MEASLES DISEASE Clinical Trial
Official title:
Comparison of Three Different Schedules of Measles Vaccination in Infants: a Pilot Randomized Controlled Trial
Measles is a preventable infectious viral disease. Since 1985, India has been administering
a single dose of measles vaccine to all infants at 9 months of age. This age was chosen to
balance the disappearance of maternal (transplacental) antibodies with the increasing risk
of developing measles. Thus infants are expected to get protection against measles by
acquired maternal measles antibodies derived trans-placentally from the mother for the first
9 months of life. Thereafter vaccine-induced antibodies are expected to protect infants.
Seroconversion after measles vaccination does not take place as long as maternal measles
antibodies persist in the infant. However, it is widely recognized that a substantial
proportion of measles infection (10 to 15%) can occur among infants before the age of
measles vaccination. Further, two small cohort studies done in our institution confirm that
the majority of infants lose maternal antibodies by six months of age, making them
susceptible to measles.This argues strongly for anticipating measles vaccination to an
earlier age. However, such early vaccination has the risk that residual maternal antibodies
(even if insufficient to protect infants) can neutralize the antigen in the vaccine,
rendering vaccination ineffective. Therefore, a careful balance has to be chosen so that low
levels of circulating maternal antibodies do not interfere with infants' response to
vaccination. However, there is no prospective study in Indian infants to determine the
seroconversion and sero-protection rate of earlier vaccination.
This study has following aims and objectives:
1. To study the level of measles specific immunoglobulin G (IgG) antibodies in a cohort of
term infants followed from birth to 9 months of age; and the pattern of antibody
decline in them.
2. To compare the levels of antibodies in infants at these time points and correlate the
levels with the antibody level in the respective mothers at the time of delivery.
3. To compare the efficacy and safety of three different measles vaccination schedules in
a cohort of term infants viz (i) vaccination at 9 months of age (current practice),
(ii) vaccination at 7.5 months and 9 months of age, and (iii) vaccination at 6 months
and 9 months of age.
Study design:
This study has two design components viz.
- Prospective enrollment of a cohort of term infants at birth; and 3 monthly follow-up at
the ages of 3 months, 6 months, 9 months and 12 months.
- Randomization at 6 months of age to three intervention groups viz (i) measles
vaccination at 9 months of age (as per current practice), (ii) vaccination at 7.5
months and 9 months of age, and (iii) vaccination at 6 months and 9 months of age.
Methods: Enrollment:
Pregnant women awaiting delivery in the Department of Obstetrics and Gynecology will be
screened for eligibility (as per the Inclusion and Exclusion criteria). Women whose infants
are likely to be eligible for participation in the study will be explained about the nature
and purpose of the study prior to delivery. They will be informed about the study protocol
and invited to participate. After delivery, mothers and their respective newborn babies,
will be enrolled with written, informed consent.
Procedure:
A brief interview will be conducted to determine history of exanthematous illness suffered
in the past by the mother, family history of similar illness and vaccinations received by
her.
At delivery, approximately 1 ml of cord blood from the infant's side will be collected in a
sterile plastic screw-capped container, labeled and transported to the laboratory. Similarly
1 ml of venous blood will be obtained from the mother in a sterile plastic screw-capped
container, labeled and transported to the laboratory. Serum will be separated from these
samples by centrifugation and deep frozen at minus 20 degree C until analysis.
The infants will be followed-up and undergo venipuncture under aseptic precautions to
withdraw 0.8-1.0 ml blood at five further visits viz. 3 months±2 weeks [corresponding to a
visit for 2nd/3rd dose of diphtheria- pertussis- tetanus (DPT) vaccine and live oral
poliovirus vaccine(OPV)], 6 months±2 weeks (corresponding to visit for 3rd dose of Hepatitis
B at 6 months of age), 7.5 months ±2 weeks, at 9 months ±2 weeks (corresponding to visit for
measles vaccine as per the current schedule), and at 12 ± 2 weeks months of age
(corresponding to visit for routine follow-up).
