Types of studies

Randomized controlled trials (RCTs).

Types of participants

People with SCD including SS, SC, SD, Sβ0, Sβ+ (confirmed by Hb electrophoresis and sickle solubility test, with family studies or DNA tests as appropriate) of all ages and both sexes, in any setting.

Types of interventions

We had planned to review all studies that compared the use of either the inactivated vaccine or an oral attenuated vaccine with a placebo. Studies that also compare the efficacy of one vaccine type over another were to be examined as follows:

1. inactivated vaccine versus placebo;

2. oral attenuated vaccine versus placebo;

3. inactivated vaccine versus oral attenuated vaccine.

Types of outcome measures

Electronic searches

We searched for relevant randomized controlled trials from the Group's Haemoglobinopathies Trials Register using the terms: (sickle cell OR (haemoglobinopathies AND general)) AND immunisation AND vaccine AND salmonella.

The Haemoglobinopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library) and weekly searches of MEDLINE. Unpublished work is identified by searching the abstract books of five major conferences: the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Caribbean Public Health Agency Annual Scientific Meeting (formerly the Caribbean Health Research Council Meeting); and the National Sickle Cell Disease Program Annual Meeting. For full details of all searching activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group's website.

Date of the most recent search of the Groups Haemoglobinopathies Trials Register: 17 October 2018.

In addition to the above search, we conducted a further subject‐specific electronic search of LILACS on the 26 June 2014 for all publication years. Please refer to the appendices section for further details (Appendix 1).

We also conducted a search of the World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch) (using the terms salmonella AND sickle cell disease) and ClinicalTrials.gov (www.clinicaltrials.gov) (using the terms sickle AND salmonella). Date of most recent search: 17 October 2018.

Searching other resources

We examined the reference lists of any potential clinical trials and the review authors' personal databases of trial reports in an attempt to identify any additional studies or those not identified in the searches. We also attempted to contact investigators of included studies by either conventional or electronic mail to ask for details of additional published and unpublished trials.

Selection of studies

Two authors Friday Odey (FO) and Uduak Okomo (UO) will independently assess the abstracts of studies resulting from the searches. We will obtain full copies of all relevant and potentially relevant studies, those appearing to meet the inclusion criteria, or for which there were insufficient data in the title and abstract to make a clear decision. We will also assess the full text papers independently and resolve any disagreement on the eligibility of included studies through discussion and consensus. Any discrepancies occurring in the trial selection will be resolved by the third author (AO). After assessment, we will eliminate from further review any remaining studies that do not match the inclusion criteria and note the reasons for their exclusion in the Characteristics of excluded studies table.

Data extraction and management

Two authors (FO and AO) will independently extract the data. One authors (FO) will enter the data into the Review Manager software (RevMan 2014), while the second author (AO) will confirm that any data entered are accurate. The authors will seek advice from the Cochrane Cystic Fibrosis and Genetic Diseases Group with regards to data synthesis when necessary.

We will collect outcome data using a pre‐determined form designed for this purpose. Extracted data will be entered into Review Manager (RevMan 2014). Friday Odey (FO) will hold the master copy. We aim to resolve any disagreements regarding data entry through discussion between the authors. If necessary, we will seek advice from the editor. We will record the following information.

1. Study methods

   1. method of allocation

   2. masking of participants and outcomes

   3. exclusion of participants after randomization and proportion of losses at follow‐up

2. Participants

   1. country of origin

   2. number of participants

   3. age

   4. sex

   5. inclusion and exclusion criteria

3. Intervention

   1. type of the vaccine

   2. dose

   3. route of administration

   4. duration and length of time in follow‐up

4. Control

   1. control or placebo

5. Outcomes

   1. primary and secondary outcomes listed in 'Types of outcome measures'. We will use dichotomous and continuous variables in analysing data. We will use this information to help assess heterogeneity and the external validity of the trials.

Assessment of risk of bias in included studies

In order to assess the risk of bias, two authors (FO and UO) will assess the selected studies independently and assess every study reporting a randomized clinical trial according to the system described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will compare the assessments and discuss and resolve any inconsistencies in the interpretation of inclusion criteria and their significance to the selected studies. We will assess the risk of bias as follows.

Measures of treatment effect

For the dichotomous outcome variables of each individual study (e.g. acute morbidity from salmonella infection (any cause); mortality; chronic complications (any cause); serum opsonic activity; limitation of physical or role activity; absence from school or work), we will calculate the odds ratio (OR). The authors also plan to report count data during the effective period of the vaccine as the endpoint may occur more than once. We will also calculate the summary weighted odds ratios and 95% confidence intervals (CIs) (fixed‐effect model) using the Review Manager software (RevMan 2014). Numbers‐needed‐to‐treat (NNT) and their 95% CIs will be calculated from the pooled OR and its 95% CI for a specific baseline risk, which is the sum of all the events in the control groups (in all studies) divided by the total participant numbers in control groups in all studies using an online calculator (Cates 2003).

For continuous outcomes (antibody levels; frequency of bodily pains; frequency of hospitalisation), we will record the mean relative change from baseline for each group or mean post‐treatment or post‐intervention values and standard deviation. If standard errors are reported, we will calculate the standard deviations. We will then calculate a pooled estimate of treatment effect by the mean difference and 95% CI (fixed‐effect model) again using Review Manager (RevMan 2014).

Dealing with missing data

If data are missing from the published studies, then the authors will contact the study investigators for clarification.

Assessment of heterogeneity

The authors plan to assess clinical heterogeneity by examining the characteristics of the studies; the similarity between the types of participants, the interventions and the outcomes. We will assess statistical heterogeneity using a Chi² test in addition to the I² test, where I² values over 50% indicate moderate to high heterogeneity (Higgins 2003).

Assessment of reporting biases

If the authors identify sufficient RCTs, we will to attempt to assess publication bias using a funnel plot (Egger 1997). If asymmetry is found, we intend to investigate the reasons for this.

Data synthesis

We will only pool the results of any clinically and statistically homogeneous trials to provide estimates of the efficacy of the interventions if the studies have similar interventions received by similar participants.

For meta‐analysis of quantitative data the authors will use the fixed‐effect model for homogeneous data sets. If we establish that there is significant heterogeneity between the studies, to take this into account we will use the random‐effects model.

Subgroup analysis and investigation of heterogeneity

If we find heterogeneity and sufficient studies are included, the authors intend investigate the causes further. We plan to perform subgroup analysis and investigate heterogeneity (clinical, methodological and statistical) among the different subgroups. Such groups will include:

1. sickle cell anaemia versus sickle cell beta‐0;

2. sickle cell SC versus sickle cell SD;

3. sickle cell beta‐0 versus sickle cell beta‐+;

4. children versus adults;

5. tropical versus temperate environment.

Sensitivity analysis

If there are sufficient studies for inclusion, we plan to conduct sensitivity analyses to assess the robustness of the review's results by repeating the analysis with the following adjustments: exclusion of studies with unclear or inadequate allocation concealment; and unclear or no blinding. In addition, we may undertake sensitivity analyses to examine the effect of randomisation, blind outcome assessment and completeness of follow‐up.