Effect of vaccine reminder and tracker bracelets on routine childhood immunization coverage and timeliness in urban Pakistan: a randomized controlled trial CURRENT STATUS: UNDER REVIEW

Background Inability to track children’s vaccination history coupled with parents’ lack of awareness of vaccination due dates compounds the problem of low immunization coverage and timeliness in developing countries. We evaluated the impact of two types of silicon immunization reminder bracelets for children in improving immunization coverage and timeliness of Pentavalent-3 and the Measles-1 vaccines. Methods Children < 3 months were enrolled in either of the 2 intervention groups (Alma Sana Bracelet Group and Star Bracelet Group) or the Control group. Children in the intervention groups were provided the 2 different bracelets at the time of recruitment. Each time the child visited the immunization center, a hole was perforated in the silicon bracelet to denote vaccine administration. Each child was followed up till administration of Measles-1 vaccine or till 12 months of age (if they did not come to the center for vaccination). Data was analyzed using the intention-to-treat population between groups. The unadjusted and adjusted Risk Ratios (RR) and 95% confidence interval (CI) for Pentavalent-3 and Measles-1 coverage at 12 months of age were estimated through bivariate and multivariate analysis. Time-to-Pentavalent-3 and Measles-1 immunization curves were calculated using the Kaplan–Meier method. Results A total of 1,446 children were enrolled in the study between July 19, 2017 and October 10, 2017. Baseline characteristics among the three groups were similar. Up-to-date coverage for the Pentavalent-3 /Measles-1 vaccine at 12 months of age was 84.6%/72.0%, 85.4%/70.5% and 83.0%/68.5% in Alma Sana Bracelet group, Star Bracelet group and Control group respectively but the differences were not statistically significant. In the multivariate analysis, neither the Alma Sana bracelet (adjusted RR = 1.01; 95% CI: 0.96-1.06), (adjusted RR: 1.05; 95% CI: 0.97-1.13) nor the Star bracelet (adjusted RR = 1.01; 95% CI: 0.96-1.06) (adjusted RR: 1.03; 95% CI:


Introduction
Estimated to prevent 23 million deaths between 2011-2020 [1], routine immunization constitutes one of the most powerful and universally cost-effective interventions in public health. Major investments in immunization across the world led to 85% global coverage of the DTP3 in 2017, up from 72% in 2000 [2]. Moreover, in the same period, the number of children who missed out on basic vaccines in Gavi-supported countries was nearly halved [3]. Despite these achievements, however, many countries still struggle with low immunization coverage and timeliness, particularly in resource-poor regions of the world. In Pakistan, only 66% of all under-2 children receive all basic vaccines, and only 51% of these are age-appropriate [4]. Low immunization coverage not only exposes individual children to the risk of illness, disability, and death but also decreases herd immunity [5], an essential component of national disease prevention strategies. While low coverage is detrimental, delays in immunization are an additional problem, as the temporal spacing of vaccines is designed to maximize immunity, and deviance from the schedule dampens vaccine efficacy (even if all doses are eventually received) [6,7]. There is thus a dire need to boost both immunization coverage as well as timeliness in countries such as Pakistan, where rates of vaccine schedule compliance are below optimal levels.
In recent years, there has been extensive evidence within public health literature indicating that suboptimal immunization coverage and timeliness is attributable not only to supply-side deficiencies, but also to demand-side problems such as caregiver complacency, forgetfulness, and unawareness of required number and timing of doses [8]. Among the main reasons for under-utilization of immunization services by caregivers is the inability to understand the vaccination schedule, and to remember the due dates for subsequent immunization visits [9]. Demand-side barriers are therefore recognized as equally detrimental to national immunization programs as the pervasive supply-side problems.
Globally, one of the most widely used methods to communicate the vaccination schedule to caregivers is the paper-based immunization card. However, immunization cards are associated with several problems, including lack of durability, potential misplacement, and failure to empower caregivers who cannot read [10,11]. Studies have confirmed that cardholder prevalence is low in the most resource-poor environments [10], and that card under-utilization is a widespread problem.
Mobile-technology based reminder-recall interventions have tried to address this issue, but their success has also been partial [12]. Like immunization cards, which require literacy, interventions requiring mobile-phone ownership fail to penetrate the lowest socio-economic strata as it is difficult to implement them in the poorest countries, where infrastructure for technological interventions is absent or subpar, thus widening the global immunization equity gap [13]. Apart from immunization cards and mobile-technology based interventions, In Pakistan, one of the strategies deployed in response to caregivers' failure to visit immunization centers on time is the implementation of door-todoor vaccination and awareness campaigns by the government. Such campaigns, however, neither optimize resource allocation, nor complement routine immunization activities and cannot be a long term sustained strategy for improving coverage.
There is thus a programmatic and research gap regarding strategies to improve immunization coverage and timeliness in low-literacy communities through cost-effective, sustainable solutions that can easily be integrated into the existing public health system and focus on transforming caregivers from passive to active recipients of immunization services.
We aimed to evaluate the effect of silicone bracelets in improving immunization coverage of Pentavalent-3 and the Measles-1 vaccines in children under 2 years, in a low-literacy, peri-urban community. The secondary outcome focused on caregiver feedback regarding the bracelet including its value, ease of use and visibility.

