Vaccinology Course 2017: Safety

Item Type Poster/Presentation

Authors Halsey, Neal A.

Publication Date 2017-01-30

Keywords adverse events; University of Maryland, Baltimore. School of Medicine; --Safety measures; Drug Contamination-- prevention & control; Injection Site Reaction; Vaccines--adverse effects; Vaccines--standards

Download date 03/10/2021 23:23:13

Item License https://creativecommons.org/licenses/by-nc-nd/4.0/

Link to Item http://hdl.handle.net/10713/8225 Vaccine Safety

Neal A. Halsey M.D. Neal Halsey: Disclosures

• Safety monitoring boards – Merck( males), Takeda(Norovirus) • Advisory board: Valneva: – Experimental vaccine • Scientific advisory board for development of a live – ILiAD Biotechnologies Objectives 1. Understand how vaccines cause adverse events 2. Types of adverse events 3. How we distinguish causal from coincidental associations General Principles

1. All vaccines cause some adverse events 2. Most adverse events are mild 3. Many serious adverse events are preventable by following guidelines Pathogenesis of Adverse Events Caused by Vaccines

1. Injection process 2. Contamination 3. Replication of live agent 4. Direct effect of vaccine component 5. Host immune response to component • normal • aberrant 15-17 yrs

www.indianetzone.com

9-10 yrs

J. Gee VSD report ACIP Oct 2008 Injection Related: Fainting

• Adolescents, Females at increased risk • Head injuries: – Neurologic sequelae, largest VICP payment – Rare deaths • Auto accidents • Prevention: sit for 15 minutes Incorrect IM Injection Site

Ulnar nerve damage following anthrax Vaccine*

*Sever et al. Pharmacoepidemiology J. Salk 1955 and drug safety 2002; 11: 189–202 13 patients: persistent pain, tendonitis

Injection in upper 1/3 of deltoid

Vaccine 2010:28; 8049 Safest Deltoid Muscle Injection

1. Hand on hip – Abduct 60o – Moves axillary nerve 2. Index finger on acromian process 3. Thumb on tuberocity 4. Inject at mid point

Cook IF. Human Vaccine 2011;7(8):845. Appropriate IM Injection Sites

Middle 1/3 of deltoid

www.immunize.org Respiratory Arrest Following Vaccine 1982-1995 • Latin America, Asia, Africa • Succinyl choline and pancuronium bromide mistaken as vaccine diluent • Vials identical size, color, and print type stored in same refrigerator 15+ Deaths in Syria 2014

Campaign suspended for months Atracurium, same color vial 10 Dose Vial plus Diluent Errors in Measles Vaccine Administration: India • Multi-dose vials • 39 incidents of fever, rash, shock • 81 deaths • Staph aureus contamination after reconstitution Prevention: discard vials after 2 (WHO 6) hours. Sterile syringe and needle for reconstituting. Smaller (5 dose) vials now used in most of India Sood et al. Vaccine 1995;13:785-6 Single Dose Vial With Diluent

More expensive More storage space Group A Streptococcal Sepsis or Abscesses Following DTP 1980’s U.S.

• Same organism in blood or abscess and residual DTP in vial • Contamination of multi-dose vial after opening by health care workers

Lesson: 1. Care in alcohol prep for every entry 2. Keep in refrigerator- not at room temp Injection Related Serious Adverse Events • Fainting • Injury to tissue: e.g. Nerve, joint • Transmission of blood-borne pathogens – Inappropriate reuse of needles and syringes • Inappropriate diluents • Contamination of multi-dose vials • Bleeding • Provocation Vaccine Factors Associated With Adverse Events • Type: live vs. killed vs subcomponent • Strain • Attenuation • Dose • Purity: – extra products in vaccine – contamination • Adjuvants • Preservatives • Stabilizers Host Factors Associated With Adverse Events

• Age • Sex • Skin color • Genetics • Prior with agent • Prior doses of vaccine • Immune competence • Preexisting hypersensitivity Joint Symptoms Associated With HPV-77 in 100 Females by Age 90 80 70 60 Percent 50 40 30 20 10 0 <13 13-16 17-19 20-24 >24 Age in Years

