The Vaccination MerryGoRound

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The Vaccination Merry-Go-Round

• Paul Lewis
• Maria Grumm
• Oregon State Public Health Division, DHS

special thanks to Paul Cieslak, MD Juventila
Liko, MD, MPH Anna Halpin, MPH Sean Schafer, MD
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Objectives

• State the type of evidence used by the FDA to
  approve TdaP. Is there efficacy data?
• Describe the morbidity and mortality from
  rotavirus worldwide and in the US and the risk of
  intussusception from the new vaccine?
• Explain why a second dose of varicella vaccine
  will soon be recommended for children.
• State the evidence supporting the efficacy of the
  HPV vaccine will Pap smears no longer be
  necessary?
• Estimate the impact of universal adolescent
  meningococcal conjugate vaccine coverage in
  Oregon. Is this larger or smaller in other
  states?
• State the efficacy of varicella vaccine to
  prevent zoster in seniors? Are vaccines with less
  than 80 efficacy worthwhile?

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Overview

• See the 2007 Schedule
• HPV, Rotavirus, Meningococcal, Pertussis,
  Varicella
• The disease
• Epidemiology, including Oregon
• The vaccine
• Basis of approval
• Efficacy
• Side effects
• Cost

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New 2007 Schedule for age 0-6 years
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New 2007 Schedule for age 7-18 years
60 yrs
Varicella
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Human Papillomavirus

• More than 100 types
• More than 60 cutaneous types
• Can lead to skin warts
• 40 mucosal types
• high risk types (particularly 16 and 18)
• cervical cell abnormalities
• certain anogenital cancers

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Human Papillomavirus

• More than 100 types
• More than 60 cutaneous types
• Can lead to skin warts
• 40 mucosal types
• high risk types (particularly 16 and 18)
• cervical cell abnormalities
• certain anogenital cancers
• Low risk types (particularly 6 and 11)
• cervical cell abnormalities- usually resolve
  spontaneously and do not lead to cancer
• genital warts
• respiratory papillomatosis

Driving Force Nice benefit
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Transmission

• Mainly via sexual intercourse
• HPV transmission per sex-act
• Modeling estimates 0.4, 0.6
• Seldom detected in virgins
• Possibly transmitted by fomites
• Vertical transmission laryngeal papillomatosis

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HPV-associated Conditions
Estimated 70 30-50 10

• HPV 16, 18
• Cervical cancer
• - High/low grade cervical
• abnormalities
• Anal, Vulvar, Vaginal, Penile
• Head and neck cancers
• HPV 6, 11
• Low grade cervical
• abnormalities
• Genital warts
• RRP

10 90 90
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Cancer Attributable to HPV - 2002
Attributable Fraction 100 90 40 40 12
Estimated Cases 12,000 3,700 4,480 1,000 10,000
Cancer Cervical Anal Vulvar/vaginal Penile Oral/ph
arynx
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Cancer Attributable to HPV Oregon 2003
Estimated Cases 116
Cancer Cervical
Deaths 43
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Human Papillomavirus Vaccine

• FDA approved vaccine contains the L1 protein from
  four types of HPV (16, 18, 6, 11)
• (A second vaccine containing HPV 16 and 18 is
  awaiting FDA approval)
• Produced using recombinant DNA technology
• L1 proteins self assemble into non-infectious
  units called virus-like particles (VLPs)
• VLPs are highly immunogenic

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Efficacy of HPV Vaccine Among 16-26 year-old
Females
Package insert Gardasil . Integrated dataset
results in the per-protocol populations CIN
cervical intraepithelial neoplasia AIS
adenocarcinoma in situ
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Human Papillomavirus Vaccine Efficacy

• High efficacy among females without evidence of
  infection with vaccine HPV types
• No evidence that the vaccine had efficacy against
  existing disease or infection
• Prior infection with one HPV type did not
  diminish efficacy of the vaccine against other
  vaccine HPV types

