1. Elaine R. Miller, RN, MPH Immunization Safety Office Division of Healthcare Quality Promotion National Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention (CDC ) Vaccine Safety Inquiries to the Centers for Disease Control and Prevention’s Immunization Safety Office Nov. 6, 2013 National Center for Emerging and Zoonotic Infectious Diseases Division of Healthcare Quality Promotion – Immunization Safety Office

2. 2 Background  Vaccines are one of the greatest public health achievements in history, but as with other medical products are not 100% safe or effective  CDC’s Immunization Safety Office (ISO) works with FDA to conduct post-licensure vaccine safety monitoring and research  ISO also responds to vaccine safety inquiries from healthcare providers, public health officials and the public

3. 3 Outline  Background on CDC’s Immunization Safety Office (ISO)  ISO inquiry response function  General information  Examples  Lessons learned

4. Immunization Safety Office (ISO) Mission  Comprehensive approach to vaccine safety includes  Surveillance to detect possible adverse events following vaccination in a timely way  Investigation of possible adverse events following vaccination to determine causality and risk factors  Development of strategies for prevention of adverse events following vaccination  Vaccine safety research  Timely communication and education to partners and the public  Work with other Federal agencies and other organizations to further vaccine safety mission To assess the safety of vaccines administered to children, adolescents and adults 4

5. CDC’s Immunization Safety Office: Postlicensure Vaccine Safety Monitoring Infrastructures SystemCollaborationDescription Vaccine Adverse Event Reporting System (VAERS) CDC and FDAUS frontline spontaneous reporting system to detect potential vaccine safety problems Vaccine Safety Datalink (VSD) CDC and Healthcare Plans Conducts active surveillance and planned research studies using large linked databases Collects medical care and vaccination data on more than 9.3 million members annually (~3% of the US population) Clinical Immunization Safety Assessment (CISA) Project CDC and Academic Centers Conducts clinical vaccine safety assessments at individual level and clinical research 5

6. Vaccine Adverse Event Reporting System (VAERS) *  National spontaneous reporting system for adverse events that occur after receipt of US-licensed vaccines  Received nearly 27,000 US reports in 2012 (>100 reports per business day)  Requires a report be filed  Accepts reports from healthcare providers, manufacturers and lay persons  Report clinical significant adverse health events that occur after vaccination  Jointly administered by CDC and FDA since 1990  Strengths include - national data and rapid signal detection  Limitations include - inconsistent data quality and generally cannot determine if the vaccine caused the adverse event 6 * http://vaers.hhs.gov/index

7. CISA Evaluation for Patient Vaccine Safety Questions  CISA provides consultation to US healthcare providers who have vaccine safety questions about a specific patient  No cost to the provider for a CISA evaluation  Advice from CISA and CDC is meant to assist in decision making rather than provide direct patient management (which is the responsibility of the treating healthcare provider)  Procedure for requesting a CISA evaluation  Send an email to CISAeval@cdc.gov  Include the vaccine safety question and pertinent patient information  For more information: http://www.cdc.gov/vaccinesafety/Activities/CISA.html http://www.cdc.gov/vaccinesafety/Activities/CISA.html 7

8. 8 ISO Inquiry Function Previous Work and Purpose  ISO has been tracking inquires in database since 2002  Tracking inquiries is an important way to gauge vaccine safety concerns among the public and stakeholders  Previous review of inquiries from 2002-2009 has been published*  Among 975 inquiries Main reasons were to obtain VAERS data (49%) clinical advice (21%) and for other safety related information (21%) Main topics were neurologic adverse events (17%), deaths after vaccination (8%) and injection site reactions (6%)  Current review describes inquiries received from July 2009 through December 2012 *Miller, Batten, Hampton et al. Tracking vaccine safety inquires to detect signals and monitor public concerns. Pediatrics 2011 127 Suppl 1: S87-91.

9. 9 Sources of Vaccine Safety Inquiries  Inquiries come to ISO mainly by phone and email  Healthcare providers, health officials from state and local health departments, parents, patients and others send inquires to CDC via:  CDC INFO: CDCINFO@cdc.gov or 1-800-CDC-INFO (1-800-232- 4636)CDCINFO@cdc.gov  NIP INFO*: NIPINFO@cdc.govNIPINFO@cdc.gov  CDC Emergency Operations Center (EOC)  Direct to CDC staff  Complex vaccine safety questions that require specific subject matter expertise and inquiries that require searches in the VAERS database are forwarded to CDC’s ISO for a response  All inquiries and responses are tracked in an electronic database *NIP – National Immunization Program