Weibel JAMA 202:805;1972 Swartz Am J Epidem 94:246;1971 Arthritis Associated With RA 27/3 Rubella Vaccines by Gender

Age(yrs) Males Females

18-30 5% 20-25%

Arthralgia: females > males following anthrax and Lyme disease vaccines Pathogenesis of Joint Symptoms Following Rubella Disease or Vaccine

• Joint pain pathogenesis? – Inflammatory cytokines? • Arthritis: wild-type or vaccine virus (HPV-77) in joint fluid • VSV ? 1. Martenis et al Arthritis Rheum 11:683, 1968 2. Grahame R Ann Rhem Dis 42:2,1987 3. Ogra PL Lancet 1:1157, 1975 4. Fraser FRE Clin Exp Rheumatol 2:287-293 Causality Assessment from Individual Case Reports • Causality established (usually): – Isolation of live vaccine agent in normally sterile body fluid (repeated observations). • (OPV) virus in CSF. • Measles vaccine virus in lung of child with leukemia. Causality Assessment from Individual Case Reports • Causality established (usually): – Isolation of live vaccine agent in normally sterile body fluid (repeated observations). • Polio vaccine (OPV) virus in CSF. • Measles vaccine virus in lung of child with leukemia. – Rule out wild type virus (genetic sequencing)

Halsey NA. The Science of Evaluation of Adverse Effects Associated with . Sem in Ped Infect Dis 2002 July;13(3):205-14 Causality Assessment from Individual Case Reports • Causality usually not established: – Antigen detection or PCR. • False positives • Contamination • Coincidental infection • Latent viruses • Residual genetic material from prior Injection site Reactions

• Swelling • Nodules • Nerve or joint injury Total Thigh Swelling After 4th DTaP

Rate = 1-2% Following 4th and 5th Doses

Courtesy M. Rennels Limb Swelling After 4th Dose of DTaP Swelling in muscle and subcutaneous tissue

Delayed hypersensitivity to some component

Sekaran NK, Edwards KM. Pediatr Infect Dis J. 2006 Apr;25(4):374-5. Rowe J Infect Immun. 2005 Dec;73(12):8130-5 Immediate Hypersensitivity Reactions

• Hives, angioedema, anaphylaxis • IgE mediated • Allergens in vaccines: – Media (e.g. egg in influenza or YF) – Gelatin – Antibiotics (neomycin, polymixin) – Yeast (, HPV) – Preservatives (thimerosal) www.allergycapital.com www.vaccinesafety.edu/components-Allergens 1,286 Hypersensitivity VAERS Reports Following 2009 H1N1 by Age and Gender 250 Female Male 200 Female to Male Ratio by Age Group

1.0 0.9 2.1 1.8 7.2 9.5 4.6 4.0 1.8 1.3 4.0 1.4

Cases 150

100 Reported 50

0 <5 5‐9 10‐14 15‐19 20‐29 30‐39 40‐49 50‐59 60‐69 70‐79 80+ unknown Age Group (Years)

Halsey et al. Vaccine 2013 Hypersensitivity (allergic) Reactions

• Pathogenesis known • Short interval (minutes) from vaccine to reaction • Unlikely for other causes • Skin testing with vaccine components • Serum IgE antibody specific for antigen in vaccine No Definitive Test Not local reaction or Immediate Hypersensitivity

• Evidence of increased risk in persons who received vaccine vs. controls Randomized Placebo

Controlled Trials Double blind evaluations Recruit Vaccine Outcomes Enroll

Partici- Randomize Population pants Placebo Outcomes Selected: healthy, age, gender? Investigating Causal Relationships Randomized Placebo Controlled Double Blind Trials

Disorder Relative yes no Risk Risk a a yes a b a+b a+b

Vaccine c c no c d c+d c+d

a+c b+d Percent of Children with Fever Following Edmonston B Measles

100 Vaccine (1963)

80 Susceptible: vaccine/GG Susceptible: GG 60

40

20 Percent with Fever >101F Fever with Percent

0 0 5 10 15 Days after Vaccine

Adapted from Martin CM. Am J of Dis of Children 1963;106:270. Percent of Children with Fever Following Edmonston B Measles

100 Vaccine (1963) 1. Some coincidental 80 Susceptible: vaccine/GG Susceptible: GG illnesses Immune: vaccine 2. No increase in fever if 60 immune

