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Combination vaccines: Problems and promise
PEDIATRICS THE JOURNAL OF
September 2000
Volume 137
Number 3
EDITORIALS
Combination vaccines: Problems and promise In this issue of The Journal, Schmitt et al1 report a comparison of two combination vaccines. Infants were randomly assigned to receive either a vaccine combining diphtheria and tetanus toxoids and acellular pertussis vaccine plus a recombinant hepatitis B vaccine plus an inactivated poliovirus vaccine or the same DTaP-HB-IPV combination, used to reconstitute a lyophilized conjugate Haemophilus influenzae vaccine, with the resulting 6-component mixture administered as a single injection. Their results illustrate the promise of combination vaccines and the problems involved in making useful new combination vaccines available in the United States. Before the introduction of acellular pertussis vaccines for use in infants in the United States, a typical infant immunization visit involved administration of two injections (one or another of the available DTP-Hib combination vaccines and an HB vaccine) plus a dose of oral poliovirus vaccine. When acellular pertussis vaccines were introduced, we all expected that DTaP-Hib combinations would become available for use in infants. As the years have Reprint requests: Michael Decker, MD, MPH, Department of Preventive Medicine, Vanderbilt University School of Medicine, A-1116 Medical Center North, Nashville, TN 37232-2637.
J Pediatr 2000;137:291-5. Copyright © 2000 by Mosby, Inc. 0022-3476/2000/$12.00 + 0 9/18/109026 doi:10.1067/mpd.2000.109026
passed, we have seen DTaP completely replace DTP and IPV replace OPV, and now a conjugate pneumococcal vaccine has been added to the recommended infant series; but we have yet to see a DTaP-Hib combination licensed in the United States for use in infants. Implementation of the currently recommended infant immunization schedule typically involves administering at least 4, if not 5, injections at the 2-month and 4-month visits. Canadian and European colleagues have numerous combination vaccines from which to choose, enabling them to administer more antigens in a single injection (Table I). Only one such combination vaccine is licensed for use in infants in the United States, an HB-Hib combination, which does not simplify the infant immunization schedule to the extent that a DTaP-based combination would.
See related article, p. 304. For reasons that remain unclear, it has proven surprisingly difficult to combine a DTaP vaccine with an Hib vaccine without impairing the immunogenicity of the Hib vaccine. A single DTaP-Hib combination is licensed in the United States, but only for use as the fourth Hib dose, at 15 to 18 months. The manufacturer applied to the US Food and Drug Administration several years ago for licensure of this vaccine for use in the infant primary series, but the FDA did not approve the application. Because of the confidentiality sur-
rounding FDA decision making, the basis for that decision was not made public, but it is widely agreed that concern regarding reduced Hib immunogenicity was a major consideration. DTaP
Diphtheria and tetanus toxoids and acellular pertussis vaccine FDA Food and Drug Administration GMCs Geometric mean antibody concentrations HB Hepatitis B vaccine Hib Haemophilus influenzae vaccine IPV Inactivated poliovirus vaccine OPV Oral poliovirus vaccine
As shown in Table II,2-14 a study2 evaluating the combination of the US-licensed 4-component acellular pertussis vaccine (DTaP4) and the same manufacturer’s conjugate Hib vaccine showed the resulting Hib geometric mean antibody concentrations to be 93% lower in the group given the combination than in the group given the Hib vaccine separately; barely half of the infants given the combination achieved antibody levels of 1.0 µg/mL (a level traditionally thought to be associated with long-term protection). Studies (including that of Schmitt et al)1,3,4 evaluating the US-licensed 3component acellular pertussis vaccine (DTaP3) combined with its manufacturer’s conjugate Hib vaccine showed that the combination produced Hib GMCs that were 41% to 72% lower (depending, perhaps, on immunization schedule) in the combination vaccine group than in the separate Hib group. Among infants given the combination vaccine, the proportion achieving 1.0 µg/mL of Hib anti291
EDITORIALS
THE JOURNAL OF PEDIATRICS SEPTEMBER 2000
Table I. Selected pediatric combination vaccines presently licensed or under development*
Producers or vendors of licensed vaccines Combination vaccine†
Licensed in USA
DTaP/IPV DTaP/Hib DTaP/IPV/Hib DTaP/HB DTaP/IPV/HB DTaP/Hib/HB DTaP/Hib/IPV/HB DTaP/Hib/IPV/HB/HA HB/Hib HB/HA MMR-V PnC/MnC PnC/MnC/Hib
AvP-US‡
Licensed outside USA NAVA, AvP-Ca, AvP-Fr, SB AvP-Fr, SB AvP-Ca, AvP-Fr, SB SB
Under development
Yes Yes Yes Yes Yes Yes
Merck SB Yes Yes Yes
DTaP, Diphtheria and tetanus toxoids and acellular pertussis vaccine; IPV, enhanced inactivated trivalent poliovirus vaccine; NAVA, North American vaccine; AvP, Aventis Pasteur (formerly Pasteur Mérieux Connaught; CA, Fr, and US indicate, respectively, the Canadian, French, and US subsidiaries); SB, SmithKline Beecham; Hib, conjugate Haemophilus influenzae type b vaccine; HB, hepatitis B vaccine; HA, hepatitis A vaccine; MMR-V, measles, mumps, rubella, and varicella vaccine; PnC, pneumococcal conjugate vaccine; MnC, meningococcal conjugate vaccine. *Products combining only multiple serotypes of a single pathogen are excluded, as are DT, DTP, DTaP, OPV, IPV, MMR, and DT- or DTP-based combinations. †Includes both products distributed in combined form and those distributed in separate containers, for combination at the time of use. ‡Licensed for the fourth (booster) dose only.
