Comparison of school based and supplemental vaccination strategies in the delivery of vaccines to 5-19 year olds in Africa - a systematic review

Background: Some vaccine preventable diseases (VPDs) still remain a public health burden in many African countries. The occurrence of VPDs in all age groups has led to the realization of the need to extend routine immunisation services to school age children, adolescents and adults. Supplemental immunisation activities (SIAs) and school based vaccinations (SBVs) are common strategies used to complement the expanded programme on immunisation (EPI). This review aimed to assess the effectiveness of SIAs compared to SBVs in the administration of vaccines to 5-19 year olds in Africa. Methods: Systematic review methods were used to address our study aim. Several electronic databases were searched up to March 30, 2017 for primary studies investigating the delivery of vaccines via SIAs or SBVs to 5-19 year olds. This search was complemented by browsing reference lists of potential studies obtained from search outputs. Outcomes considered for inclusion were: vaccination coverage, costs of the strategy or its effect on routine immunisation services. Results: Out of the 4938 studies identified, 31 studies met the review inclusion criteria. Both SIAs and SBVs showed high vaccination coverage. However, the SIAs reported higher coverage than SBVs: 91% (95% CI: 84%, 98%) versus 75% (95% CI: 67%, 83%). In most settings, SBVs were reported to be more expensive than SIAs. The SIAs were found to negatively affect routine immunisation services. Conclusions: Both SIAs and SBVs are routinely used to complement the EPI in the delivery of vaccines in Africa. In settings where school enrolment is suboptimal, as is the case in many African countries, our results show SIAs may be more effective in reaching school age children and adolescents than SBVs. Our results re-iterate the importance of evaluating systematic evidence to best inform African authorities on the optimal vaccine delivery strategies targeting school age children and adolescents.


Introduction
The Expanded Programme on Immunisation (EPI) was founded in 1974 to provide immunisation services to children, both nationally and globally 1 . The EPI has proven to be a cost effective public health strategy, with reports suggesting that because of the programme, millions of infants' lives globally have been saved against vaccine preventable diseases (VPDs) 1 . Despite the widespread implementation of EPI, some VPDs still remain a public health burden in most of the African countries 2,3 . Suboptimal vaccination coverage rates in children targeted by the EPI and the inability to expand vaccination services to populations not targeted by the routine immunisation are some of the likely contributors to the high prevalence of VPDs in Africa 4,5 .
Routinely, school aged children and adolescents are not the primary target of EPI and as a result, an immunisation gap among these age groups has been observed in many settings 6 . To address the immunisation gap, the WHO has recommended the inclusion of several vaccines targeting school aged children and adolescents in national immunisation programmes (NIPs). The WHO recommended vaccines for older children include those against the following pathogens: human papillomavirus (HPV), diphtheria, tetanus, pertussis, measles, rubella, hepatitis B and meningococcus 6,7 . A majority of the High Income Countries (HICs) have implemented the WHO recommendations of vaccinating the older children, but this is not the case with the Low and Middle Income Countries (LMICs) [8][9][10] .
Several reasons justify the inclusion of school aged children and adolescents into NIPs. First, infants who miss routine vaccinations remain susceptible to VPDs later in life 6,11 . Second, immunity acquired through infant immunisation for some VPDs like tetanus and pertussis wanes over time, thus requiring booster doses later in life 12 . Third, there are epidemiological changes of some VPDs like rubella where more infection rates have shifted from infancy to adolescence, thus requiring a review of immunisation policies 13 . Lastly, new vaccines under development such as against HIV and tuberculosis (TB) are likely to target older children and adolescents. In the absence of structured vaccine delivery programs for school age children and adolescents, many settings use school based vaccinations (SBVs) and supplementary immunisation activities (SIAs).
Supplementary immunisation activities, also known as mass vaccination campaigns refer to an immunisation strategy where a large number of people are vaccinated within a defined geographical area and period, regardless of previous vaccination status 14 . The success of SIAs in disease outbreak control as well as in the eradication of smallpox is well documented 14-17 . However, there are reports suggesting negative effects of SIAs on the routine health services, including EPI 18,19 .
School based vaccinations (SBVs) target school going children on school premises and within school hours. The SBVs delivery strategy is newer to the EPI compared to SIAs 20 , particularly in Africa. Currently, and in Africa, the main vaccine administered through SBVs is against HPV. Advantages of SBVs include high vaccination coverage and the possibility to extend other health services offered to school age children [21][22][23] . However, in Africa, there are millions of children not attending school 24 and are missed by SBVs strategy.
Our study aimed to compare the effectiveness of using SIAs or SBVs to deliver vaccines to 5-19 year olds in Africa.

