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Report of the Expert Panel VIII New vaccines, especially new combined vaccines
EUROPEAN COMMISSION COST/STD INITIATIVE Report of the Expert Panel VIII
NEW VACCINES, ESPECIALLY NEW COMBINED VACCINES
Chairman:
Members:
Dr. Rino RAPPUOLI ISTITUTO RICERCHE IMMUNOBIOLOGICHE Via Fiorentina 1 I-53 100 SIENA
- SIENA
Dr. Camille LOCHT INSTITUT PASTEUR DE LILLE 1 rue du Prof. Calmette LILLE F-59019
Dr. Jan POOLMAN NATIONAL INSTITUTE FOR PUBLIC HEALTH & ENVIRONMENT Lab. for Vaccine Development & Immune Mechanisms NL-3720 BA
BILTHOVEN
Dr. Frangis ANDRE SMITHKLINE BEECHAM Rue de 1’Institut 89 B-1330 RIXENSART
Prof. Gordon DOUGAN IMPERIAL COLLEGE Dept. of Biochemistry Exhibition Road UK-LONDON SW7 2AZ
691
692
List of Contents
1. INTRODUCTION
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2.
ADVANTAGES
3.
POINTS FOR CONSIDERATION COMBINED
OF COMBINED
VACCINES
VACCINES
. .. .. .. .. .. .. .. .. .. ... . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. .. .. .. . 693
IN THE DEVELOPMENT
OF
.. .. .. .. .. .. ... .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. .. .. . .693
3.1. Technical and scientific hurdles .....................................................................................
.693
3.1. Economical and political considerations ........................................................................
.694
4.
PROPOSALS
5.
SELECTED
FOR THE RATIONAL
REFERENCES
DESIGN OF COMBINED
VACCINES
.. . .. .. .. .. . .. 695
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ... . ... . ... . .. .. .. .. .. .. .. .. .. .. .. . ... . .. .. . 699
693
1. INTRODUCTION 2. ADVANTAGES OF COMBINED VACCINES The increasing cost of modern health care, that relies heavily on the direct treatment of on-going disease, is leading to a need to reappraise current medical practice. It is becoming highly desirable to place more emphasis on preventive medicine. An attractive and highly cost-effective preventive approach is the use of vaccines (l-2). Traditionally, vaccination has been focused on immunization of infants against infectious diseases. To make vaccination an even more cost-effective option, we could develop a vaccination policy aiming at the introduction of safe and efficacious vaccines against a broader range of diseases in all age groups. Combining several vaccines into a single formulation for immunization against different diseases is a practice which has been commonly used in the past. The combination of diphtheria (D), tetanus (T) and whole cell pertussis (Pw) vaccines into the DTPw vaccine, that of polioviruses serotypes 1, 2 and 3 into a single vaccine against poliomyelitis, measles, mumps into a triple vaccine, and rubella vaccines meningococcal A, C, Y and W 135 polysaccharide vaccines into a tetravalent vaccines, and a 23-valent pneumococcal vaccines are just five examples of successful “combined vaccines” that have been widely used in clinical practice for many years (3,4,5,6). The recent commercialisation of new vaccines such as those against Haemophilus injluenzae type b, hepatitis B and A, and our steadily increasing potential to develop novel vaccines will make it necessary to further combine vaccines, which has to take into account not only the presently available vaccines but also those that are likely to come in the future. in immunology, molecular New advances biology, and biotechnology allow us now to realistically approach diseases for which vaccines were previously unfeasible. These advances have already led to the improvement of existing vaccines such as those against hepatitis B and the replacement of reactogenic Pw vaccines by fully defined, safer acellular vaccines. In addition, some vaccines may prevent or stop the development of cancers and there is a real potential for preventive and therapeutic vaccination against tumours, auto-immune and allergic diseases. We can also exploit new technologies to improve the delivery and immunogenicity of vaccines. The nature of the immune response can be influenced to elicit specific protective mechanisms needed for specific diseases. Given the number of new vaccines which are likely to be introduced during the next 10 to 15 years as a result of recent technological breakthroughs, great attention must be paid to the design of a global strategy which will bring optimal benefit from the potential advantages while minimizing the disadvantages that combined vaccines may have.
Vaccination against several diseases by using a single preparation that can be administered in one inoculation, either by injection or by mucosal delivery, offers a number of obvious advantages (7). The first is the decrease of the number of vaccine inoculations. Already, especially with newborns and infants, we are approaching the point where the number of injections required to provide optimal immunity reaches unacceptable levels. As the range of potential vaccines increases the combination of vaccines becomes even more mandatory (8). The decreased number of inoculations when vaccines are combined implies a decreased number of clinical visits that are necessary to achieve complete immunization. Consequently, there will be an increased compliance to vaccination schedules with a resulting increased vaccine coverage. This will ultimately allow better disease control. While these are important advantages for developed countries, in the developing world, where compliance to vaccination decreases dramatically with the number of visits, the combination of vaccines to reduce the visits to the minimum possible, is a condition sine qua non. Additional advantages of combined vaccines are the reduced costs of storage, and transport administration, since there will be fewer vials, ampoules, syringes and needles needed. Given the fact that on a worldwide basis more than 90% of the cost of vaccination is caused by such logistic costs, this advantage is certainly not negligible, even in the developed countries. An optimal use of combined vaccines requires that vaccine schedules be harmonized. Today, vaccine schedules vary widely throughout the different European countries. If several vaccines are combined, vaccine schedules will be simplified. This will facilitate vaccination record keeping and offers an opportunity to develop a rational approach to global vaccination.
3.