body ranged from 66% to 77%. The combination of the US-licensed 2-component DTaP (DTaP2) and its manufacturer’s conjugate Hib vaccine (the combination that was denied the infant indication by the FDA) demonstrated the best performance among these studies of combinations based on US-licensed DTaP vaccines; there was a 39% reduction in Hib antibody GMC for this combination, compared with administration of Hib, with 85% of recipients achieving 1.0 µg/mL of Hib antibody.5 Numerous studies of a French DTaP2 product combined with Hib have demonstrated similar reductions in Hib immunogenicity.9-14 Nonetheless, as noted in Table I, the DTaP-Hib combinations based on the DTaP3 and the French DTaP2 vac292
cines are licensed in Europe and elsewhere. Does this mean that either their licensing authorities have been too lax or ours too strict? Not necessarily; the differing outcomes might simply reflect different approaches. One approach is to consider whether the reduced Hib antibody level achieved with a combination vaccine is sufficient to ensure protection; but this can be a difficult question when taken in isolation, because there is still considerable uncertainty regarding the minimum antibody level necessary for protection after the primary series, the importance of high antibody levels in controlling carriage, and the role of the kinetics of the anamnestic response. Another approach is to note that the Hib GMCs and seroprotection rates for most of
the combination vaccines in Table II, albeit lower than those seen with the same conjugate Hib vaccine given separately, nonetheless are comparable with those seen after separate administration of other licensed conjugate Hib vaccines with proven efficacy.15-17 The US FDA “Guidance for Industry for the Evaluation of Combination Vaccines” specifies that the safety and immunogenicity of combination vaccines should be evaluated in comparison with the separately but simultaneously administered individual vaccines that comprise the combination.18 Although reasonable on its face, this practice has an unintended consequence; that is, a combination formed (for example) from the two licensed parent vaccines of highest immunogenicity in their respective categories must, to meet this requirement, achieve a higher absolute level of performance than the combination formed from the two licensed parent vaccines of lowest immunogenicity. If the immunogenicity of the weaker combination equals that of its weak parent vaccines, it is eligible for approval, whereas if the immunogenicity of the stronger combination falls more than 10% below the performance of its strong parent vaccines (the FDA’s usual standard in these matters), it has failed to make the grade, even though it might actually have outperformed the weaker combination. Happily, when this issue was raised at the International Symposium on Combination Vaccines held at the National Institutes of Health in February 2000, FDA staff indicated that reconsideration was being given to the practice of comparing combinations only with their parent vaccines, without reference to their performance relative to other licensed products. As discussed by Schmitt et al,1 additional factors might have influenced European and other licensing authorities to accept, for use in infants, DTaPHib combinations with performance similar to that of the combination rejected by the FDA, including consider-
EDITORIALS
THE JOURNAL OF PEDIATRICS VOLUME 137, NUMBER 3 Table II. Selected studies evaluating DTaP–Hib or DTaP–IPV–Hib vaccines among infants
PRP antibody levels Place
Age (mo)
DTaP component licensed in USA 2, 4, 6 USA2 3, 4, 5 Germany3 Canada4 2, 4, 6 Germany1 2, 3, 4 USA5 2, 4, 6 DTaP component licensed in Canada 2, 4, 6 Taiwan6 2, 4, 6 Canada7,8 2, 4, 6 Canada7,8 DTaP component not licensed in USA or Canada 2, 3, 4 Germany9 Belgium10 3, 4, 5 10 Turkey 3, 4, 5 Chile11,12 2, 4, 6 France13,14 2, 3, 4
Vaccines*
Percent >1.0 µg/mL
GMC (µg/mL)
GMC ratio, combined/separate†
1.15, 16.4 2.02, 7.20 1.57, 3.22 2.62, 4.45 4.29, 7.0
0.07‡ 0.28‡ 0.49‡ 0.59‡ 0.61‡
DTaP4 ± HbOC DTaP3 ± PRP-T2 DTaP3–IPV ± PRP-T2 DTaP3 ± PRP-T2 DTaP2 ± PRP-T1
55, 94‡ 72, 91 66, 77 77, 89 85, 100‡
DTaP5 ± PRP-T1 DTaP5–IPV ± PRP-T1§ DTaP5–IPV ± PRP-T1
95, 99 85, 89 89, 89
11.8, 13.0 5.04, 3.83 4.86, 3.83
0.91 1.32 1.27
DTaP2 ± PRP-T1 DTaP2–PRP-T1 DTaP2 ± PRP-T1 DTaP2–IPV ± PRP-T1 DTaP2–IPV ± PRP-T1
91, 99 67, 92 90, 96 97, 96 71, 88‡
2.83, 4.3 1.78, 6.19 5.02, 11.7 7.46, 14.1 1.9, 5.2
0.66‡ 0.29‡ 0.43‡ 0.53‡ 0.36‡
PRP, Polyribosylribitol phosphate; GMC, geometric mean concentration of antibody; DTaP, diphtheria and tetanus toxoids and acellular pertussis vaccine; HbOC, PRP-diphtheria CRM197 protein conjugate vaccine; PRP-T, PRP-tetanus toxoid protein conjugate vaccine; IPV, inactivated poliovirus vaccine. *aP2 = Tripedia, Triavac, or similar Bekin-type aP vaccine; aP3 = Infanrix or similar 3-component aP vaccine; aP4 = ACEL-IMUNE or similar Takeda-type aP vaccine; aP5 = Tripacel or similar 5-component aP vaccine. PRP-T1 = ActHib (Pasteur Mérieux Connaught); PRP-T2 = Hiberix (SmithKline Beecham). †A ratio <1 indicates that mean antibody levels were lower with the combined vaccine than with separate injections; a ratio higher than one, that levels were higher with combined than separate injections. ‡Difference significant at P ≤ .05. §DTaP5–IPV used to reconstitute lyophilized PRP-T. DTaP5–IPV–PRP-T combined, fully liquid, in vial.
