Supplementary Figure legends

Supplementary Figure 1. Risk of bias assessment graph of included randomized controlled trials.

Supplementary Figure 2. Risk of bias assessment summary.

Supplementary Figure 3. Arthralgia results of random effect meta-analysis using R meta package.

Supplementary Figure 4. Arthralgia linear regression test of funnel plot asymmetry using R meta

package.

Supplementary Table legends

Supplementary Table 1. PRISMA 2009 Checklist.

Supplementary Table 2. Manipulation guides for online database searches.

Supplementary Table 3. Detailed search strategy for tweleve database searches.

Supplementary Table 4. Baseline characteristics of the patients in the included studies.

Supplementary File legends

Supplementary File 1. Prospero protocol template file.

Supplementary File 2. Extraction equations that can be used prior to analysis to get missed variables.

Supplementary File 3. R codes and its guidance for meta-analysis done for comparison between

EBOLA vaccine A and placebo.

Supplementary Data 1. Extraction and quality assessment sheets for EBOLA case example.

Supplementary Data 2. Imaginary data for EBOLA case example.

Supplementary Table 1. PRISMA 2009 Checklist

Section/topic # Checklist item Reported on page

#
TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both.

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study
eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results;
limitations; conclusions and implications of key findings; systematic review registration number.

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known.

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions,
comparisons, outcomes, and study design (PICOS).

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available,
provide registration information including registration number.

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years
considered, language, publication status) used as criteria for eligibility, giving rationale.

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to
identify additional studies) in the search and date last searched.
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it
could be repeated.

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if
applicable, included in the meta-analysis).

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and
any processes for obtaining and confirming data from investigators.

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any
assumptions and simplifications made.

Risk of bias in individual 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether
studies this was done at the study or outcome level), and how this information is to be used in any data
synthesis.

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means).

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of
consistency (e.g., I2) for each meta-analysis.

Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias,
selective reporting within studies).

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if
done, indicating which were pre-specified.

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for
exclusions at each stage, ideally with a flow diagram.
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up
period) and provide the citations.

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

Results of individual 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for
studies each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15).

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see
Item 16]).

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their
relevance to key groups (e.g., healthcare providers, users, and policy makers).

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete
retrieval of identified research, reporting bias).

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future
research.

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of
funders for the systematic review.
Supplementary Table 2. Manipulation guides for online database searches
No. Databases Explanation
(Total 12)

1 PubMed 1. Perform PubMed search.

2. Choose the reports that the reviewer wants to export (if reviewer does not choose any report, PubMed system will automatically
select all).0
3. Click on Send To, choose File.
4. Choose MEDLINE format.
5. Click Create File.
6. Move PubMed file to a suitable directory.
2 Scopus 1. Perform Scopus search.
2. Select all articles.
3. Click on Export.
4. On the new interface, choose RIS format.
5. At Choose the Information to export, choose All available information.
6. Click on Export.
7. Move Scopus file to a suitable directory.
3 ISI (WOS) 1. Perform ISI search.
2. Select all articles.
3. In the Save to panel, click on EndNote.
4. Move ISI file to a suitable directory.
4 GHL 1. Perform WHO Global Health Library search.
2. Click on Send Results, tab Export.
3. Choose All references.
4. Choose RIS for export format.
5. Click on Send.
6. Move WHO-GHL file to a suitable directory.
5 VHL 1. Perform VHL search.
2. Click on Export button (next to the Print button).
3. At Export format, choose RIS.
4. At Export, choose All references.
5. Move VHL file to a suitable directory.
6 POPLINE 1. At Export Search Results, click on RIS to download to get Popline file for
2. Move Popline file to suitable directory.
3. Perform the same task for the rest pages until reviewers get all necessary files.
4. Finally, move all files to a suitable directory.
7 Cochrane 1. Perform Cochrane search.

8 EMBASE 1. Perform EMBASE search.

9 mRCT 1. Perform mRCT search.

