Assessing Vaccine Safety Post Licensure Neal A. Halsey Johns Hopkins University
Inactivated Respiratory Syncytial Virus Vaccine: 1960 s Formalin inactivated Administered to infants Minimal reactions Induced neutralizing antibody Kapikian AZ. Amer. J. Epid., 1969, 89:405-21 Kim HW et al 1969
Kapikian AZ. Amer. J. Epid., 1969, 89:405-21 Kim HW et al 1969 Enhanced RSV Disease 9-10 Months Following Inactivated RSV Vaccine RSV Vaccine No Vaccine Pneumonia 9/13 (69%) 4/47(9%) p<.001 RSV Vaccine Paraflu Vac. Hospitalization 80% 5% p<.001
Randomize Recruit Randomized Placebo Controlled Trials Vaccine Enroll Double blind evaluations Outcomes Population Participants Placebo Outcomes Selected: healthy, age, gender?
Vaccine no yes Investigating Causal Relationships Randomized Placebo-Controlled Double Blind Trials Disorder yes no Risk Rel Risk a b a a+b a a+b c d c c+d c c+d a+c b+d
Sample sizes required for identification of relative risks. Ellenberg S S Clin Infect Dis. 2001;33:S319-S322 2001 by the Infectious Diseases Society of America
Intussusception after Rotavirus Vaccines Pathogenesis unknown Intussusception/100,000: Rhesus(Rotashield): 10-20 RV1 (Rotarix) and RV5 (Rotateq) No increased risk in trials of ~30,000) ILEO-ILEOCOLIC INTUSSUSCEPTION *1-2/100,000 in some populations US: RV1 > RV5 ILEOCOLIC INTUSSUSCEPTION Weintraub NEJM 2014 Shaw Annu. Rev. Med. 2013. 64:165 74 Patel. Expert Rev Vaccines. Source: Netter. The CIBA Collection of 2009 Nov;8(11):1555-64. Medical Illustrations, Vol 3, 1962. pg134.
Post-licensure Safety Studies 1. Surveillance for AEFI in all countries 2. Individual case investigation of SAEs 3. Signal detection 4. Special studies
Vaccine no yes Individual AEFI Disorder yes no Risk Risk Ratio a b a a+b a a+b c d c c+d c c+d a+c b+d
False Assumptions of Causal Relationships based on Temporal Association Post hoc, ergo propter hoc After this, therefore because of this Unexpected reports of serious adverse events have resulted in stoppage of national programs to introduce hepatitis B, Hib, pneumococcal, MMR and HPV vaccines.
Global Vaccine Safety Blueprint Vision Effective vaccine pharmacovigilance systems are established in all countries Vaccine pharmacovigilance is the science and activities relating to the detection, assessment, understanding, prevention and communication of adverse events following immunization WHO/IVB/12.07 Courtesy C. Vellozzi 16
Global Vaccine Safety Blueprint: Minimal Capacity for Vaccine Safety Surveillance National dedicated vaccine pharmacovigilance capacity Encourage reporting of vaccine safety issues Reporting form for individual case safety reports National database or system for collating, managing and retrieving AEFI reports Harmonized methods and tools for the monitoring and investigation of AEFI WHO/IVB/12.07; *www.brightoncollarboration.org Courtesy C. Vellozzi 17
Global Vaccine Safety Blueprint: Enhanced Capacity for Vaccine Safety Surveillance The ability to carry out active surveillance rather than relying solely on spontaneous reporting of AEFI alone for the purpose of signal detection The ability to carry out epidemiological studies to test hypotheses WHO/IVB/12.07 Courtesy C. Vellozzi 18
Vaccine Safety Signal: Definition The Council for International Organizations of Medical Sciences (CIOMS) definition: Information from one or multiple sources, which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action. Courtesy C. Vellozzi Source: Report of CIOMS Working Group VIII, Practical Aspects of Signal Detection in Pharmacovigilance. Geneva 2010. 19
Vaccine Safety Signal Management Guidance Guidance for Industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) March 2005 Clinical Medical http://www.fda.gov/cder/guidance/index.htm Courtesy C. Vellozzi 20
Vaccine Safety Signal Management Framework Signal detection Interim signal assessment Decision to end Prioritization and Decision Decision to end Final signal assessment Verified Ruled Out Courtesy C. Vellozzi 21
Causality Assessment
