Everything You Always Wanted to Know About Vaccines (But Were Afraid to Ask)

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1 Topics Covered Everything You Always Wanted to Know About Vaccines (But Were Afraid to Ask) Gary S. Marshall, M.D. Professor of Pediatrics Chief, Division of Pediatric Infectious Diseases Director, Pediatric Clinical Trials Unit University of Louisville School of Medicine Vaccine development Immunization policy and recommendations Why the routine schedule changes Vaccine financing Monitoring vaccine delivery and safety Federal requirements for vaccinators Rules by which to vaccinate Contraindications and precautions Vaccine administration Economic Evaluation Economic Evaluation Comparative evaluation of alternative lines of action that includes effects as well as costs Vaccines that produce health benefits and cost savings are inherently cost-effective Vaccines that produce health benefits but do not save costs: decision to use depends on willingness to pay Costs Medical: medication, tests, hospitalization Vaccine: development, purchase, administration, side effects Societal: lost productivity Ess. Clin Infect Dis 2002;35:294 Ess. Clin Infect Dis 2002;35:294 Types of Analysis Types of Analysis Cost-benefit analysis: health benefits are expressed in monetary value Force explicit decision because costs and benefits measured in same units Difficulty assigning monetary value to outcomes Cost-effectiveness analysis: incremental costs compared to incremental benefits measured in natural units (eg, cases avoided, lives saved) Cost-utility analysis: outcomes measured in quality-adjusted life years gained Sensitivity analysis: change in conclusions when assumptions changed ( eg, incidence of disease) Ess. Clin Infect Dis 2002;35:294 Ess. Clin Infect Dis 2002;35:294

2 Quality-Adjusted Life Year Quality-Adjusted Life Years Each year in perfect health is assigned the value of 1.0 Death has a value of 0 Years lived in less than full health are assigned a value between 0 and 1 Weighting based on survey responses (eg, time trade-off) How is the weight assigned? Is there more weight given to adverse physical outcomes? Are there health states worse than death? Is there a prohibitive cost per QALY saved? What about the effect of a patient s health on caregivers? Cost-Effectiveness Analysis Decreased effectiveness DOMINATED DECISION QUADRANT Increased cost DECISION QUADRANT DOMINATING AND COST-SAVING Increased effectiveness Biases Against Vaccines in Cost- Effectiveness Analysis Benefits do not occur immediately Present value is unfairly low ( over-discounting ) Herd immunity effects not accounted for Force of infection: static versus dynamic Inputs Incidence Duration of protection Coverage rates Cost= resources allocated-resources saved Decreased cost Biases Against Vaccines in Cost- Effectiveness Analysis Costs <$10,000 per QALY Saved Infants Candidate Vaccine Target Group Tools for eliciting utilities Indirect impact on caregivers (productivity, quality of life) Chlamydia (genital) Helicobacter pylori Hepatitis C Herpes simplex virus Human papilloma virus 12 year olds Infants Infants 12 year olds 12 year olds Tuberculosis 12 year olds Neisseria gonorrhea 12 year olds Respiratory syncytial virus Infants, 12-year-old females Stratton. IOM Report: Vaccines for the 21st Century, 2000

3 Costs $10,000-$100,000 per QALY Saved Costs >$100,000 per QALY Saved Candidate Vaccine Parainfluenza virus Rotavirus Group A streptococcus Group B streptococcus Target Group Infants, women during first pregnancy Infants Infants High-risk adults, 12-year-old females or women during first pregnancy (low utilization) Candidate Vaccine Lyme disease Coccidioides immitis Enterotoxigenic E. coli Epstein-Barr virus Histoplasmosis Meningococcus serogroup B Target Group Resident infants born in or immigrants to high-risk areas Resident infants born in or immigrants to high-risk areas Infants and travelers 12 year olds Resident infants born in or immigrants to high-risk areas Infants Shigella Infants and travelers or travelers only Stratton. IOM Report: Vaccines for the 21st Century, 2000 Stratton. IOM Report: Vaccines for the 21st Century, 2000 From Bench to Bedside Center for Biologics Evaluation and Research Sets standards Purity Consistency Potency Preclinical Development (academia, industry, government) Clinical development (industry) Biologics License Application Vaccines and Related Biological Products Advisory Committee FDA Licensure Good Manufacturing Practices Good Laboratory Practices Good Clinical Practices Product Information Label Package Insert Average cost to develop a new vaccine: $500-$700 million Marshall. The Vaccine Handbook. PCI Books, Inc.; 2010 Vaccine Clinical Development Recommendations for Use Phase 1 Safety, tolerability May not involve target population ACOG Phase 2 Safety, immunogenicity, dosing Performed in target population 100s Phase 3 Safety, immunogenicity, longevity of immune response, concomitant use, efficacy 1000s ACIP (CDC) AAP AAFP Phase 4 Post-licensure Safety 100,000s SAM ACHA Marshall. The Vaccine Handbook. PCI Books, Inc.; 2010

