This systematic review was conducted using a predefined protocol and in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) and meta-analysis of observational studies in epidemiology (MOOSE) checklists (Multimedia Appendices 1 and ). A literature review was conducted on February 23, 2017 (date last searched) using MEDLINE (Medical Literature Analysis and Retrieval System Online), Scopus, and Web of Science databases. Gray and white literature was also identified on the Communication Initiative Network, TechNet-21, and PATH websites. Search terms were grouped into three categories: those relating to vaccination, such as inoculation and immunization; mHealth, for example, mobile phone or telemedicine; and geographical location. No restrictions were placed on language. Details of the search terms are located in Multimedia Appendix 3. Titles and then abstracts were searched, potentially relevant papers were read, and those that did not meet the predefined inclusion criteria were removed. The inclusion criteria specified the country (Angola, Cambodia, Democratic Republic of the Congo, Ethiopia, India, Indonesia, Iraq, Kenya, Mali, Malawi, Nepal, Niger, Nigeria, Pakistan, the Philippines, Senegal, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe); any form of mhealth (including mobile phone calls, phone apps, text messages, Internet, and email); and an outcome pertaining to vaccination (including uptake of vaccinations, attendance at vaccination appointments, and completeness of vaccination protocol for individuals or for regions). Reference lists of the selected studies and relevant reviews were also searched for additional publications.

Prospective interventional and observation studies that evaluated mHealth interventions on any part of a vaccination program were of interest if they were based in the relevant countries listed previously. These countries were chosen, as they include the 10 countries where more than 60% of children were unvaccinated for the final dose of Diphtheria-tetanus-pertussis vaccination as of 2014 [11], in addition to 11 countries that also have low routine vaccination uptake where the authors identified ongoing large-scale mHealth initiatives.

Data were extracted by 4 authors and a predesigned data abstraction form was used. Any conflicts over inclusion were resolved by discussion. Relevant information included location, age of participants, study design, numbers included in the study, type of mobile phone intervention and frequency, duration of the study, outcome measures, and results. Where multiple publications from the same study were found, only the most up-to-date or comprehensive information was extracted.

The quality of peer-reviewed studies was rated for the risk of bias. Randomized control trials (RCTs) were assessed using the Cochrane Collaboration tool [12]. This tool considers seven different scales: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. Observational studies were evaluated using the Newcastle-Ottawa Scale [13], which uses a star system to assess three aspects: participant selection, comparability of study groups, and ascertainment of outcomes. Studies that received a score of nine stars were judged to be at low risk of bias, studies that scored seven or eight stars were medium risk, and those that scored six or less were at high risk.

Descriptive summary tables were constructed to display the results. Due to the small number and heterogeneity of studies identified, it was not possible to either conduct a statistical analysis of the results or assess publication bias through funnel plots.

The literature search identified 23,157 potentially relevant citations. After screening titles and abstracts, 58 peer-reviewed papers remained for further evaluation, and following detailed assessment, a further 48 were excluded (Figure 1). The remaining 10 unique papers, plus 11 studies from the gray and white literature, were included within this review.

Of the 21 studies fulfilling the inclusion or exclusion criteria, 10 were peer-reviewed, of which 3 were RCTs. Tables 1 and 2 outline the key characteristics of studies included in this review, and Table 3 summarizes geographical locations. The interventions evaluated in these papers ranged from SMS messages sent to families to remind and encourage them to take their children to the health center for vaccinations, to using mobile phones to record which settlements have been covered by vaccination campaigns, to mobile phone apps helping health workers to update and access relevant data to facilitate vaccination campaigns.

Eleven initiatives were identified from gray and white literature; eight took place in India, two in Pakistan, and one in Zambia. Several programs involved more than one intervention, including messages sent to parents to encourage their children to get vaccinated, information about vaccination made freely accessible via mobile phone, tools to identify unvaccinated children with the health authority using SMS, data management tools for health workers (such as electronic vaccination records and a mobile phone app to track where vaccinations have been administered and control supplies), and tools to help health workers persuade hesitant families.

Eight peer-reviewed studies reported the use of phone calls or SMS reminders for vaccinations, two of which additionally offered cash incentives. The three studies that did not offer cash incentives included an RCT by Bangure et al [14] conducted in Zimbabwe. SMS reminders were sent to parents (n=152) when their baby was 6, 10, and 14 weeks old, in addition to routine health education. The control group received health education alone (n=152). At all three time points, the percentage of children fully vaccinated with the relevant dose of polio, pentavalent, and pneumococcal vaccines was significantly higher in the intervention than the control group (<.001), and the delay in receiving the vaccinations was significantly less in the intervention than the control group (<.001). Another RCT by Brown et al [15] conducted in Nigeria identified increased coverage rates relative to the usual care when receiving phone call reminders 2 days and 1 day before a vaccination appointment (Relative risk 1.72, 95% CI 1.50-1.98). Uddin et al [16] similarly found that SMS reminders increased the odds of vaccination uptake in both urban and rural areas; odds ratio (OR) 2.3 (95% CI 1.1-5.5) and OR 3.6 (95% CI 1.5-8.9), respectively. Garcia-Dia et al [17] assessed coverage rates in an RCT in the Philippines after 75 parents were sent either a plain text message (short service message, SMS), a text message with pictures, or a verbal reminder. Although vaccination rates did not differ by reminder, text reminders with and without a picture were associated with a shorter delay in receiving the vaccination than verbal reminders. Crawford et al [18] sent SMS or voice messages to either the personal or community phone of 2611 caregivers of children under the age of 1 year. Pushed SMS messaging (where a message is sent to a phone’s notification center or status bar) was the most successful mode of delivery (64.10%, 13,053/20,363, of sent messages were received). However, most women did not own a mobile phone, so similar numbers of messages were delivered by retrieved voicemail to community phones and pushed SMS to personal phones. No control group was included, but the majority of individuals who received messages trusted (98.8%; 263/266) and could recall (72.2%; 200/277) those messages.

