How Vaccines Cause Adverse EventsEvents

Neal A. Halsey

Pathogenesis of Adverse Events Caused by Vaccines

1. Injection process2 Contamination2. Contamination3. Replication of live agentp g4. Direct effect of vaccine component5. Host immune response to component6 Unknown6. Unknown

Injections alone can trigger i d tserious adverse events

15-17 yrs

www.indianetzone.com

9-10 yrs

J. Gee VSD report ACIP Oct 2008

Injection Related: FaintingInjection Related: Fainting

• Falls can lead to serious head injuries

• Neurologic sequelae rare deaths• Neurologic sequelae, rare deaths

• Auto accidents

MMWR 57(17): 2008;457-460

Incorrect Injection Site

Ulnar nerve damage following anthrax Vaccine*

SJ. Salk*Sever et al. Pharmacoepidemiology and drug safety 2002; 11: 189–202

UNICEF Website 2007

Incorrect administration of TT -wrong site

Appropriate IM Injection Sites

www.immunize.org

Respiratory Arrest Following Measles Vaccine

• Latin America, Asia, AfricaLatin America, Asia, Africa

• Succinyl choline and pancuronium bromide mistaken as vaccine diluent

• Diluent and drug vials identical size, color and print type Stored in samecolor, and print type. Stored in same refrigerator g

10 Dose Measles Vaccine Vial plus Diluentplus Diluent

Bacterial Contamination of MeaslesBacterial Contamination of Measles Vaccine Vials: India 1985-1994

• Multi-dose vials

• 39 clusters of fever, rash, shock: day of vaccination

• 81 deaths81 deaths

• Bacterial contamination after reconstitution– Staph aureus and other

Prevention: discard vials after 2 (WHO 6) hoursPrevention: 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

( )

Group A Streptococcal Infections From 15 dose DTP Vials: U SFrom 15-dose DTP Vials: U.S.

Year NumberYear Number

Indiana 1981 7Indiana 1981 7

Georgia 1982 12Georgia 1982 12

Oklahoma 1982 7

Source: Bernier et al Am J Dis Child. 1981 Sep;135(9):826-8.

Bacterial Contamination of Multi-dose vials Associated with

Severe DiseaseSevere Disease • MeaslesMeasles• DTP• Yellow fever• BCG• BCG

Contamination by health care worker after opening the vial

Injection Related jSerious Adverse Events

1. Fainting-head injury

2 Injury to tissue: e g Nerve joint2. Injury to tissue: e.g. Nerve, joint

3. Inappropriate diluentspp p

4. Contamination of multi-dose vials5. Bleeding 6. Transmission of blood-borne pathogensp g

• Inappropriate reuse of needles and syringes

7 Provocation polio: incubating WT polio7. Provocation polio: incubating WT polio

• Increased risk of paralysis in injected limb

Vaccine Factors Associated WithVaccine Factors Associated With Adverse Events

1. Type: live vs. killed vs subcomponent2 Strain2. Strain3. Attenuation4 Dose4. Dose5. Adjuvants6 P ti6. Preservatives7. Stabilizers8. Purity:

• contamination• extra products in vaccine

Bacterial StructureStructure

http://www.bact.wisc.edu/Bact330

Adverse Events Following Whole Cell gand Acellular Pertussis Vaccines

Days 0-3 (DTwP vs DTaP)Days 0-3 (DTwP vs DTaP)

4550

30354045

Percent

15202530

DTwPDTaP 1

With Reaction

05

1015 DTaP 2

0Fever>38.4

Swelling>20mm

Pain Fussiness

Decker Pediatrics 96:557;1995

Limb Swelling After 4th Dose of DTaPg

Pathogenesis unknown

Sekaran NK, Edwards KM. Pediatr Infect Dis J. 2006 Apr;25(4):374-5.

Edmonston B Measles Vaccine

195424 passages human kidney tissue24 passages human kidney tissue

John Enders

28 passages primary human amnion tissue

Vaccine 19636 passages chick embryos

Chick embryo cellsSam Katz

Fever and Rash Following Measles Vaccination With and WithoutVaccination With and Without

Immune Globulin (GG)

80

100

Fever > 103 F

60

80

cent

Rash

20

40Perc

0

20

Natural Edmonston Edmonston Further FurtherNatural Measles

(33)

Edmonston "B"

No GG(175)

Edmonston "B"

+ GG0.01-0.02

Further Attenuated

No GG(569)

Further Attenuated GG 0.2 ml

(452)( )ml/LB(854)

( ) ( )

Krugman 1965

Percent of Children with Fever Following Edmonston B Measles

Vaccine (1963)Vaccine (1963)

80

100

1F Susceptible: vaccine/GG

60

80

ever

>10

1 Susceptible: vaccine/GGSusceptible: GGImmune: vaccine

40

60

t with

Fe

20

Perc

ent

00 5 10 15

Adapted from Martin CM. Am J of Dis of Children 1963;106:270.

