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PEER REVIEW HISTORY
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ARTICLE DETAILS
TITLE (PROVISIONAL)
AUTHORS
Immunogenicity and safety of early vaccination with two doses of a
combined measles-mumps-rubella-varicella vaccine in healthy
Indian children from 9 months of age: a phase III, randomized, noninferiority trial.
Lalwani, Sanjay; Chatterjee, Sukanta; Balasubramanian, Sundaram;
Bavdekar, Ashish; Mehta, Shailesh; Datta, Sanjoy; Povey, Michael;
Henry, Ouzama
VERSION 1 - REVIEW
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Mathuram Santosham and Srinivas Acharya
JHSPH, USA
21-Jan-2015
1st line of the abstract – there is a typo. MMR expansion is given as
Measles mumps varicella instead of rubella.
Page 5, 1st line of paragraph on strengths and limitations of this
study – minor change in sentence to – “This Indian study provides
data for the first time on”
Page 6, last line, para titled Introduction - Would be better if the
statement about waning coverage leading to epidemics in developed
countries is contextualized with some references or data. Otherwise
it might suffice to say that the problem of measles outbreaks persists
even in developed country settings.
Page 6, last para on Rubella, 1st line - The data from the cited study
(ref12) does not represent the entire the entire Indian subcontinent
as implied by the authors. The study was carried out only n few
blocks of Tamil Nadu and the authors themselves conclude that the
results are not generalizable. Please modify statement accordingly.
Page 25, Section – Discussion, 2nd paragraph, line 6 - Suggest that
the exact seropositivity rate be mentioned from the study ref#11 .
The authors need to acknowledge that the observe antibodies in
some of the children could also be the result of past measles
infection in the subjects in the cited study.
Page 28, Section – Conclusion, line 5 “Introduction of MMRV
vaccine may achieve higher coverage rates in India by increasing
compliance for two-dose MMR and Varicella vaccines, and thereby
improving the limited success of the MMR vaccination program”. --This statement is not supported by this study. The introduction of an
MMRV would not automatically increase compliance since there are
many complex health systems issues that influence compliance.
This sentence should be removed.
Downloaded from http://bmjopen.bmj.com/ on June 17, 2017 - Published by group.bmj.com
REVIEWER
REVIEW RETURNED
Steven Black, MD
Professor of Pediatrics
Cincinnati Children's Hospital
Cincinnati, Ohio USA
02-Mar-2015
GENERAL COMMENTS
This manuscript clearly describes a comparative clinical trial. I only
have three minor comments.
1. The statement " This study had no limitations" is not appropriate
and is never true. Results interpretation are always limited by
sample size and the population might not be representative of all of
India, for example. I think this statement should be removed or
amended.
2. There is not sample size calculation -- how was the trial size
determined?
3. In Table 1, the column "SC" has values for seroconversion for the
"pre" values ( 1.3, 1.9, 2.7 for example in the first such row)... it is
not clear to me what this means as this is pre-vaccination. This
should be clarified or changed.
REVIEWER
Dr Victoria Allgar
University Of York
26-Mar-2015
REVIEW RETURNED
GENERAL COMMENTS
Overall a well written paper with a clear analysis plan and clearly
presented data.
From my statistical review, I could not replicate the power calculation
due to limited detail in the paper "A sample size of 130 evaluable
subjects in each treatment group and 65 evaluable subjects in the
control group was planned, which gave a power of at least 93.91%
to meet the co-primary objectives." Could more detail be provided
should the detailed calculations in research proposal not be
available. Also need to mention that considering that up to 25% of
the subjects enrolled may be non evaluable, a total of 450 subjects
(180 subjects in each of the treatment groups and 90 subjects in the
control group) would be enrolled in the study.
There was no adjustment for any confounding factors in the analysis
e.g. centre. This should be discussed.
VERSION 1 – AUTHOR RESPONSE
Reviewers: Mathuram Santosham and Srinivas Acharya
1) Below 1st line of the abstract – there is a typo. MMR expansion is given as Measles mumps
varicella instead of rubella.
Response: This has now been corrected to Measles-mumps-rubella on page 3, line 39.
2) Page 5, 1st line of paragraph on strengths and limitations of this study – minor change in sentence
to – “This Indian study provides data for the first time on”.
Response: This has now been corrected to, “This Indian study provides data for the first time on” on
page 5, line 72.