40

20 Percent with Fever >101F Fever with Percent

0 0 5 10 15 Days after Vaccine

Adapted from Martin CM. Am J of Dis of Children 1963;106:270. Prospective Randomized Trials for Detection of Adverse Events • Designed for detection of reactions: – Common – Acute

• Not generally designed to detect: – Uncommon – Vague onset – Delayed onset Prelicensure Studies to Evaluate Adverse Events from Vaccines

Number Rate Studied Detectable

Phase I 10-100 10%-20%

Phase II 100-1000 1%-10%

Phase III 500-20,000 0.5%-5% Adverse Events Following Whole Cell and Acellular Pertussis Vaccines Days 0-3 (DTwP vs DTaP)

50 45 40 35 30 25 DTwP 20 DTaP 1 15 DTaP 2 10 5 0 Fever Swelling Pain Fussiness >38.4 >20mm

Decker Pediatrics 96:557;1995 After Licensure: Passive Surveillance

• Essential for signal detection • Many limitations • Data commonly misinterpreted http://vaers.hhs.gov

http://vaers.hhs.gov/index VAERS

• Anyone can report events • Database open to the public • Standardized coding (COSTART) – >1300 terms, searchable • 128,717 reports in 10 yrs ending Dec 31, 2001 • >1.9 billion doses of vaccines distributed

MMWR. 2003 Feb 14;52(06):113 Reporting Efficiency Estimates

• 1% rash: MMR • 50% intussusception: rhesus • 72% for VAPP: OPV

Pediatr Infect Dis J. 2004 Apr;23(4):287-94. VAERS Limitations

1. Incomplete data 2. Diagnoses not verified 3. Temporal does not equal casual 4. Cannot be used for true incidence rates – Faulty numerators and denominators – Reporting bias 5. Cannot be used for calculating true relative risks 6. Primarily hypothesis generating

MMWR. 2003 Feb 14;52(06):113 Pediatr Infect Dis J. 2004 Apr;23(4):287-94. Investigating Causal Relationships Case Report, Case Series or VAERS* Disorder Risk yes no Risk Ratio a a yes a b a+b a+b c c Vaccine no c d c+d c+d

a+c b+d * Changes in incidence provide a “signal’ Investigating Causal Relationships Case-Control Studies

Disorder Case Control Odds Ratio

Yes a b a/b ad = c/d bc

Vaccine no c d

Potential problems: -Not randomized -Selection bias? -Matching? Multi-state Case-control Study Matched Odds Ratio of Intussusception after RRV-TV Dose 1 Onset Cases OR* 95% CI 0-2 days 0 -- -- 3-7 35 37.2 12.6-110.1 8-14 8 8.2 2.4-27.6 15-21 2 1.1 0.2-5.4

*Adjusted Murphy T. N Engl J Med (2001) Introduction of IPV U.S. 1955 • April 14: Francis Field Trial Results Announced by March of Dimes

• April 15, Nationwide Immunization

• April 24, First cases of paralysis Poliomyelitis Among Children Inoculated in School Clinics April 17 - May 14, 1955 25 Reported 20 Expected 15

Cases 10

5

0 Cutter Lilly Parke, Pitman- Wyeth Davis Moore Vaccine Manufacturer

Source: Nathanson. Am J Hyg 1963;78:46. Poliomyelitis Among Children Inoculated in School Clinics April 17 - May 14, 1955 25 Reported 20 Expected 15

Cases 10

5

0 Cutter Lilly Parke, Pitman- Wyeth Davis Moore Vaccine Manufacturer

Source: Nathanson. Am J Hyg 1963;78:46. Cutter-associated50 Polio Cases 40 Vaccinated Cases 30 Non-paralytic 20 Paralytic 40 10 300 16 23 30 7 14 21 28 4 11 18 25 2 9 20 Family Contact Cases 20 10

0 10 16 23 30 7Community14 Contact21 Cases 28 4 11 18 25 2 9 N u m b e r o f C a s e s o f N u m b e r

0 1616 23 3023 7 14 2130 28 4 117 18 2514 2 9 21 28 4 11 18 25 2 9 April Effects of Virus-Formaldehyde Contact Upon Rate of Destruction of Virus Infectivity

