Disclosure Statements. That vaccine s got you covered or does it? Learning objectives. Vaccine-Mediated Immunity. Response to Disease

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1 That vaccine s got you covered or does it? Disclosure Statements Wes Nuffer, PharmD Janssen Pharmaceuticals: Speaker with honorarium Wesley Nuffer, PharmD LaToya Jones Braun, PhD Science in Action: Translating Research to Pharmacy Practice October 25, 213 LaToya Jones Braun, PhD Dr. Jones Braun has no financial relationships to disclose. Learning objectives After this presentation, you should be able to Explain the mechanisms of how vaccines stimulate the immune response Describe common causes of reduction in vaccine efficacy during transport and in the clinic Evaluate research approaches to improved vaccine stability Develop steps a pharmacist can take to ensure vaccine quality Vaccine-Mediated Immunity Response to Disease Polysaccharide Vaccines Stimulate B cells but not T cells T-cell independent Less immunologic memory Lose booster effect Ineffective in immature immune system Children under 2 need conjugate Link to protein (tetanus, diptheria) Now T cell immunity stimulated

2 Inactive and Live Vaccines Inactive vaccines won t cause illness! Do not reproduce Utilize inert proteins/portions of the pathogen May administer inactive vaccines together Live vaccines must reproduce to cause immunity Delay in immune response Theoretical risk to immunocompromised patients Dosing intervals may be relevant Can give two live vaccines simultaneously If not administered together, need to wait 28 days Diptheria Live vs Inactive Vaccines Live Vaccines - Live attenuated influenza (LAIV) - Herpes zoster - Varicella - Measles, mumps, rubella - Rotavirus - Yellow fever - Oral typhoid Inactive Vaccines - Inactivated influenza - Pneumococcal - Tdap & DTap - Hepatitis A - Hepatitis B - Human papillomavirus (HPV) - Inactive poliovirus - Meningococcal - Haemophilus influenzae - Rabies - Typhoid injection Measles Vaccines Under Development HIV Tuberculosis Salmonella Hepatitis C E Coli Bioterrorism agents (anthrax, smallpox, ricin) Epstein-Barr Malaria Rabies Streptococci group A & B Cytomegalovirus Timing of Vaccine Intervals Minimal interval is important Administering doses too early won t count towards series Utilize CDC catch up schedule No true maximal interval Do not start series over Delaying full schedule delays best immunity Immunizations Preventing Disease Disease Max. Year Cases Cases Cases Cases Cases Cases Cases Cases Diphtheria 26, Hib ~2, 198 s Measles 894, Mumps 152, , Pertussis 265, ,616 15,632 1,454 1,7 16,858 27,55 18,719 Paralytic 21, Poliomyelitis Rubella Million 1965 CRS ~3, Tetanus Varicella 221, ,931 32,242 4,146 3,386 2,48 15,427 11,81 Vaccination Rates Vaccine (Recommended Vaccination rate (%) population) Influenza (Age 5-64) 44.5% Influenza (Age >65) 66.6% Influenza (HCP) 63.4% Pneumococcal (High risk pts) 18.5% Pneumococcal (Age >65) 59.7% Tetanus in the past 5 years 52.3% Hepatitis B 42.% Hepatitis B (HCP) 63.2% Zoster (Age >6) 14.4% Adapted from APhA Pharmacy-Based Immunization Delivery National Health Interview Survey JAMA 3/212

3 Vaccine Rates by Race/Ethnicity Race/Ethnicity Influenza (%) Pneumococcal (%) Hispanic 41.9% 39.% Black 56.1% 46.2% White 67.7% 63.5% Myths & Barriers affecting Vaccinations Risk vs benefit Perceived susceptibility and seriousness of the disease Perceived risks of the vaccination Logistical barriers Time, travel, cost of vaccine National Health Interview Survey 21 Vaccine Safety/Misinformation Question of safety of vaccines Link to autism? Neurologic disorders Sudden infant death syndrome VAERS reporting essential! Misinformation Hot lots exist within vaccine products Too many vaccinations overwhelm the immune system Websites appearing credible that spread misinformation The Cold Chain Consistent temperature regulation Must be maintained throughout Success! We immunized them! But Are the delivered vaccines we provide effective??? Matthias, DM, Robertson, J, Garrison, MM, Newland, S, and Nelson, C. Freezing temperatures in the vaccine cold chain: A systematic literature review. Vaccine 27; 25, /25/27 LaToya Jones Braun -- UCDHSC 18

