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\begin{document}

\title{Efficacy of cell-culture derived Influenza vaccines for children: A
systematic review and meta-analysis}



\author[1]{Meenu Singh}%
\author[1]{Kulbir Kaur}%
\author[1]{Meenakshi Sachdeva}%
\author[1]{Monika Rana}%
\author[1]{Anil Chauhan}%
\author[1]{Ragini Bhatia}%
\author[1]{Pranita Pradhan}%
\author[1]{Shivani Saini}%
\affil[1]{Post Graduate Institute of Medical Education and Research}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
\textbf{Objectives:} To determine the efficacy of cell culture based
influenza vaccines in children. \textbf{Methods:} Embase, PubMed,
Cochrane and clinical trials were searched.14 randomised controlled
trials in children were selected. The current systematic review was done
as per the PRISMA guidelines. The pooled estimate of seroconversion and
GMT rate was calculated as mean difference. Data was analysed using the
Cochrane Collaboration Review Manager Version software. Risk of bias was
done as per Cochrane risk of bias tool. The quality of evidence was
adjudged using Grading of Recommendations, Assessment, Development, and
Evaluation (GRADE) using the Grade pro software. \textbf{Results:}
Significant results for efficacy were reported for half dose MF59
influenza vaccine control group for GMT at day 1 with a mean difference
of 0.78, 95\%CI, 0.50 to 1.07, p\textless{}0.00001 as compared to full
dose MF59 influenza vaccine experimental group .No significant results
were reported in half dose MF59 influenza vaccine for GMT at Day 43(mean
difference 151.57,95\% CI,-29.36 to 332.50 ,p=0.10). Significant results
were reported for seroconversion rate for half dose MF59 influenza
vaccine control group at day 22 with a mean difference of
17.92,95\%CI,10.08 to 25.75,p\textless{}0.00001 as compared to half dose
MF59 influenza vaccine group at day 43 with a mean difference of
5.00,95\%CI,-4.80 to 14.80,p=0.32 . \textbf{Conclusion:} The current
systematic review demonstrated that half dose cell derived influenza
vaccines was well tolerated and more immunogenic and resulted in high
seroconversion rate and Geometric Mean Titres rate in paediatric
population.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Influenza viruses (A, B, C and D) causes flu or seasonal influenza, an
acute respiratory infection which equally affects all parts of the world
and has predilection for children under 5 years with a rapid
transmission rate. Illnesses range from mild to severe and even death.
Hospitalization and death ensue mainly among high-risk groups. According
to WHO, annual epidemics are estimated to result in about 3 to 5 million
cases of severe illness, and about 290 000 to 6, 50,000 respiratory
deaths. Given the fact that children play a major role in virus
transmission, children are being prioritized for giving influenza
vaccinations in many countries {[}1{]}. Vaccines are available for
prevention, although immunity wanes off over time and also due to a
higher mutation rate of the viruses, annual boosters are recommended.
The most commonly used vaccines are inactivated influenza vaccines,
although newer vaccines have been developed and showed good efficacy
{[}2{]}.

Cell culture method has now replaced the obsolete egg-based method as it
leads to changes in viral antigens owing to an increased adaptability of
virus to avian receptors compromising the effectiveness of vaccine. In
addition, cell-culture derived viruses are cultured in cells of
mammalian origin and potentially omit the egg-adapted changes, enhancing
manufacturing control resulting in increased vaccine efficacy with
reduction in production lead times as an added advantage {[}3{]}. The
inactivated quadrivalent subunit Influenza vaccine prepared from virus
propagated in MDCK cells (IIV4c; FlucelvaxQuadrivalent, Seqirus) was
immunogenic seen with less side-effect in paediatric population. The
study done by Terence Nolan investigated the efficacy of IIV4c against
influenza diagnosed children as well as adolescents in three seasons
{[}4{]}.Flucelvax Quadrivalent is the only cell-based inactivated flu
vaccine that has been licensed by the FDA for use in the United States
(https://www.fda.gov/vaccines-blood-biologics/vaccines/flucelvax-quadrivalent).
Further, policy makers would require a cumulative data of such studies,
either in the form of observational studies or randomized controlled
trials conducted in children {[}5{]}. Recently, a randomized controlled
trial in NEJM (2021) had reported efficacy of a cell-culture-derived
quadrivalent Influenza vaccine in more than 4500 children from different
countries {[}6{]}. Several other randomized controlled trials also
corroborated upon these findings {[}7,8, 9{]}.

