RANDOMIZED CONTROLLED TRIAL OF TEXT MESSAGE TO INCREASE PNEUMOCOCCAL VACCINATION IN ADULTS IN CHILE.

Background and Rationale Streptococcus pneumoniae is a globally distributed pathogen responsible for a wide spectrum of diseases, with the highest burden concentrated in children under 5 years and adults over 50 years. In Chile, invasive pneumococcal disease represents a growing public health threat among older adults: between epidemiological weeks 1 and 30 of 2024, reported cases increased by 9% compared to the previous year, with adults aged 60 years and older accounting for 47.7% of all registered isolates.

Despite the availability of the 23-valent pneumococcal polysaccharide vaccine (PPV23) free of charge through Chile's National Immunization Program (Programa Nacional de Inmunizaciones, PNI) since 2007, vaccination coverage among adults turning 65 years has remained consistently insufficient. The cohort born in 1957 reached 25.6% coverage in 2022; the 1958 cohort reached 25.0% in 2023; and the 1959 cohort reached 30.1% in 2024. These figures fall well below established public health targets and reflect a structural gap that conventional communication strategies have failed to close.

Text message reminders have emerged as a promising intervention to improve vaccination coverage. They are low-cost, scalable, rapidly deployable, and applicable at the population level. The most recent systematic review and meta-analysis of randomized controlled trials on this topic demonstrated that text message reminders significantly increase vaccination coverage by 9% (95% CI: 6-13%), an effect that is consistent regardless of message content, country income level, or target population age. Chile offers particularly favorable conditions for this type of intervention, with over 30 million active mobile phones, 94.1% internet access, and 75% social media users, positioning it as one of the most digitally connected countries in Latin America.

Study Design Is an open-label, parallel-group, randomized controlled trial conducted within the operational framework of Chile's National Immunization Program. Adults born in 1961 who turn 65 years of age in 2026, have a valid mobile phone number registered in the National Immunization Registry (Registro Nacional de Inmunizaciones, RNI), and have no prior record of pneumococcal vaccination will be eligible for inclusion. Individuals identified as deceased in the RNI will be excluded.

From an estimated base cohort of 175,000 adults born in 1961, approximately 43,000 individuals are expected to meet the eligibility criteria and constitute the study population. All eligible individuals will be included by convenience sampling, with no additional active selection process. Participants will be randomized 1:1 to the intervention or control group using stratified randomization by sex and region of Chile.

The study will be conducted during July and August 2026, with a total follow-up period of six weeks per participant.

Intervention

Intervention group - text message reminder:

Participants assigned to the intervention group will receive a WhatsApp text message developed by the PNI communications team in collaboration with the Ministry of Health's Communications Unit, based on the Yale-UNICEF Vaccine Messaging Guide. The message will be sent by the Ministry of Health through Rayén Salud - the official provider of the RNI - using its artificial intelligence contactability platform EMILIA, which is the institutional and official contactability platform of the National Immunization Program.

The message will include: (1) an official presentation identifying the Ministry of Health of Chile as the sender; (2) a reminder that the recipient is eligible for free pneumococcal vaccination upon turning 65 years of age; (3) confirmation that the vaccine is guaranteed and available at no cost; and (4) the name, address, and operating hours of vaccination centers in the participant's municipality of residence.

The first message will be sent on day 0 of the intervention. Vaccination status will be verified at days 7 and 13. Participants who have not been vaccinated by day 13 will receive a second reminder message on day 14. All participants will be followed until day 42, at which point final vaccination status will be recorded. The date of vaccination will be registered for all participants who receive the vaccine during the study period.

Control group - usual care:

Participants assigned to the control group will not receive a text message reminder. They will be informed of the pneumococcal vaccination recommendation through the usual PNI communication channels, including written press, digital media, and official social media accounts of the Ministry of Health and the Undersecretary of Public Health. Vaccination status will be assessed at the same time points as the intervention group (days 7, 21, and 42), and the date of vaccination will be recorded for those vaccinated during the study period.