POINTS FOR CONSIDERATION IN THE DEVELOPMENT OF COMBINED VACCINES
While the advantages outlined above make an overwhelming case for the introduction of combined vaccines, this may not be as straightforward as it might seem. There are several technical and scientific, as well as political and economical issues that need to be addressed. 3.1. Technical and scienti.c
hurdles
An unexpected problem of combined vaccines is the recently identified negative influence that one vaccine may have on the other in a combination. It has
694
been found that when two existing vaccines are simply mixed, one or both usually lose their potency (4,7, 8, 9, 10). Unfortunately, this cannot always be predicted by the use of currently established potency tests in the laboratory. Many laboratory models used to measure the potency of vaccines appear to lose their predictive power for protective efficacy in man when applied to combined vaccines. In the absence of more adequate laboratory models, much clinical research and development is therefore necessary before a combined vaccine can reach the public. This may be as complex as the development of a new vaccine. A typical example of this has been recently reported at the ICAAC meeting in October 1995. Several independent studies reported that when Hib is combined with whole cell pertussis vaccine there is no interference between the two vaccines, while when this is combined with acellular pertussis vaccines there is a substantial loss of the Hib immunogenicity. It was shown that when Hib is combined with DTaP, it maintains its immunogenicity if given at separate sites, while the immunogenicity is 5-15 times lower when the vaccines are administered combined at the same site. The reported titers for separate versus combined administration were 3.9 and 0.32 (ll), 3.1 and 0.52 (ll), 5.4 and 1.2 (12), 16.1 and 1.15 (13), respectively. This unexpected result confirms that combining two existing vaccines is not simple and often gives very unpredictable results that are not detected during the studies in animal models, and that are observed only after extensive clinical testing.
component over the other in combined vaccines, one can also envisage an unexpected increase in reactogenicity of one or several components, especially if one antigen expresses up to now unidentified pharmacological effects that are only uncovered in combination with other antigens. If increased reactogenicity is observed, it will be very difficult to identify the responsible component in the combined vaccine. This difficulty increases exponentially with the number of vaccines in a given combination.
The absence of laboratory surrogates that correlate with clinical protection may also significantly complicate the production and quality control of combined vaccines (14). Indeed, tests that have been developed for the determination of potency, safety, stability and consistency of single vaccines cannot necessarily be directly applied to the testing of combined vaccines. A tyical example of this problem is provided by the results of several efficacy trials on acellular pertussis vaccines (reported in Rome, October 30 - November 2, 1995). These trials confirmed that there is no correlation between antibody titers and protection. This finding indicates that the antibody titers that we measure do not correlate with protective efficacy of vaccines, and therefore that any modification to the vaccine (for instance, the addition of another component to make a combination vaccine), may influence vaccine This efficacy without changing the antibody titers. raises the question of how we can combine vaccines for which we do not have a correlate of protection, without risking to change the efficacy. It is clear that we do not have any answer to this. An interesting suggestion to solve this problem was given at the meeting in Rome by D. Granoff, who proposed to include in combination vaccines only those vaccines for which a correlate of protection is known (Hib, IPV, HBV, MenC, MenA), and to leave out of the combinations those vaccines for which a correlate does not exist (DTaP).
Among the economical issues, a major aspect is the unexpectedly large cost of developing combined vaccines (4). While a few years ago it was believed that combining two already existing vaccines would be a simple and inexpensive operation, it has become obvious that the development of a combination requires a long time and a budget which is often similar to that necessary for the development of a new vaccine.
Similar to an effect on immunogenicity
of one
Even after the combination has been optimized, a slight decrease in immunogenicity of some of the individual components is usually observed (15). Although this decrease has probably no significant effect on immediate vaccine efficacy, it will ultimately limit the number of possible vaccines that can be included into a combination without decreasing the potency of each compound below an acceptable level. In addition, a decrease in immunogenicity may have an impact on long-term duration of protection. Shelf-life of combined vaccines may also be different from that of the individual components. Therefore, stability has to be tested for all components in the combination, and the ultimate stability and shelflife of the combined vaccine will be dictated by the least stable component in the vaccine. 3.2. Economical
andpolitical
considerations
Unless better laboratory tests are designed, quality control of combined vaccines will also be far more expensive than previously anticipated. Failure of combined vaccines to pass lot release tests is likely to be more costly than for single vaccines, because many good antigens may have to be discarded if one of the components in the combined vaccine does not pass the potency test after the final blending. If combined vaccines are to be used optimally throughout Europe, vaccine schedules will have to be adapted and probably changed in many countries. In addition, if adapted combined vaccines are not available, some countries will have to consider vaccination against diseases which are less important in that particular geographical area. Because of the high costs involved, at the current stage only big companies with large R&D budgets and manufacturing capacities will be able to develop and
695
produce all the different components necessary to manufacture polyvalent combined vaccines. This fact alone may be sufficient to eliminate private and public vaccine manufacturers that do not have the entire vaccine portfolio to make complete combinations. This problem can be solved in part by licenses, alliances, acquisitions and consolidations between existing private and public manufacturers. During the last several years we have already seen the fusion of Pasteur, Connaught and Merieux into a single company, that later made a strategic alliance with Merck Sharp & Dohme. Other examples are: i) the acquisition of Praxis by Lederle, and the subsequent consolidation of this fusion into American Home Products; ii) the acquisition of Sclavo SpA by Biocine, a joint venture between Chiron Corporation and Ciba Geigy; and, iii) the collaboration between the public sector manufacturers in Scandinavia and the Netherlands into the Dutch-Nordic consortium. The impact of intellectual property on vaccine combinations and the future of vaccination generated a lot of discussion within the panel and outside experts that were interviewed on this matter. Since a consensus would not reflect the diversity of opinions that were expressed, we will report a summary of the different views. There was a very good agreement on the fact that intellectual property is an absolute requirement for the development of vaccines by private companies. The high costs required for research and development can, in fact, be sustained only if they lead to the development of proprietary knowledge, which assures a reasonable return on investment. Innovation comes very often from research institutions and small biotech companies, for which intellectual property is the driving force. in the case of combination vaccines, However, intellectual property may play a role which extends beyond the scope of the patent claims (16). In fact, if an antigen covered by a patent is introduced into a combined vaccine which is widely recommended, this could, in theory, give the monopoly of the market to the manufacturer that owns the patent. A single proprietary component would be enough to provide a monopoly over all vaccines that are present in the combination, even if these are not covered by patents. On this issue two very contrasting opinions were expressed: one was that this is a non-existing problem for which a commercial solution will be naturally found through agreements, licenses, acquisitions, etc.; the other felt that, although negotiations are theoretically combinations represent an possible, vaccine unprecedented problem of intellectual property which, unless properly dealt with, will result in a monopolized market that may cause a drop-out of small vaccine manufacturers, may force larger vaccine manufacturers to draw back from investing in vaccine research and development, and ultimately decrease the number of vaccines that will be available in the future.