What do we mean when we say a vaccine causes an adverse event? Population: The vaccine increases the risk of the event. Individual: The vaccine was a factor in the patient developing the adverse event. Coggan and Martyn Lancet 2005; 365: 1434 37
Usual criteria for determining a causal relationship between vaccines and adverse events Epidemiologic Studies: Evidence of increased risk in vaccine recipients vs controls, or Definitive laboratory tests linking disease to vaccine component A few exceptions
Bradford Hill Causality Criteria 1. Strength 2. Consistency 3. Specificity 4. Temporality 5. Biologic gradient 6. Plausibility 7. Coherence 8. Experimental evidence 9. Analogy K. Rothman. Causation and Causal Inference. In: Rothman KR and Greenland S, Modern Epidemiology. Lippincott; 1998
Causality Assessment from Individual Case Reports Causality established (usually): Isolation of live vaccine agent in normally sterile body fluid. Yellow fever vaccine virus in liver. Polio vaccine (OPV) virus in CSF. Measles vaccine virus in lung of child with leukemia. Sem in Ped Infect Dis 2002 July;13(3):205-14
Causality Assessment from Individual Case Reports Causality established (usually): Isolation of live vaccine agent in normally sterile body fluid. Yellow fever vaccine virus in liver. Polio vaccine (OPV) virus in CSF. Measles vaccine virus in lung of child with leukemia. Rule out wild type virus (genetic sequencing) Sem in Ped Infect Dis 2002 July;13(3):205-14
Causality Assessment from Individual Case Reports Causality not established: Antigen detection or PCR without sequencing. False positives Contamination Coincidental infection
Causal Associations Usually Cannot by Determined from Passive Reports of Individual Cases Without Isolation of Vaccine Agent Possible exceptions: 1. Injection site reactions 2. Immediate hypersensitivity reactions 3. Repeat challenge(no clear criteria) 4. Disorders where general causality has already been established and alternative causes ruled out
Immediate Hypersensitivity Reactions Hives, angioedema, anaphylaxis Pathogenesis known Short interval from vaccine to reaction Unlikely for other exposures Skin testing with vaccine components
Post-licensure Investigation of Individual Case Reports of AEFI
CISA Review of Case Reports of Adverse Events Following Immunizations Causality Work Group of CISA AEFI Case Report Other diagnosis No 1. Is the diagnosis correct? Yes Uncertain Indeterminate, diagnosis uncertain Inconsistent with causal association, other cause identified 2a. Is the evidence definitive? Yes No Indeterminate Yes Not available If continue, include statement regarding evidence for other cause in conclusion 5. Is the AEFI an Infection? Not definitive No or Uncertain 2. Is there evidence for other causes? No 3. Is there a known causal association with the vaccine? No 4. Is there strong evidence against a causal association? Yes Yes No Inconsistent with causal association If continue, include statement regarding uncertain diagnosis in conclusion 3a. Was the event within the time window of increased risk? 3b. Are there qualifying factors? Yes No Yes Consistent with causal association Halsey et al. Vaccine 2012:30(39):5791-8.
Review of Case Reports of Adverse Events Following Immunizations Causality Work Group of CISA Febrile seizure 12 month old 7 days after MMR AEFI Case Report Other diagnosis No 1. Is the diagnosis correct? Yes Uncertain Indeterminate, diagnosis uncertain Inconsistent with causal association, other cause identified 2a. Is the evidence definitive? Yes No Indeterminate Yes Not availabl e If continue, include statement regarding evidence for other cause in conclusion 5. Is the AEFI an Infection? Not definitive No or Uncertain 2. Is there evidence for other causes? No 3. Is there a known causal association with the vaccine? No 4. Is there strong evidence against a causal association? Yes No Inconsistent with causal association If continue, include statement regarding uncertain diagnosis in conclusion Yes 3a. Was the event within the time window of increased risk? 3b. Are there qualifying factors? Yes No Yes Consistent with causal association
Vaccine 2012: 30(39):5791-8.
