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Hepatitis B vaccination in infants of mothers infected with human immunodeficiency virus
70
Zuccotti et al.
The Journal of Pediatrics July 1994
Hepatitis B vaccination in infants of mothers infected with human immunodeficiency virus G. V. Z u c c o t t i , MD, E. Riva, MD, P. Flumine, MD, V. Locatelli, MD, A. Fiocchi, MD, GI T o r d a t o , MD, a n d M. Giovannini, MD From the Fifth Pediatric Department, University of Milan, Milan, Italy, and the Laboratory of Biochemicals, Ospedale S. Paolo, Milan, Italy
Eighteen infants of mothers with human immunodeficiency virus (HIV) infection were given hepatitis B vaccine at birth. Seroconversion occurred inal113 infants whose HIV antibody disappeared, versus one of five HIV-infected children. The four of five HIV-infected infants who did not mount an antibody response progressed rapidly to full-blown acquired immunodeficiency syndrome. Thus HIVinfected infants respond poorly to hepatitis B vaccine. (J PEDIATR1994;125:70-2) Hepatitis B vaccination of children results in seroconversion in almost all cases. An antibody response has been demonstrated in both adults and children with acquired immun0deficiency syndrom@ "5 but the more ad~,anced the stage Of the disease, the greater is the likelihood of a poor response. Eighteen infants born to mothers infected with human immunodeficiency virus were studied to determine whether early vaccination would induce seroconversion. METHODS Eighteen infants (13 boys) born to HIV-infected mothers were studied at the Fifth Pediatric Department of the University of Milan. The mothers were at risk of acquiring HIV infection because of drug addiction. None of the mothers had hepatitis B surface antigen at the time of delivery. All infants were born at term (between 38 and 41 weeks of gestation), and their weights (2700 to 3400 gin) were adequate for their gestational age. None of the infants had evidence of HIV infection at birth. There was no immunologic evidence of vertical transmission, and no infant had p24 antigen: An adult dose (20/~g) of second-generation, recombinant hepatitis B vaccine (Engerix-B) was administered in the anterolateral region of the thigh a few hours after birth. The same dose was again given at 1 and 6 months of age, and, in the case of nonresponders, a fourth dose was administered 3 to 4 months after the third.
Submitted for publication Oct. 18, 1993; accepted Jan. 25, 1994. Reprint requests: Gian Vincenzo Zuccotti, MD, Fifth Pediatric Department, University of Milan, Ospedale San Paolo, Via A di Rudini, 8, 20142 Milan, Italy. Copyright © 1994 by Mosby-Year Book, Inc. 0022-3476/94/$3.00 + 0 9/22/54778
Anti-hepatitis B surface antibody levels were determined by the immunoenzymatic method (IMX system, Abbott Laboratories Diagnostic Division Abbott Park, Ill.) 1 month after the first dose, 1 to 3 months after the second dose, and 2 to 3 months after the third dose. In the case of nonresponders, the anti-HBsAb level was evaluated again 2 to 3 months after the booster dose. Anti-HBsAb titers were expressed in international units per liter. The children were examined monthly, and laboratory evaluation was obtained every 3 months for at least 18
See related articles, pp. 72, 74, and 77.
ELISA HBsAb HIV
Enzyme-linked immunosorbent assay Hepatitis B surface antibody Human immunodeficiency virus
[
L
months. The HIV-infection status of each child was classified on the basis of the schedul e provided by the Centers for Disease Control and Prevention (CDC), Atlanta, Ga. 6 The following laboratory studies were done: (1) lymphocyte subpopulation count s by flow cytometry, expressed as an absolute number per cubic millimeter, and the CD4/ CD8 ratio, (2) antigen p24 determination by an immunoenzymatic method (ELISA; Abbott), with values expressed in picograms/per milliliter, and (3) anti-HIV antibody by immunoenzymatic method (ELISA), confirmed by Western blot. The subject was considered to be uninfected with HIV (CDC class P-3) if HIV antibodies, detected by ELISA and the Western blot test, disappeared by 18 months of age. Statistical analyses were carried out with the MannWhitney U test.
The Journal o f Pediatrics Volume 125, Number 1
Z u c c o t t i et al.
