Haemophilus influenzae Type b Conjugate Vaccine

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1 Committee on Infectious Diseases Haemophilus influenzae Type b Conjugate Vaccine On Dec 22, 1987, the first conjugate vaccine was licensed by the FDA for the prevention of infections due to Haemophilus influenzae type b. This vaccine is a conjugate ofh influenzae type b capsular polysaccharide and diphtheria toxoid and is officially designated as Haemophilus b conjugate vaccine (diphtheria toxoid-conjugate). The purpose of this statement is to provide background information, perspective, and recommendations for the use of this product. BACKGROUND H influenzae type b is a major cause of serious infections in infants and children, about 3% of which occur in children 18 months of age and older. 2 American licensure of the first-generation vaccines, the Haemophilus b polysaccharide vaccines or plain capsular polysaccharide vaccines (often referred to as PRP), was based on a field trial conducted in Finland.3 In this study which started in 1975, 48,977 children 3 to 71 months of age received a polysaccharide vaccine similar to those that were later licensed in the United States. Protection was correlated with the production of an anticapsular antibody concentration that exceeded 1..tg/mL in serum obtamed 3 weeks after immunization. In children immunized at 18 to 71 months of age, the efficacy was 9% (95% confidence interval, 55% to 98%).23 Among those immunized at 18 to 23 months of age, the small number of cases in the vaccinees and the control group precluded a definitive conclusion about vaccine efficacy. In 8,453 children immunized at 2 years of age (24 to 35 months), the efficacy was 8% (95% confidence interval, 7% to 94%)#{149}4No efficacy was observed in children 3 The recommendations in this statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. PEDIATRICS (ISSN 31 45). Copyright 1988 by the American Academy of Pediatrics. to 17 months. These data led the AAP Committee on Infectious Diseases to recommend immunization with polysaccharide vaccine (PRP) for all children at 24 months of age.5 The results of postmarketing case-control studies after licensure in 1985 indicate that PRP is effective,68 although its efficacy in 2-year-old American children may be lower than that found in Finland. Lack of efficacy has been reported in Minnesota9 and, in addition, several investigators have suggested that there may be a slight excess in infections occurring in the week after immunization with PRP6 8 9 before any protective effect from the vaccine would be expected. These data were addressed in two previous statements from the Committee (AAP News, July 1987, p 7; AAP MemberAlert, Nov 13, 1987). The search for a vaccine that might be more consistently immunogenic, particularly in younger children, led Schneerson and coworkers #{176} to covalently link the capsular polysaccharide of H influenzae to a protein carrier. Subsequently, several manufacturers have prepared conjugate vaccines suitable for testing in children. These are summarized in the Table. At this time, it is uncertain as to whether differences in the safety, chemical composition, immunogenicity, protective efficacy, or cost of these conjugate vaccines will dictate preferences for the use of one vaccine or another. The Committee may, therefore, update its recommendations upon licensure of other second-generation vaccines if such differences become clinically relevant. The diphtheria toxoid conjugate vaccine (often referred to as PRP-D) is currently the only conjugate vaccine against H influenzae type b approved by the FDA. More than 12, doses of PRP-D were administered to more than 3, individuals 2 months of age or older, the majority of whom were Finnish. No serious adverse reactions have been observed other than those attributable to simultaneous administration of diphtheria-tetanus-pertussis vaccine (DTP). Among 98 PEDIATRICS Vol. Downloaded 81 No. 6from Junewww.aappublications.org/news 1988 by guest on August 16, 218