Therefore, a systematic review and meta-analysis integrating results of
all these RCTs becomes imperative and would be helpful in policy making
and taking informed decisions.We performed a systematic review and
meta-analysis of cell-culture derived influenza vaccines for preventing
influenza/flu in healthy children and adolescents. This systematic
review evaluated the efficacy and safety of different formulations of
cell-derived adjuvenated and non adjuvenated vaccines in healthy
children below 18 years of age.

\textbf{Material and Methods:}

This systematic review was conducted as per the PRISMA guidelines
{[}10{]}. Studies were included if they were randomized controlled
trials (RCTs). The search was carried out by two independent reviewers
in PubMed, EMBASE, and The CochraneLibrary (CDSR) and clinical trials.
The following databases were searched for maximum retrieval of published
and unpublished articles.No restrictions in terms of language or search
options was applied for performing online search. Articles published
till date (year 2022) were considered. The search term used were :(((
children OR child OR infant OR paediatrics OR preschool children) AND
(((Cell culture) OR (cell cultures)) OR (stem cell culture))) AND
((((influenza vaccine) OR (influenza vaccination)) OR (influenza
vaccines)) OR (''Influenza Vaccines''{[}Mesh{]})).The protocol has been
registered with PROSPERO (registration no: CRD42022312493).

\textbf{Eligibility criteria:}

\textbf{Inclusion Criteria:} Randomised controlled trials (RCTs) on
healthy children/adolescents (less than 18 years of age) were included.

\textbf{Exclusion criteria:} Systematic reviews and non-randomized
studies were excluded. Studies where there is presence of any acute
illness, immunosuppressive medications, prior influenza vaccination, and
laboratory-confirmed influenza disease within 6 months before enrolment
were excluded.

\textbf{Interventions:} Cell-culture based influenza vaccines

\textbf{Comparator:} Placebo, non-influenza vaccine or egg-based
influenza vaccine

\textbf{Outcomes}

\textbf{1. Primary Outcome Measures}

Vaccine related adverse events (Local and systemic adverse events after
each dose of vaccination).

\textbf{2. Secondary Outcome Measures}

Seroconversion rate

Geometric mean titres

\textbf{Data extraction}

For data extraction, two independent reviewers were involved: one
reviewer screened all the identified abstracts and citations of articles
for possible inclusion in the systematic review and the second reviewer
checked the extracted data. This was followed by thorough investigation
of full text articles for data extraction. We had created a PRISMA
flowchart to summarize the flow of process for inclusion and exclusion
of studies. A proforma to record the details including the general
publication details, design, participants, interventions and outcome
measures was developed. The data extraction process has undergone a
quality check by a third reviewer. For clarification of data, authors
were contacted.

The pooled estimate from individual studies was calculated as mean
difference. The heterogeneity was checked by chi-squared test and in
such cases; random-effect model was used. Data was analyzed using the
Cochrane Collaboration Review Manager Version software by one author who
was confirmed by a second author for accuracy.

\textbf{Risk of bias assessment}

Two independent reviewers assessed the quality of evidence as per
theCochrane risk of bias assessment criteria for adequate sequence
generation, allocation concealment, performance and selection, data
attrition, detection bias and other risk of bias {[}11{]}. To resolve
the discrepancy between the 2 reviewers, a third reviewer has made the
final decision after discussion.

\textbf{GRADE assessment (Summary of findings table)}

GRADE pro GDT software was used to create the summary of findings table
.The data was imported from RevMan5 version 5.4 (Review manager software
2014) for the comparison of Seroconversion rate and GMT rate of MF 59
influenza vaccine in full dose vaccine compared to half dose vaccine
group in children. The quality of evidence was adjudged using Grading of
Recommendations, Assessment, Development, and Evaluation (GRADE) using
the Grade pro software {[}12{]}.

