INTRADERMAL HEPATITIS B VACCINATION Michael P. Rivey and John Peterson
See also pages 617 and 671. ABSTRACf: The availability of vaccine since 1982for immunization against hepatitisB virus (HBV) has had minimal impacton the disease; mass immunization has been suggested. Intradermal vaccination, which has precedent in prophylaxisof other infectiousdiseases, has been investigated as a low-costalternativeto traditional intramuscular HBV vaccination. Results of open and comparativetrials indicatesimilar seroconversion rates for intradermal and intramuscularHBV vaccination routes in healthy adults. However, antibody titers and, presumably, duration of antibody protection appear to be decreased with intradermal HBV vaccination. Limited data suggest that demographicfactors such as age and gender may affect vaccine responsiveness to intradermal HBV vaccine. Adverse skin reactionsare common but do not represent a deterrentto continued intradermal HBV vaccination. There is a need for large-scale prospectivecomparativetrials to substantiatethe value of intradermal HBV vaccination. Nevertheless, the potentialeconomic and epidemiologic benefitof intradermal vaccinationjustifies continued investigation for preventionof HBV infection. DICP Ann Pharmacother 1991;25:628-34.
HEPATITIS B VIRUS (HBV) infection remains a major health issue in the US. In 1989, the Centers for Disease Control (CDC) recorded 23419 HBV cases, a number comparable to that of prior years and acknowledged to represent part of an estimated 300 (){)() infected individuals.i> The scope of this problem is further magnified by the HBV-infected carrier pool, estimated to include 750000-1 (){)() 000 persons in the US alone.e Although the annual incidence of HBV has declined slightly since 1985, the availability of HBV vaccine since 1982 appears to have had minimal impact on the disease. Present CDC strategy continues to target only high-risk groups for HBV vaccination.t Healthcare workers and homosexuals are the only high-risk groups characterized by decreased rates of infection since 1981 (75 and 62 percent, respectively). However, these decreases were offset by concomitant increases of 80 percent in parenteral drug users and 38 percent in high-risk heterosexual groups. More importantly, the percentage of patients with HBV with no identifiable risk factors (30-40 percent) has not changed.ss In light of the failure of present strategy to significantly lessen the incidence of HBV infection, it has been suggested that universal vaccination of groups such MICHAEL P. RIVEY, M.S.. is an Assistant Professor of Clinical Pharmacy, School of Pharmacy, University of Montana, Missoula, MT 59812; and JOHN PETERSON, Phann.D., is a Visiting Lecturer, School of Pharmacy, University of Montana. Reprints: Michael P. Rivey, M.S.
This article is approved for continuingeducation credit.
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Dltl}', The Annals ofPharmacotherapy •
as infants or adolescents be required. People would then be vaccinated before exposure to high-risk activity.v Compliance with intramuscular HBV vaccination programs has been modest. Crossley et al. reported that only 38 percent of 1193 hospital personnel requested vaccinations offered free of charge by two hospitals in 1982. Over 90 percent of 487 persons declining this free offer were aware of their risk for infection; however, more than 50 percent wanted to know more about the vaccine.s The CDC published survey results of compliance rates for intramuscular HBV vaccination in 1987, Only 24 percent of physicians responding to a survey in three large cities, 44 percent of dentists responding to a 1986 national survey, and 44 percent of hemodialysis staff participating in a 1985 national survey had been vaccinated,» Reasons for avoidance of vaccination include desire for additional HBV vaccine testing, concern regarding human immunodeficiency or other virus transmission with use of the plasma-derived (PD) HBV vaccine, and cost of the recommended intramuscular regimen.i Although the introduction of new recombinant vaccines has presumably served to partially alleviate vaccine contamination concerns, these products offer little cost reduction compared with PD vaccine and still require additional testing.vt Intradermal HBV vaccination, typically using one-tenth of an intramuscular dose, has been investigated as an alternative to traditional intramuscular vaccination. This route of administration has already demonstrated success in the treatment of other infectious diseases, including rabies.s Intradermal vaccination is based on the presence of dermis Langerhans' cells that have been shown to capture antigen in a macrophage-like fashion and present it to T cells.s If justified, intradermal vaccine use could exert a major impact on the epidemiology of HBV infection. Cost savings associated with intradermal vaccination may increase compliance with existing vaccination programs and perhaps facilitate implementation of universal vaccination. The following issues are important when considering the use of intradermal HBV vaccine: Is the immunoresponsiveness comparable to that of the intramuscular preparation? What is the degree and duration of HBV protection achieved with seroconversion? Who best responds (or fails to respond) to intradermal HBV vaccine? Are there special considerations regarding the intradermal route of administration? Finally, how frequently do adverse effects occur and could they lessen the utility of an intradermal HBV vaccine program?
1991 June, Volume 25
Immunoresponsiveness ofIntradermal Hepatitis B Virus Vaccine
Seroconversion following HBV vaccine administration is defined as formation of an initial antibody concentration ~~O mlU/mL in response to hepatitis B surface antigen-s this concentration has been associated with a decreased risk of late infection." Alternatively, some investigators have defined seroconversion as a PIN ratio unit (ratio of antibody count per minute of tested positive sample to mean of negative control samples) of~2.1.u Results of intradermal HBV vaccine studies indicate that approximately 90 percent of healthy persons develop seroconversion six to nine months after initiation of a three-dose regimen (Tables I and 2). Moreover, data from comparative studies suggest that initial seroconversion rates are similar following both intradermal and intramuscular vaccination (Table 2). Results of a study with PO HBV vaccine demonstrated that seroconversion rates achieved with both intradermal and intramuscular vaccine adIJ.linistration (100 and 94 percent, respectively) were supenor to the seroconversion rate achieved with subcutaneous vaccination (42 percent);" this lower seroconversion rate is expected because of the absence of Langerhans' cells in subcutaneous tissue. In contrast, other studies with PO vaccine describe comparable immunoresponsiveness associated with the subcutaneous route.26.J4 ~everal observations can be made about existing studies of intradermal HBV vaccine. Most investigations have been conducted in healthy young adults. Nevertheless, results of limited studies conducted in neonates and children s.uggest similar immunoresponsiveness in these populatIons.15.24.30 Intradermal HBV vaccine studies have not been conducted in homosexual, hemodialysis, or drug abuse populations. The intradermal vaccine dosage most commonly used has been PO vaccine 2 ug given at 0, 30, and 180 days. Increased doses or shortened dosing regimens have not been shown to increase the seroconversion