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HPV Vaccine Schedule

• Approved for females 9-26 years of age
• 3 doses at 0, 2, and 6 months
• Minimum intervals
• 4 weeks between doses 1 and 2
• 12 weeks between doses 2 and 3

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HPV Vaccine ACIP Recommendations

• Routine vaccination of females 11 or 12 years of
  age
• The vaccination series can be started as young as
  9 years of age at the clinician's discretion
• Vaccination is recommended for females 13-26
  years of age who have not been previously
  vaccinated
• Ideally vaccine should be administered before
  onset of sexual activity but . . . . .
• Females who are sexually active should be
  vaccinated

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HPV Vaccine and Cervical Cancer Screening

• Cervical cancer screening recommendations have
  NOT changed for females who receive HPV vaccine
• 30 of cervical cancers caused by HPV types not
  prevented by the quadrivalent HPV vaccine
• Vaccinated females could subsequently be infected
  with non-vaccine HPV types
• Sexually active females could have been infected
  prior to vaccination
• Providers should educate women about the
  importance of cervical cancer screening

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Cost, Cost benefit

• 3 shots _at_ 120 each 360 for the series
• Cost benefit analyses (Goldie 2004, Sanders 2003,
  Kulasingam 2003)
• Assume
• coverage of 70-100
• Efficacy 75-90
• Cost 200-400/series
• Female only vaccination
• Cost per quality adjusted life year
• 12,000-25,000

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Rotavirus Vaccine, Round 2
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Burden of Rotavirus Disease in the United States

• Most common cause of severe gastroenteritis in
  infants and young children
• May cause severe dehydrating diarrhea with
  vomiting and fever
• Almost all children infected by 5 years of age
• Annually responsible for
• 3 million infections
• more than 400,000 physician visits
• 160,000 emergency dept visits
• 55,000-70,000 hospitalizations
• 20-60 deaths

Source MMWR 200655 (RR-12)
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Incidence of Rotavirus Hospitalization by Age,
Oregon, 19952004
Infants
average 111
Age 1
average 2.7
ICD-9 code 008.61
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Remember Rotashield ?

• Reassortant vaccine based on rhesus rotavirus
  strain
• Safety mild fevers on day 3-5
• Efficacy 70 against mild rotavirus
  gastroenteritis, 85 against severe disease
• ACIP recommended routine immunization of all US
  infants with 3 doses given at 2,4,6 months
• Withdrawn from market after association with
  intususception

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RotaTeq Rotavirus Vaccine

• Contains five strains of live rotavirus developed
  from human and bovine rotavirus strains
• Non-human rotaviruses have low pathogenicity for
  humans
• Replicate but do not cause disease
• Oral administration
• 3-dose series beginning at about 2 months of age

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Phase III Studies, Including Rotavirus Efficacy
and Safety Trial (REST)
Sample size 71,799 (36,203 PRV 35,596 P)
Countries 80 in US and Finland Age 6
to 12 weeks at first dose Dose regimen 3 oral
doses with 4 to 10 week interval
Vesikari et al NEJM 2006 35422-33
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Efficacy of PRV by Severity of Rotavirus
Gastroenteritis
Number of Cases
Vaccine (N3484)
Placebo (N3499)
Disease Severity
Efficacy
95 CI
Any Severe
97 1
369 57
73.8 98.2
67.2,79.3 89.6,100.0
Per protocol population (includes only cases
that occurred at least 14 days after Dose 3)
Vesikari et al NEJM 2006 35422-33
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Confirmed Intussusception Cases in REST
PRV Placebo Within 42 days 6 5 Within 1
year 12 15
Day 42
Unadjusted for multiplicity.
Courtesy P. Heaton, MerckCo
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Rotavirus Vaccine Recommendations