10. 10 Resources ISO uses to Answer Questions on Vaccine Safety Topics  VAERS database  Information from published studies – ISO publications available at http://www.cdc.gov/vaccinesafety/library/ http://www.cdc.gov/vaccinesafety/library/  CISA Project consult service for healthcare providers via email to CISAeval@cdc.gov CISAeval@cdc.gov  Vaccine Package Inserts-available at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedPro ducts/ucm093833.htm http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedPro ducts/ucm093833.htm  Advisory Committee on Immunization Practices (ACIP) Guidelines- available at http://www.cdc.gov/vaccines/pubs/acip-list.htmhttp://www.cdc.gov/vaccines/pubs/acip-list.htm  The Institute of Medicines’ 2011 Review of Adverse Effects of Vaccines-available at http://www.iom.edu/Reports/2011/Adverse- Effects-of-Vaccines-Evidence-and-Causality.aspxhttp://www.iom.edu/Reports/2011/Adverse- Effects-of-Vaccines-Evidence-and-Causality.aspx  CDC Subject Matter Experts  Published studies from peer reviewed journals-available via Pub Med search at http://www.ncbi.nlm.nih.gov/pubmedhttp://www.ncbi.nlm.nih.gov/pubmed

11. 11 Resources ISO uses to Answer Questions on Vaccine Safety Topics (cont.) Vaccine Package Inserts-available at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093833.htm http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093833.htm

12. 12 Resources ISO uses to Answer Questions on Vaccine Safety Topics (cont.) Advisory Committee on Immunization Practices (ACIP) Guidelines-available at http://www.cdc.gov/vaccines/pubs/acip-list.htm

13. 13 Resources ISO uses to Answer Questions on Vaccine Safety Topics (cont.) Institute of Medicine 2011 Review of Adverse Effects of Vaccines-available at http://www.iom.edu/Reports/2011/Adverse-Effects-of-Vaccines-Evidence-and-Causality.aspx

14. 14 Summary of Vaccine Safety Inquiries to ISO from July 1, 2009 to December 31, 2012 667 total inquiries received (~ 2 inquiries for every 3 business days) Type of requestor (top 5) Healthcare provider205 (31%) State/local heath official150 (22%) General public112 (17%) CDC staff53 (8%) Media30 (4%) Primary reason for inquiry (top 3) VAERS data285 (43%) Clinical information118 (18%) Other vaccine safety information 91 (14%)

15. 15 Summary of Vaccine Safety Inquiries to ISO from July 1, 2009 to Dec. 31, 2012 (continued) Main subject of the inquiry (top 3) VAERS 1 130 (19%) Neurologic adverse events 2 92 (14%) Vaccine administration errors 40 (6%) Vaccines (top 5) 3 Seasonal influenza177 (27%) All or all childhood vaccines169 (25%) Human papillomavirus63 (9%) 2009 H1N1 influenza53 (8%) Tetanus, diphtheria and pertussis (Tdap) 32 (5%) 1. VAERS subject inquiries included questions on VAERS public data access, data sharing, privacy policy, reporting, follow-up on VAERS reports, etc. 2. Neurologic events do not include neurodevelopmental events such as autism spectrum disorders 3. Not necessarily mutually exclusive

16. 16  Concern  “…20 …personnel were given inactivated influenza vaccine intranasally. This was not live influenza vaccine. Please provide guidance.”  Response  VAERS contained a total of 72 patients who had received the inactivated influenza vaccine administered in error into the nose and none reported adverse events  The 20 personnel should be considered unvaccinated, advised of this, and should be re-vaccinated with either inactivated vaccine given IM or live vaccine given intranasally in one week Example 1: Vaccine Administration Error involving Influenza Vaccine

17. 17 Example 2: General Information Related to Hepatitis B Vaccine  Question  “…Can a person test positive for hepatitis from (hepatitis B) vaccines?”  Response 1-2  Transient positive hepatitis B surface antigens (HBsAg) following hepatitis B vaccine has been described  Is a false positive that will revert back to negative within 18 days  Vaccinee is not infectious when they test positive for HBsAg  However, since most persons are not tested prior to vaccination, cannot completely attribute a positive HBsAg to vaccination- confirmatory testing required 1.De Schryver, A., et al. (2004). Hepatitis B surface antigenaemia following vaccination with a combined vaccine against hepatitis A and B. Journal of Viral Hepatitis, 11(1), 88-90. 2. Mast E, et al. (2006). A comprehensive immunization strategy to eliminate transmission of hepatitis B virus Infection in the US. CDC. MMWR 55(RR16);1-25.

