Varicella Vaccine 2 dose schedule A natural evolution

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Varicella Vaccine 2 dose scheduleA natural
evolution?
And other things you wanted to know

• Dennis A. Clements MD PhD MPH
• NC Immunization Conference
• 2007

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Why ask the question ?

• Varicella vaccine was the first vaccine approved
  that required follow-up studies of up to 15
  years.
• What is the natural epidemiology of varicella
  after beginning routine varicella vaccination
• Are we better off with one or two doses?
• What else do we need to think about?

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Observations Since Introduction of 1-Dose
Regimen

• Reduction in severe varicella disease and its
  related complications in healthy children in the
  US1
• 88 decline in varicella-related hospital
  discharges, 1994 20022
• Reduction in varicella-related mortality
• 100 deaths per year reported prior to 1995
  vaccine licensure3
• From 2003 through mid-2004, 8 varicella-related
  deaths were reported 6 occurred in unvaccinated
  persons4
• Primary vaccine effectiveness (835 866)
• Pool of varicella susceptibles remains after
  administration of a single injection of vaccine1
• Insufficient herd immunity to prevent outbreaks2

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Potential Impact from Accumulation of Susceptibles

• The CDC estimates the total number of
  susceptibles is rising, including persons
  vaccinated with 1 dose and unvaccinated persons1
  
• Varicella outbreaks are occurring in elementary
  and middle school and are likely to occur in high
  school and college in the future unless students
  are protected1
• Increased risk for outbreaks later in life when
  disease can be more severe2
• Risk of complication and death from varicella is
  1020 times higher for adolescents and adults
  than for children ages 142
• Significant cost to public health and other
  institutions3

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Varicella History

• 1767 Differentiation of varicella from smallpox
• 1875 Demonstration of infectious nature of
  varicella
• 1892 Varicella noted after exposure to herpes
  zoster
• 1943 Consideration of herpes zoster as
  varicella reactivation
• 1943 Varicella isolated in tissue culture
• 1972 Varicella vaccine first used by Takahashi
• 1981 First trials USA in immuno-compromised in
  remission
• 1986 First trials in Durham
• 1995 Vaccine licensed in USA
• 2002 88 decline in hospital varicella-related
  discharges

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Varicella Pathogenesis and Clinical Features

• Varicella virus enters through the respiratory
  tract and conjunctiva
• Replication likely in nasopharynx and regional
  lymph nodes
• Repeated episodes of viremia
• Multiple tissues, including sensory ganglia,
  infected during viremia

• Incubation period 1416 days (range 1021 days)
• Mild prodrome for 12 days
• Rash generally appears first on head most
  concentrated on trunk
• Successive crops (24) of pruritic vesicles

Centers for Disease Control and
Prevention. 9th ed. Washington DC Public Health
Foundation, 2006.
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VZV Latency
Dorsal root
VZV moves along the sensory nerve to the
dorsal root ganglia
ganglion
Spinal cord
Varicella
rash
Skin
VZV established latency in the dorsal root
ganglion
Viral latency is established during primary
infection (varicella).1 Transport of virus up
sensory nerve from infected dermal sites2
Dormant in dorsal root ganglion2
.
1. Straus SE, Oxman MN. Varicella and
herpes zoster. In Freedberg IM, Eisen AZ, Wolff
K, et al, eds. Fitzpatricks Dermatology in
General Medicine. 5th ed. Vol 2. New York, NY
McGraw-Hill 199924272450. 2. Silvertsein S,
Straus SE. In Arvin AM, Gershon AA, eds.
Varicella-Zoster Virus Virology and Clinical
Management. Cambridge, UK Cambridge University
Press 2000123-141.
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Varicella Epidemiology

• Reservoir Humans only
• Transmission Airborne droplet Direct contact
  with lesions
• Temporal pattern Peak in winterearly spring
  (US)
• Communicability 12 days before to 45
  days after onset of rash May be longer
  in immunocompromised

Centers for Disease Control and
Prevention. 9th ed. Washington DC Public Health
Foundation, 2006.
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Varicella Epidemiology

• Before Vaccination
• 4 million cases a year
• 11,000 hospitalizations
• 100 deaths
• 50 children
• 50 adults
• 10 of adults non-immune
• Primarily a Childhood disease