Days after Vaccine

Percent of Children with Fever by Week after First or Second Dose of MMRafter First or Second Dose of MMR

First dose1-2 years

Second Dose 4-6 or 10-12 yrs

LeBaron, C. W. et al. Pediatrics 2006;118:1428

Transient Arthritis/Arthralgia gAssociated With Rubella Vaccines

in Women by Strainin Women by Strain

Vaccine Strain Joint Symptoms

HPV 77 Dog kidney 35 63%HPV-77 Dog kidney 35-63%

HPV-77 duck embryo 27-33%

Cendehill 8-10%

RA 27/3 13-15%

Polk Am J Epidemiol 115:19;1982

Host FactorsJ i t S t A i t d WithJoint Symptoms Associated With

HPV-77 Rubella Vaccine in Females by Age

8090

100

50607080

Percent

20304050Percent

010

<13 13-16 17-19 20-24 >24Age in Years

Weibel JAMA 202:805;1972Swartz Am J Epidem 94:246;1971

Arthritis Associated With RA 27/3Arthritis Associated With RA 27/3 Rubella Vaccines by Gendery

Age(yrs) Males Females

18-30 5% 20-25%

Arthralgia: females > males: AnthraxLyme diseaseYellow fever vaccines

Pathogenesis of Joint SymptomsPathogenesis of Joint Symptoms Following Rubella Vaccinesg

• HPV 77 vaccine virus in joint fluid• HPV-77 vaccine virus in joint fluid– RA 27/3?

• Arthralgia pathogenesis?C t ki di t d?– Cytokine mediated?

– Also with inactivated vaccines

Host Related Factors AssociatedHost Related Factors Associated With Adverse Events

• Age• Gender• Prior doses of vaccine• Prior infection with agent• Skin color• Skin color• Preexisting hypersensitivity• Immune deficiency• Genetics

Immediate Hypersensitivity ReactionsImmediate Hypersensitivity Reactions

• Hives, angioedema, anaphylaxis

• IgE mediatedIgE mediated

• Allergens in vaccines:– Media (e.g. egg in influenza or YF)

– Gelatin

– Antibiotics (neomycin, polymixin)

Yeast (hepatitis B HPV)– Yeast (hepatitis B, HPV)

– Preservatives (thimerosal)

www.allergycapital.com www.vaccinesafety.edu/components-Allergens

IgE Mediated Allergyg gy

Allergen +

h k darapaho.nsuok.edu

Delayed Hypersenstivity: Erythema Multiformeafter Smallpox Vaccinep

Vincent A. Fulginiti, M.D.

Erythema

10 days after

multiforme

10 days after varicella vaccine

Do vaccines cause serumsickness?sickness?

Course of the Platelet Count afterMeasles Immunization in 5 InfantsMeasles Immunization in 5 Infants350

MEASLESVACCINE

250

300

350

0/m

m3

150

200

250

lets

100

0

50

100

150

Plat

el

501 3 5 7 9 11 13 15

Days after ImmunizationyOski and Naiman. NEJM 1966;275(7):352.

Clinical thrombocytopenia (ITP) ~1/30,000y p ( ) ,Black C et al. Br J Clin Pharmacol. 2003;55(1):107-11.Miller E et al. Arch Dis Child 2001 ;84(3):227-9.

Guillain-Barre syndrome relative risks for population over 17 years by week of onsetpopulation over 17 years by week of onset

after A/New Jersey influenza vaccination, US 10/3/76 - 1/29/77*10/3/76 1/29/77

18

20

ees Attributable Risk

Expected Incidence

12

14

16

n Va

ccin

e Expected Incidence

8

10

12

er M

illio

n

2

4

6

Case

s pe

0

2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Weeks after VaccinationWeeks 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.

Action potentials propagated along the nerve fibre.

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

tipropagation.

Vucic et al. J Clin Neuro 2009;16:741.

Attributable Risk of GBS followingAttributable Risk of GBS following influenza vaccine

• 1976 1977* 1/100 000• 1976-1977 1/100,000

• 1978-1991 01978 1991 0

• 1992-1994 ~1/1,000,000*

• 1995-2008 ?

• 2009-10 (H1N1) ?

Chen NEJM 1998* “Swine influenza”

E h t f th T tEnhancement of the Target Disease

Inactivated Respiratory SyncytialInactivated Respiratory Syncytial Virus Vaccine: 1960’s

• Formalin inactivated

• Administered to infants

• Minimal reactions

• Induced neutralizing antibody

Kapikian AZ. Amer. J. Epid., 1969, 89:405-21Kim HW et al 1969

Enhanced RSV Disease 9-10 Months Following Inactivated

RSV VaccineRSV VaccineRSV Vaccine No Vaccine

Pneumonia 9/13 (69%) 4/47(9%)( ) ( )p< .001

RSV V i P fl VRSV Vaccine Paraflu Vac.