Outcomes The primary outcome is pneumococcal vaccination coverage at day 42 from the start of the intervention, defined as the proportion of randomized adults in each group who received the PPV23 vaccine during the follow-up period.

Secondary outcomes include:

1. pneumococcal vaccination coverage at day 7 from the start of the intervention.
2. pneumococcal vaccination coverage at day 21 from the start of the intervention.
3. time from randomization to pneumococcal vaccination, analyzed using Kaplan-Meier survival analysis with log-rank testing.
4. the association between sex or geographic region and pneumococcal vaccination coverage, estimated using a log-binomial regression model.

Data Sources and Management All data will be obtained exclusively from the RNI. The following variables will be collected: sex, municipality, region, influenza vaccination in the past year, text message assignment (yes/no), date of first text message, date of second text message (if applicable), pneumococcal vaccination (yes/no), and date of pneumococcal vaccination.

Data extraction, custody, and management will be the responsibility of the PNI's Data Management and Development Unit (Patricia Cabezas Olivares, Paulina Muñoz Cortés, Iván Brstilo Cerda), under the supervision of the Head of the National Immunization Program and the principal investigator. The final database will be anonymized by assigning a unique numeric code to each participant, dissociating personal identity from vaccination data and randomization group assignment. The linkage table will be stored separately on an encrypted server with restricted access and will be securely destroyed upon study completion. Results will be reported exclusively in aggregate form, with no possibility of direct or indirect participant identification. All data handling complies with Chilean Law No. 19,628 on the Protection of Private Life.

Statistical Analysis The statistical analysis will follow an intention-to-treat approach. Baseline characteristics will be described for each group; categorical variables will be expressed as absolute numbers and percentages, and continuous variables as mean and standard deviation or median and interquartile range according to distribution.

Pneumococcal vaccination coverage will be estimated at days 7, 21, and 42 for both groups, with the numerator defined as the number of vaccinated adults in each group and the denominator as the total number of randomized adults in each group. The association between the intervention and the outcome will be assessed using a chi-square test. The magnitude of the association will be expressed as relative risk with 95% confidence intervals. The number needed to message (NNM) will be calculated as the reciprocal of the absolute risk reduction.

Time-to-vaccination will be analyzed using Kaplan-Meier survival curves, with time zero defined as the date of randomization and the event of interest defined as pneumococcal vaccination. Participants not vaccinated by the end of follow-up will be censored at day 42. Differences between survival curves will be assessed using the log-rank test. The association between sex or geographic region and vaccination outcome will be estimated using a log-binomial model. All statistical analyses will be performed using RStudio (Version 2025.09.1+401) and Stata 18 (StataCorp, College Station, TX).

Sample Size An a priori power calculation was conducted to detect an absolute difference of 9% in vaccination coverage between the intervention and control groups. Assuming a baseline coverage of 10% in the control group and 19% in the intervention group, with a two-sided significance level of 0.05 and 21,500 participants per group, the estimated statistical power exceeds 99% using a two-proportion z-test.

Ethical Considerations This study will be submitted for review to the Research Ethics Committee of the Pontificia Universidad Católica de Chile. Given the minimal risk of the intervention, the programmatic nature of the study within the National Immunization Program, the operational impracticability of obtaining individual informed consent from approximately 43,000 geographically dispersed participants without introducing systematic selection bias, and the clear social and scientific value of the study, a waiver of individual informed consent will be formally requested. This request is grounded in CIOMS 2016 Guidelines (Guideline 10) and the Declaration of Helsinki. The study complies with Chilean Law No. 19,628 on the Protection of Private Life regarding the use of personal data for research purposes.

Funding This study is funded entirely through the budget of the National Immunization Program, under Subtitle 24 of Chile's Public Sector Budget Law for 2026. No private funding is involved.