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• Varicella Age-Specific Incidence United States,
  199019941

Rate per 100,000 population. National Health
Interview Survey data
Centers for Disease Control and
Prevention. Washington DC Public Health
Foundation, 2006.
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• Varicella Fatality Rate in Healthy Persons

Deaths per 100,000 cases
Centers for Disease Control and
Prevention. Washington DC Public Health
Foundation, 2006.
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Groups at Increased Risk of Complications of
Varicella

• Healthy adults
• Immunocompromised persons
• Newborns of women with rash onset within 5 days
  before to 2 days after delivery

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Complications of Varicella in Healthy Children

• Secondary Skin infections Impetigo or less
  commonly fasciitis
• Staphylococcus aureus
• Group A ß-hemolytic streptococcus
• CNS Disease
• Acute Cerebellar Ataxia
• Encephalitis
• Secondary bacterial meningitis
• Pneumonia

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Complications of varicella in Healthy Adults

• Pneumonia
• Skin Infections
• Encephalitis
• Acute Glomerulonephritis
• Herpes Zoster (common in older age group)

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Varicella Zoster
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Complications in Immunocompromised

• Dissemination
• Slower healing of lesions
• Visceral involvement
• Death

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Varicella Zoster Complications
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Complications of Varicella in Pregnancy

• During Pregnancy
• Fetal abnormalities
• Rash
• Limb hypoplasia
• Peripartum Disease
• Devastating disease 5 to 2 days of delivery
• Baby gets virus but no antibodies

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Varicella requirements

• For Day care entry gradually expanding in all
  states
• For School entry gradually expanding in all
  states
• For University entry gradually expanding in all
  states

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Varicella Vaccine Immunogenicity

• Seroconversion in Clinical Trials
• Children (lt13 years) 97
• 2 doses 99
• Adults Adolescents (gt12years)
• 1st dose 75-94
• 2nd dose 99

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Varicella vaccine Effectiveness

• Study Method Dose/Population Results
• Double-blind Single dose in 100 1st year
• Placebo controlled Children (491/163) 96 2nd
  year
• After household Single dose in 77 reduction
• Exposure Children (259) in attack rate
• After household Adolescent/Adults 70 reduction
• Exposure 2 doses (64) in attack rate

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Clements paper
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Post-vaccination Rash
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Breakthrough Disease
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Clinical Features of Wild Type and Breakthrough
Varicella Disease
Wild-type varicella
Breakthrough disease
Photo courtesy of Barbara Watson, MD2
Photo courtesy of American Academy of Pediatrics,
Red Book Online, 2003

• Lesions predominantly maculopapular and usually
  lt50
• Frequency and severity of fever are generally
  lower
• Rash averages 5 days

• Lesions are predominantly vesicular and
  250-500 in number
• Fever is generally higher
• Rash averages 12 days

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North Carolina Day Care Study

• OBJECTIVES
• To document the change in varicella epidemiology
  in day care centers after the implementation of
  varicella vaccination.
• To document the rate of uptake of varicella
  vaccine in day care children.

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Age specific Vaccination coverage
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Proportion of children susceptible to varicella
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Disease incidence in vaccinated children
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Disease incidence in unvaccinated children
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Cumulative incidence of varicella vs. percent
vaccinated
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Discussion point

• By age 48 months, only 80 of children are
  immune to varicella due to vaccination or from
  wild type disease.
• As varicella disease becomes increasingly
  infrequent, there may be a decreased motivation
  to obtain vaccine for eligible children.

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Conclusions stated in 2004

• Partial uptake is sufficient to produce herd
  immunity.
• Even though school entry requires varicella
  vaccine there is a cohort of aging children who
  are unvaccinated and who have not had the disease.

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What is happening elsewhere?

• Disease incidence
• Zoster incidence
• Disease in infants and adults
• Vaccination rates

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Incidence of VaricellaAntelope Valley, CA
Seward JF et al. JAMA 2002287(5)606-611
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Varicella Active Surveillance Project West
Philadelphia 1995-1999
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Varicella Epidemiology

• Before Vaccination
• 100 deaths
• 50 children
• 50 adults
• Primarily a childhood disease
• After Vaccination
• 20-26 deaths total since 2000
• Will it become a more common adult disease?