10 Clinical 1. Perform Clinical trial search.

trial.gov

11 Google 1. Perform Google Scholar search.

2. Click on Settings.
Scholar
3. At Results per page, change to 20.
4. At Bibliography manager, choose Show links to import citations into EndNote, then click Save.
5. On Navigation Toolbar in Google chrome browser, click on the Zotero icon.
6. Choose Select All in the drop down window, and then click OK.
7. Move to the next pages and perform the same task (step (5) and (6)).
8. At the bottom-right corner of the browser (on Add-on Bar), click on the Zotero
9. On the new interface, click on Actions button, choose Export library.
10. Choose RIS format.
11. Click OK.
12. Move the exported Google Scholar file to a suitable directory.
12 SIGLE 1. Perform SIGLE search.
2. Click on the Zotero icon in the URL bar to export references to Zotero.
3. Then, do the same steps described above for Google Scholar.
Supplementary Table 3. Detailed search strategy for twelve database searches

No. Databases Search Terms Results

(Total 12)
Total = 1785

1 PubMed (ebola OR ebola virus OR ebola virus disease OR EVD) AND (vaccine OR vaccination OR 205
vaccinated OR immunization) AND ("clinical trial"[Publication Type] OR "clinical trials as
topic"[MeSH Terms] OR "clinical trial"[All Fields])
2 Scopus TITLE-ABS-KEY 282
( ( ebola OR ebola AND virus OR ebola AND virus
AND disease OR evd ) AND ( vaccine OR vaccination OR vaccinated OR immunizat
ion ) AND "clinical trial" )
3 ISI (WOS) 91
4 EMBASE 457
5 GHL (ebola OR ebola virus OR ebola virus disease OR EVD) AND (vaccine OR vaccination OR 245
vaccinated OR immunization) AND "clinical trial"
6 VHL 80
7 Cochrane 65
8 Google Where my words occur: in the title of the article: 272 + 5 = 277
Scholar 1. With all of the words: ebola virus
With at least one of the words: vaccine vaccination vaccinated immunization
2. With all of the words: EVD
With at least one of the words: vaccine vaccination vaccinated immunization
9 Clinical Condition or disease: ebola OR ebola virus OR ebola virus disease OR EVD 62
trial.gov
Other terms: vaccine OR vaccination OR vaccinated OR immunization
10 mRCT (ebola OR ebola virus OR ebola virus disease OR EVD) AND (vaccine OR vaccination OR 4
vaccinated OR immunization) AND "clinical trial"
11 POPLINE 14
12 SIGLE (ebola OR EVD) AND (vaccine) 3
Supplementary Table 4. Study and patient characteristics of the included studies

Author/Year/ Study design Sample Mean Male Study Arms (event/total) Quality Follow up
Country of patients size age event (Arthralgia outcome) assessment grade (months)
(years (%) Vaccine Placebo (Score)
)
Study1/2016/Japan Cohort 220 32 100 (45.5) 30/120 20/100 Good (10) 3
Study2/2018/Vietnam Cohort 160 35 95 (59.4) 15/90 12/70 Fair (7) 5
Study3/2017/USA Cohort 200 30 100 (50) 25/110 24/90 Good (11) 8
Study4/2015/Egypt Cross-sectional 165 25 50 (30.3) 17/85 14/80 Good (12) 2
Study5/2012/India Cross-sectional 132 50 70 (53) 14/72 12/60 Fair (9) 7
Study6/2012/UK Cross-sectional 225 53 150 (66.7) 23/115 18/100 Poor (5) 7
Supplementary File 1. Prospero protocol template file

PROSPERO International prospective register of systematic reviews

Review title and timescale

1 Review title
Give the working title of the review. This must be in English. Ideally it should state succinctly
the interventions or exposures being reviewed and the associated health or social problem being
addressed in the review.

2 Original language title

For reviews in languages other than English, this field should be used to enter the title in the
language of the review. This will be displayed together with the English language title.
3 Anticipated or actual start date
Give the date when the systematic review commenced, or is expected to commence.

4 Anticipated completion date

Give the date by which the review is expected to be completed.

5 Stage of review at time of this submission

Indicate the stage of progress of the review by ticking the relevant boxes. Reviews that have
progressed beyond the point of completing data extraction at the time of initial registration are
not eligible for inclusion in PROSPERO. This field should be updated when any amendments
are made to a published record.
The review has not yet ×
started

Review stage Started Completed

Preliminary searches Yes Yes
Piloting of the study selection process Yes Yes
Formal screening of search results against eligibility criteria Yes No
Data extraction No No
Risk of bias (quality) assessment No No
Data analysis No No

Provide any other relevant information about the stage of the review here.