ation of the proportions achieving 0.15 µg/mL of antibody to Hib (a level that might correlate with at least short-term protection), the proportions that were seroresponsive, and the proportions demonstrating anamnestic responses on subsequent challenge. Perhaps most importantly, surveillance data fail to demonstrate any increase in invasive Hib disease in those countries in which use of these DTaP-Hib combinations is widespread. Many of these data were not available at the time the FDA rejected the DTaP2-Hib combination for use is infants, and perhaps they will influence future FDA decisions. What are the prospects in the United States for combinations that will ease
the infant immunization schedule? As noted in Table II, there is one DTaPHib combination that does not appear to result in reduced Hib immunogenicity as compared with separate administration: the combination based on the Canadian 5-component DTaP.6-8 Unfortunately, neither this combination nor its underlying DTaP vaccine is presently licensed in the United States. Studies of these vaccines are currently being conducted in the United States, but it is unlikely that this combination will be available in less than 2 to 3 years. An alternative approach that sidesteps the Hib immunogenicity problem is to formulate a combination that does not include Hib, such as the
DTaP-HB-IPV combination used as the control vaccine in the study by Schmitt et al.1 This combination has been submitted to the FDA for licensure. Although the clinical data are encouraging, the IPV component is not presently licensed in the United States, which means that licensure is required not only for the product but also for the production process and facility (often a more lengthy procedure); nonetheless, it is possible that this combination might be licensed within the next year. Another obstacle might arise to block the licensure of combination vaccines in the United States. Attendees at the previously mentioned International Sym293
EDITORIALS
THE JOURNAL OF PEDIATRICS SEPTEMBER 2000
Table III. Pediatric combination vaccines that might be licensed by the end of 2003
Producers or vendors of licensed vaccines Combination vaccine†
Licensed in USA
Licensed outside USA
DTaP/IPV
AvP
DTaP/Hib DTaP/IPV/Hib
AvP-US‡ AvP, SB
SB
NAVA, AvP-Ca, AvP-Fr, SB AvP-Fr, SB AvP-Ca, AvP-Fr, SB SB SB
SB
SB
Merck SB Merck, SB WL
Merck SB Merck, SB WL
DTaP/HB DTaP/IPV/HB DTaP/Hib/HB DTaP/Hib/IPV/HB DTaP/Hib/IPV/HB/HA HB/Hib HB/HA MMR-V PnC/Hib
DTaP, Diphtheria and tetanus toxoids and acellular pertussis vaccine; IPV, enhanced inactivated trivalent poliovirus vaccine; AvP, Aventis Pasteur (formerly Pasteur Mérieux Connaught; Ca, Fr, and US indicate, respectively, the Canadian, French, and US subsidiaries); NAVA, North American vaccine; SB, SmithKline Beecham; Hib, conjugate Haemophilus influenzae type b vaccine; HB, hepatitis B vaccine; HA, hepatitis A vaccine; MMR-V, measles, mumps, rubella, and varicella vaccine; PnC, pneumococcal conjugate vaccine; WL, Wyeth Lederle Vaccines and Pediatrics. *Products combining only multiple serotypes of a single pathogen are excluded, as are DT, DTP, DTaP, OPV, IPV, MMR, and DT- or DTP-based combinations. †Includes both products distributed in combined form and those distributed in separate containers, for combination at the time of use. ‡Licensed for the fourth (booster) dose only.