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Varicella zoster rate

• After vaccination significant decrease
• 21 million doses distributed
• 1.5/100,000 zoster cases actual
• 110/100,000 expected lt5 yrs.
• 23 cases vaccine strain
• 15 cases wild type

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Michigan Outbreak

• 85 protective against all disease
• 98 protective against moderate to severe disease
• 5x risk of breakthrough if vaccinated gt4 years
  before
• Vaccinated - 85 had mild disease, unvaccinated -
  20 with mild disease

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Varicella Outbreaks 2001-2005

• Occurred in elementary schools
• Vaccine effectiveness 72-85
• Highest attack rates occurred among the younger
  students.
• Outbreaks lasted about two months
• Vaccinated children played a role in transmission
  although their disease was mild
• Overall attack rates among vaccinated children
  11-17

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Successes

• 85 reduction in disease
• Less Zoster
• Mild disease is common when breakthrough occurs
• Few outbreaks
• Vaccination coverage high
• Varicella deaths declined 78
• Varicella hospitalizations down gt60

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So what are the issues ?(From 2005 presentation)

• Varicella outbreaks in highly vaccinated cohorts
  like day care/school why?
• Will lack of wild type disease change
  epidemiology? More adult disease both varicella
  and zoster?
• How to vaccinate those who missed vaccination?
• Do we need a second dose? At what cost?
• Should it be combined with MMR?
• If the disease burden shifts to older patients
  there will be more complications.
• Need refrigerator stability

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Rate of Breakthrough Disease 1-Dose and 2-Dose
Regimens of VARIVAX Varicella Virus Vaccine
Live (Oka/Merck) Over 10 Years
2,216 children 12 months to 12 years of age with
a negative history of varicella were randomized
to receive either 1 dose of VARIVAX or 2 doses
given 3 months apart. Subjects were followed on
an annual basis for 10 years after vaccination.
94 98 7.5 2.2
Plt0.001 Breakthrough infection was defined
as any case of varicella occurring gt42 days
postvaccination.
Kuter B et al. Pediatr Infect Dis J.
200423132137.
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Factors about vaccination

• There was a 3.4-fold lower risk of developing
  breakthrough disease in children who received
  2 doses of varicella vaccine compared with
  children who received 1 dose of varicella
  vaccine.
• The duration of protection from varicella
  obtained using VARIVAX in the absence of
  wild-type boosting is unknown.

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Varicella Vaccine Recommendations MMWR - 22 June
2007

• Implement a routine 2 dose varicella schedule
  12-15 months 4-6 years
• A second catch-up dose for anyone who had only
  one dose in the past.
• Routine immunization of varicella naïve healthy
  people gt12 years of age
• Prenatal assessment and postpartum vaccination
• Expand use in HIV patients
• Children CD4T lymphs 15-24
• Adol adults with CD4T lymphs gt200cells/uL.
• Establish middle high school and college entry
  vaccination requirement.

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Things to remember

• These are the issues to remember
• Disease epidemiology
• Vaccine type
• Vaccine storage
• Breakthrough

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Skin lesions
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Complications
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Deaths are declining
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Deaths per 1 million by age
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Deaths by age by time period
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So why is this happening?

• Immunization generally cannot provide the
  protection that surviving natural disease can.
• Time since vaccination appears to play some part
  in the process
• Age of exposed is a factor also.

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Varicella Vaccines

• All three vaccines contain the same live
  Oka-Merck varicella vaccine virus but in
  different concentrations
• -Varivax - 1,400 pfu
• ProQuad - 9,800 pfu (7x Varivax)
• Zostavax - 19,000 pfu (14x Varivax)

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Varicella Vaccine (Varivax)

• Live virus (Oka-Merck strain)
• Efficacy
• Infection 70-90
• Severe disease 95
• Duration of immunity At least 10 yrs
• Schedule 2 doses

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Varicella Breakthrough Disease

• Varicella in a previously vaccinated person
• Breakthrough disease much milder than in
  unvaccinated persons
• Can occur in up to 30 of recipients of one dose
  of varicella vaccine

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Clinical Features of Wild Type and Breakthrough
Varicella Disease
Wild-type varicella
Breakthrough disease
Photo courtesy of Barbara Watson, MD2
Photo courtesy of American Academy of Pediatrics,
Red Book Online, 2003