4 Considerations ACIP Actions Characteristics of the product Routine recommendation Principles of active and passive immunization Epidemiology and burden of disease Every person in specified age group eg: PCV13 at 2, 4, 6, months Safety Catch-up recommendation Cost analysis of preventive measures Defined cohorts and time periods Published and unpublished studies eg: second dose of VAR for all who had 1 dose Expert opinion Risk-based recommendation Risk factors for disease or complications eg: PPSV23 for adult smokers Rodewald. ACIP Meeting, October 2009 ACIP Actions Notes Permissive statement Allow use but no recommendation eg: HPV4 for males New provisional recommendations released 3 times/year Recommendations have been harmonized since 1995 but there are still differences Insurance companies may not cover new vaccines until the recommendations are published ACIP vote determines coverage by VFC All vaccination mandates are local Rodewald. ACIP Meeting, October 2009 Notes Why the Routine Vaccine Schedule Changes The Package Insert is a legal document Determines what marketing can and cannot say Differences between label and recommendations New vaccine for old disease Old vaccine for new disease Improved vaccine Expansion to new age group HepA; varicella; rotavirus; HPV Zoster vaccine DTaP; PCV13; MCV4; LAIV HepA at 12 mo; Tdap for adolescents Example: timing of RV doses From targeted to universal program HepB; HepA; MCV4 for adolescents Change in dosing schedule Elimination of OPV at 6 mo New program goal MMR #2; VAR #2; influenza for all Altered risk/benefit ratio All-IPV schedule Safety issue Withdrawal of RRV-TV Eradication Withdrawal of vaccinia

5 Cost of Vaccines Childhood Vaccines: Source of Funding 2000 VFC Contract (Boys) VFC Contract (Girls) Estimated Private Market (Boys) Estimated Private Market (Girls) U.S. Dollars Year Marshall. The Vaccine Handbook. PCI Books, Inc.; 2010 Vaccine Manufacturers Biologics Surveillance Data, 2005 (influenza not included) Public Vaccine Financing Actions Required Under VFC Resolutions Source Attribute 317 Funds VFC Annual discretionary appropriation Mandatory Eligibility No restrictions Medicaid-eligible Uninsured Native American Alaska native Underinsured Stability Significant fluctuations Stable funding stream Must receive vaccine at Federally Qualified Health Centers or Rural Health Clinics Action Provider expected to offer vaccine to VFC-eligible children Provider may offer vaccine to VFC-eligible children Provider expected to vaccinate VFC-eligible children on request Program expected to promote recommendation Uptake is a measure of performance Yes Yes Yes Yes Yes ACIP Recommendation Affirmative Permissive No Yes Yes, if available; if not, refer No No Rodewald. ACIP Meegting, October 2009 Public Vaccine Financing Monitoring Vaccine Delivery National Immunization Survey Conducted annually since 1994 Random digit-dialing telephone survey of households Historically focused on children mo of age Expanded in 2006 to include adolescents Validating data obtained from providers Includes >21,000 provider-reported vaccination records Lance Rodewald, NCIRD, CDC

6 Coverage Rates Among Young Children Coverage Rates Among Adolescents 3 DTaP or equivalent 4 DTaP or equivalent 4:3:1 plus 3 Hib 4:3:1:3 plus 3 HepB 4:3:1:3:3 plus 1 varicella 4:3:1:3:3:1 plus 4 PCV Tdap 1 MCV4 1 HPV 3 HPV Percent Vaccinated Percent Vaccinated Year Year CDC. MMWR 2003;52(RR-4):728; CDC. MWR 2008;57:961 CDC. MMWR 2010;59:1018 Timeliness of Immunizations by Mo Monitoring Vaccine Delivery At Least One Vaccine Delayed (med 232 days) 74% < 1 Mo 34% 1-6 Mo 29% No Delays 26% >6 Mo 37% National Health Interview Survey Conducted since 1957 Current target: 35,000 households containing 87,500 persons Behavioral Risk Factor Surveillance System Conducted since 1984 State-level, random digit-dialing survey of noninstitutionalized civilians 18 years of age Covers 350,000 adults each year Useful for influenza vaccine and PPSV23 Luman. JAMA 2005;293:1204 (N=14,810; 2003 NIS data, mo) Coverage Rates Among Adults Monitoring Vaccine Delivery Percent Vaccinated Influenza vaccination (past year) Pneumococcal vaccine (ever) School surveys Most common form of state and local surveillance Data lag behind current performance Special area and population surveys Geographic Medicaid participants Nursing home residents Year BRFSS. (08/15/08)