• Routine immunization of all infants without
  contraindications
• 3 oral doses at 2, 4, and 6 months of age
• Series may be started as early as 6 weeks of age
• First dose should be administered age 6 to 12
  weeks last by age 32 weeks doses at least 4
  weeks apart

Source MMWR 200655 (RR-12)
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Rotavirus Vaccine

• Provided in single dose (2 mL) plastic tube with
  a twist-off cap
• Liquid vaccine is buffered-stabilized solution
  that is pale yellow or pink
• Store at refrigerator temperature for 24 months
• Protect vaccine from light
• Do not freeze or administer vaccine that has been
  exposed to freezing temperature

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Spectrum of Meningococcal Infections

• Meningococcemia (purpura fulminans, sepsis,
  chronic bacteremia, occult bacteremia)
• Meningitis
• Septic arthritis
• Pneumonia
• Pericarditis
• Cellulitis
• Conjunctivitis

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Meningococcal Disease

• Aerobic Gram-negative bacteria
• Worldwide 171,000 deaths yearly
• 2,0003,000 cases each year in US
• Case fatality rate 7-10
• 6 in Oregon (2000-05)
• 13 serogroups
• Most invasive disease caused by serogroups A, B,
  C, Y, and W-135

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Meningococcal Infectionknown SerogroupsU.S.
Oregon, 20032004
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Serogroup C, Y, W-135 Meningococcal Disease
Incidence, by Age Oregon U.S., 20012004
Cases/100,000/year
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Oregon Incidence Rates

• Incidence rates steadily declined since peak in
  1994
• Higher meningococcal incidence rate overall
  (1.7/100,000) than the US (1.0/100,000)
• The Oregon rate for serogroup B is 4.5 times the
  US rate

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Meningococcal Vaccines
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What is MCV4 (Menactra) ?

• Quadrivalent conjugate meningococcal vaccine
• Effective in preventing serogroup types A, C, Y,
  and W-135, not B
• FDA approval based on non-inferiority to
  meningococcal polysaccharide vaccine
• Immunogenicity assumed to equal efficacy
• Historical data strongly supports serologic
  correlates of immunity
• The size of an efficacy trial would be very large
  since the incidence of meningococcal disease is
  low (200,000 subjects)

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Menactra Compared to MenomuneSeroresponse Rate
(11-18 years old) SBA-BR
SBA-BR response defined as 4-fold Increase in
antibody titer post-vaccination, compared to
baseline
L Lee FDA
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Tdap and Meningococcal Conjugate Vaccine (MCV4)

• MCV4 recommended for all adolescents at the 1112
  year visit
• Provider should administer Tdap and MCV4 to
  during the same visit, if both vaccines indicated
  and available
• If simultaneous administration of MCV4 and Tdap
  not feasible, can be administered at any time
  before or after each other

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Purported Benefits of Menactra (but remember
how it was studied)

• Stimulates immune memory
• Has a booster effect
• Offers long-term protection
• May lead to herd immunity

Granoff DM, et al. In Vaccines. 2004959.
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What are the ACIPs recommendations for Menactra?

• Routine vaccination of young adolescents
• 1112 years of age (at pre-adolescent health
  visit)
• At high school entry (15 years), catchup
• College freshmen who will be living in a
  dormitory
• Other adolescents who wish to reduce their risk
  for meningococcal disease

MMWR 200554(RR-7).
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MCV4 (Menactra) in Oregon

• Makes as least as much sense as elsewhere in the
  US
• Costly everywhere, costly here (see supplementary
  info)
• Predominance of serogroup B in Oregon means our
  rates, for now, wont change much

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2006 through August
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Major Pertussis Vaccination Challenges

• Adolescents/Adults
• Immunity wanes 510 years after completing
  childhood vaccination
• Can be source of infection
• Young infants
• Not protected before 3-dose DTaP series
• Increased risk of pertussis-related death

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Tdap Approved June 2005

• Adolescent and adult formulation
• Basis of approval serologic response
• 2 products
• Glaxo Boostrix (dTpa) age 1018 yr
• Aventis Adacel (Tdap), age 1164 yr