rate.21•24 Results from two studies using recombinant vaccine I ug suggest that rate of seroconversion is decreased to approximately 80 percent with the decreased dose.ls.31 However, it should be noted that only one group of investigators has compared the seroconversion rate associated with an uncommon (4-f.!g) dose with that of the common 2-f.!g dose using the same vaccine and dosing regimen in the same population." Limited data on the use of yeast-derived recombinant HBV vaccines (either 10 or 20 ug/ml.) have suggested that these vaccines possess immunogenic properties comparable to those of PO vaccine.' Open studies of recombinant vaccine I or 2 ug given intradennally have resulted in seroconversion rates of approximately 80 percent.F-" Bryan et al. reported a similar seroconversion rate in volunteers randomized to receive recombinant vaccine I ug intradermally; the rate was significantly lower than that observed in subjects receiving PO vaccine 2 ug (p=0.05),31 In contrast, Kurtz et al. compared the immunogenicity of 2 ug doses of both recombinant and PO HBV vaccine in 95 medical students randomized to receive either vaccine intradennally. The percentage of responders was less in the recombinant group than in the PO group (87.2 vs. 97.6 percent, respectively); however, this difference was not statistically significant." Oata from.a .sma~l number of comparative studies suggest that administration of one-tenth of a typical dose of intramuscular vaccine may result in similar seroconversion rates and antibody titers as intradermal vaccine administration.24.30,32 Duration ofIntradermal Vaccine Protection
The greatest concern regarding intradermal HBV vaccination has focused on the duration of protection achieved with the vaccine. It must be noted that the magnitude and duration of antibody response vary among individuals and have not been completely described for recombinant vac-
Table I. Open Studies of Intradermal Hepatitis B Vaccine ANTI-HBs (mIU/mL) POPULATION
Healthcare workers Healthcare workers Medical students Gambian children ($10 y) Medical students Healthcare workers Healthcare workers Medical students/healthcare workers Mentally retarded people
PATIENTS
DOSING REGIMEN"
(n)
(ug)
14 88 47 166 34 20 42 47 216 32 92
PD2 PD2'
62
PD2 PD4,d PD2 RC2 RC2 f RC If PD2 PD4
SEROLOGY TIME (mo)
GMT (mIU/mL)
6-7 3 14 7-9 30
>100 >IO b
8S.7 8S.2
91.S 89.2 79.4
4.S
7-9 7-9 7-9 7 6 12 9 12
2400' 600
127 396
97.6 87.2 80.9 81.3
92g 9Sg 83.9 82.3
(%)
69.3 78.3 76.S
41.2 100.0
32.S
S8g 8g 60 g 60g
>1000
38.6 28.2 SI.2 14.7
REF.
II 12 13,14 IS 16
4.2
17
sg
18 19
3Sg 20
"Dosing at O. I, and 6 months unless otherwise specified. "Alternatively, PIN ratio (the ratio of antibody counl per minute of tested positive sample to mean of negative control sample) ~2.1. 'Dosing at 0, I, and 2 months. "By jetgun. 'Median titer (p1000
REF.
84.6 95.0 100.0 100.0 100.0 77.8 100.0 96.0 100.0 91.7 95.8 93.8 94.7 100.0 84.2 96.3 88.5 100.0 95.8 100.0 80.0 82.7 65.5 89.9 87.5 100.0 42.1 93.8 94.7 17.6 87.5 73.7 94.7 92.0 96.8 91.0 97.0 100.0 77.6 89.8 100.0 93.9 90.4 100,()i 100.Qi 100.Qi lOO.Qi
52.3 78.3 90.7 77.8 100.0 44.4 77.8
1.5 1.7 13.3
15
21.22
23
24
25
26
100.0 36.8 87.5 63.2 17.6 75.0
27
28 29 30
31
82.9 78.3
32.9 37.3
"Merck Sharp & Dohme or Smith Kline & Beecham vaccine. "Dosing at O. I. and 6 months unless otherwise specified. 'Alternatively. PIN ratio (the ratio of antibody count per minute of tested positive sample to mean of negative control samples) ~2.1. dBy jet gun. 'Dosing at O. I. and 2 months. 'Dosing at O. I. and 4 months. gDosing at 0, 2. and 4 months. "Dosing at O. I. and 5 months. 'Four doses at O. I. 2. and 6 months. JSignificantly higher titers in im group (p 1000 mIU/mL measured 6-12 months after administration of the first intramuscular vaccine dose have been associated with a >90 percent rate of protection five years following vaccination. In contrast, titers between 100 and 999 mIU/mL appear to maintain five-year seroconversion in In comparative trials, the intramuscular route was associated with a 17-47 percent incidence of muscle pain or stiffness compared with a 31-80 percent incidence of local skin reactions associated with the intradermal route. 23,28,31..39 Hyperpigmented maculas at the intradermal injection site occur in 50-78 percent of patients and persist for more than one year in over 60 percent of patients. I 1,18.19 There is no correlation between the absence or presence of a skin reaction and degree of immunologic response.F-" A number of investigators have hypothesized that the alum adjuvant in HBY vaccine is responsible for the local skin reactions.u· 17,23,43 However, Zoulek et al. found no skin reactions in ten control patients given intradermal adjuvant" and Clarke et al. determined that local reactions were characteristic of transient immune rather than foreign-body reactions.'? No difference in the incidences of local skin reactions associated with intradermal injections of recombinant versus PO vaccine has been observed." Despite common skin reactions, the intradermal route has a high acceptance rate; 90-100 percent of intradermal HBY vaccine recipients indicate they would recommend this route to coworkers.Pw-' Limited data suggest that the intradermal route is preferred to intramuscular HBY vaccination by adults.Fr" Milne et al. reported that the intradermal route was less well tolerated in children than low-dose intramuscular vaccination.>' However, this finding primarily appeared to reflect increased skin reactions, especially itching associated with intradermal vaccination, rather than patient preference. Summary
Sufficient data exist to prove the irnmunogenicity of intradermal HBY vaccine in young healthy adults; the seroconversion rate appears to be comparable to that of the intramuscular product. Limited data have suggested the utility of intradermal vaccine in neonatal and pediatric populations; however, there is need for further studies as these populations primarily would be targeted for universal vac632 •