posium were dismayed to hear FDA staff support the suggestion that prelicensure safety studies be expanded by an order of magnitude (to incorporate 100,000 subjects) to ensure detection of adverse events too rare to detect with present prelicensure studies. Even if sufficient study sites and subjects could be enrolled for such studies, the huge associated costs would almost certainly convince manufacturers not to seek licensure of new combinations of existing vaccines. Given our high compliance with the recommended immunization schedule, availability of a combination vaccine cannot increase US vaccine sales (for example, instead of selling a vial of DTaP plus a vial of IPV, the manufacturer instead sells one vial of DTaP-IPV). As long as the monocomponent vaccines remained available, 294
there would be a limit to the premium that vaccine purchasers would be willing to pay for the combination, and thus a limit to the manufacturer’s ability to recoup these extra costs—a limit that would not exist if the same research dollars were spent on developing a new entity with a price that would not face the same limitation. Consequently, development of combinations would halt. We hope that these concerns will be addressed when the question of prelicensure study size is considered further at an FDA workshop tentatively scheduled for November 2000. We have discussed the problems of combination vaccines; what of the promise? Table III is, we hope, not too optimistic a projection of the combination vaccines that might be available by the end of 2003. Clinical and devel-
opmental data for these vaccines are encouraging, but only time, and the FDA, will tell. Michael D. Decker, MD, MPH Professor of Preventive Medicine and Medicine (Infectious Diseases) Vanderbilt University School of Medicine Kathryn M. Edwards, MD Professor of Pediatrics Vanderbilt University School of Medicine Nashville, TN 37232-2637
REFERENCES 1. Schmitt HJ, Knuf M, Ortiz E, Sänger R, Uwamwezi MC, Kaufhold A. Primary vaccination of infants with diphtheria-tetanus-acellular pertussis–hepatitis B virus–inactivated polio virus and Haemophilus influenzae type b vaccines given as either separate or mixed injections. J Pediatr 2000;137:304-12. 2. Shinefield H, Black S, Ray P, Lewis E, Fireman B, Hohenboken M, et al. Safety of combined acellular pertussis DTaP-HbOC vaccine (Lederle-Praxis) in infants. In: Abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco (CA): American Society for Microbiology; 1995. Abstract G79. 3. Schmitt HJ, Zepp F, Muschenborn S, Sumenicht G, Schuind A, Beutel K, et al. Immunogenicity and reactogenicity of a Haemophilus influenzae type b tetanus conjugate vaccine when administered separately or mixed with concomitant diphtheria-tetanus-toxoid and acellular pertussis vaccine for primary and for booster immunizations. Eur J Pediatr 1998;157:208-14. 4. Halperin SA, King J, Law B, Mills E, Willems P. Safety and immunogenicity of Haemophilus influenzae tetanus toxoid conjugate vaccine given separately or in combination with a three component acellular pertussis vaccine combined with diphtheria and tetanus toxoids and inactivated poliovirus vaccine for the first four doses. Clin Infect Dis 1999;28:995-1001. 5. Pichichero ME, Latiolais T, Bernstein DI, Hosbach P, Christian E, Vidor E, et al. Vaccine antigen interactions after a combination diphtheria-tetanus toxoidacellular pertussis/purified capsular polysaccharide of Haemophilus influenzae type b-tetanus toxoid vaccine in two-, four- and six-month-old infants. Pediatr Infect Dis J 1997;16:863-70. 6. Lee C-Y, Huang L-M, Lee P-I, Chiu
EDITORIALS
THE JOURNAL OF PEDIATRICS VOLUME 137, NUMBER 3 H-H, Lin W, Thipphawong J, et al. An acellular pertussis DTacP combined with a lyophilized Haemophilus influenzae type b (PRP-T) vaccine is safe and immunogenic in Taiwanese infants. In: Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington (DC): American Society for Microbiology; 1997. Abstract G-93. 7. Thipphawong J, Baretto L, Mills E, Meekison W, Russell M, Cunning L, et al. A fully-liquid, acellular pertussis vaccine combined with IPV and Hib vaccines (DTaP-IPV-PRP-T) is safe and immunogenic without significant interactions. In: Abstracts of the International Conference on Acute Respiratory Infections; 1997 July 7-10; Canberra, Australia. Workshop W3E. 8. Mills E, Russell M, Cunning L, Guasparini R, Meekison W, Thipphawong J, et al. A fully liquid acellular pertussis vaccine combined with IPV and Hib vaccines (DTaP-IPV-PRP-T) is safe and immunogenic without significant interaction. In: Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington (DC): American Society for Microbiology; 1997. Abstract G-95. 9. Liese JG, Harzer E, Hosbach P, Froeschle J, Meschievitz CK, Belohradsky BH. Hib antibody response of a combined DTaP-PRP-T conjugate vaccine compared to separate injections in infants. In: Abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington (DC): American Society for Microbiology; 1996. Abstract G105.
