VHPB - Malta 22-23 October 2001

1. VHPB - Malta 22-23 October 2001 Summary conclusions: 1: Generalizations 2: Drawbacks, concerns and issues 3: Data and information

2. Goals of vaccine programmes • Prevention and control of disease, also eradication/elimination of pathogens • Successes: • eradication of smallpox • progress towards eradication of poliomyelitis, measles, and other disease • progress towards control of hepatitis B and Hib

3. Vaccines • Safe and effective • most cost-effective medical and public health intervention against infectious diseases • hepatitis B vaccine: one of the safest and most effective vaccines ever developed • Development time reduced • Need for high-quality and affordable vaccines • Costs falling or can be reduced through cooperative bidding and other mechanisms

4. Combined vaccines • Not new (e.g. influenza (AAB), OPV 1, 2 & 3, DTP, MMR, bacterial + viral vaccines, polyvalent vaccines) • Accelerated development and licensure, despite complexities • Safe and immunogenic • Effective - reducing disease and not altering pathogen circulation

5. Combined vaccines - continued • Agreed principles for administration • e.g. acceptability of giving an extra dose of antigen • non-interchangeability of vaccines from different manufacturers • Quality assurance secured • accreditation of quality control laboratories (ISO system) • EU release certificate • Audits (EDQM, WHO - national regulatory authorities and manufacturers)

6. Benefits • Simplified immunization programme implementation • increased acceptance, decreased global cost, increased disease control • decreased disease prevalence and burden • fewer health service visits and lower programme costs • increased vaccine coverage

7. Benefits - continued • Reduced number of injections per visit and fewer injections given overall • reduced waste • increased safety - although limited role of combination vaccines in developing countries • less or no exposure to thiomersal • lower costs of storage, transport, cold chain (except developing countries)

8. Benefits - continued • harmonization of antigens • ease of adding new antigens in existing programmes • data collection facilitated and documentation eased

9. Drawbacks, concerns and issues • Wide variation in immunization schedules across Europe and compared with USA • national and federal approaches • different epidemiological patterns • issues of compulsory/obligatory and voluntary immunization • testing of each formulation for each immunization schedule in EU - ethical issues • school entry requirements

10. Immunization schedules • history of attempts to harmonize • cross-roads in decision-making process • consequences for local production and global vaccine supply (e.g. DTP shortage and monovalent HB glut) • change in antigens (Pw  Pa, OPV  IPV) • maternal screening and routine immunization of newborns - unnecesary?

11. Legislation and regulatory issues • Licensing, availability, usage - not the same • EU-wide licensing, but trials for each schedule • licensing of components, new formulations, increasingly complex with polyvalent Vs • post-marketing conditions • need to assess models for combined Vs

12. Legislation and regulatory issues - continued • Legislation needs to be adapted to introduce new vaccines/antigens • inflexibility of programmes • Regulations for bidding and procurement • Compulsory immunization and legal consequences • legislation more powerful than education of physicians in driving immunization of schoolchildren

13. Legal and regulatory issues • Thiomersal issue - lawsuits in litigious societies • manufacture of vaccines in industrialized countries for use in developing countries • role of national regulatory authorities in developing countries • flexibility of some countries (e.g. Italy)

14. Clinical development and trials • Increasing complexity and cost • each component to be tested for safety and efficacy • number of arms increases exponentially with number of components, leading to trials with huge numbers of participants to test against different immunization schedules - “unethical” • Interference (immunological and chemical)

15. Clinical development and trials - continued • Need to establish new minimum potency and protection levels • Need for new reference materials • Analysis of adverse reactions • Surrogate markers

16. Financial issues • Prices • combined vs monovalent • premiums (e.g. Latin America) • trade off: fewer injections and side effects vs price • Who pays for vaccines and immunization? • Public/private sectors • Incentives (physicians/families) • Which vaccines are paid for by state? • Wide variations in EU, USA...

17. Economic issues • Lower administrative costs • time of vaccinators • less pain for children, and parents save time and money • high willingness to pay for reduction from 4 to 3 and 2 to 1 injections • Complexity of health insurance. EU

18. Funding mechanisms • Global Alliance for Vaccines and Immunization (GAVI) • Pan American Health Organization-type revolving funds • Other

19. Hexavalent combined vaccines • Advantages: • increased compliance, • increased vaccine coverage, • facilitated data collection, • decreased costs compared to sum of separate vaccines (at least in Germany), • decreased storage and logistic requirements

20. Hexavalent vaccines - continued • Quality issues (intermediates) • Efficacy • “Combination is more than mixing” • need for better/other markers of protection • Formulation issues • liquid, powder • Hib responses may be lower, but are protective (possibly related to pertussis component)

21. Hexavalent vaccines - continued • Issues • how long does protection last? • few breakthrough infections - hepatitis B • memory immunity • variations in immunogenicity • reasons for reduced immunogenicity (ethnic differences in Sweden) • increased likelihood of adverse reactions? • limits to number of antigens?

22. Manufacture and supply • Sole-source supply/source of antigens • Reliability of manufacturers to fulfil contracts or deliver • Procurement and bidding practices • Pre-qualification/availability • Manufacturers’ responses - strategic alliances (e.g. purchase of national companies)

23. New data • “Combining is more than mixing” • Country updates - Europe is more than EU • Belgium, Finland, France, Germany, Israel, Italy, Lithuania, Switzerland, Turkey, USA • How anti-HBs protects • Genetic correlates of non-response to HB • strategies to overcome non-responsiveness • Production process • HB immunization schedules in Europe to be further updated

24. Data needed • Vaccine production capacity • Manufacturers’ (general) future plans • Demand forecasting and data (national immunization programmes) • Disease burden/demographic data (e.g. births on developing countries) • Reasons for decreased immunogenicity of components in combined vaccines

25. Data needed • Science • Reasons for decreased immunogenicity of components in combined vaccines • HB virus-binding site on hepatocytes • Mechanisms of action of anti-HBs • Mucosal immunity • Economic evaluation of combined vaccines

26. Information and communication • Reasons for non-vaccination • insufficiency of information about diseases, vaccines and immunizations - parents’ view • missed appointments - common reason • doctors do not propose or recommend immunization • ideological opposition to vaccines - rare • Increase public sensitivity to safety issues • Campaigns needed • on benefits and safety of vaccines and combined vaccines • dispel myths (antigenic exhaustion/overload)

27. Information and communication • Campaigns (cont) • targeted at • whole medical community - training in medical schools - particular focus on paediatricians, family physicians, practice nurses, health care workers • industry and professionals • parents • media (for balanced information) • Close communication and coordination between manufacturers and health authorities • WHO vaccine use database

28. Conclusions • Combined vaccines with hepatitis B component are: • safe, effective, licensed, available, used, not (yet) cheap • present challenges and opportunities • added value • likely demand from parents, health-care workers and decision makers • German recommendation: “use whenever possible and applicable”