3) Page 6, last line, para titled Introduction - Would be better if the statement about waning coverage
leading to epidemics in developed countries is contextualized with some references or data.
Downloaded from http://bmjopen.bmj.com/ on June 17, 2017 - Published by group.bmj.com
Otherwise it might suffice to say that the problem of measles outbreaks persists even in developed
country settings.
Response: References to support the statement have now been included on page 7, line 105, “Thus,
even developed settings may be prone to epidemics if coverage wanes.7-10”
4) Page 6, last para on Rubella, 1st line - The data from the cited study (ref12) does not represent the
entire Indian subcontinent as implied by the authors. The study was carried out only n few blocks of
Tamil Nadu and the authors themselves conclude that the results are not generalizable. Please
modify statement accordingly.
Response: The sentence has now been modified on page 7, lines 110-112 to read, “A study
conducted in 2006 revealed that 82.2% children aged between 1 and 5 years, and 13.5% aged
between 10 and 15 years are susceptible to rubella in the state of Tamil Nadu in southern India.12”
5) Page 25, Section – Discussion, 2nd paragraph, line 6 - Suggest that the exact seropositivity rate be
mentioned from the study ref#11 . The authors need to acknowledge that the observe antibodies in
some of the children could also be the result of past measles infection in the subjects in the cited
study.
Response: The statement now has the seropositivity rates included from ref #11 on page 26, lines
340-343, “However, it should be noted that this finding is inconsistent with a notable Indian study
conducted approximately a decade ago that suggested the persistence of high circulating maternal
antibodies at 9 months of age with baseline seropositivity rates of 15% for measles and 20% each for
mumps and rubella.11”
6) Page 28, Section – Conclusion, line 5 “Introduction of MMRV vaccine may achieve higher coverage
rates in India by increasing compliance for two-dose MMR and Varicella vaccines, and thereby
improving the limited success of the MMR vaccination program”. --- This statement is not supported
by this study. The introduction of an MMRV would not automatically increase compliance since there
are many complex health systems issues that influence compliance. This sentence should be
removed.
Response: In accordance with the comment received, the statement has now been removed. Please
view the revision made in track changes in the manuscript.
Reviewer 2: Steven Black
This manuscript clearly describes a comparative clinical trial. I only have three minor comments.
1. The statement " This study had no limitations" is not appropriate and is never true. Results
interpretation are always limited by sample size and the population might not be representative of all
of India, for example. I think this statement should be removed or amended.
Response: The authors agree with the reviewer’s comment. We have now added a limitation in the
discussion section on page 29, lines 401-405, “A few limitations of the study that should be
considered: (1) the six tertiary care centers where the study was conducted are not representative of
the entire Indian population, (2) investigator-bias while reporting AEs due to the the open design of
the study, and (3) there were no adjustments made for confounding factors (eg: centers) in the
analysis.”
2. There is not sample size calculation -- how was the trial size determined?
Response: In response to the reviewer’s comment, we have now added more information on the
sample size estimation. The methods section of the manuscript now has an additional statement on
page 13, lines 217-222, “Considering that up to 25% of the subjects enrolled could be non-evaluable,
a total of 450 subjects (180 subjects in each of the treatment groups and 90 subjects in the control
group) were to be enrolled in the study. A sample size of 130 evaluable subjects in each treatment
group and 65 evaluable subjects in the control group was planned, which gave a power of at least
93.91% to meet the co-primary objectives.”
Downloaded from http://bmjopen.bmj.com/ on June 17, 2017 - Published by group.bmj.com
3. In Table 1, the column "SC" has values for seroconversion for the "pre" values ( 1.3, 1.9, 2.7 for
example in the first such row)... it is not clear to me what this means as this is pre-vaccination. This
should be clarified or changed.
Response: The authors would like to clarify that the pre-dose values are the basline seropositivity
rates, and this has now been made clear with an asterix sign and explained in the footnote. The
footnote on page 17, line 265 now reads, “*Pre-dose values refer to baseline seropositivity rates
before vaccination.”
Reviewer 3: Dr Victoria Allgar
Overall a well written paper with a clear analysis plan and clearly presented data
1. From my statistical review, I could not replicate the power calculation due to limited detail in the
paper "A sample size of 130 evaluable subjects in each treatment group and 65 evaluable subjects in
the control group was planned, which gave a power of at least 93.91% to meet the co-primary
objectives." Could more detail be provided should the detailed calculations in research proposal not
be available. Also need to mention that considering that up to 25% of the subjects enrolled may be
non evaluable, a total of 450 subjects (180 subjects in each of the treatment groups and 90 subjects
in the control group) would be enrolled in the study.