\textbf{RESULTS}

A total of 324 articles were retrieved from the various electronic
database searches (Embase, PubMed, Cochrane and clinical trials), of
which 36 duplicate articles were deleted and 288 articles were screened
for full text retrieval. Titles and abstracts of the remaining 40
articles were screened for full text retrieval of articles. Finally, 14
randomised controlled trials were included in the systematic
review\textbf{(Figure 1).} 26 articles were excluded (supplementary
table 1).Out of the included trials , 7 trials compared the cell culture
influenza vaccines with egg derived influenza vaccines
{[}4,6,7,9,13,14,15{]} , 4 trials compared the half dose vaccine with
the full dose vaccine of MF 59 influenza vaccine {[}3,8,17,18{]} and the
remaining 3 trials where results could not be pooled and have been
discussed {[}16, 19, 20{]}.

\textbf{Risk of Bias}

Random sequence generation (selection bias) was judged as low risk of
bias in 13 studies, as all the details of the randomisation method were
described. Allocation concealment was judged as low risk of bias in 2
studies as the allocation was concealed satisfactorily and the remaining
12 studies were judged as high risk of bias as the allocation
concealment was not mentioned. Performance Bias was assessed as high
risk of bias in 8 studies as the participants were not blinded, 6
studies reported low risk of performance bias as the participants and
personnel were blinded .11 studies reported as at low risk of detection
bias as the outcome assessors were blinded to the intervention group and
the 3 studies were assessed as at high risk of detection bias as the
outcome assessors were not blinded. Attrition bias was reported as at
low risk of bias in 14 studies as the loss to follow up was less than
10\%.Reporting Bias was judged as low risk of bias in 13 studies as the
outcomes were assessed properly and 1 study reported as high risk of
bias as the outcomes were not properly addressed. No other bias was
reported in 14 studies and was judged as at low risk of other bias

\textbf{(Figure 2(a) and 2(b)).}

\textbf{Synthesis of results}

\textbf{Any vaccine related adverse events}

Due to non-uniformity of reporting of data on adverse events across
different studies, the data could not be pooled. The data has been
summarised and presented in the form of Table and bar graphs.

\textbf{a.Cell culture influenza vaccines versus egg derived influenza
vaccines}

Out of the 7 studies, 6 studies reported local and systemic adverse
reactions in both the groups and 1 study did not report the adverse
events. Out of the 6 studies,3 studies reported less local adverse
events in cell culture influenza vaccine group as compared to egg
derived vaccines control group {[}7,13,14{]} and 5 studies reported more
systemic adverse events in cell culture vaccine experimental group as
compared to egg derived vaccine control group {[}4,6,7,9,14{]}

\textbf{(Table 1).}

The most commonly reported local adverse events were pain , redness ,
swelling, erythema and induration and were more reported in egg derived
influenza vaccine group as compared to cell culture influenza vaccine
group \textbf{(Bar graph 3(a)).} similarly, systemic adverse events (eg.
fever, muscle pain, irritability , diarrhoea , appetite, headache,
fatigue, antipyretics , vomiting and myalgia)were more reported in cell
culture vaccine experimental group as compared to egg derived control
group \textbf{(Bar graph 3 (b).}

\textbf{b.MF 59 influenza vaccine (full dose vaccine and half dose
vaccine control group)}