Review team details

6 Named contact
The named contact acts as the guarantor for the accuracy of the information presented in the
register record.

7 Named contact email

Enter the electronic mail address of the named contact.
8 Named contact address
Enter the full postal address for the named contact.

9 Named contact phone number

Enter the telephone number for the named contact, including international dialing code.

10 Organisational affiliation of the review

Full title of the organisational affiliations for this review, and website address if available. This
field may be completed as 'None' if the review is not affiliated to any organisation.
Website address:

11 Review team members and their organisational affiliations

Give the title, first name and last name of all members of the team working directly on the
review. Give the organisational affiliations of each member of the review team.
Title First name Last name Affiliation

12 Funding sources/sponsors
Give details of the individuals, organizations, groups or other legal entities who take
responsibility for initiating, managing, sponsoring and/or financing the review. Any unique
identification numbers assigned to the review by the individuals or bodies listed should be
included.

13 Conflicts of interest
List any conditions that could lead to actual or perceived undue influence on judgements
concerning the main topic investigated in the review.
Are there any actual or potential conflicts of interest?

14 Collaborators
Give the name, affiliation and role of any individuals or organisations who are working on the
review but who are not listed as review team members.
Title First name Last name Organisation details

Review methods

15 Review question(s)
State the question(s) to be addressed / review objectives. Please complete a separate box for
each question.

16 Searches
Give details of the sources to be searched, and any restrictions (e.g. language or publication
period). The full search strategy is not required, but may be supplied as a link or attachment.

17 URL to search strategy

If you have one, give the link to your search strategy here. Alternatively you can e-mail this to
PROSPERO and we will store and link to it.

18 Condition or domain being studied

Give a short description of the disease, condition or healthcare domain being studied. This could
include health and wellbeing outcomes.
19 Participants/population
Give summary criteria for the participants or populations being studied by the review. The
preferred format includes details of both inclusion and exclusion criteria.

20 Intervention(s), exposure(s)
Give full and clear descriptions of the nature of the interventions or the exposures to be
reviewed

21 Comparator(s)/control
Where relevant, give details of the alternatives against which the main subject/topic of the
review will be compared (e.g. another intervention or a non-exposed control group).

22 Types of study to be included

Give details of the study designs to be included in the review. If there are no restrictions on the
types of study design eligible for inclusion, this should be stated.

23 Context
Give summary details of the setting and other relevant characteristics which help define the
inclusion or exclusion criteria.

24 Primary outcome(s)
Give the most important outcomes.
Give information on timing and effect measures, as appropriate.

25 Secondary outcomes
List any additional outcomes that will be addressed. If there are no secondary outcomes enter
None.
Give information on timing and effect measures, as appropriate.

26 Data extraction (selection and coding)

Give the procedure for selecting studies for the review and extracting data, including the number
of researchers involved and how discrepancies will be resolved. List the data to be extracted.

27 Risk of bias (quality) assessment

State whether and how risk of bias will be assessed, how the quality of individual studies will be
assessed, and whether and how this will influence the planned synthesis.
.
28 Strategy for data synthesis
Give the planned general approach to be used, for example whether the data to be used will be
aggregate or at the level of individual participants, and whether a quantitative or narrative
(descriptive) synthesis is planned. Where appropriate a brief outline of analytic approach should
be given.

29 Analysis of subgroups or subsets

Give any planned exploration of subgroups or subsets within the review. ‘None planned’ is a
valid response if no subgroup analyses are planned.

Review general information

30 Type and method of review

Select the type of review and the review method from the drop down list.

31 Language
Select the language(s) in which the review is being written and will be made available, from the
drop down list. Use the control key to select more than one language.
Will a summary/abstract be made available in English?

32 Country
Select the country in which the review is being carried out from the drop down list. For multi-
national collaborations select all the countries involved. Use the control key to select more than
one country.

33 Other registration details

Give the name of any organisation where the systematic review title or protocol is registered
together with any unique identification number assigned. If extracted data will be stored and
made available through a repository such as the Systematic Review Data Repository (SRDR),
details and a link should be included here.