2 TABLE. Conjugate Vaccines Manufacturer Carrier Protein Saccharide Spacer Reference No. National Institute of Child Tetanus toxoid Poly 6 carbon 11 Health and Human Development Connaught Diphtheria toxoid Poly 6 carbon 12 Praxis CRM197 (a nontoxic Oligo None 13 mutant diphtheria toxin) Merck, Sharp & Dohme OMP (an outer membrane protein of Neissenia meningitidis) Poly Complex, involving a thioether infants in the United States between 15 and 24 months of age who received a single dose of either PRP or PRP-D, the rates of occurrence of local reactions and fevers were comparable in the two group5. 5 Local reactions were noted in 1.3% and 12.5% of PRP and PRP-D recipients, respec- tively. A rectal temperature exceeding 39#{176}Coc- curred in 1.4% and.7% of PRP and PRP-D re- cipients, respectively. Thrombocytopenia was observed in one adult immunized with PRP-D but has not been observed in children. There have been no reports to date of increased incidence of H influenzae type b disease during the first 2 weeks following immunization with PRP-D. Evidence from children in Finland and the United States showed that PRP-D can be safely administered simultaneously with DTP or mac- tivated poliovirus vaccine (IPV). 5 7 No serologic data are available concerning simultaneous ad- ministration of PRP-D and oral poliovirus (OPV) or measles, mumps, rubella vaccine (MMR), but in Finland MMR and PRP-D were given together without The immunogenicity of PRP-D is significantly greater than that observed with PRP. For ex- ample, in a study comparing the immunogenicity of an experimental PRP preparation with that of PRP-D, 5 the geometric mean preimmunization and postimmunization anticapsular antibody con- centrations for 56 children 17 to 18 months of age immunized with PRP were.31 and.112 g/ ml, respectively. Corresponding geometric mean values for 51 children of comparable age immu- nized with PRP-D were.27 and i.g/ml. The percentage of children whose postimmuni- zation anticapsular antibody concentration ex- ceeded 1. tg/ml was significantly greater in the children immunized with PRP-D (23.1% v 58.%). Three of the four lots of PRP used in this study were heat-sized, a process used in prelicensure lots which may have lowered immunogenicity. However, even those children who received the nonheat-sized lot had anticapsular antibodies to H influenzae type b in concentrations that were lower than those measured in PRP-D recipients. Also, in another study of 36 children with sickle cell anemia aged 1/2 to 5 (mean 3.3) years, 94% had a serum anticapsular antibody concentration greater than 1. ji.g/ml 3 weeks after immunization with PRP-D. 8 No efficacy study has been performed with PRP- D in children 18 months of age or older. The decision to license PRP-D was based on the enhanced immunogenicity of this vaccine in cornparison to the response elicited by unconjugated PRP, as indicated by both significantly higher I Dstvaccination antibody concentrations and greater percentage of antibody responders. 5 The field trial conducted in Finland with PRP,3 which served as the basis for its licensure, demonstrated a close correlation between protection and antibody concentration and, thus, justifies the decision to recommend the new vaccine on the basis of immunogenicity data. Based on the observed enhanced antibody responses, PRP-D should be effective even in geographical areas where the efficacy of PRP has been reported to be lacking. Additional data will be required to determine whether a booster dose(s) will be needed, but the anticapsular antibody concentrations demonstrated in 64 children 15 to 24 months of age 1 year after immunization 9 suggest that boosters will probably not be necessary. RECOMMENDATIONS 1. The Committee recommends that all children receive a single dose of PRP-D (Haemophilus b Conjugate Vaccine [Diphtheria Toxoid-Conjugate]) at 18 months of age. A special effort should be made to immunize children at high risk of invasive H influenzae type b disease, such as those in day care. 2. Children who received a dose of PRP (polysaccharide vaccine) when 18 to 23 months of age should be immunized with a single dose of PRP- D, although at least 2 months should be allowed to elapse between the two immunizations. Downloaded from AMERICAN by guest ACADEMY on August 16, 218 OF PEDIATRICS 99