71
T a b l e I. Clinical and immunologic findings in HIV-infected children at first appearance of symptoms
Age at first symptom (mo)
CDC stage
CD4 count (absolute No./mm 3)
CD4/CD8 ratio
p24 antigen (pg/ml)
1610 1672 891 816 794
1.77 0.44 0.77 0.70 0.56
40 >250 50 132 0
2183 1027-4746
1.8 1.0-2.9
Infected children 1
2 3 4 5 Uninfected children Median Range
P-2 P-2 P-2 P-2 P-2
6
5 3 5 2
A,B,F B B A A,F
T a b l e II. Anti-HBs Ab response versus clinical stage, absolute CD4, number C D 4 / C D 8 ratio, and p24 antigenemia in
HIV-infected children
HIV-infected children After second dose 1 2 3 4 5 After third dose 1 2 3 4 5
CDC stage B B B
CD4 (absolute No./mm 3)
CD4/CD8 ratio 1.50 0.44 0.77 1.30 0.56 0.65 0.43 1.05 0.83 0.50
P-1 P-2 P-2 P-0 P-2
A,F
2640 1672 891 858 794
P-2 P-2 P-2 P-2 P-2
A,B,F B B A,F A,F
836 1491 2160 1247 1260
RESULTS Thirteen children (nine boys) had no anti-HIV antibodies by the age of 18 months (average, 15 months; range, 10 to 18 months). Five children (four boys) had clinical symptoms suggestive of H I V infection (mean, 4.2 months; range, 2 to 6 months) and were classified as in stage P-2 of disease. Table I presents the clinical and immunologic status of the HIV-infected subjects at the time their first symptoms appeared. Seroconversion was detected by antiH B s A b in 14 children (10 boys). The mean response was 586 I U / L , ranging from 20 I U / L to >1000 I U / L after the third dose. One child had seroconversion only after the first injection (156 I U / L ) and no longer had positive test results after three further doses. Three children (2 boys) did not have seroconversion. The 13 uninfected children had seroconversion. Only one of the five HIV-infected children had an anti-HBsAb response (Table II). DISCUSSION Current opinion favors an early vaccination cycle in HIV-infected children to challenge the intact immune sys-
p24 antigen (pg/ml) 40 >250 50 0 0 128 248 70 116 5.1
HBsAb (IU/L) <10 <10 <10 161 <10 <10 25 <10 86 <10
tern and promote a lasting antibody response. There is no evidence that stimulation with various antigens promotes H I V infection in children. The effectiveness of early hepatitis B vaccination among neonates exposed to HIV, however, remains an open question. W e wanted to investigate whether a double dose of recombinant hepatitis B vaccine, administered at birth to infants born to mothers with seropositivity, is an adequate strategy to avoid a high percentage of HIV-infected nonresponders. No sustained antibody response to hepatitis B virus was found among those infants eventually found to have H I V infection. None of our clinical or laboratory findings provides reasons for a diminished response to the vaccine in the neonate. W e conclude that the response of HIV-infected children to the hepatitis B vaccine is poor, even when an adult dose of the vaccine is administered at birth. A rapid fall in levels of antibody to hepatitis B virus is observed when a response is present. It is likely that immunologic damage is already present at birth, although undetected by current immunologic examinations. Absence of seroconversion after hepatitis B vaccination at birth may indicate a poor prognosis for infants born to mothers with H I V infection.
72
Rudy, Rutstein, and Pinto-Martin
REFERENCES 1. Stevens CE, Alter H J, Taylor PE, et al. Hepatitis B vaccine in patients receiving hemodialysis: immunogenicity and efficacy. N Engl J Med 1984;311:496-501. 2. Hillerman RE. Hepatitis B and AIDS and the promise for their control by vaccines. Vaccine 1988;6:175-9. 3. Odaka N, Eldred L, Cohn S, et al. Comparative immunogenicity of plasma and recombinant hepatitis B virus vaccines in homosexual men. JAMA 1988;24:3635. 4. Lane HC, Masar H, Edgar LC, et al. Abnormalities of B-cell
The Journal of Pediatrics July 1994
activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 1983;309:453-8. 5. Hadler SC, Hudson FN, O'Malley PM, et al. Outcome of hepatitis B virus infection in homosexual men and its relation to prior human immunodeficiency virus infection. J Infect Dis 1991;163:454-9. 6. Centers for Disease Control. Classification system for human immunodeficiency virus (HIV) infection in children under 13 years of age. MMWR 1987;36:225-35.