H it li ti 80% 5%Hospitalization 80% 5%p< .001

Kapikian AZ. Amer. J. Epid., 1969, 89:405-21Kim HW et al 1969

Formalin Inactivated (Killed)Formalin Inactivated (Killed) Measles Vaccine

• Licensed 1963

• Administered in 3 doses

• Induced HI antibody responses (protective)

• Protected against measles for up to 2 yrs

Atypical Measles in Child Who Received Killed Measles Vaccine 12Received Killed Measles Vaccine 12

Years Earlier

Increased Rates of Pneumonia in Atypical MeaslesAtypical Measles

A i l M d l f At i l M lAnimal Model for Atypical MeaslesRhesus Macaques

• Immune complexes and eosinophils in lungs of animals with atypical measles

• Waning protection from neutralizingWaning protection from neutralizing antibody following formalin inactivated vaccinevaccine

• No cytotoxic T-cell response

Polack et al. Nat Med. 1999 :629-34

Rotavirus VaccinesRotavirus Vaccines

• Rhesus “Rotashield” (RRV)Rhesus Rotashield (RRV)

• Bovine “Rotateq” (RV5)q ( )

• Human “Rotarix” (RV1)( )

David Sack WHO

Intussusception after Rhesus Rotavirus V i (R t hi ld)Vaccine(Rotashield)

ILEO-ILEOCOLICINTUSSUSCEPTION

Pathogenesis unknown: Probable edema or

INTUSSUSCEPTIONlymphoid hyperplasia

No increased risk withRotateq or RotarixRotateq or Rotarix

P l E R V i ILEOCOLICINTUSSUSCEPTION

Patel. Expert Rev Vaccines. 2009 Nov;8(11):1555-64.

Source: Netter. The CIBA Collection ofMedical Illustrations, Vol 3, 1962. pg134.

Live Vaccines: UnrecognizedLive Vaccines: Unrecognized immune Deficiencies

• Age related• Age-related• Defects in innate immune system• B cell deficiency

HIV infection• HIV infection• Severe Combined Immune Deficiencyy

Lymphadenitis after BCG

Differences in rates by vaccineDifferences in rates by vaccine strain, technique, and age

Bolger Arch Dis Child 2006

Age-Specific Estimated Risks for Complications After Administration ofComplications After Administration of

BCG Vaccine

Incidence per 1 MillionComplication

Incidence per 1 Million Vaccinations

Age <1 yr Age 1− 20 yrAge <1 yr Age 1− 20 yrLocal subcutaneous abscess regional 387 25abscess, regional lymphadenopathy.

387 25

Musculoskeletal 0 39 0 89 0 06Musculoskeletal lesions 0.39− 0.89 0.06

Connelly Smith. in Plotkin, Orenstein, and Offit. Vaccines 5th ed 2008

Areas of Risk for Yellow FeverReported Cases and Vector Present

Source: HIIT

Yellow Fever Vaccine-Associated Viscerotropic Disease:

Yellow Fever-like illness

O t 2 5 d t i ti• Onset 2-5 days post-vaccination• Fever, myalgia, arthralgia• Elevated liver enzymes & bilirubin• Thrombocytopenia, lymphocytopenia• Rhabdomyolysis• Hypotension Probable defect inypote s o• Renal failure • Respiratory failure

Probable defect in innate immune system,thymus disorders• Respiratory failure

• Case fatality >50%thymus disorders,age >60?

Michelle Russell, MPHHayes Trans R Soc Trop Med Hyg. 2007;101:967-71

Yellow Fever Vaccine AssociatedYellow Fever Vaccine Associated Encephalitis p

• >9 months ~1Rate per millionAge

>9 months 1

• < 4 months 400-5000– 1000 fold increase1000 fold increase

Monath in Plotkin and Orenstein Vaccines 2004

Yellow Fever Vaccine Transmitted via Breast Feeding: Brazil

• Mother: YF vaccine 15 days post partum• Infant: Encephalitis at 23 days of ageInfant: Encephalitis at 23 days of age

– CSF: 128 wbc17DD YF i i b PCR i CSF– 17DD YF vaccine virus by PCR in CSF

– YF specific IgM antibody in sera and CSF• Recovered completely

Mallmann Couto. MMWR / February 12, 2010 / Vol. 59 / No. 5

Delayed Onset of Severe Adverse yEvents Following Live Attenuated

Measles VaccinesMeasles Vaccines

• Pneumonia in children with leukemia or patient with AIDS: 3-9 mo.p

I l i b d h liti 5 k 6• Inclusion body encephalitis: 5 wk - 6 mo.

