Thermostability of Vaccines Lessons Learned and Future Directions

1. Thermostability of VaccinesLessons Learned and Future Directions TECHNET CONSULTATION Kuala Lumpur, Malaysia November 29-December 3, 2010 Debra Kristensen, Group Leader, Vaccine Technologies

2. Introduction • For more than a decade, PATH has been exploring both the technical and commercial feasibility of stabilizing vaccines for use in developing countries. • To date, we have conducted research on 7 antigen types with 11 vaccine producers and 22 technical collaborators. • This presentation will summarize lessons learned over the past 10 years. • Funding:Bill & Melinda Gates Foundation • Reference: Kristensen D, Chen D. Stabilization of vaccines: Lessons learned. Human Vaccines. 2010; 6:229–231.

3. Lesson 1: Integrate stabilization efforts into early vaccine development

4. Integrate Stabilization Efforts Early • Once a vaccine has an established record of safety and clinical efficacy, there are risks and costs associated with reformulation. • Improvements in vaccine stability will almost always be less expensive if addressed during initial vaccine development.

5. Lesson 2: There are circumstances where it makes sense to stabilize existing vaccines

6. Stabilizing Existing Vaccines Can Make Sense When: • Stability of the product is unacceptable or inferior to other marketed products. • Reformulation is needed for other reasons. • Proof of principle is needed for a new stabilization method. It is often easier to assess new stabilization methods with existing vaccines with established assay methods.

7. Lesson 3: Freeze stabilization is possible for vaccines containing aluminum adjuvants

8. Freeze Sensitivity of Vaccines • Aluminum salt adjuvants are the most prevalent adjuvants in human vaccines. They irreversibly agglomerate when frozen, reducing vaccine potency. • The following vaccine types contain aluminum adjuvants: • diphtheria • hepatitis A • hepatitis B • human papillomavirus (HPV) • inactivated Japanese encephalitis • pertussis • pneuomococcal • tetanus

9. Impact of Accidental Vaccine Freezing • Reduces vaccine effectiveness. • Exposure of vaccine to freezing temperatures may have contributed to recent increases in pertussis rates in Texas (US).1 • Results in vaccine wastage. • US CDC estimates that the federal Vaccines for Children program alone incurs more than $20 million in vaccine waste annually from accidental freezing.2 1. McColloster P, Vallbona C. Graphic-output temperature data loggers for monitoring vaccine refrigeration: Implications for pertussis. American Journal of Public Health. Published online ahead of print November 18, 2010: e1–e2. 2. Welte, M. (2007), Vaccines ruined by poor refrigeration, USA Today, December 4, available at http://www.usatoday.com/news/health/2007-12-04-spoiled-vaccines_N.htm (accessed January 14, 2010).

10. Protecting Vaccines From Freeze Damage • Aluminum adjuvant-containing vaccines can be protected from freeze damage through inclusion of a safe and commonly used excipient in the formulation (e.g., propylene glycol). Cost is ≈ $0.001 per dose. • PATH and collaborators have validated the method with hepatitis B, diphtheria-tetanus-pertussis (DTP), and pentavalent (DTP-hepatitis B -Hib) vaccines. • PATH has placed the freeze-protection technology in the public domain for use without charge by all vaccine producers.

11. Lesson 4: Heat stabilization requires a more customized approach and results will be variable

12. Heat Stabilization Examples • Major success→ Hepatitis B vaccine • Stability improved from 1 month to 12 months at 37°C.1 • Minor success →Measles vaccine • Stability improved from 1 week to 8 weeks at 37°C.2 • Jones Braun L, Jezek J, Petersen S, et al. Characterization of a thermostable hepatitis B vaccine formulation. Vaccine. 2009;27:4609–4614. • Ohtake S, Martin RA, Yee L, et al. Heat-stable measles vaccine produced by spray drying. Vaccine. 2010; 28:1275–1284.

13. Lesson 5: The full benefits of stable vaccines will only be realized after changes are made to storage guidelines

14. Controlled Temperature Chain Controlled ambient temperature: using vaccines at temperatures higher then the traditional 2° to 8°C. • For a limited period of time. • With controls to prevent excursions beyond the specified threshold temperature (e.g., 25° or 37°C). • Guidelines determined by the vaccine’s stability profile and context of use.

15. Benefits of Using Vaccines at Controlled Ambient Temperatures • Increase immunization coverage: • Reach the unreached. • Ease logistics of outreach and improve timeliness of vaccine delivery to specific populations: • HPV vaccine to schools. • Tetanus toxoid vaccine to women. • Hepatitis B vaccine birth dose. • Reduce risks of freezing. • Conducive to integrated supply chains. • Reduces reliance on expensive, specialized equipment.

16. Four Streams of Work Needed for Success • COUNTRY-LEVEL EVIDENCE • Identifying strategies and conditions where ambient temperature storage makes sense. Adoption of Controlled Temperature Chain • CHANGES TO STORAGE GUIDELINES • Working to license vaccines, especially new vaccines, to their true stability. • TEMPERATURE MONITORING • Vaccine vial monitors (VVM), threshold heat indicators, electronic temperature monitors, etc. • PROGRAMMATIC GUIDELINES • Protocols. • Training.

17. Ongoing Initiatives • Vaccines in Canada are being relicensed for short-term storage up to 25°C. • US CDC has created an “International Vaccine Stability Work Group” which is exploring a similar initiative for the United States. • Project Optimize is working with hepatitis B vaccine producers and regulatory agencies to attempt to re-label hepatitis B vaccine for storage up to 37°C. • A sub-group of WHO’s Immunization Practices Advisory Committee is looking at guidelines for using vaccines at controlled ambient temperatures

18. Lesson 6: Trade-offs may need to be made between the heat stability and the format characteristics of a vaccine

19. Need reconstitution syringe Stability lost after reconstitution Safety issue: No preservative; contamination potential Safety issue: Wrong type or amount of diluent High vaccine wastage rates Some Heat Stability Improvements Result in Sub-Optimal Product Formats For example, stable lyophilized vaccines: Liquidvaccine Lyophilized Higher shipping/storage costs versus

20. Other Heat Stability Technologies May Yield Superior Product Formats For example: • Spray drying can yield free-flowing powders of controlled particle size facilitating aerosol delivery, dry powder jet injection, coated microneedles, and erodible implants. • Freeze drying can be used to create fast-dissolving tablets for convenient oral delivery.

21. Lesson 7: Products with enhanced stability can benefit both vaccine producers and purchasers

22. Stable Vaccines: Benefits to Vaccine Producers • Enhance product features and competitiveness. • Potential reduction in costs through bulk production efficiencies. • Reduced risk of recalls when the cold chain is breached during shipment. • Decreased shipping and storage costs.

23. Stable Vaccines: Benefits to Purchasers and End-Users • Improved vaccine effectiveness. • Reduced vaccine wastage and cost.* • Widened reach of immunization. • Relieved pressure on the cold chain. *Levin A, Levin C, Kristensen D, et al. An economic evaluation of thermostable vaccines in Cambodia, Ghana and Bangladesh. Vaccine. 2007; 25: 9645–9657.

24. How can we help ensure that countries can benefit from thermostable vaccines? • Incentivize vaccine producers/developers to optimize vaccine stability during product development. • Through target product profiles. • Push and pull mechanisms. • Promote informed purchases that take into account vaccine product attributes. • Work to advance labeling of vaccines for use in controlled ambient temperatures. • Helping to realize the full benefits of stable vaccines.