < 20 mIU/mL were higher, but not statistically different, compared with the nine infants whose prevaccination anti-HAV was $20 mIU/mL (128 mIU/mL vs 72 mIU/ mL, P = .41). In addition, antibody concentrations at age 15 months among group 3 infants with prevaccination antibody < 20mIU/mL were lower than antibody concentrations among group 1 infants (128 mIU/mL vs 231 mIU/mL, P = .29). There was no significant difference in antibody levels at 15 months of age between group 2 and 3 infants with anti-HAV levels $20 mIU/mL at 8 months of age (84 mIU/mL vs 72 mIU/mL, P = .49).
Vaccine Reactogenicity The frequency of adverse reactions within 72 hours after vaccination among infants who received hepatitis A vaccine (groups 1 and 2) was compared with the frequency of such 330
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events among infants who received hepatitis B vaccine at the same ages (group 3). To minimize potential recall bias, this analysis was based on data from the cards given to parents at the time of vaccination and mailed back to the study site. Cards were received from parents after the administration of 61% of the hepatitis A vaccine doses and 68% of the hepatitis B vaccine doses. After vaccination at 2, 4, and 6 months of age, hepatitis A vaccine had a significantly greater frequency of warmth at the injection site (Table II). The frequency of adverse events after vaccination at 8 and 10 months with either vaccine was exceedingly rare (< 1%; data not shown). There were no serious adverse events associated with any of the vaccines used during the study.
DISCUSSION This study showed that infants born to anti-HAVnegative mothers respond well to hepatitis A vaccine. Nearly all study infants developed protective levels of antibody after two doses of the 360 ELU vaccine, and all had protective levels of antibody 9 months after the third dose (at 15 months of age). However, infants born to mothers who were anti-HAVpositive had a poorer response to the vaccine series; antibody concentrations were 66% lower compared with infants of antiHAV-negative mothers vaccinated on the same schedule. In addition, infants with pre-existing maternal antibody when vaccinated at an older age (group 3) demonstrated a steady antibody decline and had lower final antibody concentrations than infants without pre-existing antibody. Of interest were the three infants born to anti-HAVpositive mothers whose prevaccination anti-HAV levels were < 20 mIU/mL at 8 months of age. Although their final antibody concentrations at 15 months showed a trend toward being higher in comparison with infants with prevaccination antibody at 8 months of age, their final antibody levels trended lower in comparison with infants born to anti-HAV-negative mothers. These nonsignificant trend data suggest that very low levels of pre-existing anti-HAV, undetectable in current immunoassays, continued to exist and inhibited the response to hepatitis A vaccine given at 8 and 10 months. Interference by maternal antibodies has been generally thought to be of more concern for live virus vaccines, such as measles vaccine, than for inactivated vaccines.21-23 However, interference by pre-existing antibody has been seen with some inactivated vaccines, including diptheria-tetanus-pertussis, and hepatitis B.24-27 Studies in adults have shown that simultaneous administration of IG and hepatitis A vaccine results in antibody levels at least 50% lower than when vaccine is administered alone.11,12 Anti-HAV levels after IG administration are generally < 100 mIU/mL and are not detectable by commercially available immunoassays that have not been modified.28 Anti-HAV levels at 2 months of age from passively acquired maternal antibody are substantially higher than those observed after IG administration and would be expected to have a similar or greater effect on the response to vaccine.29 All vaccinated infants of anti-HAV-positive mothers had protective levels of anti-HAV at 15 months of age that were lower than levels of infants born to anti-HAV–negative The Journal of Pediatrics March 2004
mothers. However, the clinical implications of these lower anti-HAV levels are unclear. Among infants in Israel vaccinated at 2, 4, and 6 months of age with hepatitis A vaccine containing 720 ELU, lower postvaccination anti-HAV levels were observed among infants born to anti-HAV–positive mothers compared with infants born to anti-HAV–negative mothers.18 Even though the anti-HAV concentrations of vaccinated infants born to anti-HAV–positive mothers continued to decline steadily until 12 months of age, all infants demonstrated an anamnestic anti-HAV response to a 720-ELU booster dose of vaccine administered at that time, suggesting that the initial vaccine series had induced priming and immune memory. In a long-term follow-up study of 11 infants from groups 1 and 2 of our study who had no detectable anti-HAV at age 6 years, all demonstrated an anamnestic anti-HAV response with a 360 ELU booster dose of vaccine. However, those infants with prevaccination antiHAV had a lower anti-HAV response compared with infants without prevaccination anti-HAV.30 Hepatitis A vaccine was well tolerated by infants born to anti-HAV-negative and to anti-HAV-positive mothers. Adverse reactions were mild, and although there was a proportionally greater frequency of adverse reactions in the hepatitis A compared with hepatitis B vaccine recipients, only heat at the injection site reached statistical significance. Hepatitis A vaccination has its greatest benefit in populations with high disease rates. In such populations, a greater proportion of women of childbearing age are likely to be anti-HAV-positive; therefore, their infants would have antibody that would interfere with a vaccine administered early in life. Vaccination of older children has been shown to reduce significantly the incidence of hepatitis A in such communities.7-10 Toddlers often have asymptomatic infection and are the source of silent transmission to susceptible persons and maintenance of the virus in a community over time.3 Therefore, sustained vaccination of children, preferably as part of the early childhood immunization schedule, will be required to prevent HAV transmission and the reintroduction of disease into communities. Our study is limited in its size, and this limitation may have been magnified by the difficulty of follow-up in a population that is highly mobile, which led to rather high dropout rates by age 15 months and wide variation in times of vaccine receipt. Further studies are needed to determine the appropriate dose and timing of immunization that would achieve a balance between optimal short-term and long-term immunogenicity and integration of hepatitis A vaccine into the childhood immunization schedule. Childhood hepatitis A vaccination has the potential to eliminate the high rates of transmission previously observed in susceptible populations that often have a high prevalence of anti-HAV-positive women of child-bearing age. We acknowledge the support and assistance of the Rapid City Indian Health Board; the laboratory and staff at Sioux San Hospital, Rapid City, South Dakota; Indian Health Service and Centers for Disease Control and Prevention employees Jeri Archer, Tom Bad Heart Bull, Marcia Beshara, MD, Sue Girga, Laurie Hrachavec, Joni Kaluba,
Effect of Maternal Antibody on Immunogenicity of Hepatitis A Vaccine in Infants
Jana Pfister, Sheila Romero, Randy Ross, Mar Than, and Deonne Warwick; the Rapid City Indian community; and parents and children who participated in the study. We also acknowledge Dr. Everett Rhoades, Director of the Indian Health Service at the time of the study, for his support and assistance in educating the Indian community on its importance.
