Comparison of Immune Response Using 2 Vaccination Schedules Using Inactivated Polio Vaccine
Condition: Poliomyelitis
MeSH terms: Poliomyelitis
Study type: Interventional

Summary: 
      As poliovirus eradication progresses rapidly, strategies to discontinue oral poliovirus
      vaccination need to be established. One strategy would be to use inactivated poliovirus
      vaccine (IPV) transitionally, and this has already occurred in the United States. It is not
      clear, however, if 3 doses of IPV provide sufficient immunogenicity when administered
      according to World Health Organization (WHO)/Expanded Programme on Immunization (EPI)
      schedule in a tropical, developing area where no wild-poliovirus circulates.

      Puerto Rico will be the study site for this randomized clinical trial. Healthy infants will
      be identified at birth in a hospital-system, enrolled within 4 weeks of birth, and randomized
      into one of two arms: United States of America (U.S.A.) schedule (8, 16, 24 weeks/2, 4, 6
      months) or WHO schedule (6, 10, 14 weeks). Both groups will receive IPV at visits 1, 2 and 3.
      Infants will receive all age-appropriate EPI childhood vaccinations along with IPV, to
      decrease confusion and inconvenience to the parent. Serum will be collected twice, at visit 1
      and visit 4 (30-45 days after IPV-3), to measure antibody titers. Sera will be measured for
      neutralizing antibodies at the Centers for Disease Control (CDC). Based on the lowest
      seroconversion rate estimate of 85%, and to have a probability of .80 that the estimate from
      this study is in error by no more than 10%, the investigators will need to enroll 220 infants
      in each arm. To compensate for attrition and retain statistical power, the investigators plan
      to enroll up to 250 infants in each arm. This study is expected to require at least 20 months
      to complete. Results will provide valuable and timely information applicable to global polio
      eradication efforts. Any participant found not to be protected after 3 doses of IPV will be
      given a booster at 9-12 months. Results will provide valuable and timely information
      applicable to global polio eradication efforts.
    

Detailed description: 
      The proposed study will be a prospective, randomized clinical trial of the immunogenicity of
      IPV among two groups of infants using different immunization schedules (WHO/EPI and US).

      Study will begin with an enrollment period up to 10 months. All infants born at San Lucas
      Hospital will be eligible unless otherwise excluded. The study will continue until 10 months
      after the last infant is enrolled. There will be four or five study visits, depending on the
      cohort.

      Study Population:

      Infants will be identified at birth at San Lucas Hospital; all babies born during the
      enrollment period at the selected hospital will be considered eligible. Mothers will be
      approached in the hospital by the study -nurse after infant's birth and be informed about the
      study. Inclusion and exclusion criteria will be assessed at this time and if the mother
      agrees to the study, informed consent will be obtained.

      Randomization will be based on what day the baby was born. Even days will be assigned to the
      WHO schedule and odd days to the US schedule. The mother will be told which cohort the infant
      is in and given an immunization card with dates that the infant is to return to receive
      vaccinations. The card will also include study contact phone numbers.

      The study will be implemented through the Ponce School of Medicine at San Lucas Hospital in
      Ponce Puerto Rico. This teaching hospital has a 24 bed well-baby nursery where approximately
      150 babies are born per month.

      Interventions:

      To avoid confusion, inconvenience and error, and to limit differences among participants,
      DTaP, Hib, PCV, and HepB (if appropriate) will be administered along with IPV on first 3
      visits in both cohorts. Both schedules meet the parameters of Advisory Committee of
      Immunization Practices (ACIP) (minimum interval at least 4 weeks between doses and minimum
      age of 6 weeks of age) 2.

      Cohort A-WHO/EPI Schedule

      Initial Study Visit: Visit 1 will be scheduled for 6 weeks (> 42 days and < 46 days) after
      birth. Blood will be drawn (sera 1) immediately prior to administration with first dose of
      IPV and other recommended vaccines. Mother will be reminded of infant's next appointment in 4
      weeks.

      Study Visit 2: Visit 2 will be scheduled for 4 weeks after last vaccination (> 28 days and <
      32 days). The 2nd dose of IPV and other recommended vaccines will be administered at this
      time. Mother will be reminded of infant's next appointment in 4 weeks.

      Study Visit 3: Visit 3 will be scheduled for 4 weeks after last vaccination (> 28 days and <
      32 days). The 3rd dose of IPV and other recommended vaccines will be administered at this
      time. Mother will be reminded of infant's next appointment in 4 weeks.

      Study Visit 4: Visit 4 will be scheduled for 4 weeks after last vaccination. A blood sample
      will be drawn from participant. Study visit should take place no earlier than 28 days since
      previous vaccination nor later than the 45th day

      Study Visit 5: According to ACIP recommendations the 3rd dose of Hepatitis B has to be
      administered after 6 months of age. For this reason, Visit 5 will be scheduled when the child
      is 24 weeks of age in order to receive the 3rd dose of Hepatitis B vaccine.

      Cohort B-US Schedule

      Initial Study Visit: Visit 1 will be scheduled for 8 weeks after birth (> 52 days and < 60
      days). Blood will be drawn (sera 1) immediately prior to administration of the first dose of
      IPV and other recommended vaccines. Mother will be reminded of infant's next appointment in 8
      weeks.

