Factors affecting age-appropriate timeliness of vaccination coverage among children in Lebanon

Background: The effect of immunization does not only depend on its completeness, but also on its timely administration. Routine childhood vaccinations schedules recommend that children receive the vaccine doses at specific ages. This article attempts to assess timeliness of routine vaccination coverage among a sub-sample of children from a survey conducted in 2016. Methods: This analysis was based on data from a cross-sectional multistage cluster survey conducted between December 2015 and June 2016 among caregivers of children aged 12-59 months in all of Lebanon using a structured survey questionnaire. The analysis used Kaplan–Meier curves and logistic regression to identify the predictors of age-appropriate immunization. Results: Among the 493 randomly selected children, timely administration of the third dose of polio vaccine, diphtheria-tetanus-pertussis (DTP)-containing vaccine and hepatitis B (HepB) vaccine occurred in about one-quarter of children. About two-thirds of children received the second dose of a measles-containing vaccine (MCV) within the age interval recommended by the Expanded Programme on Immunization (EPI). Several factors including socio-demographic, knowledge, beliefs and practices were found to be associated with age-appropriate vaccination; however, this association differed between the types and doses of vaccine. Important factors associated with timely vaccination included being Lebanese as opposed to Syrian and being born in a hospital for hepatitis B birth dose; believing that vaccination status was up-to-date was related to untimely vaccination. Conclusions: The results suggest that there is reason for concern over the timeliness of vaccination in Lebanon. Special efforts need to be directed towards the inclusion of timeliness of vaccination as another indicator of the performance of the EPI in Lebanon.


Introduction
Full immunization coverage is one of the key public health measures to prevent morbidity and mortality worldwide 1 . Yet, the effect of immunization does not only depend on its completeness but also on its timely administration 2 . If a child is not immunized appropriately or if immunization is delayed, then the child is at a higher risk of falling sick from a preventable disease 3 . According to the World Health Organization (WHO), an invalid vaccine dose is defined as any dose of vaccine administered earlier than the recommended age 4 . Risk factors for a child to receive untimely vaccine doses can be multifold and may relate to existing immunization practices, logistical aspects of providing vaccines, perceived contraindications, beliefs and attitudes towards vaccines or socioeconomic determinants 5-8 . Demographic characteristics, including the age, educational level and employment status of children's caregiver, can be crucial for a child receiving timely vaccination or not 9,10 .
Demographics in Lebanon are dynamic and underlie constant changes due to the social, economic and political fluctuations inside and outside the country 11 . The influx of Syrian refugees is the most recent shift, impacting on various spheres of life of the Lebanese population 12 . With regard to immunization coverage, the demand for vaccines increased greatly as nationwide vaccination campaigns were introduced to ensure optimal coverage levels and to prevent disease outbreaks 13 . Despite the prominent resilience of the Lebanese health care system, low immunization rates among Syrian refugee children persisted and are indicative of deficiencies in managing routine vaccination coverage during the crisis 14,15 . Furthermore, the variety of providers offering vaccines, as well as the multiplicity of schedules used, may result in different practices around the timeliness and simultaneity of vaccination.
Few studies exist that show how knowledge and awareness among parents influence a child's immunization status in Lebanon 16 and no study on vaccination timeliness exists. Therefore, it is crucial to extend our understanding about attitudes and behaviors to establish evidence-informed interventions. In the region, studies have shown that parental knowledge and practices are associated with complete vaccination 10 . In addition, the integration of immunization services in antenatal care may enhance vaccination take-up and timely administration 17 .
In 2016, a district-based immunization coverage cluster survey was conducted in Lebanon following the Syrian crisis; it included potential determinants for vaccination 18 . In order to further understand gaps in vaccine administration, this study analyzed vaccination timeliness and adherence to the national vaccination schedule set by the Ministry of Public Health (MoPH). Furthermore, key socio-demographic, knowledge, belief and practice factors associated with timely vaccination among Lebanese and Syrian children aged 12-59 months old were investigated.

Survey background
A national cross-sectional survey was conducted among caregivers of children aged 12-59 months following a stratified cluster sampling design. The survey was implemented from December 2015 to June 2016 in all districts of Lebanon with the exception of Nabatieh due to inaccessibility and was designed to provide district-based vaccine coverage estimates 18 .

