US Efforts in Vaccine Safety Roger Baxter, MD California Immunization Coalition Summit 2011
Conflicts of interest I receive research grants from Sanofi Pasteur, GSK, Merck, MedImmune, Novartis, Pfizer, and Protein Sciences
Vaccination scenarios A mother asks you to spread out her child s vaccines to decrease the likelihood of causing autism.
Vaccination scenarios Several parents refuse to let their child get the HPV vaccine because it is so dangerous, and they ve heard it causes MS, blood clots, and fainting. Not to mention that it encourages sexual activity.
Are vaccines safe? How are vaccines developed, and are they safe? What is done to ensure vaccine safety in the US?
Gillray, 1802 Anti-Vaccine Society
False scares UK, 1998: allegation of possible link between MMR and autism Immediate fall in rates of MMR Ireland, 2000: >1600 measles cases 350 hospitalized 3 deaths No confirmation of link Discredited results
Thimerosal scare timeline 1999: government report reveals that childhood vaccines might expose infants to more mercury than anyone had realized no evidence of harm Immediately, USDPH and ACIP call for a plan to eliminate or reduce as expeditiously as possible the mercury content of vaccines Public reaction is swift: thimerosal is unsafe
Thimerosal 2004: Institute of Medicine unanimous decision that thimerosal is not causally linked to autism 2009: Rejection by Special Masters that autistic children are entitled to benefits under the vaccine injury act.
But vaccines are not always safe
Cutter IPV Incident, 1955 Polio virus not killed in several vaccine lots Vaccine recipients infected with polio 149 vaccinated cases (6 deaths) Public confidence in vaccines shaken
Influenza Vaccine & Guillain-Barré Syndrome (GBS) Feb 1976: outbreak of Swine flu Mass vaccination campaign: 40 million vaccinated from Oct-Dec 1976 Over 500 GBS cases reported, 25 deaths Vaccination program suspended
Overall the benefits of vaccines far outweigh the risks
Vaccine Preventable Diseases US Disease Pre-vaccine Era* 2001 % change Measles 503,282 108 99.98 Diphtheria 175,885 2 99.99 Mumps 152,209 226 99.80 Pertussis 147,271 5,420 96.30 Rubella 47,745 20 99.95 Polio paralytic) 16,316 0 100.00 H.Influenzae type b 20,000 290 98.60 Tetanus 1,314 27 97.90 Cong. Rubella Synd. 823 2 99.80 Total 1,064,854 6,095-99.43 Vaccine Adverse Events 0 13,526 * Maximum cases reported in pre-vaccine era and year + Estimated because no national reporting existed in the prevaccine era
Need for Ongoing Vaccine Safety Program Public confidence in vaccine safety is critical Decreases in disease risks lead to increased attention on vaccine safety
Vaccine vs. Drug Safety Higher standard of safety Vaccinees are generally healthy and may be very young Vaccinations may be universally recommended or mandated Lower risk tolerance: Vaccine: less than 1/100,000 vs. drug: 1/1-1/1000
Vaccine pre-licensure studies 1st: Laboratory and animal studies Then: Human studies Phase I: gross toxicity (N: ~ 10) Phase II: dosing range/ reactogenicity (N: 10-100) Phase III: efficacy (N: 1000-10,000)
Vaccine pre-licensure studies Advantages: Close, detailed follow-up Randomized blinded placebo-controlled design Disadvantages: Rare or delayed reactions are difficult to detect Often cannot study subpopulations
Post-Licensure Surveillance Passive surveillance VAERS Active surveillance Phase IV trials (N =10,000-50,000) Mandated by FDA Many done at the KP Vaccine Study Center Large-linked databases Up to > 100,000 vaccinees
CDC s Immunization Safety Office (ISO) Vaccine Safety surveillance Research on vaccine safety
ISO Key Components Vaccine Adverse Event Reporting System (VAERS) Clinical Immunization Safety Assessment Network (CISA) Vaccine Safety Datalink project (VSD)
VAERS - Passive Surveillance FDA/CDC collaboration since 1990 Reports of suspected VAEs from physicians, patients, etc. Web-based reporting and public access to data (www.vaers.hhs.gov)
VAERS - Strengths National in scope Timely Relatively inexpensive/cost-effective Generation of hypotheses ( signals )
VAERS - Weaknesses Underreporting Biased reporting (lawyers, news events) Mix of causal and coincidental events Inadequate report quality Lack of denominators and control group Generally unable to address causality
CISA Clinical Immunization Safety Assessment Network
CISA National network of six medical research centers with expertise in immunization safety Established in 2001 Goal: to improve the scientific understanding of vaccine safety at the individual level.