Methods
This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Checklist (Supplementary File 1). The protocol was registered with PROSPERO (CRD42017057475) 25 .

Study selection
The following criteria was used to select primary studies for inclusion: (1) the study was either a randomised controlled trial (RCTs), non-RCT, cluster-RCT, interrupted time series, controlled before-and-after, cohort, cross-sectional or case-control; (2) participants were school aged children or adolescents (5-19 years) living in Africa; (3) SIAs or SBVs were the vaccination strategies under investigation; (4) vaccination coverage, cost of vaccine delivery or effects of either strategy (SIAs or SBVs) on routine health services including EPI were reported as any of the outcomes. Retrieved articles were independently screened by two reviewers (HEC and LA). Where study eligibility was unclear, a review was carried out by a third independent study team member (BK).

Data extraction
HEC and LA independently reviewed each included study and extracted data using a piloted data extraction form. Where discrepancies arose HEC, LA and BK reached a consensus by discussion. Corresponding authors were contacted for any missing data needed during the extraction process.

Quality assessment of included studies
Experimental studies were assessed using the Cochrane Collaboration's tool for assessing risk of bias 26 , while the Hoy et al., modified tool was used for cross-sectional studies 27 . Using the Cochrane checklist, studies were scored as 'High risk' or 'Low risk'. Using the Hoy et al., checklist, cross-sectional studies were scored as High risk' or 'Moderate risk' or 'Low risk' of bias. Studies with high risk of bias were rated as poor quality while studies with moderate and low risk of bias were rated as moderate and high quality respectively. Where discrepancies in quality assessment occurred, HEC and LA discussed to arrive at a consensus. The quality of studies reporting the cost effectiveness was not assessed since our main interest was only the delivery costs.

Data synthesis and analyses
Data was analysed using Stata v. 14.0. Results from the studies reporting vaccination coverage were expressed as percentages. Reported costs of the delivery strategies were standardised to United States Dollars (USD) if reported in a different currency. The costs of the strategies (SBVs or SIAs) and effects of the strategy on routine vaccination were presented in a narrative form.
A meta-analysis for vaccination coverage using a random effects model with inverse variance proportion was carried out. Pooled statistics for vaccination coverage were expressed as proportions with 95% confidence interval (95% CI). Subgroup analyses were carried to evaluate vaccination coverage per strategy, stratified by study settings or type of vaccine. Missing values were imputed in order to enable a complete case analysis. A sensitivity analysis was then carried out where imputations were done to assess if the results significantly differed due to the data imputations.
Visual inspection of the forest plots, the Chi-squared test for homogeneity with a significance level set at 10% and the I 2 statistic were used to assess and quantify any heterogeneity between study results. Heterogeneity was rated as 'low' for ≤ 49% and 'moderate' for 50-74% and 'high' for ≥ 75% using the I 2 statistic.

Literature search
Three thousand seven hundred and nineteen (3719) studies were identified through searching the electronic databases. A further 1461 were identified from grey literature. An additional five studies were identified from the reference lists of all the search outputs. After duplicates were removed, 4938 studies were left for screening. The titles and abstracts of the 4938 studies were screened and 4872 were not relevant and therefore excluded. The full text of the remaining 65 were retrieved and assessed for eligibility. From the 65 studies, 31 met our inclusion criteria (Supplementary File 2).

Characteristics of included studies
A total of 31 studies were included in this review. There were 20 cross-sectional studies 23,28-46 , eight economic evaluation studies 47-54 , one cluster-randomised trial 55 , one epidemiological report 56 and one interrupted time series 57 . The included studies were published between 1993 and 2016; only three studies were published before 2000 45,46,56 . A total of 17 African countries ( Figure 1) and five different vaccines were represented from the included studies. Except for four of the included studies that were written in French 44,46,50,53 , the rest were in English. One of the study team members (HEC) is French literate and translated the four articles. In terms of vaccine delivery strategy, 20 and 11 studies assessed SIAs and SBVs respectively. Out of these 32 studies, 20 reported on vaccination  (Table 1 and Table 2), nine on the cost of the vaccination strategy (Table 3) and three on the effect on routine immunisation ( Table 4).