Algorithm Advantages 1. Visual 2. Standardized 3. Transparent 4. Tracking assessments 5. Revise assessments as new data become available
WHO Causality Assessment Tool http://www.who.int/iris/bitstream/10665/80670/1/9789241505338_eng.pdf Tozzi et al. Vaccine 2013;31(44):5041-6
3. Algorithm No No No
4. Classification
Investigating Individual Case Reports No Known Causal Association No Specific Laboratory Test
Case Reports and Temporal Associations for Diseases of Unknown Etiology The number of cases reported can serve as a signal, but not for determining causal relationship. 1, 10, 100, or 1,000 Need epidemiologic studies to determine increased risk in vaccinated or in risk window after vaccination
Post-licensure Population Based Studies
Retrospective or Non-concurrent Cohort Studies Defined population. Identify vaccinated and unvaccinated prior to risk period. Identify all cases in defined time period. Compare rates of disease in vaccinated and unvaccinated.
Vaccine no yes Investigating Causal Relationships Retrospective or Non-concurrent Cohort Studies Disorder yes no Risk Rel Risk a b a a+b a a+b c d c c+d c c+d a+c b+d Potential Problem: Self selection for vaccine?
Relative Risk of Sudden Infant Death Syndrome by Day after DTP: Tennessee 10 Relative Risk 1 0.1 0.01 0-3 4-7 8-14 15-30 >30 Days after DTP Healthy Vaccinee Effect: children with illnesses not vaccinated DTP does not increase the risk of SIDS Griffin et al. NEJM 1988;319:618-23
Vaccine no yes Investigating Causal Relationships Case-Control Studies Disorder case control Odds Ratio a b a/b c/d ad bc c d Potential Problems: Not randomized Selection bias? Matching?
Bell s Palsy www.elib.gov.ph/edatabase
Switzerland: Odds Ratios for Receipt of Vaccines <91 Days Prior to Bell s Palsy Vaccine Case Patients (N=250) Controls (N=722) Adjusted Odds Ratio (95%CI) Intranasal inactivated influenza 63 (25.2%) 7 (1.0%) 84.0 (20.1-351.9) Parenteral inactivated influenza 10 (4.0%) 41 (5.7%) 1.1 (0.6-2.0) Mutsch M, et al. NEJM 2004;350:896.
Vaccine no yes Vaccine Only Studies Disorder yes no a b Potential Problems: Selection bias? Need to include all cases c d a+c b+d
Vaccine Only Studies Vaccination Risk window Control window 0 7 30 60 Days after vaccination Compare the incidence of disease In risk window with control window after receiving vaccine
Risk of febrile seizures on days 0-1 vs 14-15 after TIV alone, PCV13 alone, and simultaneous TIV and PCV13 Increased Risk of Febrile Seizures With Simultaneous TIV and PCV13
K. Vannice MenAfriVac Rollout in Mali Campaigns 2010 and 2011 ~6 million vaccinated
K. Vannice, in preparation risk control Risk Washout Control window window Depicts individuallevel assessment in vaccinated areas Seasonality of other diseases e.g. malaria and respiratory disease
Vaccine no yes Case Only Studies Disorder yes no a b Potential Problems: Selection bias? Need to include all cases c d a+c b+d
Self Controlled Case Series Case Only Studies Vaccination Vaccination Disease Onset 90 60 30 7 Days prior to onset Compare the incidence of receiving vaccines in different time periods prior to onset of disease
Conclusions 1. Post-licensure monitoring for safety is essential in all countries 2. Poor understanding of causality assessment is a problem 3. Expect the unexpected 4. Plan for objective investigations 5. Demand good science