4.
PROPOSALS FOR THE RATIONAL DESIGN OF COMBINED VACCINES
Despite the complex issues described above, there will be an increasing need for combined vaccines based on defined antigens and adjuvants or geneticallydefined attenuated microorganisms in the future. Thus, there is an unavoidable requirement for careful forward planning to design the most efficient vaccination regimes, taking into account both the scientific and technological difficulties, as well as the political and economical problems. To solve the scientific and technological problems research and development programs could be designed that address the following five basic questions:
1)
What are the relevant laboratory surrogates correlate with clinical protection ?
that
2)
What are mechanisms agents ?
and
3)
Is it possible to develop a single animal model to test the potency of all vaccines present in a combination?
4)
What is the basis of immune protection, immune competition and interference caused by multiple antigens in man ?
the relevant animal models of pathogenesis of infectious
5)
What are the most effective vaccine delivery systems? In many instances even for vaccines that have proven their efficacy over the years, we do not know the mechanism of immune protection. Therefore, the in vitro and in vivo models that correlate with protection in humans are lacking. Currently, potency tests can only be performed to assure consistency of the manufacture of components that have been proven efficacious in field trials. It is hoped that research aiming at the understanding of the mechanisms of immunoprotection, either through natural infection or, better still, through vaccination, will provide meaningful new laboratory tests that directly correlate potency tests in the laboratory with efficacy in the field. Such relevant models should also be applicable to combined vaccines and will help us to accurately predict the efficacy of a given combination. The development of relevant animal models, and the molecular and cellular understanding of the pathogenic mechanisms for a given disease, will help to identify those antigens that provide the highest levels of protection in individual as well as in combined vaccines. This will also lead us to the best vaccine formulation, guide our choice of adjuvants and of the methods of presentation and delivery. For some diseases, where the pathogenesis can be reduced to the action of one or two
696
factors, successful vaccines have long been developed and used. However, for most diseases, the mechanisms of pathogenesis are more complex and vaccine development has been hampered. The study of pathogenesis and the design of efficacious vaccines requires adequate animal models. New technologies, including the development of transgenic animals, may be of appreciable benefit. Even the best available animal models do not allow us to directly extrapolate conclusions to protection in humans. More knowledge is needed concerning the human immune system. Understanding the mechanisms of induction of a desired, well-defined immune response is an essential step towards the effective development of new and combined vaccines. Studies on the mechanisms of immune regulation, including immune exclusion, antigenic competition and interference, and memory are to be suppression, tolerance, encouraged. We also need to know what mechanisms underlie the reactogenicity in individual or in combined vaccines. Finally, new developments in biotechnology applied to vaccine research is likely to provide us with new powerful ways to present antigens in individual or combined forms for the induction of the highest levels of immune protection with the longest duration. Several approaches are workable, such as the development of live attenuated bacteria and viruses, nucleic acid vaccines, semi-synthetic vaccines, microencapsulation, new adjuvants, and new delivery systems including These new mucosal administration of vaccines. technologies should aim at approaching the ideal vaccine formulations. An ideal vaccine should provide effective protection against disease and possibly against infection. The most successful vaccine would also allow the eradication of the disease. Although not feasible with most vaccines available or in development, the ultimate goal of an ideal vaccine should be to induce long-term protection even after a single dose. Vaccines should only induce protective immune responses with no side-effects. They should be easy and safe to administer, and be available for everyone, including those in the developing world. Increasing knowledge about mechanisms of chronic diseases, in addition to new technological possibilities, will also lead to chances for preventive (and therapeutic) immunization against tumors. At the present state of knowledge, it is unlikely that all possible vaccines can be combined into a single inoculum. We will therefore have to define particular target groups and design combined vaccines appropriate for each group. The real need of vaccines, as dictated by the epidemiology of infectious and chronic diseases at different ages and in different geographical areas, will have to be taken into account. The different groups, toddlers, infants, children, such as newborns, adolescents, adults, elderly and special groups including travellers, military, groups at high risks for sexually transmitted diseases, and pregnant women, will have
different needs (17-18). A summary of available, in development, and desirable, and risk group has been combined in Table The table takes into account some of the
the vaccines, for each age I (p.7-9). recent studies
(19). Now the routine immunization in early childhood is well accepted and health care policies are designed to achieve optimal immunization coverage in this age group. This machinery is so well designed that when new vaccines become available, they are included in infant immunization schedule, even if not necessarily needed at this age, just because we have no mechansim to get in touch, in a systematic way, with adolescents, adults, and elderly. However, it is well recognized that adolescence is the age with the greatest risk for exposure to sexually transmitted infectious diseases (see Table I). As several vaccines targeted to this age group are likely to become available in the near future, health care policies and vaccine combinations should be designed to provide an optimal coverage throughout life. Implementing this vaccination policy would not only provide the most effective means of preventing infectious diseases, but it would also anchor adolescents, adults and elderly into a chartered channel of comprehensive preventive health care. For manufacturing and regulatory reasons, when possible, the same combination should be used for more than one category. Epidemiological surveys are thus as important as are the establishment of professional centers able to perform clinical trials. In addition, a network of public health services linking all European countries would be desirable. This would enable us to follow people throughout life and help to provide complete coverage at every age bracket. The routes by which vaccines can effectively be administered need also to be carefully evaluated. We now have the choice of several possible routes. Classically, there are injections and mucosal administrations. Within each of these two main routes there are several options. Injections can be carried out using needles, vaccine guns, needle free injections, or trehalose crystals. Mucosal vaccines can be administred by the oral, nasal, respiratory, rectal or vaginal route. Research on new vaccines has to consider a combination with already existing ones even at the first stages of development. However, all the scientific and technological advances will only lead to successful developments of new and combined vaccines if the political and economical issues resulting from such developments are solved. Harmonization of the usage of combined vaccines in different countries seems to be important. If all these conditions are met, there is no real reason why we should not be able to efficiently vaccinate everyone against as many diseases as possible. This would be of tremendous benefit for public health, social security budgets, and each individual in Europe as well as abroad.