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19. Centers for Disease Control Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40(RR-13):1-25. 20. Dean AG, Dean JA, Coulombier D, Burton AH, Brendel KA, Smith DC, et al. Epi Info, version 6: a word-processing, database, and statistics program for public health on IBM-compatible microcomputers. Atlanta (GA): Centers for Disease Control and Prevention; 1994. 21. Schluederberg A, Lamm SH, Landrigan PJ, Black FL. Measles immunity in children vaccinated before one year of age. Am J Epidemiol 1973;97:402-9. 22. Shelton JD, Jacobsen JE, Orenstein WA, Schulz KF, Donnell HD Jr. Measles vaccine efficacy: influence of age at vaccination vs. duration of time since vaccination. Pediatrics 1978;62:961-4. 23. Wilkins J, Wehrle PF. Additional evidence against measles vaccine administration to infants less than 12 months of age: altered immune response following active/passive immunization. J Pediatr 1979;94:865-9. 24. Sarvas H, Kurikka S, Seppala IJ, Makela PH, Makela O. Maternal antibodies partly inhibit an active antibody response to routine tetanus toxoid immunization in infants. J Infect Dis 1992;165:977-9.
25. Englund JA, Anderson EL, Reed G, Decker MD, Edwards KM, Pichichero ME, et al. The effect of maternal antibody on the serologic response and the incidence of adverse reactions after primary immunization with acellular and whole cell-pertussis vaccines combined with diphtheria and tetanus toxoids. Pediatrics 1995;96:580-4. 26. Siegrist C-A, Cordova M, Brandt C, Barrios C, Berney M, Tougne C, et al. Determinants of infant responses to vaccines in presence of maternal antibodies. Vaccine 1998;16:1409-14. 27. Xu Z-Y, Duan S-C, Margolis HS, Purcell RH, Ou-yang P-Y, Coleman PJ, et al. Long-term efficacy of active postexposure immunization of infants for prevention of hepatitis B virus infection. J Infect Dis 1995;171:54-60. 28. Lemon SM. Immunologic approaches to assessing the response to inactivated hepatitis A vaccine. J Hepatol 1993;18(Suppl 2):S15-9. 29. Linder N, Karetnyi Y, Gidony Y, Ohel G, Levin E, Kuint J, et al. Placental transfer of hepatitis A antibodies in full term and preterm infants. Ped Infect Dis J 1997;162:245-7. 30. Fiore AE, Shapiro CN, Sabin K, Labonte K, Darling K, Culver D, et al. Hepatitis A vaccination of infants: effect of maternal antibody status on antibody persistence and response to a booster dose. Pediatr Infect Dis J 2003;22:354-9.
50 Years Ago in The Journal of Pediatrics THE TONSIL PENDULUM Editor’s column. J Pediatr 1954;44:235-6 The Editor congratulates the end of an era of unnecessary excess of tonsillectomies, recommending that the process of decision-making to perform this procedure should be based on the same rigor used for a more complex surgery such as an appendectomy. Fifty years later, although the frequency of amigdalectomies has decreased and indications have been clearly defined, it continues to be one of the most common surgical interventions in pediatrics. This indicates that the enormous progress in medical knowledge that has occurred during the last half century has not been accompanied at a same pace by an advance in medical judgment and critical medical assessment. The Editor supports the conservation of the tonsils with the argument, accepted in those days, that the more severe form of polio, bulbar polio, was commonly preceded within a few weeks by the surgical extraction of them. The Editor cites three studies reporting an excess of fatal cases in patients without tonsils and adenoids, even if the extraction had been performed years before, proposing the hypothesis that this severe complication may have been not so much a consequence of the surgical trauma but, ‘‘perhaps the loss of a filter, so to speak.’’ Advances in the field of immunology have showed that this ‘‘perhaps’’ was in the right track because adenoids and tonsils are currently considered highly relevant in protecting against pathogen invasion of the upper respiratory tract, reacting through stimulation of both the humoral and cellular components of the immune response. Medicine in the 1950s was based largely on observation, not always supported by the more complete laboratory research of today, and thus for not uncommonly reaching erroneous conclusions. Appropriately used though, observation will remain to be a much needed scientific tool for the generation of new ideas, maintaining in a way, a healthy oscillation of the pendulum. Perhaps. . . Walter Ledermann, MD Service and Department of Pediatrics Hospital Luis Calvo Mackenna, Universidad de Chile Antonio Varas 360, Santiago, Chile YMPD627 10.1016/j.jpeds.2003.11.003
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The Journal of Pediatrics March 2004