10. Hoppenbrouwers K, Kanra G, Roelants M, Ceyhan M, Vandermeulen C, Yurdakök K, et al. Priming effect, immunogenicity and safety of an Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T) and diphtheriatetanus-acellular pertussis (DTaP) combination vaccine administered to infants in Belgium and Turkey. Vaccine 1999;17:875-86. 11. Lagos R, Kotloff K, Hoffenbach A, San Martin O, Abrego P, Ureta AM, et al. Clinical response to pentavalent parenteral diphtheria, tetanus, acellular pertussis (DTaP), inactivated polio (eIPV) and Haemophilus influenzae b (Hib) conjugate vaccine in 2, 4 & 6 mo old Chilean infants. In: Abstracts of the 35th Annual Meeting of the Infectious Diseases Society of America. Alexandria (VA): Infectious Diseases Society of America; 1997. Abstract 609. 12. Lagos R, Kotloff K, Hoffenbach A, San Martin O, Abrego P, Ureta AM, et al. Clinical acceptability and immunogenicity of a pentavalent parenteral combination vaccine containing diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis and Haemophilus influenzae type b conjugate antigens in two-, four-, and six-month-old Chilean infants. Pediatr Infect Dis J 1998;17:294-304. 13. Langue J, David T, Roussel F, Pines E, Hoffenbach A. Safety and immunogenicity of DTaP-IPV and Act-HIB vaccines administered either combined or separately to infants at 2, 3, and 4 months of age. In: Abstracts of the 15th Annual Meeting of the European Society for Paediatric Infectious Diseases. Paris: ESPID; 1997. Abstract 79.
14. Hoffenbach A, Langue J, Mallet E, Roussel F, David T, Pines E, et al. Influence of combining DTaP-IPV and Act-HIB vaccines and of changing the primary immunization schedule on the antibody response to Haemophilus influenzae type b. In: Abstracts of the 15th Annual Meeting of the European Society for Paediatric Infectious Diseases. Paris: ESPID; 1997. Abstract 80. 15. Decker MD, Edwards KM, Bradley R. Palmer P. Comparative trial in infants of four conjugate Haemophilus influenzae type b vaccines. J Pediatr 1992;120:184-9. 16. Greenberg DP, Lieberman JM, Marcy SM, Wong VK, Partridge S, Chang SJ, et al. Enhanced antibody responses in infants given different sequences of heterogeneous Haemophilus influenzae type b conjugate vaccines. J Pediatr 1995;126:206-11. 17. Capeding MR, Nohynek H, Kayhty H, Pascual LG, Sunico ES, Tamundong AA, et al. Antibody responses of three Haemophilus influenzae type b conjugate vaccines after one, two and three doses in Filipino children. Vaccine 1998;16:1004-8. 18. Guidance for industry for the evaluation of combination vaccines for preventable diseases: production, testing and clinical studies. Docket No. 97N0029. US Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research, April 1997 [cited 2000 May 20]. Available from: URL:http://www.fda.gov/cber/gdlns/ combvacc.pdf.
295
September 2000
Volume 137
Number 3
EDITORIALS
Combination vaccines: Problems and promise In this issue of The Journal, Schmitt et al1 report a comparison of two combination vaccines. Infants were randomly assigned to receive either a vaccine combining diphtheria and tetanus toxoids and acellular pertussis vaccine plus a recombinant hepatitis B vaccine plus an inactivated poliovirus vaccine or the same DTaP-HB-IPV combination, used to reconstitute a lyophilized conjugate Haemophilus influenzae vaccine, with the resulting 6-component mixture administered as a single injection. Their results illustrate the promise of combination vaccines and the problems involved in making useful new combination vaccines available in the United States. Before the introduction of acellular pertussis vaccines for use in infants in the United States, a typical infant immunization visit involved administration of two injections (one or another of the available DTP-Hib combination vaccines and an HB vaccine) plus a dose of oral poliovirus vaccine. When acellular pertussis vaccines were introduced, we all expected that DTaP-Hib combinations would become available for use in infants. As the years have Reprint requests: Michael Decker, MD, MPH, Department of Preventive Medicine, Vanderbilt University School of Medicine, A-1116 Medical Center North, Nashville, TN 37232-2637.
J Pediatr 2000;137:291-5. Copyright © 2000 by Mosby, Inc. 0022-3476/2000/$12.00 + 0 9/18/109026 doi:10.1067/mpd.2000.109026
passed, we have seen DTaP completely replace DTP and IPV replace OPV, and now a conjugate pneumococcal vaccine has been added to the recommended infant series; but we have yet to see a DTaP-Hib combination licensed in the United States for use in infants. Implementation of the currently recommended infant immunization schedule typically involves administering at least 4, if not 5, injections at the 2-month and 4-month visits. Canadian and European colleagues have numerous combination vaccines from which to choose, enabling them to administer more antigens in a single injection (Table I). Only one such combination vaccine is licensed for use in infants in the United States, an HB-Hib combination, which does not simplify the infant immunization schedule to the extent that a DTaP-based combination would.