697
Table I. Proposed vaccination different target populations
Vaccination
scheme, designed to optimize the coverage against disease at different ages and in
Comments
Vaccines
age
Newborns
Hepatitis B (Hepatitis C) Acellular pertussis
Infants
BCG Diphtheria Tetanus Pertussis (acellular) Polio (IPV or OPV)
At risk infants born from seropositive
mothers
During epidemic periods
IPV will be supplied in combination with the other vaccines. OPV will be delivered separately by oral administration.
Existing vaccines Hepatitis B vaccination of infants is important in those areas of high endemic incidence. In the other countries it may be enough to vaccinate at risk newborns and postpone the general vaccination to the adolescent age when the sexual activity exposes the population to the risk of infection .
Hepatitis B
Haemophilus
influenzae
I
Conjugate vaccines. Delivered mostly in combination other infant vaccines.
with the
Meningococcus A, B, C
Conjugate vaccines against meningococcus C (MenC) have already been tested in infants and are likely to become part of infant combinations in Europe and USA where there is a high incidence of MenC. Similar conjugates for Meningococcus A (MenA) have been tested and may become part of infant combinations in Africa, Middle East and Asia where MenA is endemic. Meningococcus B vaccines should be part of infant vaccines if they become available.
Pneumococcus New measles Parainfluenza type III Respiratory syncytial virus
Otitis media Subunit
Desirable vaccines in development
Recombinant
glycoprotein
698 Table Z (cont’d)
Vaccination
age
Toddlers and children
Adolescents
Vaccines
Comments
Measles Mumps Rubella Varicella Diphtheria Tetanus Pertussis
Booster immunizations 6 years of age. (Acellular)
Diphtheria Tetanus Pertussis
Booster immunization diphtheria vaccine. (Acellular)
Hepatitis B Hepatitis A Existing vaccines
at 12- 18 months
and 4
using low dose
Primary immunization series . Booster, if infants had already been immunized
Measles Mumps Rubella Varicella
Desirable vaccines in development
Epstein Barr Virus Herpes simplex virus Gonococcus Chlamydia Human immunodef. virus Hepatitis C virus Papillomavirus Cytomegalomavirus Tuberculosis Conjugates for Meningococcus A/C+B
Adults
Diphtheria Tetanus Pertussis
Elderly
Pneumococcus Influenza Respiratory syncytial virus(booster) Tuberculosis Non typable hemophilus
Booster immunization repeated every 5 10 years, using a low dose diphtheria vaccine.
699
TableI (cont’d) Target population
Travellers
comment!s
Vaccines
Rotavirus Enterotoxigenic Cholera Shigella Salmonella Enteric fever
Diarrheal vaccines to be used for travellers and for all children in developing nations E. coli
Pregnant women/mothers
Streptococcus B Cytomegalomavirus
New important diseases
Giarda lambia Entameba histolytica Helicobacter Malaria Lyme
1. World Bank. World Development Report: Investing in Health. Oxford University, New York, 1993. 2. Department of Health and Human Services. Disease Prevention through Vaccine Development and Immunization: The National Vaccine Plan - 1994. National Vaccine Program Office, Washington DC, 1994. 3. Parkman, P.D. Combined and Simultaneously Administered Vaccines. A Brief History. In: Combined Vaccines and Simultaneous Administration. Current Issues and Perspectives (Eds Williams, J.C., Goldenthal, K.L., Burns, D.L., Lewis, B.P., Jr.). The New York Academy of Sciences, New York, 1995, pp.l-9. 4. Andre, F.E. Development of Combined Vaccines: Manufacturers’ Viewpoint. Biologicals 1994, 22, 317-321. 5. Combined Vaccines for Europe. Pharmaceutical, Regulatory and Policy-making Aspects. Proceedings of the 2nd European Conference on Vaccinology (Brussels, 18-20 May 1994). In: Biologicals (Ekls. Andre F., Cholat J., Furminger, I.). 1994,22, 297-436.
6. Combined Vaccines and Simultaneous Administration. Current Issues and Perspectives. The New York Academy of Sciences, New York, 1995, pp. xi-404. 7. Hadler, S.C. Cost benefit of combining Biologicals 1994, 22,415-418.
antigens.
8. Goldenthal, K,L,, Burns, D,L,, McVittie, L.D., Lewis, B.P., Williams, J.C. Overview - Combination Vaccines and Simultaneous Administration. Past, Present, and Future. In: Combined Vaccines and Simultaneous Administration. Current Issues and Perspectives (Eds Williams, J.C., Goldenthal, K.L., Burns, D.L., Lewis, B.P., Jr.). The New York Academy of Sciences, New York, 1995, pp. xi-xv. 9. Clemens, J., Brenner, R., Rao, M. Interactions between PRP-T Vaccine against Haemophilus influenzae Type b and Conventional Infant Vaccines. Lessons for Future Studies of Simultaneous Immunization and Combined Vaccines. In: Combined Vaccines and Simultaneous Administration. Current Issues and Perspectives (Eds Williams, J.C., Goldenthal, K.L., Burns, D.L., Lewis, B.P., Jr.). The New York Academy of Sciences, New York, 1995, pp. 255-266.