Study design and participants
We conducted a multicenter, three-arm parallel group, randomized control trial undertaken at 4 immunization centers in Karachi, Pakistan. The study was conducted in Landhi Town which constitutes one of the largest peri-urban towns in the south of Karachi city, in Pakistan's Sindh province with an estimated population of around one million and an annual birth cohort of 41,000 children in 2017-18.
Administratively, Landhi Town is subdivided into 12 Union Councils (UCs), 5 of which are primarily Pashtun dominated while the rest are represented by Urdu speaking, Punjabi and Sindhi ethnicities with income levels ranging from lower middle income to low-income communities. The town also contains a large industrial zone with a substantial proportion of the workforce employed as factory workers and migration being a distinctive feature within the overall population.
Health care provision in Landhi Town falls under a network of both public and private health care providers. Specifically, immunizations are provided by government-run EPI centers consisting of a network of 29 vaccinators who administer vaccines. Out of a total 17 EPI centers in the Town, we selected 4 contiguously located high volume centers, whose catchment areas included 7 out of 12 union councils in Landhi Town. As per the Pakistan Demographic and Health Survey (2017-18) [4], 82% of all 12-23 month old children in Sindh province had received the BCG vaccination. The coverage for Pentavalent-3 and Measles-1 vaccine was 59% and 61% respectively.
The eligible participants were children presenting to any of the four selected immunization centers for BCG or Pentavalent-1 vaccination, accompanied by a primary caregiver, healthy, and had been residents of the catchment area for more than six months. Exclusion criteria included children older than 3 months of age or their caregivers planning to visit a non-study immunization center for the follow-up immunizations. Verbal informed consent was obtained from the parents or caregivers of all children.
The study was approved by the Committee on the Use of Human Subjects at Harvard University, USA and the Institutional Review Board of Interactive Research and Development, Pakistan. The trial was registered with ClinicalTrials.gov, number NCT03310762.

EPI vaccination Schedule
Pakistan's routine immunization schedule in 2018 included BCG (Bacille Calmette-Guérin) vaccine at 0-6 weeks of age, three doses of pentavalent (DPT, HepB, Hib) vaccine, three doses of pneumococcal vaccine (PCV) and three doses of oral polio vaccine at 6, 10 and/or 14 weeks of age, and two doses of measles vaccine at 9 and 15 months of age.
Procedures Among the caregiver-child pairs visiting the centers, eligible children identified through the screening process were approached by our trained field staff for obtaining written consent. Those who consented to participate were enrolled in the study, randomized and information was collected about the child's current and past vaccination as well as demographic characteristics and socio-economic status. Depending upon the child's allocated group, the child was provided the intervention (detailed below). After that, data was collected on the child's vaccination status each time the child visited the immunization center, and if the child was in the treatment group, the relevant intervention procedures were followed (detailed below). As per the recommended EPI schedule, each child was due to visit the center 3-4 times (depending on enrollment vaccine) up till the final vaccine visit for the study at Measles 1 vaccine. At the Measles 1 vaccine visit, a completion form was administered to collect data on experiences of using the bracelets as well as self-reported compliance of wearing the bracelet.
For children who did not visit the center for the recommended number of visits by 12 months of age, we conducted phone calls to document the child's immunization status. The primary caregiver who had brought the child for immunization was asked to refer to the child's immunization card to determine the vaccines given and their dates. In case the immunization card was lost, the caregiver could not read the immunization card or the caregiver's phone number was not available, a household visit was done to document the child's immunization history. During the household visit, the immunization status was determined through the official EPI card and if this was not available, a verbal recall for the immunization history was taken.