Two studies used cash incentives to increase vaccination uptake while sending SMS reminders. Kazi et al [19] used SMS messages sent to 5880 caregivers in Pakistan, along with a conditional cash transfer in the form of approximately US $0.20 of phone credit, to monitor polio vaccination coverage. Response rates to the SMS messages were low (74.90%, 4404/5880, of participants did not respond). The initial nonresponders who were followed up by phone call had similar rates of vaccination uptake to those who responded to the SMS messages. Wakadha et al [20] conducted a pilot study exploring the feasibility of setting up an integrated mobile phone–based system to remind and incentivize mothers (n=72) to vaccinate their children in rural Kenya. Mothers received SMS reminders of vaccination dates and conditional cash transfers of either mPESA (a mobile-based money transfer service) credit or phone credit, if the child was vaccinated within 4 weeks of the scheduled date. The small sample size and lack of a comparison group meant that it was not possible to draw conclusions about the program’s effectiveness, but enrolled mothers reported mostly positive experiences at the end of the study, and most mothers did have access to a phone. Importantly, this study was limited by its focus on a single facility. Caregivers who took children to nearby facilities for vaccinations were recorded as unvaccinated by the first facility and thereafter, were not sent additional SMS.

Three studies used mobile-based interactive learning apps to aid or track the progress of health workers in vaccination. Touray et al [21] utilized the global positioning system of Android phones to track where vaccination teams had been, which helped reduce the number of settlements in northern Nigeria that were not covered in the last three campaigns from 5833 in 2014 to 1257 in 2015. Balakrishnan et al [22] found no improvement in coverage for tetanus when health workers used a mobile phone tool that created electronic vaccination records and registered when vaccination was due and administered. Mbabazi et al [23] evaluated a mobile phone app used by health workers that was designed to assess the awareness and intention to take part in a measles vaccination campaign before the campaign’s onset at house visits, as well as to evaluate the uptake of the vaccinations after the campaign. Of the more than 150,000 households included in the survey, approximately half were aware of the vaccination campaign, and once informed, 74.99% (123,482/164, 643) of households planned to bring their children in for vaccination. After the campaign, 95.99% (168,592/175,617) of households reported their child had received a measles vaccination, and 92.00% (161, 568 of 175,617) had this independently confirmed. This intervention was found to reduce misconceptions about vaccination, and the use of the mobile phone app to assess uptake of vaccination helped inform service delivery plans.

Of the 10 peer-reviewed studies, three studies did not evaluate controls or individuals unexposed to the intervention, so it was not possible to evaluate their risk of bias using the Newcastle-Ottawa Scale or the Cochrane Collaboration tool. In the eight studies that could be evaluated, the risk of selection bias affecting the results was judged to be low for one RCT by Bangure et al but with a higher risk of bias in the other two RCTs (Table 4). The risk of bias in the observational studies was also deemed to be high, with most of the concern regarding the possibility of outcome bias and bias arising from a lack of comparability (Table 5).

Of the eleven initiatives identified, six showed some evidence of impact on vaccination rates. Implementation of the MIRA channel [24] (an integrated mobile phone channel providing health information to women and connecting them with health services) corresponded with a 41% increase in vaccination rates. A program using the Mobile Kunji program [25,26] (in which the health worker can play a health message to the family via their mobile phone) recorded a 5% decrease in the percentage of children (6-11 months) unvaccinated with the first diphtheria vaccine and a 6% increase in children receiving the second diphtheria vaccine. Another successful strategy included the involvement of India’s national telecom authority who replaced the dial tone on mobile phones with a recorded message that reminded the public of National Immunization Day [27], whereas the Mobilink mobile operator in Pakistan recorded 13,000 SMS messages about unvaccinated children during the annual polio vaccination campaign in 2010 and circulated seven million SMS reminders in 2009 [28,29]. Aarogyam [30] reported improved vaccination uptake through the use of automatic voice calls and SMS reminders sent to parents about vaccination appointments, among other postnatal care.