700
10. Insel, R.A. Potential Alterations in Immunogenicity by Combining or Simultaneously Administering Vaccine Components. n: Combined Vaccines and Simultaneous Administration. Current Issues and Perspectives (Eds Williams, J.C., Goldenthal, K.L., Burns, D.L., Lewis, B.P., Jr.). The New York Academy of Sciences, New York, 1995, pp.35-47. 11. Eskola, J., Olander, R-M., Litmanen, L., Saarinen,L., Bogaerts, H., Kayhty, H. Hib Antibody Response after Two Doses of Combined DTPa-Hib Conjugate Vaccine as Compared to Separate Injections. In: Abstract Book of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 17-20 Sep., 1995 12. Schmitt, H.J., Bock, H., Bogaerts, H., Clemens, R. Single injection of a combined DTPa-Hep B and Hib tetanus conjugate vaccines: a feasibility study. In: Abstract Book of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 17-20 Sep., 1995 13. Shinefield, H., Black, S., Ray, P., Lewis, E., Fireman, B., Hohenboken, M., Hackell, J.G. Safety of Combined Acellular Pertussis DTaPHbOC Vaccine in Infants. In: Abstract Book of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 17-20 Sep. 1995 14. Corbel, M.J. Control Testing of Combined Vaccines: A Consideration of Potential Problems and Approaches. Biologicals 1994,22,353-360.
15. Paradiso, P.R. Combination Vaccines for Diphtheria, Tetanus, Pertussis, and Haemophilus influenzae Type b. In: Combined Vaccines and Simultaneous Administration. Current Issues and Perspectives (Eds Williams, J.C., Goldenthal, K.L., Burns, D.L., Lewis, B.P., Jr.). The New York Academy of Sciences, New York, 1995, pp. 108-l 13. 16. Saldarini, R.J. Strategies for Developing Combination Vaccines. In: Combined Vaccines and Simultaneous Administration. Current Issues and Perspectives (Eds Williams, J.C., Goldenthal, K.L., Burns, D.L., Lewis, B.P., Jr.). The New York Academy of Sciences, New York, 1995, pp. 17-22. 17. Breese, C. Adolescent Immunization: The Access and Anchor for Health Services? Pediatrics 1995, 936-937. 18. Eskola, J. Epidemiological Views into Possible Components of Paediatric Combined Vaccines in 2015. Biologicals 1994, 22, 323-327. 19. DMID/NIAID/NIH. The Jordan Report. Accelerated Development of Vaccines 1994. DMIDMIAIDINIH, Bethesda, 1994, pp. l-106.
NEW VACCINES, ESPECIALLY NEW COMBINED VACCINES
Chairman:
Members:
Dr. Rino RAPPUOLI ISTITUTO RICERCHE IMMUNOBIOLOGICHE Via Fiorentina 1 I-53 100 SIENA
- SIENA
Dr. Camille LOCHT INSTITUT PASTEUR DE LILLE 1 rue du Prof. Calmette LILLE F-59019
Dr. Jan POOLMAN NATIONAL INSTITUTE FOR PUBLIC HEALTH & ENVIRONMENT Lab. for Vaccine Development & Immune Mechanisms NL-3720 BA
BILTHOVEN
Dr. Frangis ANDRE SMITHKLINE BEECHAM Rue de 1’Institut 89 B-1330 RIXENSART
Prof. Gordon DOUGAN IMPERIAL COLLEGE Dept. of Biochemistry Exhibition Road UK-LONDON SW7 2AZ
691
692
List of Contents
1. INTRODUCTION
.. .. .. .. .. .. . .. .. ... . ... .. .. .. ... . ... .. .. .. .. .. .. .. .. .. ... . ... .. .. . .. ... .. .. .. .. . ... . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. 693
2.
ADVANTAGES
3.
POINTS FOR CONSIDERATION COMBINED
OF COMBINED
VACCINES
VACCINES
. .. .. .. .. .. .. .. .. .. ... . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. .. .. .. . 693
IN THE DEVELOPMENT
OF
.. .. .. .. .. .. ... .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. .. .. . .693
3.1. Technical and scientific hurdles .....................................................................................
.693
3.1. Economical and political considerations ........................................................................
.694
4.
PROPOSALS
5.
SELECTED
FOR THE RATIONAL
REFERENCES
DESIGN OF COMBINED
VACCINES
.. . .. .. .. .. . .. 695
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ... . ... . ... . .. .. .. .. .. .. .. .. .. .. .. . ... . .. .. . 699
693
1. INTRODUCTION 2. ADVANTAGES OF COMBINED VACCINES The increasing cost of modern health care, that relies heavily on the direct treatment of on-going disease, is leading to a need to reappraise current medical practice. It is becoming highly desirable to place more emphasis on preventive medicine. An attractive and highly cost-effective preventive approach is the use of vaccines (l-2). Traditionally, vaccination has been focused on immunization of infants against infectious diseases. To make vaccination an even more cost-effective option, we could develop a vaccination policy aiming at the introduction of safe and efficacious vaccines against a broader range of diseases in all age groups. Combining several vaccines into a single formulation for immunization against different diseases is a practice which has been commonly used in the past. The combination of diphtheria (D), tetanus (T) and whole cell pertussis (Pw) vaccines into the DTPw vaccine, that of polioviruses serotypes 1, 2 and 3 into a single vaccine against poliomyelitis, measles, mumps into a triple vaccine, and rubella vaccines meningococcal A, C, Y and W 135 polysaccharide vaccines into a tetravalent vaccines, and a 23-valent pneumococcal vaccines are just five examples of successful “combined vaccines” that have been widely used in clinical practice for many years (3,4,5,6). The recent commercialisation of new vaccines such as those against Haemophilus injluenzae type b, hepatitis B and A, and our steadily increasing potential to develop novel vaccines will make it necessary to further combine vaccines, which has to take into account not only the presently available vaccines but also those that are likely to come in the future. in immunology, molecular New advances biology, and biotechnology allow us now to realistically approach diseases for which vaccines were previously unfeasible. These advances have already led to the improvement of existing vaccines such as those against hepatitis B and the replacement of reactogenic Pw vaccines by fully defined, safer acellular vaccines. In addition, some vaccines may prevent or stop the development of cancers and there is a real potential for preventive and therapeutic vaccination against tumours, auto-immune and allergic diseases. We can also exploit new technologies to improve the delivery and immunogenicity of vaccines. The nature of the immune response can be influenced to elicit specific protective mechanisms needed for specific diseases. Given the number of new vaccines which are likely to be introduced during the next 10 to 15 years as a result of recent technological breakthroughs, great attention must be paid to the design of a global strategy which will bring optimal benefit from the potential advantages while minimizing the disadvantages that combined vaccines may have.
