Notice to Readers FDA Approval for Infants of a Haemophilus influenzae Type b Conjugate and Hepatitis B (Recombinant) Combined Vaccine

The Advisory Committee on Immunization Practices (ACIP); the Committee on Infectious Diseases, American Academy of Pediatrics; and the American Academy of Family Physicians recommend that all infants receive Haemophilus influenzae type b (Hib) conjugate vaccine and hepatitis B vaccine (1-4). On October 2, 1996, the Food and Drug Administration (FDA) licensed a combined Hib conjugate and hepatitis B (recombinant) vaccine (COMVAX TM) * for infants. Since 1991, the antigenic components of COMVAX TM have been used routinely in separate vaccines and have contributed to the declining incidence of infant Hib disease and hepatitis B virus (HBV) infection in the United States (5,6). Vaccine Description

COMVAX TM is made of the antigenic components used in PedvaxHIB{Registered} and RECOMBIVAX HB{Registered} manufactured and distributed by Merck & Co., Inc. (West Point, Pennsylvania). Each 0.5-mL dose of COMVAX TM contains 7.5 ug of Haemophilus influenzae type b polyribosylribitol phosphate (PRP), 125 ug of Neisseria meningitidis outer membrane protein complex (OMPC) and 5 ug of hepatitis B surface antigen (HBsAg) with an aluminum hydroxide adjuvant and pH stabilizer in normal saline. Indications and Usage

COMVAX TM is indicated for vaccination against invasive Hib disease and HBV infection in infants born to HBsAg-negative women. Three doses of COMVAX TM should be administered at ages 2, 4, and 12-15 months. This vaccine must not be administered to infants younger than age 6 weeks because of potential suppression of the immune response to PRP-OMPC with subsequent doses of COMVAX TM.

For complete protection against invasive Hib disease, infants should receive their first dose of Hib conjugate vaccine at age 2 months and should complete the full series by age 12-15 months (1). If the series is started late, the required number of doses of a vaccine containing PRP-OMPC (i.e., COMVAX TM or PedvaxHIB{Registered}) depends on the child's age -- three if started at age less than or equal to 10 months, two if started at age 11-14 months, and one if started at age 15-71 months. However, three doses of hepatitis B vaccine are required regardless of the child's age when the series is started. Children who receive one dose of hepatitis B vaccine at or shortly after birth may be administered COMVAX TM at ages 2, 4, and 12-15 months.

The use of COMVAX TM has not yet been studied in infants born to women who are HBsAg-positive or women of unknown HBsAg status. However, there has been no evidence of diminished effectiveness of postexposure prophylaxis in populations that have received the initial doses of hepatitis B immune globulin and hepatitis B vaccine at birth followed by PedvaxHIB{Registered} and RECOMBIVAX HB{Registered} vaccines at 6-10 weeks of age and subsequently completed each vaccine series (CDC, unpublished data, 1994). Safety and Immunogenicity

Adverse experiences (AEs) were evaluated in clinical trials in which 6705 doses of COMVAX TM were administered to 2612 healthy infants aged 6 weeks-15 months. AEs observed less than or equal to 5 days after each dose were generally similar in type and frequency to those observed in a group of infants who received liquid PedvaxHIB{Registered} and RECOMBIVAX HB{Registered} in concurrent injections at separate sites. No serious vaccine-related AEs were observed. The type, frequency, and severity of observed AEs in a group of infants (n=126) who were administered one dose of hepatitis B vaccine shortly after birth and three doses of COMVAX TM on the recommended schedule were similar to AEs among a group that received only the three-dose COMVAX TM series (Merck Research Laboratories, unpublished data, 1996).

The efficacy of COMVAX TM is expected to be comparable to existing monovalent vaccines (7-9). Findings of prelicensure clinical trials indicate that the immunogenicity of COMVAX TM is equivalent to that of the monovalent vaccines. After two doses of COMVAX TM, 95% of approximately 570 subjects had antibodies to PRP at levels greater than 0.15 ug/mL. After three doses, 93% had antibodies to PRP at levels greater than 1.0 ug/mL, and 98% had antibodies to HBsAg at levels greater than or equal to 10 mIU/mL (Merck Research Laboratories, unpublished data, 1995).