4 Vaccines possessed by many of the 45 providers audited by DHHS for vaccine management practices were at risk A. Adherence to the CDC s Temperature Monitoring Requirement Providers who did NOT meet the requirement = 4 (89%) B. Extent of vaccine freezing danger Providers who had refrigerators with temperatures < 2 C for 5+ cumulative hours over a 2-week period = 19 (42%) Matthias, DM, Robertson, J, Garrison, MM, Newland, S, and Nelson, C. Freezing temperatures in the vaccine cold chain: A systematic literature review. Vaccine 27; 25, Figure prepared using data from a report published by DHHS in June (last accessed 9/16/12) Freezing vaccine linked to public health concerns Vaccines that have documented losses of potency due to freezing accidentally frozen atnorth memorial golden valley clinic between whooping cough outbreak and vaccinestorage Washington html Haemophilus influenzae type b (Hib) Hepatitis B Tetanus Pertussis Diphtheria Inactivated polio virus Influenza Cold Chain Myths The cold chain is completely reliable If you don t put ice in the container, the product won t freeze If you mark the package DO NOT FREEZE, it won t be frozen. You only have to worry about cold chain failures in underdeveloped locales Research to improve vaccine stability Focus on aluminumcontaining adjuvants

5 All vaccines with aluminum-containing adjuvants are susceptible to freezethaw damage 1. Vaccine particle agglomeration and possibly 2. Antigen degradation Table from: Rappuoli et al, Nature Reviews Immunology 11, (December 211) doi:1.138/nri385 Importance of particle size Vaccine particles a few microns in diameter Internalization by APC best if particle diameter < 1 microns Agglomeration = reduced activity. (Shake test) Figure from Morefield et al. Vaccine 23; (25). Some successful research strategies for preventing agglomeration an preserving activity Spray freeze-drying with appropriate excipients Minimizes agglomeration BUT requires additional costly processing steps Preventing freezing with excipients (example follows) Normalized potency (% reference) Effect of 3 F/T cycles on potency Control 3 F/T cycles As little as 2.5% can be used to preserve particle size. % particles 1.5 to 3. microns 1 Frozen and damaged Frozen but not damaged %.31%.62% 1.25% 2.5% 5% 1% 3% 5% control Concentration of propylene glycol Adapted from Braun LJ, et al., Vaccine. 29 Jan 1;27(1):72-9. Epub 28 Oct 28. Did not freeze & was not damaged

6 Normalized Potency (% reference) 12 1 All concentrations of examined preserved in vitro potency & in vivo anti- HBsAg titers control vaccine +% +5% +1% +2% +25% +3% 1. control no excipient PEG P.5 GLYCERIN. Adapted from Braun LJ, et al., Vaccine. 29 Jan 1;27(1):72-9. Epub 28 Oct wavelength, nm Normalized fluorescence intensity (arbitrary units) Emisssion peak position, nm Control No excipient PEG-3 Propylene glycol Formulation Glcerin VACCINE PACKAGING SCHEMES Conventional Alternative All FT formulations agglomerate, + HBsAg Adsorbed on Al Adjuvant HBsAg Al Adjuvant Positive Control Conventional stored at 4 C Negative Control Conventional exposed to 3FT cycles at -2 C and adjuvant-free vaccine Sample Alternative plenty of particles are in correct range The immediate mix strategy did not work

7 Pay attention to shipping/transport materials and logs What can you do? Know and verify storage temperatures 2 to 8 C: Do not freeze All inactivated and subunit vaccines Influenza vaccines vaccines with aluminumbased adjuvants Certain live vaccines Influenza Rotavirus typhoid & yellow fever -5 to -15 C: Frozen Live, attenuated varicella vaccine Varivax All vaccines containing live, attenuated varicella Shingles (Zostavax) MMRV (ProQuad) Learn how to spot damaged vaccines (e.g., Shake test) When in doubt. Discard. Do not use. People and Funding UC Denver My Lab Tanya Clapp Kelly Arthur Jessica Cummiskey Sabrina Peterson Paul Siebert Anil Tyagi Numerous PharmD students John Carpenter Chris Vessely Tia Estey Uday Kompella Ruchit Trivedi CU Boulder Deborah Wuttke Aimee Eldridge Theodore Randolph KU - Russ Middaugh (and group) DynPort Vaccine Company Ian Henderson HTD Rajiv Nayar Julianne Cooper PATH Dexiang Chen (and group) Debbie Kristensen Mark Guy Funding Butcher Biotechnology Initiative (LJB and DW) PATH (LJB) National Institute of Allergy and Infectious Diseases (NIAID) U1 AI (JFC and TWR) rbonte(hc) Biological Process Development Facility at the University of Nebraska, Lincoln E. coli culture w/ T4* lysozyme vector Brian Matthews (U of Oregon) National Jewish Health Pippa Marrack Michael Munks