Vaccination against several diseases by using a single preparation that can be administered in one inoculation, either by injection or by mucosal delivery, offers a number of obvious advantages (7). The first is the decrease of the number of vaccine inoculations. Already, especially with newborns and infants, we are approaching the point where the number of injections required to provide optimal immunity reaches unacceptable levels. As the range of potential vaccines increases the combination of vaccines becomes even more mandatory (8). The decreased number of inoculations when vaccines are combined implies a decreased number of clinical visits that are necessary to achieve complete immunization. Consequently, there will be an increased compliance to vaccination schedules with a resulting increased vaccine coverage. This will ultimately allow better disease control. While these are important advantages for developed countries, in the developing world, where compliance to vaccination decreases dramatically with the number of visits, the combination of vaccines to reduce the visits to the minimum possible, is a condition sine qua non. Additional advantages of combined vaccines are the reduced costs of storage, and transport administration, since there will be fewer vials, ampoules, syringes and needles needed. Given the fact that on a worldwide basis more than 90% of the cost of vaccination is caused by such logistic costs, this advantage is certainly not negligible, even in the developed countries. An optimal use of combined vaccines requires that vaccine schedules be harmonized. Today, vaccine schedules vary widely throughout the different European countries. If several vaccines are combined, vaccine schedules will be simplified. This will facilitate vaccination record keeping and offers an opportunity to develop a rational approach to global vaccination.
3.
POINTS FOR CONSIDERATION IN THE DEVELOPMENT OF COMBINED VACCINES
While the advantages outlined above make an overwhelming case for the introduction of combined vaccines, this may not be as straightforward as it might seem. There are several technical and scientific, as well as political and economical issues that need to be addressed. 3.1. Technical and scienti.c
hurdles
An unexpected problem of combined vaccines is the recently identified negative influence that one vaccine may have on the other in a combination. It has
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been found that when two existing vaccines are simply mixed, one or both usually lose their potency (4,7, 8, 9, 10). Unfortunately, this cannot always be predicted by the use of currently established potency tests in the laboratory. Many laboratory models used to measure the potency of vaccines appear to lose their predictive power for protective efficacy in man when applied to combined vaccines. In the absence of more adequate laboratory models, much clinical research and development is therefore necessary before a combined vaccine can reach the public. This may be as complex as the development of a new vaccine. A typical example of this has been recently reported at the ICAAC meeting in October 1995. Several independent studies reported that when Hib is combined with whole cell pertussis vaccine there is no interference between the two vaccines, while when this is combined with acellular pertussis vaccines there is a substantial loss of the Hib immunogenicity. It was shown that when Hib is combined with DTaP, it maintains its immunogenicity if given at separate sites, while the immunogenicity is 5-15 times lower when the vaccines are administered combined at the same site. The reported titers for separate versus combined administration were 3.9 and 0.32 (ll), 3.1 and 0.52 (ll), 5.4 and 1.2 (12), 16.1 and 1.15 (13), respectively. This unexpected result confirms that combining two existing vaccines is not simple and often gives very unpredictable results that are not detected during the studies in animal models, and that are observed only after extensive clinical testing.
component over the other in combined vaccines, one can also envisage an unexpected increase in reactogenicity of one or several components, especially if one antigen expresses up to now unidentified pharmacological effects that are only uncovered in combination with other antigens. If increased reactogenicity is observed, it will be very difficult to identify the responsible component in the combined vaccine. This difficulty increases exponentially with the number of vaccines in a given combination.
The absence of laboratory surrogates that correlate with clinical protection may also significantly complicate the production and quality control of combined vaccines (14). Indeed, tests that have been developed for the determination of potency, safety, stability and consistency of single vaccines cannot necessarily be directly applied to the testing of combined vaccines. A tyical example of this problem is provided by the results of several efficacy trials on acellular pertussis vaccines (reported in Rome, October 30 - November 2, 1995). These trials confirmed that there is no correlation between antibody titers and protection. This finding indicates that the antibody titers that we measure do not correlate with protective efficacy of vaccines, and therefore that any modification to the vaccine (for instance, the addition of another component to make a combination vaccine), may influence vaccine This efficacy without changing the antibody titers. raises the question of how we can combine vaccines for which we do not have a correlate of protection, without risking to change the efficacy. It is clear that we do not have any answer to this. An interesting suggestion to solve this problem was given at the meeting in Rome by D. Granoff, who proposed to include in combination vaccines only those vaccines for which a correlate of protection is known (Hib, IPV, HBV, MenC, MenA), and to leave out of the combinations those vaccines for which a correlate does not exist (DTaP).
Among the economical issues, a major aspect is the unexpectedly large cost of developing combined vaccines (4). While a few years ago it was believed that combining two already existing vaccines would be a simple and inexpensive operation, it has become obvious that the development of a combination requires a long time and a budget which is often similar to that necessary for the development of a new vaccine.