• Lesions predominantly maculopapular and usually
  lt50
• Frequency and severity of fever are generally
  lower
• Rash averages 5 days

• Lesions are predominantly vesicular and
  250-500 in number
• Fever is generally higher
• Rash averages 12 days

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Breakthrough Infection

• Retrospective cohort study of 115,000 children
  vaccinated in 2 HMOs during January 1995 through
  December 1999
• Risk of breakthrough varicella 2.5 times higher
  if varicella vaccine administered less than 30
  days following MMR
• No increased risk if varicella vaccine given
  simultaneously or more than 30 days after MMR

MMWR 200150(47)1058-61
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Nonsimultaneous Administrationof Live Virus
Vaccines

• If varicella vaccine is not administered on the
  same day as MMR or live attenuated influenza
  vaccine, the vaccines should be separated by at
  least 4 weeks
• If separated by less than 4 weeks the vaccine
  given second should be repeated

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Varicella VaccinePostexposure Prophylaxis

• Varicella vaccine is recommended for use in
  persons without evidence of varicella immunity
  after exposure to varicella
• 70-100 effective if given within 72 hours of
  exposure
• not effective if administered more than 5 days
  after exposure but will produce immunity if not
  infected

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Zoster Following Vaccination

• Most cases in children
• Risk from vaccine virus appears to be less than
  from wild-type virus
• Usually a mild illness without complications

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Transmission of Varicella Vaccine Virus

• Asymptomatic transmission of vaccine virus may
  occur
• Risk of transmission is increased if the
  recipient develops a rash

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Varicella VaccineStorage and Handling

• Store frozen at 5F (-15C ) or lower at all
  times
• May be stored up to 72 hours at 35o-46o F
• Unused vaccine must be discarded after 72 hours
  at this temperature
• Discard if not used within 30 minutes of
  reconstitution

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MMRV Storage and Handling

• Store frozen at 5F (-15C ) or lower at all
  times
• May NOT be stored at refrigerator temperature AT
  ANY TIME
• Discard if not used within 30 minutes of
  reconstitution

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Herpes Zoster Vaccine (Zostavax)

• Contains the same live attenuated varicella virus
  as Varivax but at a much higher titer of vaccine
  virus
• Approved by FDA for persons 60 years of age and
  older
• Administered by the subcutaneous route

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Herpes Zoster Vaccine Efficacy

• Compared to the placebo group the vaccine group
  had
• 51 fewer episodes of zoster
• Less severe disease
• 66 less postherpetic neuralgia
• No significant safety issues were identified

NEJM 2005352(22)2271-84.
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What do I do with the teen who is not sure if
they had Varicella?

• Draw a varicella titer/elisa
• Give a dose of vaccine
• Wait for lab data to return
• If neg then get a second dose
• If pos then congratulations you have had your
  booster.

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National Immunization ProgramContact Information

• Telephone 800.CDC.INFO
• Email nipinfo_at_cdc.gov
• Website www.cdc.gov/nip

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• Varicella Vaccination in Pregnancy Registry

800.986.8999
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• Varicella Vaccine Information

800-9VARIVAX
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U.S. National Immunization Survey Estimated
Coverage by State Among Children 1935 Mos. (2005)
Rates vary from state to state (6896)
82.9 (NH)
76.6
68.5 (VT)
84.2
75.5
87.2
83.3
76.2
95.4(MA)
77.4
87.0
85.7
87.6
96.2 (RI)
93.4
77.2
91.0(CT)
89.2
83.4
89.9
84.4
83.8(NJ)
86.3
86.3
82.8
81.2
89.5(DE)
87.2
90.7 (MD)
81.1
89.5
89.9
87.9
81.5
90.6(DC)
83.3
91.3
89.8
83.6
85.8
85.9
86.3
87.4
85.9
91.9
93.5
88.4
88.9
91.1
89.0
89.4 (HI)
81.2
2005 national varicella vaccination coverage
levels among children 1935 months of age
(?1 dose) ? 87.9
Adapted from Centers for Disease Control and
Prevention. MMWR. 2006 55(36)988993.
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• THE END
• Thank you for your attention