3 3. Children who are now 19 to 23 months old and who have not received PRP should receive a dose of PRP-D. 4. For those 24 months of age and older who have not yet been immunized against H in/luenzae type b disease, immunization is recommended through the 5th year of life (ie, until 6 months ofage). For these children, administration of PRP-D is preferred to PRP because of the greater immunogenicity of the former. However, either vaccine is acceptable. 5. Children who have already received PRP when 24 months of age or older need not be irnmunized with PRP-D, although no contraindications exist to the use of PRP-D in this situation. 6. Children who experienced invasive H in/luenzae type b disease before 24 months of age should receive a dose of PRP-D, because the disease may not have rendered them immune. Contrariwise, children whose disease occurred at that age or later do not need immunization, because the disease most likely induced an immune response. 7. Simultaneous administration of the conjugate vaccine and DTP or IPV at a separate site can be performed if desired. There are no known contraindications to simultaneous administration of OPV and MMR, although no serologic data are available. 8. The need for a booster dose of PRP-D has not been established and a booster is not currently recommended. 9. Immunization with PRP-D does not substitute for routine diphtheria immunization. 1. Irrespective of immunization status, rifampin prophylaxis is recommended for all appropriate contacts exposed to an individual with invasive H in/luenzae type b disease. These will usually be household contacts defined in these circumstances as an individual residing in the residence of the index patient or a nonresident who spent 4 or more hours with the index patient for at least five of the seven days preceding hospital admission of the index patient. 11. Children 5 years of age or older with a chronic illness known to be associated with an increased risk for H in/luenzae type b disease should also be given a single dose of PRP-D. Examples include children with anatomic or functional asplenia, sickle cell anemia, or those who have undergone splenectomy. Until further data are available, patients with Hodgkin disease should be immunized in the manner considered optimal for PRP, ie, ten to 14 days or more prior to the initiation of chemotherapy, or, if this cannot be accomplished, 3 months or more after the cessation of chemotherapy. No known contraindications exist to simultaneous administration of PRP-D with pneumococcal vaccine or meningococcal vaccine when they are given in separate syringes at different sites. 12. No increased incidence ofh in/luenzae type b disease during the first 2 weeks postimmunization with PRP-D has been demonstrated. However, PRP-D cannot be expected to be protective during the first 1 to 2 weeks after immunization until antibody formation occurs. Cases of invasive H in/luenzae type b disease anchor important adverse reactions to the vaccine occurring at any time following immunization should be reported promptly to state and local health departments, the manufacturer, the FDA, or the Centers for Disease Control. 13. PRP-D is not currently recommended for use in children less than 18 months of age, although in the future one or more ofthe conjugate vaccines are likely to prove useful in young infants. Recent data from an ongoing Finnish study, in which approximately 3, children were immunized with PRP-D at ages 3 months, 4 months, and 6 months, documented an efficacy of 87% (95% confidence interval, 5% to 96%). Further analysis of these and newer data are needed before the Committee can recommend PRP-D immunization for younger children. COMMITTEE ON INFECTIOUS DISEASES, Stanley A. Plotkin, MD, Chairman Robert S. Daum, MD G. Scott Giebink, MD Caroline B. Hall, MD Martha Lepow, MD Edgar K. Marcuse, MD George H. McCracken, Jr, MD Carol F. Phillips, MD Gwendolyn B. Scott, MD Harry T. Wright, Jr, MD Ex-Officio Georges Peter, MD Liaison Representatives Alan R. Hinman, MD (Centers for Disease Control) Paul Parkman, MD (Food and Drug Administration) Ronald Gold, MD (Canadian Paediatric Society) AAP Section Liaison James G. Easton, MD (Section on Allergy and Immunology) 91 H!NFLUENZAE Downloaded VACCINE from by guest on August 16, 218