Similar to an effect on immunogenicity
of one
Even after the combination has been optimized, a slight decrease in immunogenicity of some of the individual components is usually observed (15). Although this decrease has probably no significant effect on immediate vaccine efficacy, it will ultimately limit the number of possible vaccines that can be included into a combination without decreasing the potency of each compound below an acceptable level. In addition, a decrease in immunogenicity may have an impact on long-term duration of protection. Shelf-life of combined vaccines may also be different from that of the individual components. Therefore, stability has to be tested for all components in the combination, and the ultimate stability and shelflife of the combined vaccine will be dictated by the least stable component in the vaccine. 3.2. Economical
andpolitical
considerations
Unless better laboratory tests are designed, quality control of combined vaccines will also be far more expensive than previously anticipated. Failure of combined vaccines to pass lot release tests is likely to be more costly than for single vaccines, because many good antigens may have to be discarded if one of the components in the combined vaccine does not pass the potency test after the final blending. If combined vaccines are to be used optimally throughout Europe, vaccine schedules will have to be adapted and probably changed in many countries. In addition, if adapted combined vaccines are not available, some countries will have to consider vaccination against diseases which are less important in that particular geographical area. Because of the high costs involved, at the current stage only big companies with large R&D budgets and manufacturing capacities will be able to develop and
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produce all the different components necessary to manufacture polyvalent combined vaccines. This fact alone may be sufficient to eliminate private and public vaccine manufacturers that do not have the entire vaccine portfolio to make complete combinations. This problem can be solved in part by licenses, alliances, acquisitions and consolidations between existing private and public manufacturers. During the last several years we have already seen the fusion of Pasteur, Connaught and Merieux into a single company, that later made a strategic alliance with Merck Sharp & Dohme. Other examples are: i) the acquisition of Praxis by Lederle, and the subsequent consolidation of this fusion into American Home Products; ii) the acquisition of Sclavo SpA by Biocine, a joint venture between Chiron Corporation and Ciba Geigy; and, iii) the collaboration between the public sector manufacturers in Scandinavia and the Netherlands into the Dutch-Nordic consortium. The impact of intellectual property on vaccine combinations and the future of vaccination generated a lot of discussion within the panel and outside experts that were interviewed on this matter. Since a consensus would not reflect the diversity of opinions that were expressed, we will report a summary of the different views. There was a very good agreement on the fact that intellectual property is an absolute requirement for the development of vaccines by private companies. The high costs required for research and development can, in fact, be sustained only if they lead to the development of proprietary knowledge, which assures a reasonable return on investment. Innovation comes very often from research institutions and small biotech companies, for which intellectual property is the driving force. in the case of combination vaccines, However, intellectual property may play a role which extends beyond the scope of the patent claims (16). In fact, if an antigen covered by a patent is introduced into a combined vaccine which is widely recommended, this could, in theory, give the monopoly of the market to the manufacturer that owns the patent. A single proprietary component would be enough to provide a monopoly over all vaccines that are present in the combination, even if these are not covered by patents. On this issue two very contrasting opinions were expressed: one was that this is a non-existing problem for which a commercial solution will be naturally found through agreements, licenses, acquisitions, etc.; the other felt that, although negotiations are theoretically combinations represent an possible, vaccine unprecedented problem of intellectual property which, unless properly dealt with, will result in a monopolized market that may cause a drop-out of small vaccine manufacturers, may force larger vaccine manufacturers to draw back from investing in vaccine research and development, and ultimately decrease the number of vaccines that will be available in the future.
4.
PROPOSALS FOR THE RATIONAL DESIGN OF COMBINED VACCINES
Despite the complex issues described above, there will be an increasing need for combined vaccines based on defined antigens and adjuvants or geneticallydefined attenuated microorganisms in the future. Thus, there is an unavoidable requirement for careful forward planning to design the most efficient vaccination regimes, taking into account both the scientific and technological difficulties, as well as the political and economical problems. To solve the scientific and technological problems research and development programs could be designed that address the following five basic questions:
1)
What are the relevant laboratory surrogates correlate with clinical protection ?
that
2)
What are mechanisms agents ?
and
3)
Is it possible to develop a single animal model to test the potency of all vaccines present in a combination?
4)
What is the basis of immune protection, immune competition and interference caused by multiple antigens in man ?
the relevant animal models of pathogenesis of infectious
5)
What are the most effective vaccine delivery systems? In many instances even for vaccines that have proven their efficacy over the years, we do not know the mechanism of immune protection. Therefore, the in vitro and in vivo models that correlate with protection in humans are lacking. Currently, potency tests can only be performed to assure consistency of the manufacture of components that have been proven efficacious in field trials. It is hoped that research aiming at the understanding of the mechanisms of immunoprotection, either through natural infection or, better still, through vaccination, will provide meaningful new laboratory tests that directly correlate potency tests in the laboratory with efficacy in the field. Such relevant models should also be applicable to combined vaccines and will help us to accurately predict the efficacy of a given combination. The development of relevant animal models, and the molecular and cellular understanding of the pathogenic mechanisms for a given disease, will help to identify those antigens that provide the highest levels of protection in individual as well as in combined vaccines. This will also lead us to the best vaccine formulation, guide our choice of adjuvants and of the methods of presentation and delivery. For some diseases, where the pathogenesis can be reduced to the action of one or two