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cination programs. No data regarding intradermal HBY vaccination in other high-risk groups are available. Factors such as age, weight, and smoking that are associated with decreased response to intradermal HBY vaccination are probably identical to those already elucidated for intramuscular vaccination, and should be evaluated when considering the intradermal route. Based on discrepant results from existing studies, the influence of gender on immune response to intradermal vaccine also should be addressed in future studies. It seems certain that intradermal HBY vaccination results in lower antibody titers compared with those reached following traditional intramuscular vaccination. However, the clinical importance of anamnestic response in initial responders developing undetectable or low antibody titers is unknown. There is a need to further delineate the duration of antibody protection following intradermal HBY vaccination. Alternatively, available data suggest that it could be very cost-effective to give booster doses of intradermal HBY vaccine on a regular basis, such as every three years. However, most of these data reflect studies conducted with PO vaccine studies of resultant antibody titers; data describing protection duration achieved with recombinant vaccines are still required. Four-dose intradermal regimens with recombinant vaccine may be needed to produce an increased percentage of adequate initial antibody titers. The potential economic value of intradermal booster dosing in all subjects, including those receiving intramuscular vaccination, needs to be validated. Moreover, ease of intramuscular administration must be considered in determining the value of intradermal versus low-dose intramuscular vaccination. Concerns regarding more complicated administration techniques and increased adverse effects associated with intradermal HBY vaccine appear to be unfounded based on results of clinical studies and experience with other vaccines. Intradermal HBY vaccination has a high acceptance rate whereas compliance with existing intramuscular programs is modest. Patient acceptance should be an important factor in any universal vaccination proposal and should be studied in a comparative manner for intradermal and intramuscular routes in target populations such as adolescents. The CDC has recently recommended that intradermal HBY vaccine be administered only under a research protocol characterized by informed patient consent and postvaccination testing to identify nonresponders.' Presently, this recommendation appears valid, and patients should be educated regarding the difference in antibody titers associated with intradermal vaccination and their relationship to protection duration. Postvaccination testing is prudent based on the lack of current recombinant vaccine data and the possibility that these vaccines may result in lower antibody titers; patients should be tested at least one month after receiving the third dose. Testing could also be valuable in predicting duration of antibody protection and patientspecific times for administration of booster doses. The cost of testing is minimal when compared with the savings associated with low-dose intradermal vaccination programs. In summary, the economic benefit associated with intradermal vaccination and its potential impact on the epidemiology of HBY infection justifies its continued investigation. Available data suggest that intradermal HBY vac-
1991 June, Volume 25
Intradermal Hepatitis Vaccine
cination is appropriate in healthy subjects, although informed consent must first be obtained. Existing results are promising; however, most studies to date have involved small sample sizes. Large prospective comparative trials need to be conducted to ascertain the immunogenicity and patient acceptance of intradermal HBV vaccination. Postvaccination testing should be used to ensure seroconversion and to define the magnitude of antibody response. Practitioners conducting vaccination programs should contribute data both to the CDC and the medical literature, which better define the role of intradermal HBV vaccination.~
References I. Centers for Disease Control. Summary of notifiable diseases, United States. 1989. MMWR 1990;38(suppI54):SI-59. 2. Immunization Practices Advisory Committee. Centers for Disease Control. Protection against viral hepatitis. MMWR 1990;39(suppl RR-2):I26. 3. ALTER MJ. HADLER sc, MARGOLIS HS, et al. The changing epidemiology of hepatitis B in the United States. Need for altemative vaccination strategies. lAMA 1990;263:1218-22. 4. KANE MA, ALTER MJ. HADLER sc, MARGOLIS HS. Hepatitis B infection in the United States. Recent trends and future strategies for control. Am 1 Med 1989; 87(suppI3A):IIS-3S. 5. CROSSLEY KB, GERDING DN, PETZEL RA. Acceptance of hepatitis B vaccine by hospital personnel. Infect Control 1985; 6: 147-9. 6. Immunization Practices Advisory Committee. Update on hepatitis B prevention. MMWR 1987;36:353-60,366. 7. STEPHENNE J. Recombinant versus plasma-derived hepatitis B vaccines: issues of safety, immunogenicity, and cost-effectiveness. Vaccine 1988;6:299-303. 8. WARRELL MJ, NICHOLSON KG. WARRELL DA, et aI. Economical multiple-site intradermal immunization with human diploid-cell-strain vaccine is effective for post-exposure rabies prophylaxis. Lancet 1985;/: 1059~2.
9. BRAATHEN L. THORSBY E. Studies on human epidermal Langerhans cells: I. Allo-activating and antigen-presenting capacity. Scand 1 Immuno/1980;11:401-8. 10. HADLER SC, FRANCIS DP. MAYNARD JE, et al. Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N Engl 1 Med 1986;315:209-14. II. MILLER KD. GIBBS RD. MULLIGAN MM, NUTMAN TB, FRANCIS DP. Intradermal hepatitis B virus vaccine: immunogenicity and side-effects in adults. Lancet 1983;2:1454-6. 12. GOLDWATER PN. WOODFIELD DG. RAMIREZ AM. STEED I. Intradermal. low dose, short course hepatitis B vaccination. N Z Med 1 1986;99:703-5. 13. IRVING WL, ALDER J, KURTZ JB, JUEL-JENSEN B. Intradermal vaccination against hepatitis B (letter). Lancet 1986;2: 1340. 14, IRVING WL. PARSONS AJ, KURTZ JB, JUEL-JENSEN BE. Intradermal hepatitis B vaccination (letter). Lancet 1987;2:561. 15. WHITTLE He. LAMB WH, RYDER RW. Trials of intradermal hepatitis B vaccines in Gambian children. Ann Trop Paediatr 1987;7:6-9. 16. KURTZ JB, ALDER MJ, MAYON-WHITE RT, JUEL-JENSEN BE, RODGERS TM, BABIC GM. Plasma-derived versus recombinant hepatitis B vaccines (letter). Lancet 1989; I :451. 17. MORRIS CA, OLIVER PR, REYNOLDS F, SELKON JB. Intradermal hepatitis B immunization with yeast-derived vaccine: serological response by sex and age. Epidemiol Infect 1989;/03:387-94. 18. LANCASTER D, ELAM S, KALSER AB. Immunogenicity of the intradermal route of hepatitis B vaccination with the use of recombinant hepatitis B vaccine. Am 1 Infect Control 1989;17:126-9. 19. CLARKE JA, HOLLINGER FB, LEWIS E, et al. Intradermal inoculation with Heptavax-B, Immune response and histologic evaluation of injection sites. lAMA 1989;262:2567-71. 20. HAYASHI J, KASHIWAGI S, NOGUCHI A, NAKASHIMA K,IKEMATSU H, KAJIYAMA W. Intradermal hepatitis B vaccination for mentally retarded patients. 1 Infect 1989;19:119-25.