Sampling
The original study population included 10,140 children from 26 districts in Lebanon, irrespective of their nationality. Population estimates obtained from the Central Administration of Statistics and United Nations High Commissioner for Refugees 19,20 were used to randomly select 26 clusters in each district with probability proportionate to estimated size, following the 2005 WHO cluster evaluation survey methodology 4 ; there were no up-to-date sampling frames that would have allowed conducting true probability sampling. In total, 15 children were selected by team supervisors from each cluster using a systematic random approach, with each child being selected from a different household during in-person house visits 4 . The teams were trained to adhere to the protocol and avoid changing pre-selected households. For this study, a sample of 500 children (a size arbitrarily defined by the study team) was randomly selected among the 3,728 children with documented vaccination in the main survey, i.e., who had a) pictures of the vaccination card available and b) at least one available date of vaccine administration on the card as age at vaccination was needed for this study. Children were excluded from this random selection if they had vaccination cards without any registered vaccination date or without a reported date of birth or if they were neither Lebanese nor Syrian.

Outcome variables
Any child without evidence of having received specific vaccine doses from the vaccination card was considered as not vaccinated. Children for whom no evidence was found on the date of vaccination for an antigen were excluded from the analysis related to this specific antigen. To assess delays in vaccination, the recommended vaccination schedule for children less than 5 years old, adopted by the Lebanese MoPH, was used 21 .
Timeliness was assessed through the age-appropriate vaccination coverage, defined as per the criteria in Table 1. These timely criteria included having received hepatitis B (HepB) birth dose in the first 72 hours after birth, three pentavalent and polio vaccines, the first dose starting from 60 days and the last one up to 195 days 1 , two measles-containing vaccines (MCV), the first dose starting from 270 days and the last one up to 555 days, and with an interval of at least 28 days between subsequent doses containing the same antigen.

Data analysis
Data was analyzed using Stata software, version 14, applying the "svyset" command for complex survey designs. National estimates took into account the sampling design (stratum, district and governorate-specific weight) in order to ensure that each selected child represents a certain number of similar eligible children from the population. Timeliness for all antigens was calculated for the sampled Lebanese and Syrian children separately with 95% confidence intervals (CI). The period of time until a child received a vaccine dose was calculated by subtracting the birth date from the date of vaccination. For each vaccine, the cumulative probability of being vaccinated at age t was estimated by inverse Kaplan-Meier survival function, or 1−SKM(t) 22 . For analysis purposes, months were considered as having 30 days.
In addition to vaccination data, information on children's socio-demographic characteristics and respondents' knowledge, beliefs and practices related to vaccination were collected using a structured questionnaire 23 administered by trained interviewers. An analysis of risk factors was conducted for non-age-appropriate vaccination. Using age-appropriate vaccination as the main outcome, crude and adjusted odds ratios (OR) were calculated by applying univariable and multivariable logistic regression models, respectively. All the independent variables significantly associated with the outcome at univariable analysis with a cut-off level at p-value < 0.2 were included initially in a multivariable model. The significance was set at 5% (p-value <0.05).

Ethical considerations
Before starting the interview with caregivers of eligible children, oral informed consent was obtained. Written consent was not obtained as this is not a common practice for this type of studies in Lebanon, given the low levels of literacy among certain populations and the non-sensitive nature of the information obtained. Confidentiality was strictly applied during all study procedures, including the storage of vaccination cards and the final database. Ethical approval was attained from the Institutional Review Board at Sagesse University as per the reference number IRB120416B.

Results
Of the 500 randomly selected children, seven who were neither Lebanese nor Syrians were excluded, leading to a final sample for analysis of 493 children. Their characteristics are described in Table 2.

Age-appropriate vaccination coverage (timeliness)
The inverse Kaplan-Meier survival curves depict the vaccination coverage of polio, HepB, diphtheria-tetanus-pertussis (DTP) and MCV at different ages (in days) after birth, as presented in Figure 1. HepB vaccination coverage within 72 hours following birth was 78.3% (95% CI: 72.7-83.1). The vaccination coverage for the third dose of polio was 64.3% (95% CI: 58.4-69.8) by 6.5 months (195 days) of age. A similar picture of vaccination coverage was presented for the third doses of HepB 66.1% (95% CI: 60.3-71.4) and DTP 65.3% (95% CI: 59.6-70.7) following 195 days. The coverage for the second dose of MCV at 15.5 (465 days) and 18.5 (555 days) months of age was calculated to be 75.2% (95% CI: 67.8-81.3) and 37.9% (95% CI: 22.4-53.4), respectively. Later doses in a series (i.e., 3 rd DTP, polio and HepB) were more likely to be delayed than first doses. This is particularly striking for the second dose of measles, mumps and rubella (MMR) when children received MMR as their first MCV dose (schedule 2).
Age-appropriate vaccination coverage estimates for the first and third doses of polio, HepB, DTP and MCV vaccines, in addition to HepB birth dose, are displayed in Table 3 There were no significant differences in age-appropriate vaccination based on children's gender and mothers' education. Similarly, taking the vaccination card when visiting the doctor or health facility for immunization, registering the administered vaccine on the vaccination card, receiving advice on next vaccination date, making decisions about vaccinating the child, knowing that vaccines are given free of cost in the public sector and knowing that the vaccination status is checked when starting school or kindergarten were not found to be significantly associated with timely vaccination.