3 studies did not report uniformly on adverse events. Therefore, we were
not able to conduct meta-analysis of these 3 studies and we have
reported the data in table and bar graph format.3 studies reported the
adverse events in full dose and half dose vaccine of MF59 influenza
vaccine. Study done by Yasuda et al 2010 with children (6 months to 18
years of age) showed better results for half dose 3.75ug as compared to
full dose 7.5ug vaccine group .These results were incorporated by Fukase
etal 2012 along with adults as subjects. Therefore for data analysis
results from fukase study were included. 2 studies {[}3,17{]} reported
more adverse events in full dose 7.5ug vaccine group as compared to half
dose 3.75ug control group and 1 study {[}8{]} reported less adverse
events in full dose 7.5ug experimental group as compared to half dose
3.75ug control group \textbf{(Table 2).} 2 studies {[}8,17{]} reported
less systemic adverse events in full dose 7.5ug vaccine group as
compared to half dose 3.75ug control group and 1 study {[}3{]} reported
more systemic adverse events in full dose 7.5ug vaccine group as
compared to half dose 3.75ug control group \textbf{(Table 2).}

The most commonly reported local adverse events were
pain,erythema,swelling and tenderness and were more reported in full
dosefull dose 7.5ug vaccine group as compared to half dose 3.75ug
control group \textbf{(Bar graph 4(a)).} The systemic adverse events
(e.g. fever, vomiting ,irritability, unusual crying ,chills, myalgia,
arthralgia, fatigue, nausea, antipyretics ) were more reported in full
dose 7.5ug vaccine group as compared to half dose 3.75ug control group
and the other systemic adverse events eg. headache, sleepiness,
diarrhoea, change eating habits ,shivering, medication) were more
reported in half dose 3.75ug control group full dose 7.5ug vaccine group

\textbf{(Bar graph 4(b)).}

\textbf{2. Secondary outcomes}

\textbf{1. Geometric mean titres (GMT)}

\textbf{a. Cell culture influenza vaccines group versus egg derived
influenza vaccines control group}

Out of 7 studies, 5 studies measured geometric mean titres at day 0 and
day 28 {[}7, 9, 13, 14, 15{]}. We were unable to pool this data in the
meta-analysis as all the studies reported geometric mean titres of
different cell culture influenza vaccines .Detailed results are
tabulated \textbf{(Table 1).}

\textbf{b.MF 59 influenza vaccine (full dose vaccine and half dose
vaccine control group)}

A total of 3 studies were included in the meta-analysis for MF59
influenza vaccine for full dose and half dose vaccine group. \textbf{Fig
5(a) and 5(b)} show forest plots of the mean difference for the
geometric mean titres at Day 1 and Day 43. Significant results were
reported for half dose MF59 influenza vaccine control group at day 1
with a mean difference of 0.78, 95\%CI, 0.50 to 1.07,p\textless{}0.00001
as compared to full dose MF59 influenza vaccine experimental group .No
significant results were reported in half dose MF59 influenza vaccine at
Day 43(mean difference 151.57,95\% CI,-29.36 to 332.50 ,p=0.10) as
compared to full dose MF 59 Influenza vaccine.

\textbf{2. Seroconversion rate}

\textbf{a. Cell culture influenza vaccines group versus egg derived
influenza vaccines control group}

Out of the 7 studies, 4 studies measured seroconversion rate at day 28
in children {[}7, 9, 13, 14{]}. We were unable to pool these studies in
the meta-analysis due to non-uniform and heterogeneous data. Detailed
results are tabulated in the table below \textbf{(Table1).}

\textbf{b. MF 59 influenza vaccine (full dose vaccine and half dose
vaccine control group)}

For this analysis 2 studies were included in the meta-analysis for MF59
influenza vaccine for full dose and half dose vaccine group. \textbf{Fig
6} shows forest plots of the mean difference for the seroconversion rate
at Day 22 and Day 43. Significant results were reported for half dose
MF59 influenza vaccine control group at day 22 with a mean difference of
17.92,95\%CI,10.08 to 25.75,p\textless{}0.00001 as compared to half dose
MF59 influenza vaccine group at day 43 with a mean difference of
5.00,95\%CI,-4.80 to 14.80,p=0.32 .