See related article, p. 304. For reasons that remain unclear, it has proven surprisingly difficult to combine a DTaP vaccine with an Hib vaccine without impairing the immunogenicity of the Hib vaccine. A single DTaP-Hib combination is licensed in the United States, but only for use as the fourth Hib dose, at 15 to 18 months. The manufacturer applied to the US Food and Drug Administration several years ago for licensure of this vaccine for use in the infant primary series, but the FDA did not approve the application. Because of the confidentiality sur-
rounding FDA decision making, the basis for that decision was not made public, but it is widely agreed that concern regarding reduced Hib immunogenicity was a major consideration. DTaP
Diphtheria and tetanus toxoids and acellular pertussis vaccine FDA Food and Drug Administration GMCs Geometric mean antibody concentrations HB Hepatitis B vaccine Hib Haemophilus influenzae vaccine IPV Inactivated poliovirus vaccine OPV Oral poliovirus vaccine
As shown in Table II,2-14 a study2 evaluating the combination of the US-licensed 4-component acellular pertussis vaccine (DTaP4) and the same manufacturer’s conjugate Hib vaccine showed the resulting Hib geometric mean antibody concentrations to be 93% lower in the group given the combination than in the group given the Hib vaccine separately; barely half of the infants given the combination achieved antibody levels of 1.0 µg/mL (a level traditionally thought to be associated with long-term protection). Studies (including that of Schmitt et al)1,3,4 evaluating the US-licensed 3component acellular pertussis vaccine (DTaP3) combined with its manufacturer’s conjugate Hib vaccine showed that the combination produced Hib GMCs that were 41% to 72% lower (depending, perhaps, on immunization schedule) in the combination vaccine group than in the separate Hib group. Among infants given the combination vaccine, the proportion achieving 1.0 µg/mL of Hib anti291
EDITORIALS
THE JOURNAL OF PEDIATRICS SEPTEMBER 2000
Table I. Selected pediatric combination vaccines presently licensed or under development*
Producers or vendors of licensed vaccines Combination vaccine†
Licensed in USA
DTaP/IPV DTaP/Hib DTaP/IPV/Hib DTaP/HB DTaP/IPV/HB DTaP/Hib/HB DTaP/Hib/IPV/HB DTaP/Hib/IPV/HB/HA HB/Hib HB/HA MMR-V PnC/MnC PnC/MnC/Hib
AvP-US‡
Licensed outside USA NAVA, AvP-Ca, AvP-Fr, SB AvP-Fr, SB AvP-Ca, AvP-Fr, SB SB
Under development
Yes Yes Yes Yes Yes Yes
Merck SB Yes Yes Yes
DTaP, Diphtheria and tetanus toxoids and acellular pertussis vaccine; IPV, enhanced inactivated trivalent poliovirus vaccine; NAVA, North American vaccine; AvP, Aventis Pasteur (formerly Pasteur Mérieux Connaught; CA, Fr, and US indicate, respectively, the Canadian, French, and US subsidiaries); SB, SmithKline Beecham; Hib, conjugate Haemophilus influenzae type b vaccine; HB, hepatitis B vaccine; HA, hepatitis A vaccine; MMR-V, measles, mumps, rubella, and varicella vaccine; PnC, pneumococcal conjugate vaccine; MnC, meningococcal conjugate vaccine. *Products combining only multiple serotypes of a single pathogen are excluded, as are DT, DTP, DTaP, OPV, IPV, MMR, and DT- or DTP-based combinations. †Includes both products distributed in combined form and those distributed in separate containers, for combination at the time of use. ‡Licensed for the fourth (booster) dose only.
body ranged from 66% to 77%. The combination of the US-licensed 2-component DTaP (DTaP2) and its manufacturer’s conjugate Hib vaccine (the combination that was denied the infant indication by the FDA) demonstrated the best performance among these studies of combinations based on US-licensed DTaP vaccines; there was a 39% reduction in Hib antibody GMC for this combination, compared with administration of Hib, with 85% of recipients achieving 1.0 µg/mL of Hib antibody.5 Numerous studies of a French DTaP2 product combined with Hib have demonstrated similar reductions in Hib immunogenicity.9-14 Nonetheless, as noted in Table I, the DTaP-Hib combinations based on the DTaP3 and the French DTaP2 vac292