50 mL Virus Suspended 500 mL in Fluid Phase and in Contact SEDIMENT CONTAINING with Formalin VIRUS PROTECTED FROM CONTACT WITH FORMALIN 1x106

12 12

1x103 9 MEASURABLE EFFECT 9 OF FORMALIN VIRUS IN per 0.5 ml per 0.5 SEDIMENT

50 0 1x10 6 T.C. 6 ID Test Neg Neg Neg + ± Neg 50 ml LOSS OF Neg Neg ++ + 1x10-3 3 Neg 500 ml 3 INFECTIVITY DUE TO AGING (NOT Theoretical Projection TO FORMALIN) of Formalin Effect 0 0 03691215 0 3 6 9 12 15 Days at 37 C Days at 37 C

1:4000 Formalin pH 7.0 Salk JE. Am J Pub Health 1956;46(1):1. The Cutter Incident

• Lessons: - Scaling up creates new problems - Quality control every change in process - Need for epidemiologic assessment of post-licensure safety Cutter Incident

• Established CDC for epidemiologic investigation of vaccine safety

• Established Division of Biological Standards, NIH (Later FDA) Inactivated Respiratory Syncytial Virus Vaccine

• Formalin inactivated • Administered to infants • Minimal reactions • Induced neutralizing and CF antibody

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

Kapikian AZ. Amer. J. Epid., 1969, 89:405-21 Kim HW et al 1969 Formalin Inactivated (Killed) Measles Vaccine • Licensed 1963 • 3 doses: – K, K, K or K, K, K, followed by live • Induced HI antibody responses (protective) • Protected against measles for up to 2 yrs Atypical Measles in Child Who Received Killed Measles Vaccine 12 Years Earlier Chest Roentgenogram Child With Atypical Measles Enhanced Disease After Killed Measles and RSV Vaccines

• Lessons: – Vaccines can enhance disease – Delayed adverse events possible CYD-TDV

• Recombinant tetravalent vaccine • Evaluated in Asia and Latin America VE against symptomatic virologically- confirmed dengue cases due to any of the 4 serotypes according to age, using kernel smoothing - CYD14 and CYD15 (2-16 years) [

<9 yrs >9 yrs VE Seroneg 14.4% 52.5% Seropos 70.1% 81.9%

Sage Backround Paper Mar 201 Relative risk of dengue hospitalization in vaccinated vs. control populations, by follow-up year

Enhancement? Why only year 3? Chance?

Gessner and Halsey ASTMH 2016 Asia

6-8 yrs 2-5 yrs

9-11 yrs 12-14 yrs (VSD) Data Linkages

Health Patient Vaccination Outcomes Characteristics Records (Hospital) (ER) (Birth Tapes) (OPD) (Census)

VSD Linked Analysis Database Investigating Causal Relationships Retrospective or Non-concurrent Cohort Studies

Disorder yes no Risk Risk Ratio a a yes a b a+b a+b

Vaccine c c no c d c+d c+d

a+c b+d Potential problems: -Self selection for vaccine? Non-concurrent (Retrospective) Cohort Studies

Vaccine Outcomes Obtain Vaccine? Self Population Provider Funding No Vaccine Outcomes

Not randomized May not be masked to vaccine status 1976 Swine Campaign

• ~4 weeks into campaign • Monday morning calls: – 3 cases of GBS in 1 neurology practice – All vaccinated same day – 2 hours later, 2 cases in 1 practice Guillain-Barre syndrome relative risks for population over 17 years by week of onset after A/New Jersey influenza vaccination, US 10/3/76 - 1/29/77* 20 Attributable Risk 18 Expected Incidence 16

14 12 GBS = temporary paralysis 10

8

6

4

Cases per Million Vaccinees Cases per Million 2

0 1 2 3 4 5 6 7 8 9 1011121314151617 Weeks after Vaccination •excluding AR, CT, DE, WA. Data for CA, FL, GA, MO, NC, NJ, NY •and TX included for 10/3-12/18/76 only. Risk of Guillain‐Barre Syndrome associated with Influenza A (H1N1) 2009 Monovalent in U.S. Studies

Small circle represents the incidence rate ratio. Vertical lines represent the 90% CI. Horizontal lines represent the 95% CI. VSD - Vaccine Safety Datalink PRISM - Post-licensure Rapid Immunisation Safety Monitoring EIP - Emerging Infections Programme

Salmon DA, et al. Lancet 2013;381(9876):1461‐8. Attributable Risk of GBS per Million Increases With Age

Uncertain if there is any increase in risk in children

Salmon DA, et al. Lancet 2013;381(9876):1461‐8. Action potentials propagated along the nerve fibre.