Responses to measles immunization in children infected with human immunodeficiency virus Bret J. Rudy, MD, Richard M. Rutstein, MD, a n d J e n n i f e r P i n t o - M a r t i n , PhD From the Division of General Pediatrics and Special Immunology Service, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
The responses to measles immunization a d m i n i s t e r e d b e t w e e n 6 a n d 12 months a n d after 12 months were c o m p a r e d in children with a n d without h u m a n immun o d e f i c i e n c y virus infection. No d i f f e r e n c e in response was found when primary measles immunization was a d m i n i s t e r e d b e t w e e n 6 a n d 12 months; however, children with h u m a n i m m u n o d e f i c i e n c y virus infection h a d a significantly poorer response when immunization was given after 12 months. Early measles immunization should be c o n s i d e r e d in children with h u m a n i m m u n o d e f i c i e n c y virus infection. (J PEDIATR1994;125:72-4)
Severe pneumonia is reported as the primary complication from measles in children with human immunodeficiency virus infection, and death may occur. 1-4 Children infected with H I V do not appear to have an increased rate of complications from measles vaccination, and the Centers for Disease Control and Prevention has recommended vaccination of all children with H I V infection. 5 However, one study reported an immunization response in only 25% of children with H I V infection) During the measles epidemic in Philadelphia from December 1990 to June 1992, infants received the single-antigen measles vaccine between 6 and 12 months; a booster was given at 15 months. This immunization schedule was
Submitted for publication Dec. 1, 1993; accepted March 4, 1994, Reprint requests: Bret J. Rudy, MD, Division of General Pediatrics and Special Immunology, 34th St. and Civic Center Blvd., Philadelphia, PA 19104. Copyright ® 1994 by Mosby-Year Book, Inc. 0022-3476/94/$3.00 + 0 9/22/55717
followed for children with H I V infection. After the epidemic, early vaccination was discontinued. In this study we determined the prevalence of maternally acquired measles antibodies before 6 months of age in infants exposed to HIV. W e also compared the antibody response of HIV-infected and uninfected infants with administration of measles vaccine at 6 to 12 months and the re-
See related articles, pp. 70, 74, and 77.
HIV MMR
Human immunodefieiency virus Measles-mumps-rubella [vaccine]
I
I
sponse to measles-mumps-rubella vaccine administered after 12 months of age in HIV-infected and uninfected children. METHODS Infection with H I V was confirmed by the persistence of antibodies after 15 months, by positive results with H I V
Zuccotti et al.
The Journal of Pediatrics July 1994
Hepatitis B vaccination in infants of mothers infected with human immunodeficiency virus G. V. Z u c c o t t i , MD, E. Riva, MD, P. Flumine, MD, V. Locatelli, MD, A. Fiocchi, MD, GI T o r d a t o , MD, a n d M. Giovannini, MD From the Fifth Pediatric Department, University of Milan, Milan, Italy, and the Laboratory of Biochemicals, Ospedale S. Paolo, Milan, Italy
Eighteen infants of mothers with human immunodeficiency virus (HIV) infection were given hepatitis B vaccine at birth. Seroconversion occurred inal113 infants whose HIV antibody disappeared, versus one of five HIV-infected children. The four of five HIV-infected infants who did not mount an antibody response progressed rapidly to full-blown acquired immunodeficiency syndrome. Thus HIVinfected infants respond poorly to hepatitis B vaccine. (J PEDIATR1994;125:70-2) Hepatitis B vaccination of children results in seroconversion in almost all cases. An antibody response has been demonstrated in both adults and children with acquired immun0deficiency syndrom@ "5 but the more ad~,anced the stage Of the disease, the greater is the likelihood of a poor response. Eighteen infants born to mothers infected with human immunodeficiency virus were studied to determine whether early vaccination would induce seroconversion. METHODS Eighteen infants (13 boys) born to HIV-infected mothers were studied at the Fifth Pediatric Department of the University of Milan. The mothers were at risk of acquiring HIV infection because of drug addiction. None of the mothers had hepatitis B surface antigen at the time of delivery. All infants were born at term (between 38 and 41 weeks of gestation), and their weights (2700 to 3400 gin) were adequate for their gestational age. None of the infants had evidence of HIV infection at birth. There was no immunologic evidence of vertical transmission, and no infant had p24 antigen: An adult dose (20/~g) of second-generation, recombinant hepatitis B vaccine (Engerix-B) was administered in the anterolateral region of the thigh a few hours after birth. The same dose was again given at 1 and 6 months of age, and, in the case of nonresponders, a fourth dose was administered 3 to 4 months after the third.