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factors, successful vaccines have long been developed and used. However, for most diseases, the mechanisms of pathogenesis are more complex and vaccine development has been hampered. The study of pathogenesis and the design of efficacious vaccines requires adequate animal models. New technologies, including the development of transgenic animals, may be of appreciable benefit. Even the best available animal models do not allow us to directly extrapolate conclusions to protection in humans. More knowledge is needed concerning the human immune system. Understanding the mechanisms of induction of a desired, well-defined immune response is an essential step towards the effective development of new and combined vaccines. Studies on the mechanisms of immune regulation, including immune exclusion, antigenic competition and interference, and memory are to be suppression, tolerance, encouraged. We also need to know what mechanisms underlie the reactogenicity in individual or in combined vaccines. Finally, new developments in biotechnology applied to vaccine research is likely to provide us with new powerful ways to present antigens in individual or combined forms for the induction of the highest levels of immune protection with the longest duration. Several approaches are workable, such as the development of live attenuated bacteria and viruses, nucleic acid vaccines, semi-synthetic vaccines, microencapsulation, new adjuvants, and new delivery systems including These new mucosal administration of vaccines. technologies should aim at approaching the ideal vaccine formulations. An ideal vaccine should provide effective protection against disease and possibly against infection. The most successful vaccine would also allow the eradication of the disease. Although not feasible with most vaccines available or in development, the ultimate goal of an ideal vaccine should be to induce long-term protection even after a single dose. Vaccines should only induce protective immune responses with no side-effects. They should be easy and safe to administer, and be available for everyone, including those in the developing world. Increasing knowledge about mechanisms of chronic diseases, in addition to new technological possibilities, will also lead to chances for preventive (and therapeutic) immunization against tumors. At the present state of knowledge, it is unlikely that all possible vaccines can be combined into a single inoculum. We will therefore have to define particular target groups and design combined vaccines appropriate for each group. The real need of vaccines, as dictated by the epidemiology of infectious and chronic diseases at different ages and in different geographical areas, will have to be taken into account. The different groups, toddlers, infants, children, such as newborns, adolescents, adults, elderly and special groups including travellers, military, groups at high risks for sexually transmitted diseases, and pregnant women, will have
different needs (17-18). A summary of available, in development, and desirable, and risk group has been combined in Table The table takes into account some of the
the vaccines, for each age I (p.7-9). recent studies
(19). Now the routine immunization in early childhood is well accepted and health care policies are designed to achieve optimal immunization coverage in this age group. This machinery is so well designed that when new vaccines become available, they are included in infant immunization schedule, even if not necessarily needed at this age, just because we have no mechansim to get in touch, in a systematic way, with adolescents, adults, and elderly. However, it is well recognized that adolescence is the age with the greatest risk for exposure to sexually transmitted infectious diseases (see Table I). As several vaccines targeted to this age group are likely to become available in the near future, health care policies and vaccine combinations should be designed to provide an optimal coverage throughout life. Implementing this vaccination policy would not only provide the most effective means of preventing infectious diseases, but it would also anchor adolescents, adults and elderly into a chartered channel of comprehensive preventive health care. For manufacturing and regulatory reasons, when possible, the same combination should be used for more than one category. Epidemiological surveys are thus as important as are the establishment of professional centers able to perform clinical trials. In addition, a network of public health services linking all European countries would be desirable. This would enable us to follow people throughout life and help to provide complete coverage at every age bracket. The routes by which vaccines can effectively be administered need also to be carefully evaluated. We now have the choice of several possible routes. Classically, there are injections and mucosal administrations. Within each of these two main routes there are several options. Injections can be carried out using needles, vaccine guns, needle free injections, or trehalose crystals. Mucosal vaccines can be administred by the oral, nasal, respiratory, rectal or vaginal route. Research on new vaccines has to consider a combination with already existing ones even at the first stages of development. However, all the scientific and technological advances will only lead to successful developments of new and combined vaccines if the political and economical issues resulting from such developments are solved. Harmonization of the usage of combined vaccines in different countries seems to be important. If all these conditions are met, there is no real reason why we should not be able to efficiently vaccinate everyone against as many diseases as possible. This would be of tremendous benefit for public health, social security budgets, and each individual in Europe as well as abroad.
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Table I. Proposed vaccination different target populations
Vaccination
scheme, designed to optimize the coverage against disease at different ages and in
Comments
Vaccines
age
Newborns
Hepatitis B (Hepatitis C) Acellular pertussis
Infants
BCG Diphtheria Tetanus Pertussis (acellular) Polio (IPV or OPV)
At risk infants born from seropositive
mothers
During epidemic periods
IPV will be supplied in combination with the other vaccines. OPV will be delivered separately by oral administration.
Existing vaccines Hepatitis B vaccination of infants is important in those areas of high endemic incidence. In the other countries it may be enough to vaccinate at risk newborns and postpone the general vaccination to the adolescent age when the sexual activity exposes the population to the risk of infection .
Hepatitis B
Haemophilus
influenzae
I
Conjugate vaccines. Delivered mostly in combination other infant vaccines.
with the
Meningococcus A, B, C
Conjugate vaccines against meningococcus C (MenC) have already been tested in infants and are likely to become part of infant combinations in Europe and USA where there is a high incidence of MenC. Similar conjugates for Meningococcus A (MenA) have been tested and may become part of infant combinations in Africa, Middle East and Asia where MenA is endemic. Meningococcus B vaccines should be part of infant vaccines if they become available.
Pneumococcus New measles Parainfluenza type III Respiratory syncytial virus
Otitis media Subunit
Desirable vaccines in development
Recombinant
glycoprotein
698 Table Z (cont’d)
Vaccination
age
Toddlers and children
Adolescents
Vaccines
Comments
Measles Mumps Rubella Varicella Diphtheria Tetanus Pertussis
Booster immunizations 6 years of age. (Acellular)
Diphtheria Tetanus Pertussis
Booster immunization diphtheria vaccine. (Acellular)
Hepatitis B Hepatitis A Existing vaccines
at 12- 18 months
and 4
using low dose
Primary immunization series . Booster, if infants had already been immunized
Measles Mumps Rubella Varicella
Desirable vaccines in development
Epstein Barr Virus Herpes simplex virus Gonococcus Chlamydia Human immunodef. virus Hepatitis C virus Papillomavirus Cytomegalomavirus Tuberculosis Conjugates for Meningococcus A/C+B
Adults
Diphtheria Tetanus Pertussis
Elderly
Pneumococcus Influenza Respiratory syncytial virus(booster) Tuberculosis Non typable hemophilus
Booster immunization repeated every 5 10 years, using a low dose diphtheria vaccine.
699
TableI (cont’d) Target population
Travellers
comment!s
Vaccines
Rotavirus Enterotoxigenic Cholera Shigella Salmonella Enteric fever
Diarrheal vaccines to be used for travellers and for all children in developing nations E. coli
Pregnant women/mothers
Streptococcus B Cytomegalomavirus
New important diseases
Giarda lambia Entameba histolytica Helicobacter Malaria Lyme
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