Risk of bias and quality assessment
Using the Hoy et al., modified tool 27 , a 10 item scale was used to assess the internal and external validity of the 20 cross-sectional studies. Ninety-five percent (19) of the studies were of high quality (low risk of bias) meaning further research is unlikely to change our confidence in the estimate of the study outcomes. Five percent (1) of the studies were of moderate quality (moderate risk of bias) meaning further research is likely to have an impact on our confidence in the estimate of the outcomes (Figure 2b). For the internal validity, the included studies defined which participants were considered to have been vaccinated (by self-report or vaccination card) and used the same data collection tool for all the participants. However, five studies did not mention if the tool used was standardised 29,34,42,45,46 . Ten studies collected information from proxies (parents or guardians of vaccinated children) [29][30][31][32]34,36,[43][44][45][46] . All the studies calculated vaccination coverage as the 'number vaccinated divided by the number of the targeted population'. For the external validity, all the studies had representative samples in terms of age and sex. Random sampling was used in all except four studies 33,35,37,39 . Similarly, majority of the studies had a low nonresponse rate except three studies 33,40,46 .
The Cochrane checklist was used to assess the clusteredrandomised trial 55 and interrupted time series 57 study ( Figure 2a).

Vaccination coverage
SIAs: Twelve studies reported vaccination coverage for SIAs. Three studies reported coverage data on meningococcal serogroup  A meta-analysis of a pooled estimate showed high vaccination coverage for SIAs 86% (95% CI: 80%, 93%) ( Figure 3a). Three studies were excluded from the pooled meta-analysis due to missing sample sizes 31,32,38 . However, after imputation of the sample sizes based on vaccination coverage, no major difference was seen in the pooled coverage (Figure 3b).

Comparison of vaccination coverage:
To compare the two vaccine delivery strategies, pooled estimates for SIAs and SBVs were evaluated. For this comparison and subsequent analyses, Huhn et al., study 36 was not included since its setting (displaced) is not similar to the other studies reporting SIAs. The SIAs showed a higher vaccination coverage than and SBVs ( Figure 5).

Subgroup analyses for vaccination coverage
Subgroup analyses were carried out to evaluate if vaccination coverage varied by the study setting or by vaccine type (for SIAs).

Study setting:
The settings evaluated were: urban only, rural and urban mixed, or rural only. For SIAs, vaccination coverage did not vary irrespective of the three study settings ( Figure 6). However, vaccination coverage was highest in urban areas (97%, 95% CI: 96, 98) and lowest in a mixed setting (88%, 95% CI: 79, 98).

Cost of vaccine delivery strategy
SIAs: Seven studies reported the costs of conducting SIAs (Table 3). The costs represent monies spent to deliver the vaccines to the total target population during the SIAs. The available data on costs of the SIAs was not age specific and therefore, the costs for 5-19 year olds only could not be calculated. The SIAs targeted children aged 6 months and older age groups with the number of vaccinated people across all studies ranging from 23921 to 12,649,448.
Majority of the total cost in SIAs was used to procure vaccines and consumables. The highest proportion (86%) for vaccines and consumables costs' was reported by da Silva et al., for the combined yellow fever and meningitis A/C campaign in Senegal 53 . Costs for salaries of health staff and international supervisors were another high expense during SIAs. Other reported minor costs were: training of personnel, social mobilisation, transport, maintenance of equipments, cold chain and management of adverse events following immunisation (AEFI).

SBVs:
Two studies reported the cost of HPV vaccination in Tanzania and Uganda 47,48 (Table 3). In Tanzania, 4211 girls were vaccinated with three doses of HPV vaccine either based on age or class. The total economic costs for the SBVs were 349,400 USD. The total cost per fully immunised girl in urban areas were 66 USD and 100 USD for class-based and age-based approach respectively; and in rural areas, 78 USD and 107 USD for classbased and age-based approach respectively.. Administration and supervision (salaries) of the project and procurement of vaccines accounted for the major expenses. The reported minor expenses in the study included training, cold chain, waste management and social mobilisation. The observed difference between costs per fully immunised girl for class-based and aged-based selection may be due to the fact that more time and logistics were needed to select girls based on their age. In Uganda, 3038 girls in a rural setting were vaccinated with three doses of HPV vaccine using a class based approach. The total economic cost (cost of all resources used regardless of who paid) was 30,646 USD excluding the cost of the vaccine. The total economic cost per fully immunised girl was 9.5 USD. Salaries of staff accounted for the greatest part of the cost followed by micro-planning, staff training, community mobilisation (start-up costs). Other expenses included supplies, cold chain, vehicles and transportation. Redeployment of health staff: During the SIAs, staff in charge of routine immunisations were either deployed as supervisors for the campaign. This led to the closure of routine immunisation services in some districts during the campaign period.