Intervention
Our two intervention groups comprised of two different types of immunization reminder bracelets.
Intervention Group A was provided with a bracelet developed by Alma Sana Inc., a 501(c)3 non-profit organization founded in Indianapolis, Indiana, US. Following a short formative phase, the bracelet was adapted to the Pakistani context through feedback from mothers and vaccinators and involved changes in the color, choice of symbols and denotation of the child's age on the bracelet, as well as adapting it to suit Pakistan's EPI schedule. The final adapted bracelet had the recommended age of the child denoted in weeks/months for receiving the vaccine followed by symbols representing each of the vaccines due at that age.
Each time the child came for vaccination, our study staff perforated a hole in the particular symbol denoting the vaccine that the child had received on that visit and explained to the caregivers the number of vaccines the child still had to receive to complete the routine immunization schedule.
Caregivers could, therefore, look at the bracelet and know which vaccines the child had already received and the recommended age of the future visits. The bracelets were manufactured in 2 different sizes to ensure they fit the child's wrist as he/she grew older.
Intervention Group B was provided with a simple silicon bracelet "Star Bracelet" that consisted of six symbols (5 crescents and one star) denoting the 6 visits that the child is supposed to make to the immunization clinic to complete the routine immunization schedule. The bracelet was designed with the rationale to motivate parents to make all 6 visits to the immunization center in order to reach the 'star' symbol on the bracelet. Similar to Intervention Group A, each time the child visited the center, the study staff punched a hole to denote the child's visit to the immunization center and explained to the caregiver to complete all 6 immunization visits to reach the star symbol on the bracelet. The bracelets were manufactured in 2 different sizes and colours (pink for girls and blue for boys).
The control group participants received the standard of care which included receiving the routine EPI vaccinations as per Pakistan's EPI Immunization schedule and the vaccinator recording the child's immunization data in the EPI immunization card provided to the caregivers. The difference between the intervention and standard care was only the provision of bracelets and no extra counselling/information was provided to the caregivers.

Sample size
We expected a 60% coverage rate of Pentavalent-3/ vaccine and a 50% coverage rate of Measles-1 vaccine in the control group, and hypothesized an increase in coverage by an absolute number of 10% in the Pentavalent-3 vaccine coverage (from 60-70%) or Measles-1 vaccine coverage (from 50-60%). With 80% power (and a 2-sided type 1 error of 5%), we estimated a sample of 1,062 participants (354 in each group) to detect a difference of 10% between intervention and control group proportion for pentavalent-3 vaccine coverage rate, and a sample size of 1,155 participants (385 in each group) to detect a difference of 10% between intervention and control group proportion for Measles-1 vaccine coverage rate. On the basis of these numbers, a sample size of 1,155 participants was needed to achieve at least 80% power to realize both objectives. Accounting for a potential dropout rate of 20% during the follow-up period, our final sample size was 1,446 infants (482 in each study group).
Intervention Group B (Star Bracelet) or control group. The randomization sequence was generated in Stata version 13 using random block sizes of 3, 6, 9 and 12. After confirming the eligibility criteria, the next available randomization number in the immunization center (in chronological order) was assigned. The allocation sequence was concealed from the study staff responsible for screening and enrolling participants in sequentially numbered, opaque, sealed envelopes and was only revealed post-randomization. The statistical analysis plan was developed prior to start of the study.

Measures
Our study outcome of interest included the coverage and timeliness of Pentavalent-3 and Measles-1 vaccines at 12 months of age in the intervention versus control groups. We also investigated the selfreported compliance of caregivers on the child actually wearing the bracelet along with some general feedback on the bracelet itself.