cines are licensed in Europe and elsewhere. Does this mean that either their licensing authorities have been too lax or ours too strict? Not necessarily; the differing outcomes might simply reflect different approaches. One approach is to consider whether the reduced Hib antibody level achieved with a combination vaccine is sufficient to ensure protection; but this can be a difficult question when taken in isolation, because there is still considerable uncertainty regarding the minimum antibody level necessary for protection after the primary series, the importance of high antibody levels in controlling carriage, and the role of the kinetics of the anamnestic response. Another approach is to note that the Hib GMCs and seroprotection rates for most of
the combination vaccines in Table II, albeit lower than those seen with the same conjugate Hib vaccine given separately, nonetheless are comparable with those seen after separate administration of other licensed conjugate Hib vaccines with proven efficacy.15-17 The US FDA “Guidance for Industry for the Evaluation of Combination Vaccines” specifies that the safety and immunogenicity of combination vaccines should be evaluated in comparison with the separately but simultaneously administered individual vaccines that comprise the combination.18 Although reasonable on its face, this practice has an unintended consequence; that is, a combination formed (for example) from the two licensed parent vaccines of highest immunogenicity in their respective categories must, to meet this requirement, achieve a higher absolute level of performance than the combination formed from the two licensed parent vaccines of lowest immunogenicity. If the immunogenicity of the weaker combination equals that of its weak parent vaccines, it is eligible for approval, whereas if the immunogenicity of the stronger combination falls more than 10% below the performance of its strong parent vaccines (the FDA’s usual standard in these matters), it has failed to make the grade, even though it might actually have outperformed the weaker combination. Happily, when this issue was raised at the International Symposium on Combination Vaccines held at the National Institutes of Health in February 2000, FDA staff indicated that reconsideration was being given to the practice of comparing combinations only with their parent vaccines, without reference to their performance relative to other licensed products. As discussed by Schmitt et al,1 additional factors might have influenced European and other licensing authorities to accept, for use in infants, DTaPHib combinations with performance similar to that of the combination rejected by the FDA, including consider-
EDITORIALS
THE JOURNAL OF PEDIATRICS VOLUME 137, NUMBER 3 Table II. Selected studies evaluating DTaP–Hib or DTaP–IPV–Hib vaccines among infants
PRP antibody levels Place
Age (mo)
DTaP component licensed in USA 2, 4, 6 USA2 3, 4, 5 Germany3 Canada4 2, 4, 6 Germany1 2, 3, 4 USA5 2, 4, 6 DTaP component licensed in Canada 2, 4, 6 Taiwan6 2, 4, 6 Canada7,8 2, 4, 6 Canada7,8 DTaP component not licensed in USA or Canada 2, 3, 4 Germany9 Belgium10 3, 4, 5 10 Turkey 3, 4, 5 Chile11,12 2, 4, 6 France13,14 2, 3, 4
Vaccines*
Percent >1.0 µg/mL
GMC (µg/mL)
GMC ratio, combined/separate†
1.15, 16.4 2.02, 7.20 1.57, 3.22 2.62, 4.45 4.29, 7.0
0.07‡ 0.28‡ 0.49‡ 0.59‡ 0.61‡
DTaP4 ± HbOC DTaP3 ± PRP-T2 DTaP3–IPV ± PRP-T2 DTaP3 ± PRP-T2 DTaP2 ± PRP-T1
55, 94‡ 72, 91 66, 77 77, 89 85, 100‡
DTaP5 ± PRP-T1 DTaP5–IPV ± PRP-T1§ DTaP5–IPV ± PRP-T1
95, 99 85, 89 89, 89
11.8, 13.0 5.04, 3.83 4.86, 3.83
0.91 1.32 1.27
DTaP2 ± PRP-T1 DTaP2–PRP-T1 DTaP2 ± PRP-T1 DTaP2–IPV ± PRP-T1 DTaP2–IPV ± PRP-T1
91, 99 67, 92 90, 96 97, 96 71, 88‡
2.83, 4.3 1.78, 6.19 5.02, 11.7 7.46, 14.1 1.9, 5.2
0.66‡ 0.29‡ 0.43‡ 0.53‡ 0.36‡
PRP, Polyribosylribitol phosphate; GMC, geometric mean concentration of antibody; DTaP, diphtheria and tetanus toxoids and acellular pertussis vaccine; HbOC, PRP-diphtheria CRM197 protein conjugate vaccine; PRP-T, PRP-tetanus toxoid protein conjugate vaccine; IPV, inactivated poliovirus vaccine. *aP2 = Tripedia, Triavac, or similar Bekin-type aP vaccine; aP3 = Infanrix or similar 3-component aP vaccine; aP4 = ACEL-IMUNE or similar Takeda-type aP vaccine; aP5 = Tripacel or similar 5-component aP vaccine. PRP-T1 = ActHib (Pasteur Mérieux Connaught); PRP-T2 = Hiberix (SmithKline Beecham). †A ratio <1 indicates that mean antibody levels were lower with the combined vaccine than with separate injections; a ratio higher than one, that levels were higher with combined than separate injections. ‡Difference significant at P ≤ .05. §DTaP5–IPV used to reconstitute lyophilized PRP-T. DTaP5–IPV–PRP-T combined, fully liquid, in vial.