34 Reference and/or URL for published protocol

Give the citation for the published protocol, if there is one.
Give the link to the published protocol, if there is one. This may be to an external site or to a
protocol deposited with CRD in pdf format.
I give permission for this file to be made publicly available

35 Dissemination plans
Give brief details of plans for communicating essential messages from the review to the
appropriate audiences.
Do you intend to publish the review on completion?

36 Keywords
Give words or phrases that best describe the review. (One word per box, create a new box for
each term)

37 Details of any existing review of the same topic by the same authors
Give details of earlier versions of the systematic review if an update of an existing review is
being registered, including full bibliographic reference if possible.

38 Current review status

Review status should be updated when the review is completed and when it is published.

39 Any additional information

Provide any further information the review team consider relevant to the registration of the
review.
Supplementary File 2. Extraction equations that can be used prior to analysis to get missed

variables

Estimation of mean and SD

When the included study had reported the mean/median, range, and the sample size, the mean and SD
were estimated by following equations [1]:

min+2 median+ max when sample size 25

mean=
4

mean= median when sample size >25

√ [ ]
2 when sample size 15
1 (min−2 median+max ⁡) 2
SD= +(max−min)
12 4

max−min when sample size >15-70

SD=
4

max−min when sample size >70

SD=
6

Estimation of unreported SD [2]

When the study reported the mean only, linear (log( SD) vs log(mean)) chart was used, in which
values were extracted from other included studies.[1,2]
log(unreported SD) = Log(reported mean)*a+b
References supplementary Table 3
[1] Hozo SP, Djulbegovic B, Hozo I (2005) Estimating the mean and variance from the median,
range, and the size of a sample. BMC Med Res Methodol 5: 13.
[2] van Rijkom HM, Truin GJ, van 't Hof MA (1998) A meta-analysis of clinical studies on the caries-
inhibiting effect of fluoride gel treatment. Caries Res 32: 83-92.
Supplementary File 3. R codes and its guidance for meta-analysis done for comparison between

EBOLA vaccine A and placebo

#Meta-analysis of Ebola vaccine safety

#1. Load meta package and xlsx package to load Excel table
library(meta)
library(xlsx)

#2. Load the data in Excel (note, naming the data is free, vaccinesafety.dat. You should not use
"space" in R for the name)
vaccinesafety.dat<-read.xlsx("D:\\Researcher\\S16\\imaginary data set.xlsx", sheetName="Safety")
#The directory is depend on where you save the file (just right click the file and choose properties,
copy paste the file location and make it similar to the format in this example)
vaccinesafety.dat
#Since many adverse events reported, we can do meta analysis to evaluate the odd of adverse event
(each of them) and subgroup analysis
#First, do meta analysis of adverse event arthralgia by applying below codes

#3. Load only arthralgia data

arthralgia.dat<-vaccinesafety.dat[1:6,] #vaccinesafety.dat[1:6,] means load row 1 to 6, all columns
arthralgia.dat

#4. Meta analysis of adverse events arthralgia (to learn about the code more, please check the
guideline of meta package in the link provided at manuscript)
OR.arthralgia = metabin (et, nt, ec, nc, studlab = Study, data = arthralgia.dat, method = "Inverse", sm
= "OR")
print(summary(OR.arthralgia), digits = 2)
forest(OR.arthralgia, comb.fixed = FALSE,lab.e="Vaccine A", lab.c="Placebo", xlab="Odds of
arthralgia", col.square = "green", col.diamond = "blue", print.Q = TRUE, print.pval.Q = TRUE)
funnel(OR.arthralgia)
metabias(k.min=6, OR.arthralgia)

#5. The meta analysis above for arthralgia should be repeated for each of the adverse events.
Start from loading the data of only specific adverse events desired (from step 3)
#Finally, subgroup analysis of adverse events related to Ebola vaccine A
OR.adverseevents = metabin (et, nt, ec, nc, studlab = Study, data = vaccinesafety.dat, method =
"Inverse", sm = "OR")
print(summary(OR.adverseevents), digits = 2)

#6. Subgroup analysis

analysis2<-update(OR.adverseevents, byvar=Adverse.events, print.byvar=FALSE)
print(summary(analysis2), digits=2)