Poliomyelitis Clinical Trial
Official title:
Immunogenicity of Inactivated Polio Vaccine in Puerto Rico; A Comparative Cohort Study of Two Vaccination Schedules
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.
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.
;
Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Double-Blind, Primary Purpose: Educational/Counseling/Training
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