Effect of vaccination strategy on routine immunisation
Cold chain management: In Mali, routine vaccines were relocated and stored at the regional and district level so fridges could be made available to store the campaign vaccine 37 .

SBVs:
One study in Rwanda reported the effect of HPV vaccination on routine immunisation 39 (Table 4). According to Torres-Rueda et al., the vaccination activity which lasted 2 days had no effect on routine immunisation services 39 . There was no change in the demand for routine immunisation and health services. The high vaccination coverage achieved by SIAs reported in this review corroborates with the past successes of smallpox eradication, achieved by complementing EPI with SIAs 58 . Interestingly, coverage of the SIAs was high irrespective of the vaccine and setting, and this attests to the robustness of the strategy. Despite being a new strategy in Africa and being used for the introduction of HPV vaccines, SBVs was able to achieve a high but variable coverage. Our findings are similar to those obtained in HICs where the SBVs strategy is more established and used for routine immunisation to this age group 59 .
In terms of vaccine coverage, our review supports what is already known: both SIAs and SBVs are good options to complement the EPI. However, other factors such as the costs of the strategy, logistical requirements, the number of vaccine doses to be administered, school attendance and existing immunisation policies have to be taken into consideration when deciding which of the two strategies to use in any given setting. Local evidence should be used to evaluate which vaccine delivery strategy is more optimal to reach school age children and adolescents in Africa.
SBVs are likely to be more cost-effective than SIAs in countries with high school enrolment. Similarly, SBVs are likely to be optimal in countries with strong inter-ministerial collaboration. Collaboration between health and education sectors is crucial to ensure smooth implementation of SBV strategy 60 . Conversely, SBVs are unlikely to be optimal in countries without sufficient financial commitment. School based vaccinations have been reported to be an expensive strategy which may be feasible on a small scale but not sustainable at a national level 61 . Our findings support the reports that SBVs are an expensive strategy although this was based on limited data of newer and more expensive HPV vaccines.
Supplemental immunisation activities, could be the preferred strategy in countries where campaigns are regularly used to complement infant immunisation. The experience in conducting SIAs and community awareness of the strategy can be used to extend the vaccination services to school age children and adolescents. Additionally, the SIAs are able to reach non-school going children. A majority of African countries have millions of nonschool going children 24 who will miss vaccines delivered by SBV programs. The negative impacts of SIAs on routine immunisation and health services due to the overlapping of resources (financial and human) is a key concern that should be minimized wherever SIAs are used.

Strengths and limitations
We comprehensively and systematically searched for the relevant literature: both peer-reviewed and non-reviewed records were obtained. This study adhered to the PRISMA guidelines of conducting systematic reviews. Nonetheless, our review had several limitations. First, age specific coverage was not reported in some of the retrieved studies. Second, we observed a high heterogeneity during the meta-analysis. The heterogeneity was likely due to differences across studies of factors such as the age groups included, study settings and period. Third, the only vaccine administered via SBVs was the HPV vaccine, a new and more expensive vaccine.
Lastly, few studies reported the effect of SIAs or SBVs on routine immunisation and health services and therefore, our findings may not accurately reflect the effects.

Implication for policy and research
Local evidence is crucial in the review and development of immunisation policies. Both SIAs and SBVs are routinely used in Africa to vaccinate older children. In settings where school enrolment is low as is the case in many African countries, our results show SIAs may be more effective in reaching school age children and adolescents than SBVs. However, caution needs to be exercised to mitigate the negative effect of SIAs on the routine health services. In Africa, the SBV has mainly been tested in the delivery of two or three dose HPV vaccine to adolescent girls while SIAs have been used for diverse vaccines and on a larger scale. Further research is therefore needed to assess the sustainability of SBVs for nationwide delivery of vaccines to school age children and adolescent in resource constraint settings as is the case in Africa. In the event that SBVs are chosen as the main delivery strategy, complementary community activities can be set up to target out of school children. Our results re-iterate the importance of systematic evidence to best inform African authorities on the optimal delivery strategies of vaccines targeted at school age children and adolescents for immunisation.

Competing interests
No competing interests were disclosed.

Grant information
The author(s) declared that no grants were involved in supporting this work.
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Supplementary File 2: PRISMA flowchart, showing the number of records identified, included and excluded.
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