Unfortunately, other initiatives did not provide quantitative results. Some pilot studies are ongoing (Khushi Baby [31]), and one provided qualitative evidence of improved knowledge [32]. No outcomes were found for three studies, one study used educational videos accessible on mobile phones [33], another looked at an app to track vaccinations [34], and two studies used SMS vaccination reminders [35-37].

The literature reviewed indicates that mobile technology can be used in a variety of ways to improve vaccination uptake. Although most studies lacked comparison groups, the results broadly suggest an improved uptake of vaccinations with mobile phone–based interventions.

SMS reminders for vaccination appointments were found to increase uptake and reduce delays in receiving vaccinations in Zimbabwe [14]. In Kenya, mothers who received SMS reminders about vaccination appointments reported mostly positive experiences [23]. A decrease in the percentage of unvaccinated children and an increase in the number of children with a vaccination card were found when health care workers used their mobile phones to play a prerecorded message to families. Furthermore, a 41% increase in vaccination rates was observed in rural India after the introduction of an integrated mobile channel providing health information and connecting mothers with health services [24].

However, some studies reported no improvement upon intervention. A study from Pakistan found low response rates to SMS messages about vaccinations, even when a financial reward was attached [19].

The studies we reviewed, as well as the related research that these studies cited to explain the design of their interventions, raise a number of challenges that can impede the integration of mobile phones into vaccination programs. Several of these studies discuss rates of phone ownership in their particular areas of intervention, including how these differ among men and women (Crawford et al, Uddin et al, and Kazi et al). In LMIC, generally, women are 21% less likely to own a mobile phone than men (increasing to 37% in Asia) [38]. As women are the primary caregivers to children, this may impact mHealth vaccination interventions. Furthermore, two-thirds of illiterate adults are women [39], which can further reduce the effectiveness of SMS messages. In households where the father owns the mobile phone, it is imperative that the father is engaged in the project, as exemplified in the study by Wakadha et al [20], where in a few cases husbands did not approve of the study.

Frequent exposure to SMS messages can result in the effectiveness of the message being weakened; in a different setting, Strandbygaard et al found that participants stopped reading reminder messages after a few weeks [40]. Therefore, the effectiveness of messages of different length and over time needs to be assessed when sending SMSs.

Developing the appropriate infrastructure [9] and ensuring adequate resources are available is important. Weaknesses in other areas of the health system may render mHealth interventions aiming to increase demand for services meaningless: mHealth can improve access to vaccines only as long as they remain consistently available from health centers [9]. Additionally, increasing demand for vaccination can have unintended consequences. One study reported that extensive and comprehensive communication campaigns for 15 new vaccines led to greater demand for vaccination in a number of LMIC. However, high demand resulted in vaccine shortages, which later thwarted the increased demand [41]. For this reason, policy makers and implementers of mHealth interventions to improve vaccination programs should be aware that eHealth interventions in general [42], and mHealth interventions in particular [6,43] are deeply complex and context-dependent.

Of the literature reviewed, the included studies were predominantly observational studies that appraised process and usage output. These had various methodological limitations such as (1) sample selection based on convenience, without randomization; (2) small sample sizes; (3) lack of information on process validation, including recruitment type, response rate, and retention rate; and (4) no control groups. These limitations make the conclusions of the observational studies less secure. Given the potential of mHealth, RCTs in LMIC to determine the efficacy of using mHealth for vaccinations are needed.

It is clear that there are a number of gaps in the literature concerning this topic in the countries of interest. Relatively more compelling evidence exists for mHealth interventions addressing demand-side barriers to service uptake, whereas fewer evaluated interventions aim to boost immunization by strengthening health systems through data management, decision support, or provider training and education. This is a notable gap because reviews of why children go unvaccinated document not only highlight gaps in household knowledge and attitudes but also issues related to poor service quality and accessibility [8,9]. Moreover, there is reason to believe that this gap can be addressed because outside immunization programs, mHealth interventions have been widely used as strengthening tools for health systems [4]. For example, given that a study on stock tracking of malaria medications in Tanzania showed a 52% reduction in medication stock-outs within 21 weeks of the induction of weekly SMS requesting stock counts [44], there is a precedent for the integration of mHealth into vaccination stock control.

There is reason to be optimistic regarding the potential for mobile phones to increase vaccination coverage in LMIC. Mobile technologies are flexible and widely available tools that can be utilized in myriad ways. This review provides evidence of potential effectiveness for SMS reminders to families regarding vaccination, as well as for educational tools for health workers.

However, the research is preliminary and limited. Further research is needed to determine the most effective mHealth interventions and to refine their use, for example, clarifying the optimal schedule of reminders for programs using SMS reminders of vaccination appointments. It will also be necessary to evaluate different mHealth interventions against each other, and against other potential programs, to examine their comparative cost-effectiveness at increasing vaccination coverage. mHealth interventions addressing vaccination stock-outs, cold storage, or other health systems strengthening challenges merit further study.

Overall, there is preliminary evidence to support the use of mHealth technology to increase vaccination coverage in LMIC. However, further research is needed to guide and improve the use of these technologies in the future and to strengthen the case for their cost-effectiveness.