Response: The following calculations (in the table below) were done for the power of the study. The
following sentence has now been mentioned in the methods section on page 13, lines 217-219,
“Considering that up to 25% of the subjects enrolled could be non-evaluable, a total of 450 subjects
(180 subjects in each of the treatment groups and 90 subjects in the control group) were to be
enrolled in the study.”
Endpoint Comparisons Reference rate Non-inferiority limit Power Type II error
Anti-measles virus concentration ( 150 mIU/mL) MeMuRu-OKA/MeMuRu-OKA vs
Priorix/Priorix+Varilrix™ 99.1% 10% 99.93% 0.07%
Anti-mumps virus concentration ( 231 U/mL) MeMuRu-OKA/MeMuRu-OKA vs
Priorix/Priorix+Varilrix™ 98.8% 10% 99.69% 0.31%
Anti-rubella virus concentration
( 4 IU/mL) MeMuRu-OKA/MeMuRu-OKA vs
Priorix/Priorix+Varilrix™ 99.9% 10% > 99.99% < 0.01%
Anti-varicella virus concentration
( 4 Dilution-1) MeMuRu-OKA/MeMuRu-OKA vs
Priorix/Priorix+Varilrix™ 99.8% 10% > 99.99% < 0.01%
Anti-measles virus concentration ( 150 mIU/mL) Priorix/ MeMuRu-OKA
vs
Priorix/Priorix+Varilrix™ 99.1% 10% 99.93% 0.07%
Anti-mumps virus concentration ( 231 U/mL) Priorix/ MeMuRu-OKA
vs
Priorix/Priorix+Varilrix™ 98.8% 10% 99.69% 0.31%
Anti-rubella virus concentration
( 4 IU/mL) Priorix/ MeMuRu-OKA
vs
Priorix/Priorix+Varilrix™ 99.9% 10% > 99.99% 0.01%
Anti-varicella virus concentration
( 4 Dilution 1) Priorix/ MeMuRu-OKA
vs
Priorix/Priorix+Varilrix™ 97.2% 10% 94.77% 5.23%
Overall power to reach all endpoints 93.91% 6.02%
2. There was no adjustment for any confounding factors in the analysis e.g. centre. This should be
discussed.
Downloaded from http://bmjopen.bmj.com/ on June 17, 2017 - Published by group.bmj.com
Response: While the authors agree with the reviewer’s comment, this study was randomised at the
center level in order to limit potential biases. So while this factor has been acknowledged as a
limitation, we have also included the fact that this study was conducted in 6 centers in India which are
not representative of the entire Indian population as another important limitation. In the article
summary on page 5, lines 82-86, the following changes have now been made to the strengths and
limitations of the study “Limitations of study: The six tertiary care centres where the study was
conducted are not representative of India, investigator-bias while reporting AEs due to the the open
design of the study and there were no adjustments made for confounding factors (eg: centers) in the
analysis.”
The discussion section on page 29, lines 401-405, now has the limitations included “A few limitations
of the study that should be considered: (1) the six tertiary care centers where the study was
conducted are not representative of the entire Indian population, (2) investigator-bias while reporting
AEs due to the the open design of the study, and (3) there were no adjustments made for
confounding factors (eg: centers) in the analysis.”
Downloaded from http://bmjopen.bmj.com/ on June 17, 2017 - Published by group.bmj.com
Immunogenicity and safety of early
vaccination with two doses of a combined
measles-mumps-rubella-varicella vaccine in
healthy Indian children from 9 months of
age: a phase III, randomised, non-inferiority
trial
Sanjay Lalwani, Sukanta Chatterjee, Sundaram Balasubramanian, Ashish
Bavdekar, Shailesh Mehta, Sanjoy Datta, Michael Povey and Ouzama
Henry
BMJ Open 2015 5:
doi: 10.1136/bmjopen-2014-007202
Updated information and services can be found at:
http://bmjopen.bmj.com/content/5/9/e007202
These include:
Supplementary Supplementary material can be found at:
Material http://bmjopen.bmj.com/content/suppl/2015/09/11/bmjopen-2014-007
202.DC1
References
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http://bmjopen.bmj.com/content/5/9/e007202#BIBL
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