\textbf{Quality of evidence (GRADE)}

Using the GRADE software, the certainty of evidence was assessed as high
for the Seroconversion rate at Day 22 and GMT at Day 1 of MF59 influenza
vaccine in half dose vaccine group as compared to full dose vaccine
group .The certainty of evidence was upgraded due to no serious risk of
bias and indirectness \textbf{(Table 3).}

\textbf{DISCUSSION}

Literature from the previous studies suggested cell culture derived
influenza vaccines to be more effective as shown by seroconversion rate
and GMT. Other benefits are that these vaccines are antibiotics and
preservatives free. Further, the cell culture derived vaccines can be
easily prevented from external contamination which is not in the case of
egg derived vaccines production process being open to the environment.
The production of cell culture vaccine can also be accelerated in times
of pandemic after identification of the viral strain {[}14{]}. Due to
the increased requirement of influenza vaccine, it is important to
develop different methods of production such as adjuvants use and modern
cell culture technology, to make sure that defined vaccines is available
universally {[}17{]}. Also, due to the fact that the vaccines are free
from egg-derived proteins, egg-allergic children can be immunized with
no adverse events.

This systematic review evaluated the safety and immunogenicity of cell
culture derived and egg derived influenza vaccines in healthy paediatric
population. The results of this review reported less local adverse
events but more systemic adverse events in cell culture derived
influenza vaccine group as compared to egg derived influenza vaccines.
The cell derived MF59 influenza vaccine showed better seroconversion
rate and GMT in half dose vaccine group in children less than 18 years
of age. Only one study reported the vaccine efficacy and is discussed
here. In the study done by Terence Nolan et al, efficacy of IIV4c
vaccine was studied in RT-PCR or culture-confirmed influenza. It was
found to be 54.0\% (95\% CI, 44.8 to 61.7) in participants with age
group of 3-18 years {[}6{]}.

Due to the heterogeneity of data three studies weren't included in the
meta-analysis. These three studies are being discussed here {[}19, 16,
20{]}. The study done by Eve Versage et al 2021 evaluated the safety and
immunogenicity of MF59-adjuvanted mammalian cell-based, A/H5N1 vaccine
through a review of four clinical trials with similar design. Recipients
of all ages were assessed for full-dose (7.5\selectlanguage{greek}µ\selectlanguage{english}gm) and (3.75 \selectlanguage{greek}µ\selectlanguage{english}gm)
formulations. Highest antibody titre was observed in children less than
3 years of age. Seroconversion criteria were met by antibody titres in
children 12 months after vaccination. This study also depicted that MF59
allowed for antigen dose sparing. All the trials showed cumulative
results of age related responses. The adolescents depicted highest
antibody titres. Also a single MF59-adjuvanted cell derived influenza
vaccine met all the CBER and CHMP licensure. Preparations carrying
7.5\selectlanguage{greek}µ\selectlanguage{english}gm and 3.75 \selectlanguage{greek}µ\selectlanguage{english}gm antigen per dose caused highest amount of antibody
titres after two doses {[}19{]}.

Another trial done on paediatric patients of the age groups (6 months to
17 years) by Pornthep C et al, 2021 suggested that when a full dose of
aH5N1c vaccine was administered in the form of two doses, three weeks
apart, reported in highest immunogenicity from baseline results for all
the five heterologous A/H5N1 strains.The findings of this study
suggested that an MF59-adjuvanted cell culture influenza vaccine
essential cross defence during the early phase of pandemic. A limitation
concern of this trial was the lack of comparator group. Smaller group of
subjects as sample size is another limitation of this trial {[}16{]}.

In another RCT done by Maikel V.W et al on children 6 months to 17 years
of age, the subjects were divided into groups Infants (6-35 months )and
children(3-8 years) of age and were randomized and administered 2
immunizations with 7.5\selectlanguage{greek}µ\selectlanguage{english}g or 3.75-\selectlanguage{greek}µ\selectlanguage{english}g hem agglutinin (HA) dose of
nonadjunvanted whole-virus A/Vietnam (H5N1 vaccine. This trial showed
that vaccine was safe with mild adverse reactions {[}20{]}.

Performance Bias was assessed as high risk of bias in 8 studies as the
participants were not blinded and 12 studies were judged as high risk of
bias as the allocation concealment was not mentioned. Using the GRADE
software, the certainty of evidence was assessed as high for the
Seroconversion rate at Day 22 and GMT at Day 1 of MF59 influenza vaccine
in half dose vaccine group.