18. Example 3: Neurologic Adverse Event after Influenza Vaccine  Question  “Can flu vaccine cause Guillain-Barre Syndrome or GBS?”  Response  In 1976 there was a small increased risk of GBS after receiving swine flu vaccine. The increased risk was approximately 1 additional case of GBS per 100,000 people who got the vaccine. The exact reason for this association remains unknown.  Studies assessing the risk of GBS after seasonal flu vaccine since 1976 have show either no risk or a small increased risk of 1 case per million doses of vaccine.  Studies looking at the 2009 H1N1 vaccine have shown a risk ranging from about 1 to 2 cases per million doses.*  A history of GBS within 6 weeks following receipt of influenza vaccine is a precaution for influenza vaccine. *Salmon DA, et al. Association between Guillain-Barré syndrome and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis. Lancet 2013; 381: 1461-68. 18

19. 19 Example 4: Neurologic Adverse Event after Influenza Vaccine  Question  “A 54 year old male received the flu vaccine and developed Bell’s palsy within 12-24 hours. Was this due to the vaccine?”  Response  The Institute of Medicine (IOM) concluded that “The evidence favors rejection of a causal relationship between inactivated influenza vaccine and Bell’s palsy.”  Three additional studies 1-3 on this topic after the IOM review were also reassuring on this issue. 1) Rowhani-Rahbar A, et al (2012). Immunization and Bell's palsy in children: a case-centered analysis. Am J Epidemiol 175(9):878-85. 2) Cano M, et al. (2012) Bell’s Palsy Cases Following Administration of Influenza A (H1N1) 2009 Monovalent Vaccine Reported to the Vaccine Adverse Event Reporting System (VAERS). J Vaccines Vaccin 3:134. 3) Lee GM et al. (2011). H1N1 and seasonal influenza vaccine safety in the vaccine safety datalink project. Am J Prev Med 41(2):121-8.

20. 20 Example 5: Request for VAERS Data  Question  I am a nurse practitioner … I recently received a flu shot that was improperly given. It was given 1-2 mm (not cm) below my acromion. At the time it felt like it went into a tendon or joint and it hurt. It was extremely painful that day and night and has since improved greatly. Are you familiar with this happening?  Response  The 2011 Institute of Medicine (IOM) report concluded that the available evidence convincingly supports a causal relationship between the injection of a vaccine and deltoid bursitis.  During the 2011-12 season, VAERS received 50 reports of the influenza vaccine being administered at an inappropriate site; 49 of the 50 reported an adverse health event such as: pain, decreased limb mobility and/or bursitis.  Outreach and education was conducted for immunization partners as a result of this and similar inquiries

21. Limitations of the Review  Not all vaccine safety questions are referred to ISO  Many vaccine safety inquiries are answered by other parts of CDC or are answered by state/local health departments or healthcare providers  Patients and parents may not be aware of resources at CDC and therefore do not contact CDC with their concerns  Referrals to ISO are more likely to involve serious, complicated or unusual issues so not necessarily representative of typical vaccine safety concerns  Classification of inquiries may not be mutually exclusive or have clearly defined categories  VAERS data is often used to answer inquiries and the limitations need to be provided with the response 21

22. Summary and Lessons Learned  Vaccine safety inquiry response is often a complex task that requires training, experience, broad expertise  Answer questions using appropriate language (healthcare provider vs. lay person), provide guidance in data interpretation especially limits of VAERS, and express empathy  Requestors are often seeking clinical information/advice  Responding to concerns about vaccine safety is an important public health function  In addition, inquiries help guide research and surveillance priorities for CDC 22

23. For Immunization Questions Call: 1- 800-CDC-INFO (1-800-232-4636) or email CDCINFO@cdc.gov or NIPINFO@cdc.gov 23

24. Acknowledgements  Karen Broder, MD  Tom Shimabukuro, MD, MPH, MBA  Beth Hibbs, RN, MPH  Claudia Vellozzi, MD, MPH  Paige Lewis, MPH 24

25. Thank you Questions? 25

26. Additional Slides 26

27. Example: Request for Information on Intussusception after Influenza Vaccine  Question  “Can rotavirus vaccine cause intussusception?”  Response*  Yes-the risk after currently licensed rotavirus vaccines ranges from about 1 in 20,000 to 1 in 100,000 vaccinations.  The benefits of both rotavirus vaccine continue to outweigh the risks associated with vaccination, including the small excess risk for intussusception. Thanks to vaccination, since 2008, between 40,000 and 50,000 hospitalizations for rotavirus disease have been prevented each year in US children under 5 years of age  CDC continues to recommend that all US infants receive rotavirus vaccination. * Source: CDC website at http://www.medscape.com/viewarticle/812044http://www.medscape.com/viewarticle/812044 27