During the follow-up visit at 6 months of age, infants will be randomized (as described
below) to one of three groups viz: Group A: vaccination at 6 months and 9 months of age;
Group B: vaccination at 7.5 months and 9 months of age; and Group C: vaccination at 9 months
of age (current practice).
Generation of random sequence: A computer programme will be used to generate a random number
sequence to allocate participants into three groups in a ratio of 1:1:1, as per the Groups
described above.
Allocation concealment: The allocation of each infant will be placed in sealed, opaque
envelopes. For each infant presenting at six months of age, one envelope will be marked with
the infant's name and then opened. At this stage, the sealed envelopes will contain one of
two options viz (i) Vaccination at 6 months or (ii) No vaccination at 6 months. Those who
receive the former will follow the protocol for Group A described below. Those who receive
the latter will be followed-up at 7.5 months of age; at which stage a second set of sealed
enveloped will be accessed. One envelope will be marked with the infant's name and then
opened. At this stage, the sealed envelopes will contain one of two options viz (i)
Vaccination at 7.5 months or (ii) Vaccination at 9 months. Those who receive the former will
follow the protocol for Group B described below; and those who receive the latter will
follow the protocol for Group C described below.
Blinding: In this randomized trial design, no attempt will be made to blind the infants
being randomized, or their parents (in order to avoid unnecessary injections through a
double dummy design). The investigator involved in randomizing the infants will also not be
blinded. However, the laboratory personnel performing the antibody level measurements will
be blinded by sending the samples with only a four digit code that does not reveal the
intervention received.Samples during any visit will be withdrawn prior to administration of
vaccine(s).
Measles vaccine will be administered as per the protocol described above by trained
personnel in the Immunization Room of the Advanced Pediatrics Center. A standard dose of the
available preparation will be administered in the dosage of 0.5 ml through the subcutaneous
route. Standard post-vaccination precaution viz observation of the infant for 30 minutes
after vaccination will be done to observe for any adverse event.
Clinical protocol:
At each visit history will be elicited to detect clinical features compatible with measles
in the baby or any other member of the family in the household contact. This includes:
Any person in whom a clinician suspects measles infection, or Any person with fever and
maculopapular rash (i.e. non-vesicular) and cough, coryza (i.e. runny nose) or
conjunctivitis (i.e. red eyes).
In addition, the investigator will make a monthly telephone call to the family of enrolled
infants asking for specific history compatible with the World Health Organization (WHO) case
definition for measles, in the infant or any household member. In case such history is
elicited, the infant and affected individual will be invited for clinical examination and a
sample of blood will be obtained. Serum will be separated as described and immunoglobulin M
(IgM) anti-measles antibody will be measured using commercially available ELISA kits as
described below.
After each vaccination, parents of vaccinated infants will be requested to complete a Diary
for three days, containing a daily record of (i) excessive crying, (ii) poor feeding, (iii)
fever, (iv) redness at injection site, (v) swelling at injection site (vi)
tenderness/apparent pain at injection site, and (vii) any other unusual behavior/appearance
in the infant.
Laboratory processing:
Clotted blood samples will be centrifuged at 3000 rpm for 15 minutes to obtain serum which
will be frozen at -20 degree Celsius till tested. Serum will be processed in batches of
30-40 and measles specific IgG antibodies will be quantified by micro-ELISA (enzyme linked
immunosorbent assay) using commercially available quantitative measles IgG kits of high
sensitivity (98-100%) and specificity (100%). IgM antibody assay will be done to confirm the
diagnosis of measles only in those infants suspected to have measles; using commercially
available quantitative measles IgG kits of high sensitivity (98-100%) and specificity
(100%). Sera from subjects, calibrators, positive and negative controls will be diluted in
serum diluents and test will be performed as recommended by the manufacturers. The obtained
optical density value for each sample will be converted into measles antibody titre in
units/ml with help of calibrator values in a standard log graph paper and these units/ml
will then be interpreted as International Units/ml taking the recommendation in the kit.
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