The Limitations of the current systematic review, that we were not able
to pool the data of the primary outcome (adverse events) in the
meta-analysis due to non --uniformity of data and therefore have
provided in narrative and table formats.

In summary, the current systematic review demonstrated that half dose
cell derived influenza vaccines were well tolerated and more immunogenic
and resulted in high seroconversion rate and GMT in paediatric
population. Further, more trials are recommended in future.

\textbf{Acknowledgement:} Author's contributions: The articles were
screened by KK, MS, MR. PP did search of articles through different
electronic databases. Data extraction was done by KK, MR. Quality
assessment tool was used by KK, AC and SS to assess the quality of the
studies. Data was analyzed by KK \& MR using Revman 5.4. MS resolved the
Discrepancies. KK and RB wrote the initial draft and the final
manuscript was approved by all the authors. AC and MS Contributed in
editing and reviewed the final draft of the manuscript.MS helped in
critical revision and supervised the revised manuscript. This work is
supported by Evidence Based Medicine (EBM-Phase 2), ICMR, and New Delhi.

\textbf{Conflict of interest} : None

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20. van der Velden MV, Fritz R, Pöllabauer EM, Portsmouth D, Howard MK,
Kreil TR, et al. Safety and immunogenicity of a vero cell
culture-derived whole-virus influenza A(H5N1) vaccine in a pediatric
population. The Journal of infectious diseases. 2014;209(1):12-23.