21. ZOULEK G, LOR BEER B, JILG W, DIENHARDT F. Evaluation of a reduced dose of hepatitis B vaccine administered intradermally. 1 Med ViroI1984;14:27-32. 22. ZOULEK G, LORBEER B, JlLG W. DlENHARDT F. Persistence of anti-HBs after intradermal inoculation of reduced doses of hepatitis B vaccine (letter). Lancet 1984;2:983-4. 23. REDFIELD RR, INNIS BL, SCOTT RM, CANNON HG, BANCROFT WHo Clinical evaluation of low-dose intradermally administered hepatitis B virus vaccine. A cost reduction strategy. lAMA 1985;254:3203-6. 24. MILNE A, ALL WOOD GK, PEARCE NE, LUCAS CR, KRUGMAN S. Low dose hepatitis B vaccination in children. N Z Med 1 1986;99:47-9. 25. HALSEY NA, REPPERT EJ, MARGOLIS HS, FRANCIS DP, FIELDS HA. intradermal hepatitis B vaccination in an abbreviated schedule. Vaccine 1986;4:228-32. 26. FADDA G, MAIDA A, MASIA e. OBINO G, ROMANO G, SPANO E. Efficacy of hepatitis B immunization with reduced intradermal doses. Eur 1 Epidemiol 1987;3: 176-80. 27. WAHL M, HER MODS SON S. Intradermal, subcutaneous or intramuscular administration of hepatitis B vaccine: side effects and antibody response.Scandl Infect Dis 1987;19:617-21. 28. FRAZER IH, JONES B, DIMITRAKAKIS M, MACKA Y IR. Intramuscular versus low-dose intradermal hepatitis B vaccine. Assessment by humoral and cellular immune responses to hepatitis B surface antigen. Med 1 Aust 1987; 146:242-5. 29. HERBERT M, BUTLER AVJ, ROOME APCH. CAUL EO. Comparison of intradermal and intramuscular hepatitis B vaccination in university students. Vaccine 1989;7:395-6. 30. COBERLY J, HALSEY N, TOWNSEND T, et al. Low-cost, low-dose hepatitis B vaccination (abstract 192). Program and abstracts of the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1989:133. 31. BRYAN J, IQBAL M, SJOGREN M, et al. Low-dose intradermal recombinant hepatitis B vaccine (abstract 196). Program and abstracts of the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1989:133. 32. HEIJTINK RA, KNOL RM, SCHALM SW. Low-dose (2mcg) hepatitis B vaccination in medical students: comparable immunogenicity for intramuscular and intradermal routes. 1 Med Viro/1989;27: 151-4. 33. MOK Q, UNDERHILL G, WONKE B, ALDOURI M, KELSFY M, JEFFRIES D, Intradermal hepatitis B vaccine in thalassemia and sickle cell disease. Arch Dis Chid 1989;64:535-40, 34. AYOOLA EA, ATOBA MA, JOHNSON AOK. Intradermal vaccination against hepatitis B virus infection in an endemic area (Nigeria), two year results. Arch ViroI1986;9/:291-6. 35. JILG W, SCHMIDT M, DlENHARDT F, ZACHOV AL R. Hepatitis B vaccination: how long does protection last? (letter) Lancet 1984;2:458. 36. LA PLANCHE A, COUROUCE A, JUNGERS P, BERHAMOU E, CROSNIER J. Hepatitis B vaccination: how long does protection last? (letter) Lancet 1984;2:866. 37. GERETY RJ, ELLIS RW. Plasma-derived vs recombinant hepatitis B vaccine (letter). lAMA 1987;258: 1474. 38. HOLLINGER FB. Factors influencing the immune response to hepatitis B vaccine, booster dose guidelines, and vaccine protocol recommendations. Am 1 Med I989;87(suppl 3A):36S-40S. 39. HOWARD PA, HALEY e. Duration of immunity from hepatitis B vaccine. Drug Intell Clin Pharm 1988;22:985-7. 40. HOROWITZ MM, ERSHLER WB, MCKINNEY P, BATTIOLA RJ. Duration of immunity after hepatitis B vaccination: efficacy of low-dose booster vaccine. Ann Intern Med 1988;108: 185-9. 41. LUNN JA. Intradermal hepatitis B vaccine (letter). Lancet 1989; I :625. 42. GOLDWATER PN. Hypersensitivity to intradermal hepatitis B vaccine (letter). Lancet 1984;2: 1156. 43. ZUCKERMAN AJ. Appraisal of intradermal immunization against hepatitis B. Lancet 1987; I :435-6.
EXTRACTO
Desde 1982, la disponibilidad de una vacuna para inmunizaci6n contra el virus de hepatitis B (HBY) ha tenido poco impacto en la enfermedad; se ha sugerido inmunizaci6n en rnasa, La vacuna intradermal que se ha usado en la profilaxis de otras enfermedades infecciosas se ha investigado como una altemativa de bajo costo a la vacuna tradicional
DICP. The Annals ofPharmacotherapy
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1991 June. Volume 25 •
633
intramuscularcontra el virus de HBY. Resultados de estudios indican grados de seroconversi6n similares para la vacuna intradermale intramuscularcontra el virus de hepatitis B en adultos saludables. Sin embargo, las titulacionesde anticuerpos y la duracion de la protecci6n de anticuerpos aparentan estar disminuidos con la vacuna intradermal contra el virus de hepatitis B. Datos limitados sugieren que factores demograficos tales como la edad y el sexo pueden afectar la respuesta a la vacuna intradermalcontra el virus de hepatitis B. Las reacciones adversas en la pieI son comunes pero no representan un impedimentoa la continua vacunaci6n intradermal contra el virus de hepatitis B. Es necesario realizar estudios comparativos prospectivos a grande escala para sustanciarel valor de la vacuna intradermal contra el virus de hepatitis B. Sin embargo, el potencial econ6mico y beneficio epidemiol6gicode la vacuna intradermaljustifica la investigacion continua para la prevencionde la infecci6ncontra el virus de hepatitis B. GLENDA SOBRINO BURGOS RESUME
Les vaccins pour l'immunisation contre Ie virus de l'hepatite B (YHB) sont disponiblesdepuis 1982et peu d'impact sur la maladie a ete
constate; une immunisation a grande echelle a ete suggeree, La vaccination intradermique, bien reconnue dans la prophylaxiedes autres maladies infectieuses,a ete investigueecomme une alternativede faible coilt par rapport ala vaccination traditionnellepar voie intramusculaire pour Ie YHB. Les resultatsdes essais ouverts et comparatifs indiquent des taux de seroconversionsembiabies pour la vaccinationcontre Ie YHB. quelque soit la voie d'administration, intradermiqueou intramusculaire, chez des adultes en sante. Cependant, les titres d'anticorps et vraisemblablementla duree de protectionfoumie par les anticorps semblent etre diminues avec la vaccinationintradermique. Des donnees limitees suggerent que des facteurs demographiques,tels l'age et Ie sexe, puissent affecter la reponse au vaccin lors de vaccinationpar voie intradermique. Les effets indesirablescutanes sont courants mais ne represententpas un obstacle ala poursuitede la vaccination par voie intradermique. Des etudes comparatives prospectives agrande echelle sont necessaires pour confirmer la valeur de la vaccination par voie intradermique. Neanrnoins,les avantages economiques et epiderniologiques potentielsde la vaccination intradermiquejustifient la poursuite des recherches dans ce domaine. MARIE LAROUCHE
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See also pages 617 and 671. ABSTRACf: The availability of vaccine since 1982for immunization against hepatitisB virus (HBV) has had minimal impacton the disease; mass immunization has been suggested. Intradermal vaccination, which has precedent in prophylaxisof other infectiousdiseases, has been investigated as a low-costalternativeto traditional intramuscular HBV vaccination. Results of open and comparativetrials indicatesimilar seroconversion rates for intradermal and intramuscularHBV vaccination routes in healthy adults. However, antibody titers and, presumably, duration of antibody protection appear to be decreased with intradermal HBV vaccination. Limited data suggest that demographicfactors such as age and gender may affect vaccine responsiveness to intradermal HBV vaccine. Adverse skin reactionsare common but do not represent a deterrentto continued intradermal HBV vaccination. There is a need for large-scale prospectivecomparativetrials to substantiatethe value of intradermal HBV vaccination. Nevertheless, the potentialeconomic and epidemiologic benefitof intradermal vaccinationjustifies continued investigation for preventionof HBV infection. DICP Ann Pharmacother 1991;25:628-34.