Analysis
All study data were collected on paper based forms and transferred to a secure electronic medium on a daily basis. The data were analyzed using STATA version 15 (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC).
We analyzed data using the intention-to-treat population between groups. The unadjusted and adjusted Risk Ratios (RR) and 95% confidence interval (CI) for Pentavalent-3 and Measles-1 coverage at 12 months of age were estimated through bivariate and multivariate analysis. Two-sided P values were reported, and the values of ≤ .05 were considered statistically significant. The variable selection was performed using a stepwise forward model (p < 0·10). Time-to-Pentavalent-3 and Measles 1 immunization curves were calculated using the Kaplan-Meier method. The intervention and control groups were compared for effect on timely completion of Pentavalent-3 and Measles-1 immunization using the log-rank test.
We also assessed the Pentavalent-3 and Measles-1 coverage at 12 months of age among the 3 allocation groups and performed chi-squared tests to determine the effect of the treatment on coverage. Additionally, caregiver feedback in the two intervention groups regarding their overall satisfaction with the bracelets and visibility of bracelet was assessed through data collected in the completion form. Caregiver satisfaction was measured through feedback on the utility of the bracelets, its ease of use and whether caregivers would recommend it to others. Visibility of the bracelet was assessed by enquiring the self-reported compliance of children wearing the bracelet and where it was kept when the child was not wearing it.

Figure 1: Study Participant Flow
The comparison across the three groups shows no significant differences in the demographic or socioeconomic characteristics of the study participants (Table 1) Almost all children in the study (91%) were born at a hospital facility with the delivery assisted by a doctor (88.8%).  Table 2). The differences in coverage rates was not statistically significant compared to the control group or between the two intervention groups (p>0.05, not shown). Up to date Measles-1 coverage at 12 months of age was slightly higher in the group A (Alma Sana Bracelet) (72.0%, 345/479) and group B (Star Bracelet) (70.5%, 339/481) as compared to the control group (68.5%, 329/480), but the differences were not statistically significant (p>0.05, not shown). The time to immunization for Pentavalent-3 and Measles-1 in the two intervention groups and the control group is shown in figure 2 (Table 3).

Caregiver Satisfaction and Bracelet Visibility
Of the 964 children enrolled in the two intervention groups, 890 (92.3%) were administered the completion form, and the data from their responses is presented in Table 4 and Table 5.  (Table 5). Around 80% (616/775) of the caregivers reported that the bracelet was somewhere within their sight when the child was not wearing it, and a similar proportion (80%) (619/775) reported that the bracelet was kept with the EPI card when the child was not wearing it.