The immunogenicity of COMVAX TM when used in a vaccination series with other vaccines containing HBsAg or Hib conjugate has not been studied. However, immunogenicity data from studies of monovalent vaccines indicate that any combination of Hib conjugate vaccines licensed for administration to infants may be used to complete the primary series (1,10). When COMVAX TM and a Hib conjugate vaccine other than PedvaxHib{Registered} are used to complete the primary series, three doses should be administered at ages 2, 4, and 6 months. Interchangeable administration of hepatitis B vaccine (e.g., one to two doses of one product and subsequent dose{s} of another) produced an immune response comparable to that resulting from three doses of a single vaccine (4). Completion of both primary vaccination series -- Hib conjugate vaccine and hepatitis B vaccine -- with the same products with which they are started is preferred. Simultaneous Vaccination

Results from clinical studies indicate that COMVAX TM may be administered at the same time as diphtheria and tetanus toxoids and pertussis vaccine, oral poliovirus vaccine, inactivated poliovirus vaccine, measles-mumps-rubella vaccine, varicella vaccine, and a booster dose of diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) at age 15 months; when administered simultaneously with other immunizing agents, separate sites and syringes for injectable vaccines should be used. No impairment of immune response to these individually tested vaccine antigens was demonstrated in clinical trials. As of November 1996, COMVAX TM had been administered concomitantly with the primary series of DTaP to 38 infants; no serious vaccine-related adverse events have been reported. Immune response data are satisfactory for COMVAX TM but are currently unavailable for DTaP. (See the manufacturer's package insert for additional information.) Additional Information

Additional product information is available from Merck, telephone (888)426-6829 ({888} 4COMVAX). ACIP recommendations for use of COMVAX TM are being developed and will be included in future published statements.

Reported by: Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration. Epidemiology and Surveillance Div, National Immunization Program; Childhood and Respiratory Diseases Br, Div of Bacterial and Mycotic Diseases; Hepatitis Br, Div of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC.

References

1. CDC. Recommendations for use of Haemophilus b conjugate vaccines and a combined diphtheria, tetanus, pertussis, and Haemophilus b vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1993;42(no. RR-13).

2. American Academy of Pediatrics. Report of the Committee on Infectious Diseases. Elk Grove Village, Illinois: American Academy of Pediatrics, Committee on Infectious Diseases, 1994.

3. American Academy of Family Physicians. Summary of policy recommendations for periodic health examination. Kansas City, Missouri: American Academy of Family Physicians, 1996.

4. CDC. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40(no. RR-13).

5. Woodruff BA, Stevenson J, Yusuf H, et al. Progress toward integrating hepatitis B vaccine into routine infant immunization schedules in the United States, 1991 through 1994. Pediatrics 1995;97:798-803.

6. CDC. Progress toward elimination of Haemophilis influenzae type b disease among infants and children -- United States, 1987-1995. MMWR 1996;45:901-6.

7. Stevens CE, Toy PT, Tong MJ, et al. Perinatal hepatitis B virus transmission in the United States. Prevention by passive-active immunization. JAMA 1985;253:1740-5.

8. Wainwright RB, McMahon BJ, Bulkow LR, et al. Duration of immunogenicity and efficacy of hepatitis B vaccine in a Yupik Eskimo population. JAMA 1989;261:2362-6.

9. Santosham M, Wolff M, Reid R, et al. The efficacy in Navajo infants of a conjugate vaccine consisting of Haemophilus influenzae type b polysaccharide and Neisseria meningitidis outer-membrane protein complex. N Engl J Med 1991;324:1767-72.

10. Greenberg DP, Leiberman JM, Marcy SM, et al. Enhanced antibody responses in infants given different sequences of heterogenous Haemophilus influenzae type b conjugate vaccines. J Pediatr 1995;126:206-11.

* Use of trade names and commercial sources is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services.

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