      Study Visit 2: Visit 2 will be scheduled for 8 weeks after last vaccination (> 52 days and <
      60 days). The 2nd dose of IPV and other recommended vaccines will be administered. Mother
      will be reminded of infant's next appointment in 8 weeks.

      Study Visit 3: Visit 3 will be scheduled for 8 weeks after last vaccination (> 52 days and <
      60 days). The 3rd dose of IPV and other recommended vaccines will be administered at this
      time. Mother will be reminded of infant's next appointment in 4 weeks.

      Study Visit 4: Visit 4 will be scheduled for 4 weeks after last vaccination. A blood sample
      will be drawn from participant. Study visit should take place no earlier than 28 days since
      previous vaccination nor later than the 45th day.

      Specimens Collection/Handling:

      Blood will be drawn to obtain serum neutralizing antibody titers prior to the first dose of
      IPV and subsequent to the 3rd dose of IPV. If >= 2% of children in either arm do not respond
      to any of the 3 types of poliovirus, two additional blood specimens will be offered to test
      immunity before and after the 4th dose of IPV among non responders.

      A minimum of 500 µl will be collected at each bleed preferably via vein using a 23-25 gauge
      butterfly into a vacutainer tube (heel stick is acceptable if infant is noted to have poor
      venous access). Specimens will be labeled with a unique identifier and be kept cold (2-8° C),
      not frozen, until specimen is spun down and sera separated which should be done at end of
      each day (specimens should not sit out for > 12 hours).

      Sera will be aliquoted and batch-stored at -20° C. A batched frozen shipment on dry ice will
      be made to CDC after Phase 1 (all participant study visits are complete).

      Lab Evaluation and Methods:

      Sera will be tested for levels of neutralizing antibody titers against poliovirus types 1, 2
      and 3 at CDC by means of a modified microneutralization assay 13. Approximately 80 to 100
      median tissue culture infective dose (TCID50) of each vaccine virus serotype and serial
      dilutions of serum (starting at 1:8 and ending at 1:1024) are incubated at 37° C for 2.5
      hours before 7.5x103 Hep-2(C) cells are added to the wells. After incubation for 5 days at
      37° C, each plate is stained with 0.05% crystal violet in 25% ethyl alcohol, with the optical
      density in each well measured by a spectrophotometer. Each specimen will be run in
      triplicate, with the final titer estimated by the method of Karber. Seropositivity will be
      defined as a neutralization titer of  1:8. It is estimated that serology results will be
      available 60 days after receipt of specimens at CDC.

      Analysis:

      This study is designed to examine and compare seroconversion in response to IPV given
      according to the WHO/EPI and US schedules. Our primary interest is to determine whether the
      seroconversion rate among children receiving the WHO/EPI schedule is no lower than 10% less
      than the rate among those using the US schedule. To determine the required number of study
      participants, we will assume that the seroconversion rate using the US schedule will be 85%
      and we want power of .80 to find a significant difference between the rates if the rate among
      the WHO/EPI schedule group is 75% or lower. Using a one-tailed test (and realizing that
      one-sided significance levels are uncommon in epidemiologic studies and give us a confidence
      level of only 90% and not the standard 95%) based on the normal approximation of the binomial
      distribution, a sample size of ~220 subjects per arm will satisfy these criteria. To
      compensate for expected attrition of ~14 % , a goal of 250 infants will be set for each arm.

      Study Drug:

      IPV is an FDA licensed drug. No investigational drugs are being used for the purpose of this
      study. No routine vaccinations are being withheld for the purpose of this study. Those
      participants randomized to the WHO/EPI schedule will receive their vaccines on a different
      time schedule than they would usually follow in Puerto Rico. However, both schedules meet the
      parameters of the Advisory Committee of Immunization Practices (ACIP) 2. Because participants
      will be followed closely for up to 6 months of life, it is likely that they will receive
      their vaccinations in a more timely manner than they might if not a part of the study.
      Parents will be given a unique immunization card showing the schedule their infant will
      follow; all vaccines administered will be recorded. The card will indicate that they are
      enrolled in a study and list study staff names and contact telephone numbers.

      Informed Consent Procedures:

      Prior to infant vaccination, parents will be given standard vaccine information statements
      (VIS) and informed consents in Spanish or English, as they would if they were to immunize
      their child with their pediatrician or health clinic. Information and risks of all
      administered vaccines will not be discussed in the study informed consent, as the form would
      be overwhelmingly long.

      Confidentiality:

      Confidentiality will be assured by keeping all identifying material in a locked cabinet in a
      locked office. All personal identifiers will be removed before data and specimens are shipped
      to CDC. Records will be held confidential to the fullest extent allowed by state and federal
      laws.

      Information collected for this study will include only a minimum degree of sensitive personal
      information in the form of demographic data. Its disclosure should pose negligible risk to
      participant and or/parent. Parents will be provided with the usual written information
      discussing pros and cons on each vaccine to be administered.
    

Intervention name(s): Vaccination with inactivated polio vaccine; Collection of serum
Intervention type(s): Biological; Procedure
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double
Primary purpose: Educational/Counseling/Training
Keywords: polio; vaccine; immunogenicity