Discussion
This study is the first to assess the age-appropriate vaccination coverage and its predictors among a subset of Lebanese and Syrian children aged 12-59 months residing in the Lebanese communities in 2016. Vaccination programs aim at attaining the highest level of protection against vaccine-preventable diseases at a young age together with high immunization coverage rates 24 . Routine vaccination timeliness and completeness are still public health challenges. Evaluating age-appropriate vaccination provides valuable insights even in populations with very high up-to-date immunization coverage 9 . Currently, timeliness is not routinely used as an indicator to evaluate immunization programs in Lebanon. Special efforts need to be directed towards the   inclusion of timeliness of vaccination as another indicator of the performance of the Expanded Programme on Immunization in Lebanon considering its crucial role in improving children's health and survival and reducing the risk of disease in children 25 .
In this study, the age-appropriate vaccination coverage has been described and graphically visualized using the inverse Kaplan-Meier survival curve. About 75% of children, among those included in this survey sub-sample, received the first doses of polio and DTP vaccines by 75 days, but few were immunized with these vaccines at the recommended age. The situation was even more worrisome in the case of the third doses of polio, HepB and DTP vaccines; while about 65% of children received these doses by 195 days; only 1 in 4 received them at the appropriate age. The doses of MCV vaccine were more timely than the third doses of polio, HepB and DTP, which can be because MCV is a two-dose series and has a longer interval between the doses. Despite the efforts made to ensure MCV timeliness, measles and mumps outbreaks emerged in Lebanon in early 2018, which may be attributed to the challenge of having a large influx of Syrian refugees 11, 26 . With the existence of such a pool of vulnerable children, outbreaks may occur much faster when untimely vaccination is coupled with low immunization coverage and reduced vaccine effectiveness 27  This study identified several factors, including socio-demographic, knowledge, beliefs and practices associated with age-appropriate vaccination; however, this association differed between the types and doses of vaccine. First, receiving HepB vaccine birth dose from the hospitals was a positive predictor for age-specific vaccination, compared to those who received vaccination in a health facility. This may reflect that health services, mainly having a better utilization of vaccination services, were more accessible by mothers who gave birth at a hospital, especially for HepB birth dose to be given within 3 days of birth 31 . Second, erroneously believing that children's vaccination is up-to-date for their age was negatively associated with the administration of timely vaccines. A mother's communication with health providers might be hindered by a low education level influencing negatively the immunization through the wrong beliefs 28,32,33 . Poor knowledge of immunization schedules among mothers may also explain this negative association. Third, using the information provided by schools and nurseries to decide about the child's vaccination rather than obtaining this information from a private physician or health facility staff was also a risk factor. Healthcare facilities and private clinics are responsible to a greater extent for the correct administration of vaccinations. These providers are expected to play an important role in determining invalid vaccinations 34 . Further studies are needed to examine the factors associated with vaccination timeliness in Lebanon, as factors related to timely vaccination were not identified for all vaccine doses.
Our study was subjected to important limitations. First, the timeliness assessment was done on a small sub-sample of 493 children, because children's vaccine status was assessed case by case. Only children with available vaccination cards with administration dates were included as this was the only way to obtain accurate information on age at vaccination. While the exclusion of caregiver's recall reduced recall bias, purely relying on vaccination cards may have resulted in an underestimation of vaccination delay, particularly those children without an available vaccination card might be more prone to untimely vaccination. Another obstacle during the assessment was the illegible cards. Although vaccination cards were assumed to have the most valid reporting of received vaccination, the handwriting of health workers created difficulty to accurately determine the date of vaccine administration. Second, the definition of timeliness was specifically developed for this assessment based on expert opinion because diverse practices exist among providers in the Lebanese vaccine system. The diversity in practice can be related to different available vaccination schedules and vaccines or vaccine combinations. These factors jeopardize the generalizability and comparability of results to other assessments, and interpretations should always consider the context of this study. Despite these limitations, our study is the first one to show that untimely vaccination is of concern in Lebanon, and to shed light on factors related to timely vaccination that could be useful when devising strategies to improve age-appropriate vaccination.

Data availability
Underlying data Owing to data protection concerns, the datasets generated and analyzed during the study are not publicly available. Readers can access data by contacting the corresponding author at saidr@crdconsultancy.org. Data will only be shared with researchers for the purpose of reanalysis and grant proposals.
This is available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

Grant information
This work was supported by the Bill and Melinda Gates Foundation (OPP1115427 and OPP1055811).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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