Oral Polio Vaccine

• Oral

Continued

OPV-Associated Paralytic PoliomyelitisVAPPVAPP

O 750 000 fi t d• One case per 750,000 first doses

• Recipients and close contacts• Recipients and close contacts

• 250-500 cases per year globallyp y g y

• Risk factors:– Age > 18

– B cell immune deficiency

– Multiple injectionsMultiple injections

Provocation PoliomyelitisA i ti B t N b f I j tiAssociation Between Numbers of Injections in Preceding 30 Days and VAPP: Romania

1000

10000

o

Case-control study

182.1100

1000

dds

Rat

io

8.127.2

10

ched

Od

1

0 1

1Mat

0.1

Number of Injections

0 1 2-9 >10

Strebel P et al. N Engl J Med. 1995 Feb 23;332(8):500-6

Polio Incidence in USA, 1964-2004and Vaccine Associated Paralytic Poliomyelitisand Vaccine Associated Paralytic Poliomyelitis

(VAPP)

100

120

VAPP

80

100Total

ases

40

60

port

ed C

a

Last wild poliovirus case

IPVIPV/OPV or OPV

20

40

Re IPV

064 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96

Year98 00 02 04

MMWR. 1997;46:79-83.MMWR. 1998;47:676-677.

YearPolio Eradication

CDC

Prolonged Excretion of T 1 P li i V i dType 1 Poliovirus Vaccine and

Paralysis 7 years After OPVa a ys s yea s te O

Y E A R S O F A G EYears of Age1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Y E A R S O F A G Eg

Immunodeficiency relatedImmunodeficiency related vaccine-derived polio (iVDPV)

Kew, et al. J Clin Microbiol 1998;36(10):2893-9.www.polioeradication.org

Type 1 iVDPV10% Divergent

15 Outbreaks of Circulating Vaccine-Derived Polio cVDPVs, 2000-2010*

MYANMAR2006-07

CHINA2004

VDPV 12 cases

DOR / HAITI

NIGER2006VDPV

VDPV 15 cases

CAMBODIA2005 06

ETHIOPIA2008-09VDPV 2

SOMALIA2008-09VDPV 2HAITI

2000-01VDPV 121 cases

22 cases

NIGERIA

2005-06VDPV 32 cases

PHILIPPINES

VDPV 24 cases

INDIA

5 cases

GUINEA2009

VDPV 2NIGERIA2005-10VDPV 2

307 cases DR CONGO

2008INDONESIA

2005

2001VDPV 13 cases

INDIA2009

VDPV 1, 2

12 cases

VDPV 21 caseOngoing:

Nigeria (307)DR Congo

2008VDPV 2

19 cases

MADAGASCARVDPV 22001-02

2005VDPV 146 cases

gEthiopiaIndia

5 cases2005

3 cases* As of May 2010 E. Asturiaswww.polioeradication.org

Smallpox Vaccine

WHO

FETAL VACCINIA

Vincent A. Fulginiti, M.D.

Eczema Vaccinatumin Contact of Vaccineein Contact of Vaccinee

Courtesy Mike LaneVincent A. Fulginiti

Underlying skin T cell disorder

Disseminated Vaccinia 1 Month after Vaccination in HIV Infected Recruit

Lesions during the first week of disseminated disease (day 5)

Extensive scarring of the resoling lesions after 9 weeks of passive ( y ) p

immunotherapy.

Source: Redfield. NEJM 1987;316(11):673-6.

Risk of Disseminated BCG

• HIV uninfected Infants: ~ 1/million– IFN-gamma-receptor deficiency– Other undefined innate immunity defects?Other undefined innate immunity defects?

• HIV infected: 110-417/100,000 – >1000 fold increased risk000 o d c eased s– Often delayed several months

Hesseling Vaccine. 2007 Jan 2;25(1):14-8

7 Cases of Persistent Rotavirus Vaccine in Children With Severe Combined Immune DeficiencyCombined Immune Deficiency

• Present at 3-6 months of age• Persistent diarrhea and growth failurePersistent diarrhea and growth failure

Catherine Yen ACIP Feb 2010W th t l J All Cli I l 2009 S 124(3) 600Werther et al. J Allergy Clin Immunol. 2009 Sep;124(3):600Patel abstracts, J Allergy Clin Immunol (2009)Uygungil. J Allergy Clin Immunol 2010 Jan; 125: 270-271

ConclusionsConclusions

1 All vaccines can cause adverse events1. All vaccines can cause adverse events

2. Multiple pathogenic mechanisms, some not yet defined

3 Many adverse events can be prevented:3. Many adverse events can be prevented:• Eliminate administration errors

• Identify persons at increased risk

• Modify vaccines to make safer