HEPATITIS B VIRUS (HBV) infection remains a major health issue in the US. In 1989, the Centers for Disease Control (CDC) recorded 23419 HBV cases, a number comparable to that of prior years and acknowledged to represent part of an estimated 300 (){)() infected individuals.i> The scope of this problem is further magnified by the HBV-infected carrier pool, estimated to include 750000-1 (){)() 000 persons in the US alone.e Although the annual incidence of HBV has declined slightly since 1985, the availability of HBV vaccine since 1982 appears to have had minimal impact on the disease. Present CDC strategy continues to target only high-risk groups for HBV vaccination.t Healthcare workers and homosexuals are the only high-risk groups characterized by decreased rates of infection since 1981 (75 and 62 percent, respectively). However, these decreases were offset by concomitant increases of 80 percent in parenteral drug users and 38 percent in high-risk heterosexual groups. More importantly, the percentage of patients with HBV with no identifiable risk factors (30-40 percent) has not changed.ss In light of the failure of present strategy to significantly lessen the incidence of HBV infection, it has been suggested that universal vaccination of groups such MICHAEL P. RIVEY, M.S.. is an Assistant Professor of Clinical Pharmacy, School of Pharmacy, University of Montana, Missoula, MT 59812; and JOHN PETERSON, Phann.D., is a Visiting Lecturer, School of Pharmacy, University of Montana. Reprints: Michael P. Rivey, M.S.
This article is approved for continuingeducation credit.
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as infants or adolescents be required. People would then be vaccinated before exposure to high-risk activity.v Compliance with intramuscular HBV vaccination programs has been modest. Crossley et al. reported that only 38 percent of 1193 hospital personnel requested vaccinations offered free of charge by two hospitals in 1982. Over 90 percent of 487 persons declining this free offer were aware of their risk for infection; however, more than 50 percent wanted to know more about the vaccine.s The CDC published survey results of compliance rates for intramuscular HBV vaccination in 1987, Only 24 percent of physicians responding to a survey in three large cities, 44 percent of dentists responding to a 1986 national survey, and 44 percent of hemodialysis staff participating in a 1985 national survey had been vaccinated,» Reasons for avoidance of vaccination include desire for additional HBV vaccine testing, concern regarding human immunodeficiency or other virus transmission with use of the plasma-derived (PD) HBV vaccine, and cost of the recommended intramuscular regimen.i Although the introduction of new recombinant vaccines has presumably served to partially alleviate vaccine contamination concerns, these products offer little cost reduction compared with PD vaccine and still require additional testing.vt Intradermal HBV vaccination, typically using one-tenth of an intramuscular dose, has been investigated as an alternative to traditional intramuscular vaccination. This route of administration has already demonstrated success in the treatment of other infectious diseases, including rabies.s Intradermal vaccination is based on the presence of dermis Langerhans' cells that have been shown to capture antigen in a macrophage-like fashion and present it to T cells.s If justified, intradermal vaccine use could exert a major impact on the epidemiology of HBV infection. Cost savings associated with intradermal vaccination may increase compliance with existing vaccination programs and perhaps facilitate implementation of universal vaccination. The following issues are important when considering the use of intradermal HBV vaccine: Is the immunoresponsiveness comparable to that of the intramuscular preparation? What is the degree and duration of HBV protection achieved with seroconversion? Who best responds (or fails to respond) to intradermal HBV vaccine? Are there special considerations regarding the intradermal route of administration? Finally, how frequently do adverse effects occur and could they lessen the utility of an intradermal HBV vaccine program?
1991 June, Volume 25
Immunoresponsiveness ofIntradermal Hepatitis B Virus Vaccine
Seroconversion following HBV vaccine administration is defined as formation of an initial antibody concentration ~~O mlU/mL in response to hepatitis B surface antigen-s this concentration has been associated with a decreased risk of late infection." Alternatively, some investigators have defined seroconversion as a PIN ratio unit (ratio of antibody count per minute of tested positive sample to mean of negative control samples) of~2.1.u Results of intradermal HBV vaccine studies indicate that approximately 90 percent of healthy persons develop seroconversion six to nine months after initiation of a three-dose regimen (Tables I and 2). Moreover, data from comparative studies suggest that initial seroconversion rates are similar following both intradermal and intramuscular vaccination (Table 2). Results of a study with PO HBV vaccine demonstrated that seroconversion rates achieved with both intradermal and intramuscular vaccine adIJ.linistration (100 and 94 percent, respectively) were supenor to the seroconversion rate achieved with subcutaneous vaccination (42 percent);" this lower seroconversion rate is expected because of the absence of Langerhans' cells in subcutaneous tissue. In contrast, other studies with PO vaccine describe comparable immunoresponsiveness associated with the subcutaneous route.26.J4 ~everal observations can be made about existing studies of intradermal HBV vaccine. Most investigations have been conducted in healthy young adults. Nevertheless, results of limited studies conducted in neonates and children s.uggest similar immunoresponsiveness in these populatIons.15.24.30 Intradermal HBV vaccine studies have not been conducted in homosexual, hemodialysis, or drug abuse populations. The intradermal vaccine dosage most commonly used has been PO vaccine 2 ug given at 0, 30, and 180 days. Increased doses or shortened dosing regimens have not been shown to increase the seroconversion