7 Monitoring Vaccine Delivery Federal Requirements for Vaccinators Health Plan Employer Data and Information Set (HEDIS) National Committee for Quality Assurance Managed health care plan performance measures Vaccine Information Statement (VIS) Give a current, take-home copy of the relevant VIS to the parent, legal representative, or adult recipient before each dose of each vaccine Use the VIS published by the CDC Mandatory for vaccines covered under the VICP Mandatory for vaccines purchased under federal contract Encouraged for all other vaccines Federal Requirements for Vaccinators Federal Requirements for Vaccinators Vaccine Information Statement (VIS) Provide VIS for each component of combination vaccines if there is no VIS for the combination Use visual or oral supplements for illiterate or blind patients Translations are available Permanent medical record or office log Name of the VIS, publication date, and date it was given to the recipient Patient signature is not required VIS should not be construed as informed consent, which may be required in some states Name and title of individual who administered the vaccine Address where the permanent record is kept Federal Requirements for Vaccinators Federal Requirements for Vaccinators Permanent medical record or office log Date of administration Manufacturer Lot number Report to VAERS Any event listed by the manufacturer as a contraindication to subsequent doses of the vaccine Any event listed in the Reportable Events Table that occurs within the specified time period after vaccination Adhere to the Occupational Safety and Health Administration Bloodborne Pathogens Standard

8 Rules by Which to Vaccinate: 1 Rules by Which to Vaccinate: 2 Any vaccines can be given at the same time (using separate sites) Exception: VAR and smallpox vaccine VAR PI warns against concomitant administration with PPSV23 (impaired response to VAR) Live vaccines not given at the same time should be separated by at least 4 weeks Exceptions YFV may be given at any time after singleantigen measles vaccine Live oral vaccines (RV and Ty21a) may be given at any time in relation to any other live vaccines LAIV is not an exception Rules by Which to Vaccinate: 3 Rules by Which to Vaccinate: 4 Different inactivated vaccines may be given at any time with respect to each other Exception: The AAP recommends a minimum interval of 1 month between Tdap and MCV4-D if not given on the same day There are minimum acceptable intervals between doses of the same vaccine Exceptions The 4-day grace period (not applicable to RAB) Early, accelerated, or compressed schedules in certain situations Caveat A minimum interval is a minimum interval except when it s not DTaP doses 3 and 4: 6 mo, but 4 is OK VAR doses 1 and 2: 3 mo, but 28 days is OK Rules by Which to Vaccinate: 5 Rules by Which to Vaccinate: 6 There are minimum ages for administration of all vaccines Exceptions HepB BCG Rabies vaccine Partial or fractional doses of a vaccine should never be used Exception: None

9 Rules by Which to Vaccinate: 7 Rules by Which to Vaccinate: 8 A multidose vaccine series should not be restarted if the recommended dosing interval is exceeded Exception: Oral typhoid Ty21a Similar vaccines made by different manufacturers are interchangeable Exception Preference for using the same brand of DTaP, HPV, and RV for the entire series Vaccination should not be deferred if same brand is not available Rules by Which to Vaccinate: 9 Rules by Which to Vaccinate: 10 There is no harm in vaccinating a person who has already had the disease or the vaccine In fact, there is reason to vaccinate when disease can be caused by multiple serotypes Exceptions Too many doses of PPSV23 or tetanus or diphtheria toxoid-containing vaccines can cause increased reactogenicity Increased reactogenicity if anthrax vaccine given to person who has had anthrax Live vaccines should be deferred after receipt of antibody-containing blood products Exceptions LAIV, Ty21a, RV, YFV, ZOS MMR and VAR should not be deferred in postpartum women who received antibodycontaining blood products during pregnancy, including anti-rho(d) globulin Administration Errors Administration Errors Vaccine Error Corrective Action Live Expired or damaged Wait 4 weeks Vaccine Error Corrective Action DTaP Adolescent or adult None Less than full dose Wait 4 weeks Tdap Infant primary series Give DTaP More than full dose None Dose 4 or 5 None Inactivated Expired or damaged Redose immediately Child 7-9 yr None (counts) Less than full dose More than full dose Redose immediately None Hib-T (Hiberix) Primary series None PPSV23 Child <2 yr Give PCV13 VAR, ZOS, MMR, MMRV, YFV, MPSV4 Given IM None HepB Given SQ Give IM VAR Adult 60 yr Give ZOS (0 or 4 wks) ZOS Child None MCV4 Given SQ None