ation of the proportions achieving 0.15 µg/mL of antibody to Hib (a level that might correlate with at least short-term protection), the proportions that were seroresponsive, and the proportions demonstrating anamnestic responses on subsequent challenge. Perhaps most importantly, surveillance data fail to demonstrate any increase in invasive Hib disease in those countries in which use of these DTaP-Hib combinations is widespread. Many of these data were not available at the time the FDA rejected the DTaP2-Hib combination for use is infants, and perhaps they will influence future FDA decisions. What are the prospects in the United States for combinations that will ease
the infant immunization schedule? As noted in Table II, there is one DTaPHib combination that does not appear to result in reduced Hib immunogenicity as compared with separate administration: the combination based on the Canadian 5-component DTaP.6-8 Unfortunately, neither this combination nor its underlying DTaP vaccine is presently licensed in the United States. Studies of these vaccines are currently being conducted in the United States, but it is unlikely that this combination will be available in less than 2 to 3 years. An alternative approach that sidesteps the Hib immunogenicity problem is to formulate a combination that does not include Hib, such as the
DTaP-HB-IPV combination used as the control vaccine in the study by Schmitt et al.1 This combination has been submitted to the FDA for licensure. Although the clinical data are encouraging, the IPV component is not presently licensed in the United States, which means that licensure is required not only for the product but also for the production process and facility (often a more lengthy procedure); nonetheless, it is possible that this combination might be licensed within the next year. Another obstacle might arise to block the licensure of combination vaccines in the United States. Attendees at the previously mentioned International Sym293
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THE JOURNAL OF PEDIATRICS SEPTEMBER 2000
Table III. Pediatric combination vaccines that might be licensed by the end of 2003
Producers or vendors of licensed vaccines Combination vaccine†
Licensed in USA
Licensed outside USA
DTaP/IPV
AvP
DTaP/Hib DTaP/IPV/Hib
AvP-US‡ AvP, SB
SB
NAVA, AvP-Ca, AvP-Fr, SB AvP-Fr, SB AvP-Ca, AvP-Fr, SB SB SB
SB
SB
Merck SB Merck, SB WL
Merck SB Merck, SB WL
DTaP/HB DTaP/IPV/HB DTaP/Hib/HB DTaP/Hib/IPV/HB DTaP/Hib/IPV/HB/HA HB/Hib HB/HA MMR-V PnC/Hib
DTaP, Diphtheria and tetanus toxoids and acellular pertussis vaccine; IPV, enhanced inactivated trivalent poliovirus vaccine; AvP, Aventis Pasteur (formerly Pasteur Mérieux Connaught; Ca, Fr, and US indicate, respectively, the Canadian, French, and US subsidiaries); NAVA, North American vaccine; SB, SmithKline Beecham; Hib, conjugate Haemophilus influenzae type b vaccine; HB, hepatitis B vaccine; HA, hepatitis A vaccine; MMR-V, measles, mumps, rubella, and varicella vaccine; PnC, pneumococcal conjugate vaccine; WL, Wyeth Lederle Vaccines and Pediatrics. *Products combining only multiple serotypes of a single pathogen are excluded, as are DT, DTP, DTaP, OPV, IPV, MMR, and DT- or DTP-based combinations. †Includes both products distributed in combined form and those distributed in separate containers, for combination at the time of use. ‡Licensed for the fourth (booster) dose only.
posium were dismayed to hear FDA staff support the suggestion that prelicensure safety studies be expanded by an order of magnitude (to incorporate 100,000 subjects) to ensure detection of adverse events too rare to detect with present prelicensure studies. Even if sufficient study sites and subjects could be enrolled for such studies, the huge associated costs would almost certainly convince manufacturers not to seek licensure of new combinations of existing vaccines. Given our high compliance with the recommended immunization schedule, availability of a combination vaccine cannot increase US vaccine sales (for example, instead of selling a vial of DTaP plus a vial of IPV, the manufacturer instead sells one vial of DTaP-IPV). As long as the monocomponent vaccines remained available, 294
there would be a limit to the premium that vaccine purchasers would be willing to pay for the combination, and thus a limit to the manufacturer’s ability to recoup these extra costs—a limit that would not exist if the same research dollars were spent on developing a new entity with a price that would not face the same limitation. Consequently, development of combinations would halt. We hope that these concerns will be addressed when the question of prelicensure study size is considered further at an FDA workshop tentatively scheduled for November 2000. We have discussed the problems of combination vaccines; what of the promise? Table III is, we hope, not too optimistic a projection of the combination vaccines that might be available by the end of 2003. Clinical and devel-
opmental data for these vaccines are encouraging, but only time, and the FDA, will tell. Michael D. Decker, MD, MPH Professor of Preventive Medicine and Medicine (Infectious Diseases) Vanderbilt University School of Medicine Kathryn M. Edwards, MD Professor of Pediatrics Vanderbilt University School of Medicine Nashville, TN 37232-2637
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THE JOURNAL OF PEDIATRICS VOLUME 137, NUMBER 3 H-H, Lin W, Thipphawong J, et al. An acellular pertussis DTacP combined with a lyophilized Haemophilus influenzae type b (PRP-T) vaccine is safe and immunogenic in Taiwanese infants. In: Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington (DC): American Society for Microbiology; 1997. Abstract G-93. 7. Thipphawong J, Baretto L, Mills E, Meekison W, Russell M, Cunning L, et al. A fully-liquid, acellular pertussis vaccine combined with IPV and Hib vaccines (DTaP-IPV-PRP-T) is safe and immunogenic without significant interactions. In: Abstracts of the International Conference on Acute Respiratory Infections; 1997 July 7-10; Canberra, Australia. Workshop W3E. 8. Mills E, Russell M, Cunning L, Guasparini R, Meekison W, Thipphawong J, et al. A fully liquid acellular pertussis vaccine combined with IPV and Hib vaccines (DTaP-IPV-PRP-T) is safe and immunogenic without significant interaction. In: Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington (DC): American Society for Microbiology; 1997. Abstract G-95. 9. Liese JG, Harzer E, Hosbach P, Froeschle J, Meschievitz CK, Belohradsky BH. Hib antibody response of a combined DTaP-PRP-T conjugate vaccine compared to separate injections in infants. In: Abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington (DC): American Society for Microbiology; 1996. Abstract G105.
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