rate.21•24 Results from two studies using recombinant vaccine I ug suggest that rate of seroconversion is decreased to approximately 80 percent with the decreased dose.ls.31 However, it should be noted that only one group of investigators has compared the seroconversion rate associated with an uncommon (4-f.!g) dose with that of the common 2-f.!g dose using the same vaccine and dosing regimen in the same population." Limited data on the use of yeast-derived recombinant HBV vaccines (either 10 or 20 ug/ml.) have suggested that these vaccines possess immunogenic properties comparable to those of PO vaccine.' Open studies of recombinant vaccine I or 2 ug given intradennally have resulted in seroconversion rates of approximately 80 percent.F-" Bryan et al. reported a similar seroconversion rate in volunteers randomized to receive recombinant vaccine I ug intradermally; the rate was significantly lower than that observed in subjects receiving PO vaccine 2 ug (p=0.05),31 In contrast, Kurtz et al. compared the immunogenicity of 2 ug doses of both recombinant and PO HBV vaccine in 95 medical students randomized to receive either vaccine intradennally. The percentage of responders was less in the recombinant group than in the PO group (87.2 vs. 97.6 percent, respectively); however, this difference was not statistically significant." Oata from.a .sma~l number of comparative studies suggest that administration of one-tenth of a typical dose of intramuscular vaccine may result in similar seroconversion rates and antibody titers as intradermal vaccine administration.24.30,32 Duration ofIntradermal Vaccine Protection
The greatest concern regarding intradermal HBV vaccination has focused on the duration of protection achieved with the vaccine. It must be noted that the magnitude and duration of antibody response vary among individuals and have not been completely described for recombinant vac-
Table I. Open Studies of Intradermal Hepatitis B Vaccine ANTI-HBs (mIU/mL) POPULATION
Healthcare workers Healthcare workers Medical students Gambian children ($10 y) Medical students Healthcare workers Healthcare workers Medical students/healthcare workers Mentally retarded people
PATIENTS
DOSING REGIMEN"
(n)
(ug)
14 88 47 166 34 20 42 47 216 32 92
PD2 PD2'
62
PD2 PD4,d PD2 RC2 RC2 f RC If PD2 PD4
SEROLOGY TIME (mo)
GMT (mIU/mL)
6-7 3 14 7-9 30
>100 >IO b
8S.7 8S.2
91.S 89.2 79.4
4.S
7-9 7-9 7-9 7 6 12 9 12
2400' 600
127 396
97.6 87.2 80.9 81.3
92g 9Sg 83.9 82.3
(%)
69.3 78.3 76.S
41.2 100.0
32.S
S8g 8g 60 g 60g
>1000
38.6 28.2 SI.2 14.7
REF.
II 12 13,14 IS 16
4.2
17
sg
18 19
3Sg 20
"Dosing at O. I, and 6 months unless otherwise specified. "Alternatively, PIN ratio (the ratio of antibody counl per minute of tested positive sample to mean of negative control sample) ~2.1. 'Dosing at 0, I, and 2 months. "By jetgun. 'Median titer (p1000
REF.
84.6 95.0 100.0 100.0 100.0 77.8 100.0 96.0 100.0 91.7 95.8 93.8 94.7 100.0 84.2 96.3 88.5 100.0 95.8 100.0 80.0 82.7 65.5 89.9 87.5 100.0 42.1 93.8 94.7 17.6 87.5 73.7 94.7 92.0 96.8 91.0 97.0 100.0 77.6 89.8 100.0 93.9 90.4 100,()i 100.Qi 100.Qi lOO.Qi
52.3 78.3 90.7 77.8 100.0 44.4 77.8
1.5 1.7 13.3
15
21.22
23
24
25
26
100.0 36.8 87.5 63.2 17.6 75.0
27
28 29 30
31
82.9 78.3
32.9 37.3
"Merck Sharp & Dohme or Smith Kline & Beecham vaccine. "Dosing at O. I. and 6 months unless otherwise specified. 'Alternatively. PIN ratio (the ratio of antibody count per minute of tested positive sample to mean of negative control samples) ~2.1. dBy jet gun. 'Dosing at O. I. and 2 months. 'Dosing at O. I. and 4 months. gDosing at 0, 2. and 4 months. "Dosing at O. I. and 5 months. 'Four doses at O. I. 2. and 6 months. JSignificantly higher titers in im group (p 1000 mIU/mL measured 6-12 months after administration of the first intramuscular vaccine dose have been associated with a >90 percent rate of protection five years following vaccination. In contrast, titers between 100 and 999 mIU/mL appear to maintain five-year seroconversion in In comparative trials, the intramuscular route was associated with a 17-47 percent incidence of muscle pain or stiffness compared with a 31-80 percent incidence of local skin reactions associated with the intradermal route. 23,28,31..39 Hyperpigmented maculas at the intradermal injection site occur in 50-78 percent of patients and persist for more than one year in over 60 percent of patients. I 1,18.19 There is no correlation between the absence or presence of a skin reaction and degree of immunologic response.F-" A number of investigators have hypothesized that the alum adjuvant in HBY vaccine is responsible for the local skin reactions.u· 17,23,43 However, Zoulek et al. found no skin reactions in ten control patients given intradermal adjuvant" and Clarke et al. determined that local reactions were characteristic of transient immune rather than foreign-body reactions.'? No difference in the incidences of local skin reactions associated with intradermal injections of recombinant versus PO vaccine has been observed." Despite common skin reactions, the intradermal route has a high acceptance rate; 90-100 percent of intradermal HBY vaccine recipients indicate they would recommend this route to coworkers.Pw-' Limited data suggest that the intradermal route is preferred to intramuscular HBY vaccination by adults.Fr" Milne et al. reported that the intradermal route was less well tolerated in children than low-dose intramuscular vaccination.>' However, this finding primarily appeared to reflect increased skin reactions, especially itching associated with intradermal vaccination, rather than patient preference. Summary
Sufficient data exist to prove the irnmunogenicity of intradermal HBY vaccine in young healthy adults; the seroconversion rate appears to be comparable to that of the intramuscular product. Limited data have suggested the utility of intradermal vaccine in neonatal and pediatric populations; however, there is need for further studies as these populations primarily would be targeted for universal vac632 •
D'[Cl", The Annals a/Pharmacotherapy