10 Other Pearls Other Pearls Indications for serology Prevaccination Adults without personal history of chickenpox Internationally adopted children (consider) Postvaccination HepB: high-risk health care workers and dialysis patients RAB: pre-exposure prophylaxis for laboratory workers Some cases of invalid dosing Physical examination not required for vaccination Gloves not routinely needed Not necessary to change needles after withdrawing vaccine from vial Rubber stopper should be swiped with alcohol Aspirating back on the syringe not necessary Injections in the same area should be separated by 1 inch Other Pearls Contraindications Syringes should not be prefilled by the end user (exception: mass influenza immunization campaigns where only 1 vaccine type is being used) Increases likelihood of a serious adverse event Vaccine should not be given Permanent contraindications for all vaccines: severe allergy to vaccine or component Precautions Notable Contraindications Might increase risk of a serious adverse event Could compromise immunogenicity Could be mistaken for a vaccine reaction Default position: defer vaccination Risk of deferral: susceptibility to disease Risk of vaccination: largely theoretical Considerations: epidemiology of disease, patient s circumstances, missed opportunities DTaP Encephalopathy within 7 days of pertussiscontaining vaccine Progressive neurological disorder (until stabilized) Allergic to components Baker s yeast: HepB, HPV Rodent or neural proteins: JEV (JE-VAX) Eggs: LAIV, IIV, YFV Gelatin or neomycin: MMR, VAR

11 Notable Contraindications Screening Questions Pregnancy: LAIV, MMR, smallpox, VAR, ZOS Immune impairment Any: smallpox, Ty21a, YFV Severe : LAIV, MMR, VAR, ZOS Aspirin or salicylate therapy: LAIV Untreated active TB: MMR, VAR, ZOS Is the patient sick today? Does the patient have severe allergies to medicines, foods, drugs, or vaccines? Has the patient had serious reactions to previous vaccinations? Has the patient had a seizure or brain or neurological problems? Does the patient have asthma or another chronic medical condition? IAC. (accessed 08/15/08) Screening Questions Screening Questions Has a health care provider diagnosed wheezing or asthma in the past year (children 2-4 years of age)? Does the patient have cancer, leukemia, a blood disorder, HIV infection, AIDS, tuberculosis, or any problem with the immune system? In the last 3 months, has the patient received any treatments that might weaken his or her immune system, such as steroids, cancer chemotherapy, or radiation? Are there any family members who have problems with their immune system? Has the patient received blood transfusions or immune globulin in the past year? Is the patient pregnant or is there a chance she could become pregnant in the next 3 months? Has the patient received any other vaccines in the last 4 weeks? IAC. (accessed 08/15/08) IAC. (accessed 08/15/08) Erroneous Contraindications Erroneous Contraindications Mild acute illness with or without fever Mild respiratory illness (including OM) Mild gastroenteritis Antibiotic or antiviral therapy Low-grade fever, redness, pain, swelling after pervious dose Prematurity (delay HepB in infants <2000 gm whose mothers are HBsAg-negative) Pregnant, unimmunized, or immunosuppressed household contact (except pre-event smallpox) Breastfeeding (except pre-event smallpox) Convalescent phase of illness Exposure to an infectious disease Positive TST without active disease Simultaneous TST Allergy to penicillin, duck meat or feathers, or environmental allergens Fainting after previous dose Seizures, SIDS, allergies, vaccine reactions in family members

12 Erroneous Contraindications Use of Live Vaccines in Households of Immunosuppressed Individuals Malnutrition Stable neurological condition (eg, CP, seizures, developmental delay) Allergy shots Extensive limb swelling after DTP, DTaP, or Td that is not an Arthus-type reaction Brachial neuritis after previous dose of tetanus toxoid-containing vaccine Autoimmune disease History of the vaccine-preventable disease Vaccine LAIV MMR RV Smallpox Ty21a VAR YFV ZOS Recommendation Contraindicated if profoundly immunosuppressed May be used May be used Contraindicated May be used May be used (avoid contact if lesions develop) May be used May be used (standard precautions is lesions develop) Precaution Scenarios Precaution Scenarios 2-month-old experiences 4 hours of inconsolable crying after DTaP Should he get the second dose at 4 months of age? Analysis Risk of recurrence: low Consequences of recurrence: temporary Risk of disease: high 6-month-old with moderate febrile illness Should he get the 6-month shots? Analysis Risk of vaccine reaction: low Consequences of reaction: attribution Risk of disease: high Risk of missed opportunity: high