Submitted for publication Oct. 18, 1993; accepted Jan. 25, 1994. Reprint requests: Gian Vincenzo Zuccotti, MD, Fifth Pediatric Department, University of Milan, Ospedale San Paolo, Via A di Rudini, 8, 20142 Milan, Italy. Copyright © 1994 by Mosby-Year Book, Inc. 0022-3476/94/$3.00 + 0 9/22/54778
Anti-hepatitis B surface antibody levels were determined by the immunoenzymatic method (IMX system, Abbott Laboratories Diagnostic Division Abbott Park, Ill.) 1 month after the first dose, 1 to 3 months after the second dose, and 2 to 3 months after the third dose. In the case of nonresponders, the anti-HBsAb level was evaluated again 2 to 3 months after the booster dose. Anti-HBsAb titers were expressed in international units per liter. The children were examined monthly, and laboratory evaluation was obtained every 3 months for at least 18
See related articles, pp. 72, 74, and 77.
ELISA HBsAb HIV
Enzyme-linked immunosorbent assay Hepatitis B surface antibody Human immunodeficiency virus
[
L
months. The HIV-infection status of each child was classified on the basis of the schedul e provided by the Centers for Disease Control and Prevention (CDC), Atlanta, Ga. 6 The following laboratory studies were done: (1) lymphocyte subpopulation count s by flow cytometry, expressed as an absolute number per cubic millimeter, and the CD4/ CD8 ratio, (2) antigen p24 determination by an immunoenzymatic method (ELISA; Abbott), with values expressed in picograms/per milliliter, and (3) anti-HIV antibody by immunoenzymatic method (ELISA), confirmed by Western blot. The subject was considered to be uninfected with HIV (CDC class P-3) if HIV antibodies, detected by ELISA and the Western blot test, disappeared by 18 months of age. Statistical analyses were carried out with the MannWhitney U test.
The Journal o f Pediatrics Volume 125, Number 1
Z u c c o t t i et al.
71
T a b l e I. Clinical and immunologic findings in HIV-infected children at first appearance of symptoms
Age at first symptom (mo)
CDC stage
CD4 count (absolute No./mm 3)
CD4/CD8 ratio
p24 antigen (pg/ml)
1610 1672 891 816 794
1.77 0.44 0.77 0.70 0.56
40 >250 50 132 0
2183 1027-4746
1.8 1.0-2.9
Infected children 1
2 3 4 5 Uninfected children Median Range
P-2 P-2 P-2 P-2 P-2
6
5 3 5 2
A,B,F B B A A,F
T a b l e II. Anti-HBs Ab response versus clinical stage, absolute CD4, number C D 4 / C D 8 ratio, and p24 antigenemia in
HIV-infected children
HIV-infected children After second dose 1 2 3 4 5 After third dose 1 2 3 4 5
CDC stage B B B
CD4 (absolute No./mm 3)
CD4/CD8 ratio 1.50 0.44 0.77 1.30 0.56 0.65 0.43 1.05 0.83 0.50
P-1 P-2 P-2 P-0 P-2
A,F
2640 1672 891 858 794
P-2 P-2 P-2 P-2 P-2
A,B,F B B A,F A,F
836 1491 2160 1247 1260
RESULTS Thirteen children (nine boys) had no anti-HIV antibodies by the age of 18 months (average, 15 months; range, 10 to 18 months). Five children (four boys) had clinical symptoms suggestive of H I V infection (mean, 4.2 months; range, 2 to 6 months) and were classified as in stage P-2 of disease. Table I presents the clinical and immunologic status of the HIV-infected subjects at the time their first symptoms appeared. Seroconversion was detected by antiH B s A b in 14 children (10 boys). The mean response was 586 I U / L , ranging from 20 I U / L to >1000 I U / L after the third dose. One child had seroconversion only after the first injection (156 I U / L ) and no longer had positive test results after three further doses. Three children (2 boys) did not have seroconversion. The 13 uninfected children had seroconversion. Only one of the five HIV-infected children had an anti-HBsAb response (Table II). DISCUSSION Current opinion favors an early vaccination cycle in HIV-infected children to challenge the intact immune sys-
p24 antigen (pg/ml) 40 >250 50 0 0 128 248 70 116 5.1
HBsAb (IU/L) <10 <10 <10 161 <10 <10 25 <10 86 <10
tern and promote a lasting antibody response. There is no evidence that stimulation with various antigens promotes H I V infection in children. The effectiveness of early hepatitis B vaccination among neonates exposed to HIV, however, remains an open question. W e wanted to investigate whether a double dose of recombinant hepatitis B vaccine, administered at birth to infants born to mothers with seropositivity, is an adequate strategy to avoid a high percentage of HIV-infected nonresponders. No sustained antibody response to hepatitis B virus was found among those infants eventually found to have H I V infection. None of our clinical or laboratory findings provides reasons for a diminished response to the vaccine in the neonate. W e conclude that the response of HIV-infected children to the hepatitis B vaccine is poor, even when an adult dose of the vaccine is administered at birth. A rapid fall in levels of antibody to hepatitis B virus is observed when a response is present. It is likely that immunologic damage is already present at birth, although undetected by current immunologic examinations. Absence of seroconversion after hepatitis B vaccination at birth may indicate a poor prognosis for infants born to mothers with H I V infection.