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cination programs. No data regarding intradermal HBY vaccination in other high-risk groups are available. Factors such as age, weight, and smoking that are associated with decreased response to intradermal HBY vaccination are probably identical to those already elucidated for intramuscular vaccination, and should be evaluated when considering the intradermal route. Based on discrepant results from existing studies, the influence of gender on immune response to intradermal vaccine also should be addressed in future studies. It seems certain that intradermal HBY vaccination results in lower antibody titers compared with those reached following traditional intramuscular vaccination. However, the clinical importance of anamnestic response in initial responders developing undetectable or low antibody titers is unknown. There is a need to further delineate the duration of antibody protection following intradermal HBY vaccination. Alternatively, available data suggest that it could be very cost-effective to give booster doses of intradermal HBY vaccine on a regular basis, such as every three years. However, most of these data reflect studies conducted with PO vaccine studies of resultant antibody titers; data describing protection duration achieved with recombinant vaccines are still required. Four-dose intradermal regimens with recombinant vaccine may be needed to produce an increased percentage of adequate initial antibody titers. The potential economic value of intradermal booster dosing in all subjects, including those receiving intramuscular vaccination, needs to be validated. Moreover, ease of intramuscular administration must be considered in determining the value of intradermal versus low-dose intramuscular vaccination. Concerns regarding more complicated administration techniques and increased adverse effects associated with intradermal HBY vaccine appear to be unfounded based on results of clinical studies and experience with other vaccines. Intradermal HBY vaccination has a high acceptance rate whereas compliance with existing intramuscular programs is modest. Patient acceptance should be an important factor in any universal vaccination proposal and should be studied in a comparative manner for intradermal and intramuscular routes in target populations such as adolescents. The CDC has recently recommended that intradermal HBY vaccine be administered only under a research protocol characterized by informed patient consent and postvaccination testing to identify nonresponders.' Presently, this recommendation appears valid, and patients should be educated regarding the difference in antibody titers associated with intradermal vaccination and their relationship to protection duration. Postvaccination testing is prudent based on the lack of current recombinant vaccine data and the possibility that these vaccines may result in lower antibody titers; patients should be tested at least one month after receiving the third dose. Testing could also be valuable in predicting duration of antibody protection and patientspecific times for administration of booster doses. The cost of testing is minimal when compared with the savings associated with low-dose intradermal vaccination programs. In summary, the economic benefit associated with intradermal vaccination and its potential impact on the epidemiology of HBY infection justifies its continued investigation. Available data suggest that intradermal HBY vac-
1991 June, Volume 25
Intradermal Hepatitis Vaccine
cination is appropriate in healthy subjects, although informed consent must first be obtained. Existing results are promising; however, most studies to date have involved small sample sizes. Large prospective comparative trials need to be conducted to ascertain the immunogenicity and patient acceptance of intradermal HBV vaccination. Postvaccination testing should be used to ensure seroconversion and to define the magnitude of antibody response. Practitioners conducting vaccination programs should contribute data both to the CDC and the medical literature, which better define the role of intradermal HBV vaccination.~
References I. Centers for Disease Control. Summary of notifiable diseases, United States. 1989. MMWR 1990;38(suppI54):SI-59. 2. Immunization Practices Advisory Committee. Centers for Disease Control. Protection against viral hepatitis. MMWR 1990;39(suppl RR-2):I26. 3. ALTER MJ. HADLER sc, MARGOLIS HS, et al. The changing epidemiology of hepatitis B in the United States. Need for altemative vaccination strategies. lAMA 1990;263:1218-22. 4. KANE MA, ALTER MJ. HADLER sc, MARGOLIS HS. Hepatitis B infection in the United States. Recent trends and future strategies for control. Am 1 Med 1989; 87(suppI3A):IIS-3S. 5. CROSSLEY KB, GERDING DN, PETZEL RA. Acceptance of hepatitis B vaccine by hospital personnel. Infect Control 1985; 6: 147-9. 6. Immunization Practices Advisory Committee. Update on hepatitis B prevention. MMWR 1987;36:353-60,366. 7. STEPHENNE J. Recombinant versus plasma-derived hepatitis B vaccines: issues of safety, immunogenicity, and cost-effectiveness. Vaccine 1988;6:299-303. 8. WARRELL MJ, NICHOLSON KG. WARRELL DA, et aI. Economical multiple-site intradermal immunization with human diploid-cell-strain vaccine is effective for post-exposure rabies prophylaxis. Lancet 1985;/: 1059~2.
9. BRAATHEN L. THORSBY E. Studies on human epidermal Langerhans cells: I. Allo-activating and antigen-presenting capacity. Scand 1 Immuno/1980;11:401-8. 10. HADLER SC, FRANCIS DP. MAYNARD JE, et al. Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N Engl 1 Med 1986;315:209-14. II. MILLER KD. GIBBS RD. MULLIGAN MM, NUTMAN TB, FRANCIS DP. Intradermal hepatitis B virus vaccine: immunogenicity and side-effects in adults. Lancet 1983;2:1454-6. 12. GOLDWATER PN. WOODFIELD DG. RAMIREZ AM. STEED I. Intradermal. low dose, short course hepatitis B vaccination. N Z Med 1 1986;99:703-5. 13. IRVING WL, ALDER J, KURTZ JB, JUEL-JENSEN B. Intradermal vaccination against hepatitis B (letter). Lancet 1986;2: 1340. 14, IRVING WL. PARSONS AJ, KURTZ JB, JUEL-JENSEN BE. Intradermal hepatitis B vaccination (letter). Lancet 1987;2:561. 15. WHITTLE He. LAMB WH, RYDER RW. Trials of intradermal hepatitis B vaccines in Gambian children. Ann Trop Paediatr 1987;7:6-9. 16. KURTZ JB, ALDER MJ, MAYON-WHITE RT, JUEL-JENSEN BE, RODGERS TM, BABIC GM. Plasma-derived versus recombinant hepatitis B vaccines (letter). Lancet 1989; I :451. 17. MORRIS CA, OLIVER PR, REYNOLDS F, SELKON JB. Intradermal hepatitis B immunization with yeast-derived vaccine: serological response by sex and age. Epidemiol Infect 1989;/03:387-94. 18. LANCASTER D, ELAM S, KALSER AB. Immunogenicity of the intradermal route of hepatitis B vaccination with the use of recombinant hepatitis B vaccine. Am 1 Infect Control 1989;17:126-9. 19. CLARKE JA, HOLLINGER FB, LEWIS E, et al. Intradermal inoculation with Heptavax-B, Immune response and histologic evaluation of injection sites. lAMA 1989;262:2567-71. 20. HAYASHI J, KASHIWAGI S, NOGUCHI A, NAKASHIMA K,IKEMATSU H, KAJIYAMA W. Intradermal hepatitis B vaccination for mentally retarded patients. 1 Infect 1989;19:119-25.