CISA Network Sites Kaiser Permanente Vaccine Study Center Boston Medical Center Columbia University Medical Center Stanford University Johns Hopkins University Vanderbilt University
CISA Goals To study the basis of adverse events following immunization (AEFI) To study risk factors associated with developing an AEFI To provide clinicians with evidence-based guidelines and consultation for Evaluating AEFIs Vaccination or revaccination in risk groups
CISA Current Activities Evaluation of individual patients with serious or unusual AEs Vaccination in children with metabolic (and mitochondrial) disorders Hypersensitivity management Vaccination/Revaccination protocols Live vaccines in DiGeorge Syndrome Revaccination of GBS patients
CISA Vaccine Safety Fellowship Sponsored at CDC Current Fellow is at KPVSC: Ali Rowhani-Rahbar, MD, PhD
How to get in touch with CISA Call me: 510-267-7529 Or email roger.baxter@kp.org or nicola.klein@kp.org
VSD Vaccine Safety Datalink Collaboration between CDC and 10 managed care organizations Enrollment of over 9.5 million 3.1% of the American population
Vaccine Safety Datalink Sites Group Health Cooperative Northwest Kaiser Permanente No. CA Kaiser Permanente So. CA Kaiser Permanente Health Partners Kaiser Permanente Colorado Marshfield Clinic CDC Harvard Pilgrim Kaiser Georgia Kaiser Hawaii
VSD Distributed Data Model
VSD Priorities Evaluate safety of: newly licensed vaccines new recommendations for existing vaccines vaccines in high-risk populations Develop new methodologies for vaccine safety assessment Test hypotheses suggested by signals from VAERS
Rapid Cycle Analysis (RCA) Ongoing surveillance of multiple vaccines Weekly updates of data Example Increased likelihood of febrile seizure 7-10 days after MMRV compared with MMR+V Klein NP, Fireman B, Baxter R., et al. Measles-mumps-rubellavaricella combination vaccine and the risk of febrile seizures. Pediatrics;126:e1-8
Seizures within 42 days of Vaccine, 2000-2008 12-23 Months of Age 45 40 35 Rate per 100K Doses 30 25 20 15 10 5 0 0 5 10 15 20 25 30 35 40 45 Days Since Vaccine MMRV MMR+V MMR VZV
Other RCA Studies Menactra Rotateq Tdap Flu vaccines HPV
VSD Studies To Evaluate Safety of Newly Licensed Vaccines Meningococcal Conjugate (Menactra ) Rotavirus (Rotateq ) Tdap (ADACEL and BOOSTRIX ) HPV (Gardasil ) Cervarix Herpes zoster (Zostavax ) Prevnar13
Investigation of vaccine adverse event associations Guillain Barré Syndrome following any vaccine Safety of repeated influenza vaccine administration Rheumatoid arthritis and various vaccines
Vaccine Safety In Special Populations High-risk newborns Pregnancy Genetic risk factors Travelers Metabolic and mitochondrial disorders Persons with history of GBS
New Research Methodologies for Vaccine Safety Studies Pioneered by KP Vaccine Study Center Case-centered analyses Exact Sequential analysis Outcomes-bases surveillance
VSD - Strengths Large sample size Electronic medical records data available for epidemiology studies Can calculate incidence rates and attributable risks Relatively quick and timely
VSD - Limitations Dynamic cohorts loss to follow up Expensive Not large enough for some hypotheses Difficult to study VAEs with delayed or insidious onset MCO members generally well-vaccinated so can be difficult to find unbiased controls
New systems for detecting vaccine AEs FDA Mini-sentinel Sentinel initiative PRISM Kaiser CESR
Conclusions There are many organizations involved in keeping vaccines safe. Hopefully this will reassure people that
about vaccine safety!
Extra slides
From: Chen et al. Vaccine 1994; 12(6):542-550