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Acellular Pertussis Vaccines for Adolescents and
Adults, US

• GlaxoSmithKline Boostrix
• approved for 1018 years of age
• pertussis components reduced quantity and similar
  to Infanrix DTaP
• diphtheria and tetanus similar to Td
• Sanofi Pasteur Adacel
• approved for 1164 years of age
• pertussis reduced quantity and similar to
  DAPTACEL DTaP
• diphtheria and tetanus similar to Td

composition of Td manufactured by sanofi pasteur
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Adult Pertussis Trial (APERT)

• Glaxo product
• 2800 subjects aged 15-65 yrs
• 8 US sites
• Random, double-blind, parallel group
• daTP vs Hepatitis A vaccine
• 2.5 yr follow-up
• All cough illness 5 d duration evaluated
• 4 case definitions

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APERT Case Definitions
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APERT Outcome
9 cases in control group
1 in pertussis vaccine group
Overall Vaccine Efficacy 95 (95 CI 32-99) For
culture/PCR confirmed VE 100
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General Principlesfor Use of Tdap and Td

• Tdap products are interchangeable
• Only Sanofi product is licensed over age 18 years
  
• Tdap preferred to Td to provide protection
  against pertussis
• Licensed only for a single dose at this time

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Adolescent Pertussis Vaccination Objectives

• Primary
• Protect vaccinated adolescents
• Secondary
• Reduce B. pertussis reservoir
• Potentially reduce incidence of pertussis in
  other age groups

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CDC TdaP Recommendations

• Current Recs
• All age 1112
• Catch-up age 1118
• if no booster yet
• if 5 yrs since Td

• ACIP New Recommendations
• Adults should get one dose when due for Td
• Esp caregivers of infants including post partum
  women (if at least 2 yrs since Td)
• HCW (if at least 2 yrs since Td)
• Pregnancy per se is not a contraindication

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PertussisRe-Vaccination for adolescents and
adults?

• Ask again in about 5 years.

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Another dose of Varicella vaccine?

• ACIP recd June 2006
• Varicella vaccine
• 12-15 months (80 efficacy)
• 2nd dose age 4-6 yrs
• 2nd dose for older kids and adults who have only
  received one dose

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Varicella Surveillance in Oregon

• Not a reportable disease but . . .
• Multnomah County Educational Service District
  performs surveillance . . 60 of cases isolated,
  40 classroom outbreaks

MMWR, March 25, 2005
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Shingles (Herpes Zoster)

• Caused by chickenpox virus that remains in nerve
  roots after disease resolves
• Nearly 1 million cases dx in US each year
• Most common after 50 yrs of age
• Postherpetic neuralgia (PHN) pain will develop in
  25-50 of zoster patients 50 years

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ZostavaxLive Zoster (Shingles) Vaccine

• A single dose of Zostavax vaccine is indicated
  for prevention of herpes zoster in adults 60
  years of age or older
• Not indicated for Rx of zoster or post-herpetic
  pain (PHN)
• Same vaccine as for kids but 14x higher dose
• Stored frozen with diluent at room temp.
• SC injection should be given within 30 mins of
  reconstitution

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Zostavax Contraindications

• Should NOT be administered to individuals
• Hx of anaphylactic reaction to gelatin or
  neomycin
• Hx of primary or acquired immunodeficiency states
• On immunosuppressive therapy
• With active untreated Tuberculosis
• Who are pregnant
• The use of Zostavax in individuals with a
  previous Hx of zoster has not been studied

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ACIP Recommends Shingles Vaccine10/26/06

• Zostavax (Merck) Vaccine recommended for all
  people age 60 years and older
• - Including those who have had a previous
  episode of shingles
• Zostavax Pre-licensure trials
• ? occurrence of shingles by 50
• ? occurrence of PHN pain by 67

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