Discussion
We found no significant impact of either the Alma Sana bracelet or the Star bracelet reminders in increasing the up-to-date coverage at 12 months of age or timeliness of Pentavalent-3 or Measles-1 vaccine.
Traditional 'wearables' have been used as visual symbols for denoting health indicators since the last several decades. One of the first such tools was a birth control necklace which was developed in collaboration with local Ethiopian women to strengthen awareness regarding the female hormonal cycles [14]. The idea gained traction and was formalized into the 'Couple/Cycle Bead Method' that conveyed complex information regarding natural family planning in a simple and visually appealing way. Studies investigating the use of these beaded bracelets found them to be a simple ,low-cost, and highly acceptable family planning method [15].
Overtime, the utility of wearables for health has expanded across different disease domains and in recent years, the line between consumer health wearables and medical devices has begun to blur [16]. The upsurge of wearables is mostly concentrated in developed countries, but the concept has gained traction in low and middle-income countries as well where wearable solutions integrating data records such as tattooed bracelets for immunization [17], Near Field Communication (NFC) powered digital pendants [18] and Vaccine Indicator Reminder (VIR) bands [19,20] are coming to the forefront.
Despite their growing influence, currently, there is limited published literature investigating the impact of these innovative tools. Our study is among the first few attempts to rigorously investigate the impact of these innovations, and our findings are corroborated by a similar study in the region which reported that a Near Field Communication (NFC) powered digital pendant worn as a necklace around the child's neck did not have any significant impact on DTP-3 vaccination adherence [18].
The underlying appeal and utility of these simple wearables stems from one or more of the following characteristics; their ability to convey complicated information in a simple and easy to comprehend manner, serving as a visual cue and a constant reminder for undertaking the desired actions and lastly, their serving as a social signal among peers.
Our hypothesis that the bracelet would improve immunization uptake was based on the first two characteristics i.e. that the bracelet would serve as a visible and durable reminder as compared to other alternatives, and was easier to understand and interpret for uneducated caregivers.
Contrary to our findings, a study conducted in Sierra Leone using different colored silicone bracelets worn by children as a social signal that the child had completed all required vaccinations saw a 14 percentage point increase in the timely and complete vaccination coverage [21].
It is worth investigating the reasons for the null impact of our study. A key assumption of our intended theory of change was that the bracelets would be a visually evident reminder since they would be visible to the caregivers at all times compared to commonly used alternatives such as immunization cards that are not always within the caregivers' sight [22]. However, a key finding in our study was the poor compliance of wearing the bracelet; almost half of the study participants only wore the bracelet before coming to the immunization center and only a negligible percentage of children wore the bracelet at all times, despite the study staff reiterating its importance at each follow-up visit.
As part of collecting feedback from caregivers we found out that the most commonly cited reasons for children not wearing the bracelets was their 'inappropriate size'. Although our findings based on measuring wrist sizes of a sub-sample of children post study showed otherwise, nevertheless this serves as an important guideline to ensure that the bracelets are size-adjustable so that they could comfortably fit the wrist of the child between 0-9 months. From a longer term perspective, adherence towards wearing the bracelet also constitutes a behavioral change process which is an important mediator for the observed health outcomes. Health literature elsewhere also highlights that adherence to self-care activities including adopting or refraining from certain behaviors plays an important role in the effectiveness of health care interventions [23]. Moreover, behavior change theories grounded in psychology also emphasize the fact that making health-related behavior changes is a complex process [24] which may lead to an 'intention-behavior' gap [25], preventing favorable process outcomes from translating into long term behavior changes. Our findings also provide evidence of the strong reliance on the immunization card being the established immunization recall method and we may also postulate that the short duration of the study did not provide enough time to 'institutionalize' the use of the bracelets.
It is worth elaborating more on the favourable feedback from parents. As discussed, a majority of the caregivers in the study found the bracelet to be helpful and expressed a desire to recommend this tool to others. This corresponds to findings from other studies where caregivers in a variety of settings have expressed the need and desire for innovative and novel reminder/recall mechanisms [26] [27]. This finding is also in line with results of the study in Udaipur, India where mothers expressed increased satisfaction and acceptability for the novel digital pendant as compared to the traditional immunization reminder mechanism [18]. Our finding, therefore, serves as an important validation of the bracelets in the context of their health-oriented value. In fact, health seeking behaviour in Pakistan specifically and South Asia in general frequently features faith healers and cultural wearables such as amulets, ta'wiz, and pendants that are commonly used for protection [28], which may have led to little resistance from caregivers and facilitated the link between the bracelets and their intended health context. We, therefore, have a strong reason to believe that our proposed intervention has potential and that certain modifications can allow it to address some of the pervasive issues with conventional reminder/recall mechanisms. Current mechanisms of reminder/recall interventions such as SMS reminders, door-to-door visits, postal reminders, telephone reminders, and community-based counselling have shown mixed results towards improving immunization coverage and timeliness which vary by settings [29]. For instance, the efficacy of SMS reminders is closely tied to the literacy levels of caregivers as well as the availability of cell phones [30], consistency of phone numbers [31] and network connectivity [13]. Similarly, door to door outreach is expensive and diverts attention away from the quality of immunization service delivery in centers. Additionally, factors such as burden on existing human resource, uncertainty about who should implement reminder services, high costs and lack of high-quality immunization records have all been cited as barriers towards the adoption of more technology dependent reminder services [32] .
Our study has certain limitations; as a result of limited time and resources, we could only follow up our study participants up till the administration of Measles 1 vaccine (recommended age 9 months) which constitutes the second last dose of the routine immunization schedule. It is difficult to predict whether we would observe a similar impact of our intervention for the Measles-2 coverage rate (recommended age 15 months) where the incidence of drop out is highest [33] [4] and retention of immunization cards is also lowest [34]. Additionally, our study only enrolled children who showed up at clinics for immunization and not those who were not vaccinating in the first place. We do acknowledge that the bracelets may have had an impact on never vaccinated children in the community due to positive externalities. However, it was beyond the scope of this study to evaluate this indirect impact and hence enrolment was only confined within the clinic setting.
Our findings also point to some critical implications for future work and for similar novel innovations

Acknowledgments:
We are thankful to Lauren Braun for her valuable input on the formative phase work for the study and helping adapt the Alma Sana Bracelet to the local context as shared by the study team. We would also like to acknowledge her contributions towards reviewing the study protocol.

20.
Timestrip.     Participants *Denominator based on children who never wore a bracelet or wore bracelet before coming to the center or wore bracelet only sometimes Age at immunization in children for Pentavalent-3 vaccine by allocation groups Figure 3 Age at immunization in children for Measles-1 vaccine by allocation groups