21. ZOULEK G, LOR BEER B, JILG W, DIENHARDT F. Evaluation of a reduced dose of hepatitis B vaccine administered intradermally. 1 Med ViroI1984;14:27-32. 22. ZOULEK G, LORBEER B, JlLG W. DlENHARDT F. Persistence of anti-HBs after intradermal inoculation of reduced doses of hepatitis B vaccine (letter). Lancet 1984;2:983-4. 23. REDFIELD RR, INNIS BL, SCOTT RM, CANNON HG, BANCROFT WHo Clinical evaluation of low-dose intradermally administered hepatitis B virus vaccine. A cost reduction strategy. lAMA 1985;254:3203-6. 24. MILNE A, ALL WOOD GK, PEARCE NE, LUCAS CR, KRUGMAN S. Low dose hepatitis B vaccination in children. N Z Med 1 1986;99:47-9. 25. HALSEY NA, REPPERT EJ, MARGOLIS HS, FRANCIS DP, FIELDS HA. intradermal hepatitis B vaccination in an abbreviated schedule. Vaccine 1986;4:228-32. 26. FADDA G, MAIDA A, MASIA e. OBINO G, ROMANO G, SPANO E. Efficacy of hepatitis B immunization with reduced intradermal doses. Eur 1 Epidemiol 1987;3: 176-80. 27. WAHL M, HER MODS SON S. Intradermal, subcutaneous or intramuscular administration of hepatitis B vaccine: side effects and antibody response.Scandl Infect Dis 1987;19:617-21. 28. FRAZER IH, JONES B, DIMITRAKAKIS M, MACKA Y IR. Intramuscular versus low-dose intradermal hepatitis B vaccine. Assessment by humoral and cellular immune responses to hepatitis B surface antigen. Med 1 Aust 1987; 146:242-5. 29. HERBERT M, BUTLER AVJ, ROOME APCH. CAUL EO. Comparison of intradermal and intramuscular hepatitis B vaccination in university students. Vaccine 1989;7:395-6. 30. COBERLY J, HALSEY N, TOWNSEND T, et al. Low-cost, low-dose hepatitis B vaccination (abstract 192). Program and abstracts of the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1989:133. 31. BRYAN J, IQBAL M, SJOGREN M, et al. Low-dose intradermal recombinant hepatitis B vaccine (abstract 196). Program and abstracts of the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1989:133. 32. HEIJTINK RA, KNOL RM, SCHALM SW. Low-dose (2mcg) hepatitis B vaccination in medical students: comparable immunogenicity for intramuscular and intradermal routes. 1 Med Viro/1989;27: 151-4. 33. MOK Q, UNDERHILL G, WONKE B, ALDOURI M, KELSFY M, JEFFRIES D, Intradermal hepatitis B vaccine in thalassemia and sickle cell disease. Arch Dis Chid 1989;64:535-40, 34. AYOOLA EA, ATOBA MA, JOHNSON AOK. Intradermal vaccination against hepatitis B virus infection in an endemic area (Nigeria), two year results. Arch ViroI1986;9/:291-6. 35. JILG W, SCHMIDT M, DlENHARDT F, ZACHOV AL R. Hepatitis B vaccination: how long does protection last? (letter) Lancet 1984;2:458. 36. LA PLANCHE A, COUROUCE A, JUNGERS P, BERHAMOU E, CROSNIER J. Hepatitis B vaccination: how long does protection last? (letter) Lancet 1984;2:866. 37. GERETY RJ, ELLIS RW. Plasma-derived vs recombinant hepatitis B vaccine (letter). lAMA 1987;258: 1474. 38. HOLLINGER FB. Factors influencing the immune response to hepatitis B vaccine, booster dose guidelines, and vaccine protocol recommendations. Am 1 Med I989;87(suppl 3A):36S-40S. 39. HOWARD PA, HALEY e. Duration of immunity from hepatitis B vaccine. Drug Intell Clin Pharm 1988;22:985-7. 40. HOROWITZ MM, ERSHLER WB, MCKINNEY P, BATTIOLA RJ. Duration of immunity after hepatitis B vaccination: efficacy of low-dose booster vaccine. Ann Intern Med 1988;108: 185-9. 41. LUNN JA. Intradermal hepatitis B vaccine (letter). Lancet 1989; I :625. 42. GOLDWATER PN. Hypersensitivity to intradermal hepatitis B vaccine (letter). Lancet 1984;2: 1156. 43. ZUCKERMAN AJ. Appraisal of intradermal immunization against hepatitis B. Lancet 1987; I :435-6.
EXTRACTO
Desde 1982, la disponibilidad de una vacuna para inmunizaci6n contra el virus de hepatitis B (HBY) ha tenido poco impacto en la enfermedad; se ha sugerido inmunizaci6n en rnasa, La vacuna intradermal que se ha usado en la profilaxis de otras enfermedades infecciosas se ha investigado como una altemativa de bajo costo a la vacuna tradicional
DICP. The Annals ofPharmacotherapy
•
1991 June. Volume 25 •
633
intramuscularcontra el virus de HBY. Resultados de estudios indican grados de seroconversi6n similares para la vacuna intradermale intramuscularcontra el virus de hepatitis B en adultos saludables. Sin embargo, las titulacionesde anticuerpos y la duracion de la protecci6n de anticuerpos aparentan estar disminuidos con la vacuna intradermal contra el virus de hepatitis B. Datos limitados sugieren que factores demograficos tales como la edad y el sexo pueden afectar la respuesta a la vacuna intradermalcontra el virus de hepatitis B. Las reacciones adversas en la pieI son comunes pero no representan un impedimentoa la continua vacunaci6n intradermal contra el virus de hepatitis B. Es necesario realizar estudios comparativos prospectivos a grande escala para sustanciarel valor de la vacuna intradermal contra el virus de hepatitis B. Sin embargo, el potencial econ6mico y beneficio epidemiol6gicode la vacuna intradermaljustifica la investigacion continua para la prevencionde la infecci6ncontra el virus de hepatitis B. GLENDA SOBRINO BURGOS RESUME
Les vaccins pour l'immunisation contre Ie virus de l'hepatite B (YHB) sont disponiblesdepuis 1982et peu d'impact sur la maladie a ete
constate; une immunisation a grande echelle a ete suggeree, La vaccination intradermique, bien reconnue dans la prophylaxiedes autres maladies infectieuses,a ete investigueecomme une alternativede faible coilt par rapport ala vaccination traditionnellepar voie intramusculaire pour Ie YHB. Les resultatsdes essais ouverts et comparatifs indiquent des taux de seroconversionsembiabies pour la vaccinationcontre Ie YHB. quelque soit la voie d'administration, intradermiqueou intramusculaire, chez des adultes en sante. Cependant, les titres d'anticorps et vraisemblablementla duree de protectionfoumie par les anticorps semblent etre diminues avec la vaccinationintradermique. Des donnees limitees suggerent que des facteurs demographiques,tels l'age et Ie sexe, puissent affecter la reponse au vaccin lors de vaccinationpar voie intradermique. Les effets indesirablescutanes sont courants mais ne represententpas un obstacle ala poursuitede la vaccination par voie intradermique. Des etudes comparatives prospectives agrande echelle sont necessaires pour confirmer la valeur de la vaccination par voie intradermique. Neanrnoins,les avantages economiques et epiderniologiques potentielsde la vaccination intradermiquejustifient la poursuite des recherches dans ce domaine. MARIE LAROUCHE
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