4 REFERENCES 1. Hay JW, Daum RS: Cost-benefit analysis oftwo strategies for prevention ofhaemophilus influenzae type b infection. Pediatrics 1987;8: Cochi SL, O Mara D, Preblud SR: Progress inhaemophilus type b polysaccharide vaccine use in the United States. Pediatrics 1988;81: Peltola H, Kayhty H, Virtanen M, et al: Prevention of Hemophilus influen.zae type b bacteremic infections with the capsular polysaccharide vaccine. N Engl J Med 1984; 31: Damn ES, Granoff DM: A vaccine against Haemophilus influen.zae type b. Pediatr Infect Dis 1985;4: Report ofthe Committee on Infectious Diseases, ed 2. Elk Grove Village, IL, American Academy ofpediatrics, 1986, pp Black SB, Shinefield HR, the Northern California Permanente Medical Care Program Departments of Pediatrics Vaccine Study Group: b-capsa I Haemophilus influen.zae, type b, capsular polysaccharide vaccine safety. Pediatrics 1987;79: Murphy TV, Shapiro ED, Wald ER: The protective efficacy (PE) of Haemophilus influerizae type b (Hib) polysaccharide vaccine, abstract 317. New York, Abstracts ofthe 27th ICAAC, Harrison LH, Hightower AW, Gaventa 5, et al: Case control efficacy study ofhaemophilus influenzae type b (Hib) polysaccharide vaccine, abstract 319. New York, Abstracts of the 27th ICAAC, Osterholm MT, Rambeck JH, White KE, et al: Lack of protective efficacy and increased risk of disease within 7 days after vaccination associated with Haemophilus in/luenzae type b (Hib) polysaccharide (PS) vaccine use in Mmnesota, abstract 318. New York, Abstracts of the 27th ICAAC, Schneerson R, Barrera, Sutton A, et al: Preparation, characterization and immunogenicity ofhaemophilus influenzae type b polysaccharide protein conjugates. J Exp Med 198;152: Schneerson R, Robbins JB, Parke JC, et al: Quantitative and qualitative analysis of serum antibody elicited in adults by Haemophilus influen.zae type b and pneumococcal type 6A capsular polysaccharide-tetanus toxoid conjugates Infect Immun 1986;52: Gordon LK: Characterization of a hapten-carrier conjugate vaccine: Haemophilus influenzae-diphtheria toxoid conjugate vaccine, in Channock RM, Lerner PA (eds): Modern Approaches to Vaccines. Cold Spring Harbor, NY, Cold Spring Harbor Press, 1984, pp Anderson P, Pichichero M, Edwards K, et al: Priming and induction ofhaemophilus influenzae type b capsular polysaccharide antibodies in early infancy by Dpo2O, an ohgosaccharide-protein conjugate vaccine. J Pediatr 1987;111: Lenoir AA, Granoff PD, Granoff DM: Immunogenicity of Haemophilus influen,zae type b polysaccharide-neisseria meningitidis outer membrane protein conjugate vaccine in 2- to 6-month.ohd infants. Pediatrics 1987;8: Berkowitz CD, Ward JI, Meier K, et al: Safety and immunogenicity of Haemophilus influenzae type b pohysaccharide and polysaccharide diphtheria toxoid conjugate vaccines in children months of age. J Pediatr 1987;11: Hendley JO, Wenzel JG, Ashe KM, et al: Immunogenicity ofhaemophilus influenzae type b capsular polysaccharide vaccines in 18-month-old infants. Pediatrics 1987;8: Eskola J, Peltola H, Takala AK, et al: Efficacy of Hasmophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine in infancy. N Engi J Med 1987;317: Frank AL, Labotka 1W, Frisone JR, et al: H. influenzae b immunization of children with sickle cell diseases, abstracted. Pediatr Res 1987;21:324A 19. Berkowitz CD, Ward JI, Hendley JO, et al: Persistence of antibody (ab) to Haemophilus influenzae type b (Hib) and response to PRP and PRP-D booster immunization in children initially immunized with either vaccine at months, abstracted. Pediatr Res 21:321A Downloaded from AMERICAN by guest on ACADEMY August 16, 218 OF PEDIATRICS 911

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6 Haemophilus influenzae Type b Conjugate Vaccine Pediatrics 1988;81;98 The online version of this article, along with updated information and services, is located on the World Wide Web at: Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 67. Copyright 1988 by the American Academy of Pediatrics. All rights reserved. Print ISSN: Downloaded from by guest on August 16, 218