Development and clinical application of new polyvalent combined paediatric vaccines
Introduction
Vaccination is recognised as being the most cost-effective medical intervention when used in properly implemented rational population-wide pro grammes1, 2. The ability of vaccines to control the considerable disease burden inflicted by infectious diseases is well documented[3]. The most acclaimed victory of medical science, the eradication of smallpox, was achieved through the use of the first vaccine developed over 200 years ago4, 5. However, it is also clear that, currently, the potential for disease control, elimination and eradication offered by vaccines is not being fully exploited in the world. The reasons for this failure are obviously very complex. They include political and socio-economic traditions that tend to favour, in healthcare as in other areas, short-term therapeutic approaches over the more fundamental but less glamorous long-term approach of prevention. Other barriers to optimal implementation of vaccination programmes are the complicated and expensive logistics, including the maintenance of a cold chain, required to administer to all children many thermolabile vaccines according to multi-injection schedules. The number of injections required to fully immunise a child against all the diseases for which vaccines exist has already reached a level which is becoming unacceptable to parents and healthcare personnel. Unjustified fear of side effects is also affecting acceptance[6]. The current boom in vaccine research, fuelled by the spectacular breakthroughs in immunology, molecular biology and genomics, will lead to many new vaccines[7]that it will be hard to add to the already overcrowded immunisation calendar for young children. The obvious solution to this growing problem is combination, in a multivalent vaccine, of antigens that induce immunity against several diseases. This will reduce the number of inoculations and medical visits required to achieve full immunisation. Combined vaccines are not new and combinations like DTP (triple vaccine against diphtheria, tetanus and pertussis), trivalent oral (OPV) and injectable (IPV) polio, measles/mumps/rubella (MMR), trivalent influenza, polyvalent pneumococcal and meningococcal vaccines have been extensively used for many decades. The advantages of combined vaccines include increased convenience for all users, higher compliance by recipients, wider coverage of the population, better disease control and, because of the simplified logistics of vaccine delivery, reduced administrative costs[8]. Over the last ten years, SmithKline Beecham Biologicals (SB BIO), the vaccine manufacturer that employs the author, has been engaged in developing new paediatric vaccines using DTP as the cornerstone on which to build more polyvalent-vaccines. The difficulties encountered, progress made, results obtained and lessons learned will be surveyed, in chronological fashion.
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Historical retrospective
In 1988, the decision was taken to develop a combined DTP hepatitis B (DTPw–HB) vaccine based on the classic (whole-cell) DTP vaccine. Hopes for a rapid successful outcome were high as simultaneous administration of these antigens had already been demonstrated to be possible[9]. International support for this combination came from the Children's Vaccine Initiative that recommended development of this vaccine as a priority in order to facilitate incorporation of hepatitis B immunisation in the
Development of acellular pertussis vaccine
In the early 1990's emphasis switched towards the development of purified antigens for the pertussis component in the DTP vaccine. After the good tolerability, safety and protective efficacy of acellular pertussis vaccine combined with diphtheria and tetanus toxoids (DTPa) had been demonstrated in large scale clinical studies[15]attention was focused on developing combined vaccines based on DTPa. The antigens considered for inclusion in the combinations were HB, IPV and Hib. At this point some
Licensure of DTPa-based combined vaccines
Four DTPa-based combined vaccines (DTPa–HB, DTPa–IPV, DTPa/Hib, DTPa–IPV/Hib) developed by SB BIO have so far been licensed. When and where the first license was obtained for these are shown in Table 3. Since the first licenses were obtained more countries have approved these vaccines and they are being introduced more widely.
DTPa–HB vaccine
Two feasibility studies conducted in Turkey[22]and Lithuania[23]established that there was no reduction in the immune response of infants to any antigen in the DTPa–HB vaccine when compared to separate administration of the two vaccines in opposite limbs. Further studies in Italy24, 25and elsewhere[20]showed that ``Infanrix™ Hep B provides at least the same level of immunogenicity compared to diphtheria, tetanus, acellular pertussis (DTPa) and hepatitis B vaccines administered separately'' (Ref.
Comment
The advantages of combined vaccines in immunisation programmes are so obvious that all major manufacturers of vaccines have in the past 10 years devoted considerable energy and resources to developing more polyvalent vaccines based on either the classic (whole-cell) or acellular DTP vaccines. Experience has shown that the development of a new combined vaccine is time-consuming and expensive[11]. There are many difficulties of a technical, regulatory, commercial and political nature to be
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