\emph{Table 1: Study characteristics table of cell culture derived
Influenza vaccine versus egg derived influenza vaccine group}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllllllll@{}}
\toprule
\begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{S. No.}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Study ID}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Setting}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Age} \textbf{(6months -- 20 years)}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Intervention Group} (Cell Culture influenza vaccine)\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Control Group} (Egg derived influenza vaccine)\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Adverse Event} \textbf{(Cell culture influenza vaccine)}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Adverse Event} \textbf{(Egg derived influenza vaccine)}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Influenza vaccine Strain}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Seroconversion} \textbf{Day 28}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Seroconversion} \textbf{Day 28}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{GMT} \textbf{Day 0 Day 28}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{GMT} \textbf{Day 0 Day 28}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{GMT} \textbf{Day 0 Day 28}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{GMT} \textbf{Day 0 Day 28}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Intervention}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Control}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Intervention}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Control}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Intervention}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Control}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
1.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Waddington et al 2010{[}13{]}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Multicentric (UK,Oxford, Bristol,Southampton,Exeter and London)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
6 month to 12 yrs.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Non-adjuvanted whole virion H1N1 influenza vaccine Dose: 0.5ml\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
AS03\textsubscript{B} adjuvanted split virion influenza vaccine Dose:
0.5ml\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse reactions (19.60\%) Systemic adverse reaction
12.01\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse reactions 32.3\% Systemic adverse reaction 15.34\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
A/H1N1\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
78.2\selectlanguage{ngerman}±1.33\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
99.3\selectlanguage{ngerman}±0.31\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
4.6\selectlanguage{ngerman}±0.1\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
4.5\selectlanguage{ngerman}±0.08\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
69.3\selectlanguage{ngerman}±3.21\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
411\selectlanguage{ngerman}±10.96\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
2.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Vesikari et al 2012{[}14{]}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Multicentric(united states and Europe(Finland,Croatia Hungary,Lithuania
,Italy and Romania)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
3 yrs. to 17 yrs.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Cell culture derived influenza vaccine (CCIV) Dose: 0.5ml\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Egg derived influenza vaccine (TIV) Dose: 0.5ml\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse reactions 12.10\% Systemic adverse reaction 7.61\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse reactions 14.12\% Systemic adverse reaction 6.87\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
A/H1N1 A/H3N2 B influenza\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
77.93\selectlanguage{ngerman}±2.629 66.16±7.58 44.90±9.57\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
69.19\selectlanguage{ngerman}±4.5 77.78±1.61 45.23±13.77\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
29.87\selectlanguage{ngerman}±21.13 85.66±21.3 11.14±5.7\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
28.80\selectlanguage{ngerman}±26.28 90.87±32.6 7.01±1.56\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
413.52\selectlanguage{ngerman}±346.88 657.9±42.25 51.81±44.06\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
365.2\selectlanguage{ngerman}±394.74 1246.39±332.79 44.09±32.49\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
3.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Nolan et al 2016{[}4{]}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Multicentric(United states,Australia,New Zealand,The Philippines and
Thailand)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
4 yrs. to 17 yrs.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Cell culture derived influenza vaccine (TIVc) Dose: 0.5ml\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Egg based influenza vaccine (TIVf) Dose: 0.5ml\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse reactions 20.40\% Systemic adverse reaction 10.18\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse reactions 17.90\% Systemic adverse reaction 8.55\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Not mentioned\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
--\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
4.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Eun et al 2016{[}7{]}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
South Korea\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
6 month to 18 yrs of age\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Cell culture derived influenza vaccine(NBP607) Dose: 0.5ml\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Egg derived vaccine(1B) Dose: 0.25 or 0.5ml\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse reactions 14.45\% Systemic adverse reaction 6.5\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse reactions 16.15\% Systemic adverse reaction 5.97\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
A/H1N1 A/H3N2 B/Yamagata B/ Victoria\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
62.8\selectlanguage{ngerman}±1.66 57.8±1.7 59.4±1.68 50±1.73\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
62.4\selectlanguage{ngerman}±3.43 57.7±3.51 57.7±3.51 23.5±3.01\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
95.1\selectlanguage{ngerman}±5.48 146.7±8.76 22.8±1.03 23.5±1.03\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
88.2\selectlanguage{ngerman}±9.8 172.2±19.53 22.2±2.06 21.2±2.06\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
432.1\selectlanguage{ngerman}±17.11 527.9±20.48 99.6±4 84.6±3.75\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
412\selectlanguage{ngerman}±37.1 589.9±49.2 86.8±7.18 49.9±4.48\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
5.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Oh et al 2018{[}9{]}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Republic of Korea\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
6 month to 18 yrs of age\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Cell culture derived influenza vaccine(NBP607) Dose: 0.5ml\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Inactivated subunit trivalent influenza vaccine Dose: 0.5ml\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse reactions 15.70\% Systemic adverse reaction 6.20\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse reactions 15.14\% Systemic adverse reaction 5.95\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
A/H1N1 A/H3N2 B influenza\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
80.8\selectlanguage{ngerman}±1.5 47.8±1.9 48.2±1.88\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
81.8\selectlanguage{ngerman}±2.86 49.4±3.88 49.4±3.71\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
67.3\selectlanguage{ngerman}±4.11 185.3±10.53 29.2±1.13\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
52.4\selectlanguage{ngerman}±6.05 211.5±29.18 25.5±2\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
625.2\selectlanguage{ngerman}±29.9 572.2±23.11 91.6±3.91\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