GBS: Demyelinating: Axonal: antibodies terminate action potential propagation.

Vucic et al. J Clin Neuro 2009;16:741. Narcolepsy with Cataplexy Hypocretin Deficiency Pathways

www. wikipedia.org

Silber M H , Rye D B Neurology 2001;56:1616-1618 www.alvaradohospital.com ©2001 by Lippincott Williams & Wilkins Increased Risk of Narcolepsy Following AS03 Adjuvanted Influenza Vaccine Age Group Study Definition of Follow up Risk Country (yrs) Design Onset Period (RR/OR) 95% CI 1. contact with 1/1/09 ‐ Finland 4‐19 RC 12.7 6.1 ‐ 30.8 HC 8/15/10 Date of dg 10/1/09 ‐ Sweden ≤19 RC 6.6 3.1‐14.5 G47.4 12/31/10 1. contact with 4/1/09 ‐ Ireland <20 RC 13.9 5.2‐37.2 HC 12/31/10 <18 Date of 4/1/09 – 6.5 2.1‐19.9 France CC 18+Referral MSLT 4/30/11 4.7 1.6‐13.9 Date of EDS by 10/1/09 ‐ Norway 4‐19 RC 10‐20 Patient 6/3010 Case‐ UK 4‐18 covera 16.2 3.84.5 ge Date of EDS by 1/1/09 – Canada 0.5‐20 RC 2.96 0.71‐12.39 Patient 12/31/10 . Hazard Ratios and 95% Confidence Intervals for Diagnosed Narcolepsy 2009‐2011 by Age at Vaccination: Sweden

Persson I, et al. J Intern Med 2014;275(2):172. Proportion of Population with HLA Type Associated with Narcolepsy

AR Finland 1 per 16,000 Canada 1 per million

http://www.pypop.org/popdata/2008/maps/DQB1‐0602.gif. Narcolepsy Diagnoses by Month Peoples Hospital Bejing China 1998-2012

Fan H et al Ann Neuro 2012 No Increase in Narcolepsy after Other H1N1 Influenza Vaccines • US 127 million doses (no adjuvant), no signal – 2 studies no increased risk • No increase in Europe with other vaccines, including LAIV and MF59 adjuvanted • Difference in virus presentation? Structurally altered viral nucleoprotein in ? McCarthy, et al Vaccine 2013. 31:5975‐5982 Ahmed, et al J. Autoimmunity 2014. 50:1‐11 Vaara et al. PLOS 1 Dec 15 2014 Vaccine Only Studies

Vaccination Disease Onset

0 7 30 60 Days after vaccination

Compare the incidence of disease in different time periods after receiving vaccines Increase in Febrile Seizures Following First dose TIV With Concomitant PCV13

206,174 Children 6‐59 mo of age Days 0‐1 vs 14‐20 Self Controlled Case Series

Age in Months

Tse A, et al. Vaccine 2012;30(11):2024. Disorders falsely attributed to vaccines in recent years

• Autism • Multiple sclerosis • Inflammatory bowel disease • SIDS • Diabetes • Asthma • Attention Deficit Disorder • Infantile Spasms 1998: Case reports of Children with Autism after MMR

www.autismpedia.org

Bad Science in Case Reports Continues

4 cases onset 4, 5, 5 and unk. mos after vaccine Decrease in HPV Acceptance in Denmark Following Promotion of Rumors by Journalists

Iceland Denmark Norway

Finland

Palle Valentiner-Branth, MD, PhD Department of InfectiousDiseaseEpidemiology Statens Serum Institut, Denmark 2016 POTS, CFS Other illnesses Summary

• Licensed vaccines are generally safe • Constant vigilance is needed to investigate for new problems • There is poor understanding of causality assessment • We need to find improved methods to communicate adverse event data