72
Rudy, Rutstein, and Pinto-Martin
REFERENCES 1. Stevens CE, Alter H J, Taylor PE, et al. Hepatitis B vaccine in patients receiving hemodialysis: immunogenicity and efficacy. N Engl J Med 1984;311:496-501. 2. Hillerman RE. Hepatitis B and AIDS and the promise for their control by vaccines. Vaccine 1988;6:175-9. 3. Odaka N, Eldred L, Cohn S, et al. Comparative immunogenicity of plasma and recombinant hepatitis B virus vaccines in homosexual men. JAMA 1988;24:3635. 4. Lane HC, Masar H, Edgar LC, et al. Abnormalities of B-cell
The Journal of Pediatrics July 1994
activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 1983;309:453-8. 5. Hadler SC, Hudson FN, O'Malley PM, et al. Outcome of hepatitis B virus infection in homosexual men and its relation to prior human immunodeficiency virus infection. J Infect Dis 1991;163:454-9. 6. Centers for Disease Control. Classification system for human immunodeficiency virus (HIV) infection in children under 13 years of age. MMWR 1987;36:225-35.
Responses to measles immunization in children infected with human immunodeficiency virus Bret J. Rudy, MD, Richard M. Rutstein, MD, a n d J e n n i f e r P i n t o - M a r t i n , PhD From the Division of General Pediatrics and Special Immunology Service, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
The responses to measles immunization a d m i n i s t e r e d b e t w e e n 6 a n d 12 months a n d after 12 months were c o m p a r e d in children with a n d without h u m a n immun o d e f i c i e n c y virus infection. No d i f f e r e n c e in response was found when primary measles immunization was a d m i n i s t e r e d b e t w e e n 6 a n d 12 months; however, children with h u m a n i m m u n o d e f i c i e n c y virus infection h a d a significantly poorer response when immunization was given after 12 months. Early measles immunization should be c o n s i d e r e d in children with h u m a n i m m u n o d e f i c i e n c y virus infection. (J PEDIATR1994;125:72-4)
Severe pneumonia is reported as the primary complication from measles in children with human immunodeficiency virus infection, and death may occur. 1-4 Children infected with H I V do not appear to have an increased rate of complications from measles vaccination, and the Centers for Disease Control and Prevention has recommended vaccination of all children with H I V infection. 5 However, one study reported an immunization response in only 25% of children with H I V infection) During the measles epidemic in Philadelphia from December 1990 to June 1992, infants received the single-antigen measles vaccine between 6 and 12 months; a booster was given at 15 months. This immunization schedule was
Submitted for publication Dec. 1, 1993; accepted March 4, 1994, Reprint requests: Bret J. Rudy, MD, Division of General Pediatrics and Special Immunology, 34th St. and Civic Center Blvd., Philadelphia, PA 19104. Copyright ® 1994 by Mosby-Year Book, Inc. 0022-3476/94/$3.00 + 0 9/22/55717
followed for children with H I V infection. After the epidemic, early vaccination was discontinued. In this study we determined the prevalence of maternally acquired measles antibodies before 6 months of age in infants exposed to HIV. W e also compared the antibody response of HIV-infected and uninfected infants with administration of measles vaccine at 6 to 12 months and the re-
See related articles, pp. 70, 74, and 77.
HIV MMR
Human immunodefieiency virus Measles-mumps-rubella [vaccine]
I
I
sponse to measles-mumps-rubella vaccine administered after 12 months of age in HIV-infected and uninfected children. METHODS Infection with H I V was confirmed by the persistence of antibodies after 15 months, by positive results with H I V