475.5\selectlanguage{ngerman}±43.81 732.5±59.03 93.2±8.93\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
6.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Moehling et al 2020{[}15{]}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
U.S.A\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
4 yrs. to 20 yrs\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Cell culture derived influenza vaccine (ccIIV4)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Egg derived vaccone (IIV4)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Not mentioned\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Not mentioned\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
A/H1N1 A/H3N2 B/Yamagata B/ Victoria\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-- -- -- --\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-- -- -- --\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
117\selectlanguage{ngerman}±10.83 100±9.83 130±11.66 109±9.83\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
111\selectlanguage{ngerman}±14.75 93±15.5 102±13.5 98±14.25\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
292\selectlanguage{ngerman}±20.16 265±26.83 193±13.66 232±21.66\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
241\selectlanguage{ngerman}±28.5 174±25.25 200±21.75 233±26.5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
7.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Nolan et al 2021{[}6{]}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Multicentric(Australia,the Philippines and Thailand)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
2 yrs. to 18 yrs.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Cell culture derived influenza vaccine (IIV4c) Dose: 0.5ml\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Meningococcal oligosaccharide diphtheria CRM197 conjugate vaccine
Dose:0.5ml\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse reactions 36.7\% Systemic adverse reaction 31.3\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse reactions 33.5\% Systemic adverse reaction 30.5\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Not mentioned\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
--\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\emph{Table 2: Study characteristics table of MF59 Influenza vaccine in
Full Dose vaccine group Versus Half Dose vaccine group}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllllllll@{}}
\toprule
\begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{S. No.}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Study ID}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Setting}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Age(6 months -18 years )}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Intervention Group} \textbf{(}Full Dose 7.5\selectlanguage{greek}µ\selectlanguage{english}g + 50\%)\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Control Group} (Half Dose 3.75\selectlanguage{greek}µ\selectlanguage{english}g + 50\%)\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Influenza vaccine Strain}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Seroconversion} \textbf{Day 22 Day 43}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Seroconversion} \textbf{Day 22 Day 43}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Seroconversion} \textbf{Day 22 Day 43}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Seroconversion} \textbf{Day 22 Day 43}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{GMT} \textbf{Day 1 Day 43}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{GMT} \textbf{Day 1 Day 43}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{GMT} \textbf{Day 1 Day 43}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{GMT} \textbf{Day 1 Day 43}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Intervention}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Control}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Intervention}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Control}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Intervention}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Control}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Intervention}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{Control}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{Mean±SD}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
1.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Fukase et al 2012{[}17{]}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Japan\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
6month to 18 yrs.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse Reactions 33.58\% Systemic Adverse Reactions 8.88\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse Reactions 29.2\% Systemic Adverse Reactions 9.76\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
A/H1N1\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
78\selectlanguage{ngerman}±5\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
56\selectlanguage{ngerman}±6.75\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
100\selectlanguage{ngerman}±1.5\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
100\selectlanguage{ngerman}±1.5\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
6.23\selectlanguage{ngerman}±0.405\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
5.24\selectlanguage{ngerman}±0.352\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
596\selectlanguage{ngerman}±70.75\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
355\selectlanguage{ngerman}±43.75\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
2.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Knuf et al 2014{[}3{]}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Multicentric(Germany,Belgium,Dominician republic and Netherlands)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
6month to 17 yrs.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse Reactions 22.8\% Systemic Adverse Reactions 14.50\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse Reactions 12.25\% Systemic Adverse Reactions 13\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
A/H1N1\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\_\_\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\_\_\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\_\_\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\_\_\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
6.89\selectlanguage{ngerman}±2.73\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
6.98\selectlanguage{ngerman}±2.58\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
743.71\selectlanguage{ngerman}±303.62\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
538.34\selectlanguage{ngerman}±224.97\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
3.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Chanthavanich et al 2019{[}8{]}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
United states and Thailand\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
6 months to 17 yrs.\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse Reactions 14.87\% Systemic Adverse Reactions 15.6\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Local Adverse Reactions 15\% Systemic Adverse Reactions 17.62\%\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
A/H5N1\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
52\selectlanguage{ngerman}±2\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
38\selectlanguage{ngerman}±2\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
96\selectlanguage{ngerman}±0.83\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
86\selectlanguage{ngerman}±1.5\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
13\selectlanguage{ngerman}±1.33\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
7\selectlanguage{ngerman}±0.66\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
262\selectlanguage{ngerman}±24.83\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
84\selectlanguage{ngerman}±8\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\textbf{Table 3 :Summary of findings table of seroconversion rate and
GMT rate in full dose vaccine versus half dose vaccine group(MF 59
influenza vaccine)}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`figures-influenza-vaccines.tiff`  available at \url{https://authorea.com/users/520703/articles/593937-efficacy-of-cell-culture-derived-influenza-vaccines-for-children-a-systematic-review-and-meta-analysis}

\selectlanguage{english}
\FloatBarrier
\end{document}

