OptiMAx Will Test Whether SQ-LNS Incentivises Vaccination Uptake in Rural Chad and Niger, With a Cost Effectiveness Analysis. It Will Also Look at Whether Having Received SQ-LNS Before Becoming Malnourished Leads to Better Outcomes for Children Treated Under the OptiMA Protocol.

OptiMAx: Incentivizing EPI Vaccination Via Distribution of SQ-LNS Nutritional Supplementation to Children From Age 6-11 Months Until 18 Months of Age in Rural Chad and Niger, With a Cost Effectiveness Analysis Protocol for a Research Study Nested in the OptiMA Research Study in Ngouri Health District, Lake Region, Chad and Mirriah Health District, Zinder Region, Niger

Malnutrition and infectious disease form a vicious circle, posing a double threat to vulnerable children in low- and middle-income countries. Malnutrition makes children more vulnerable to infectious diseases, while infectious diseases increase the risk of malnutrition. When caught in this cycle, children are far more likely to die or suffer adverse effects on their health and development. High rates of wasting and low immunization coverage also constitute a weakening double burden for already fragile health systems. Every year in these contexts, hundreds of thousands of children are treated for severe wasting, while at the same time suffering repeated and prolonged epidemics of vaccine-preventable diseases such as measles. Rural areas of Chad and Niger are at the heart of this dynamic, recording some of the worst indicators of malnutrition and low vaccination coverage rates.

Small-quantity lipid-based nutritional supplements (SQ-LNS) are a category of ready-to-use, nutrient-dense food supplements fortified with micronutrients, designed to prevent malnutrition and improve child survival, growth and development. A recent meta-analysis on SQ-LNS reveals that giving a child just one sachet of SQ-LNS a day for a year can reduce the risk of mortality by 27%, iron-deficiency anemia by 64%, severe wasting by 31% and severe stunting by 17%. The recent World Health Organization (WHO) guideline on complementary feeding of infants and young children aged 6 to 23 months recently recommended the use of SQ-LNS in certain contexts of food insecurity, based on evidence deemed "very safe".

The distribution of SQ-LNS is also promising as an incentive for vaccination, as well as for other health services, such as participation in infant growth monitoring programs. Various operational experiences suggest that it is likely to have an impact on increasing vaccination coverage, and a modeling simulation suggests that it would lead to a significant reduction in measles morbidity and mortality.

The main objective of OptiMAx is to estimate the effectiveness of a mass SQ-LNS supplementation program coupled with the routine immunization program compared with the routine immunization program alone in terms of vaccination coverage against pentavalent 1 (Niger) and measles 1 (Chad), after 12 months of program implementation, in children aged 12 to 23 months as part of an annual cross-sectional household survey.

Secondary objectives include:

• Estimate the effectiveness of a mass SQ-LNS supplementation program combined with the routine Essential Program on Immunization (EPI) compared with the routine EPI alone in children aged 6-18 months, after 12 months of program implementation, in terms of 1) coverage of pentavalent 3 vaccine, malaria and other childhood vaccines, 2) on-time immunization for age-eligible children.
• Evaluate the feasibility and reliability of combining measles and pentavalent coverage measurements during annual MUAC-family training campaigns;.
• Evaluate outcomes of acutely malnourished children who received SQ-LNS supplementation prior to RUTF treatment (as part of their inclusion in the OptiMA study) versus those who did not receive SQ-LNS supplementation

The specific objectives of the process evaluation (with a sub-study on gender), modeling and economic evaluation are as follows:

1. Conduct a process evaluation of the OptiMAx intervention to understand how it works, for whom and where;
2. Understand to what extent and how gender-related facilitations and barriers affect the interaction and uptake of intervention, both on the demand side (health-seeking/intervention behaviors) and the supply side (provision of intervention services).
3. Estimate the health impact of the OptiMAx intervention, in terms of nutrition and vaccine-preventable diseases, using mathematical modeling approaches.
4. Quantify the relative costs associated with the OptiMAx intervention compared with the costs associated with existing vaccination activities in Mirriah, Niger, and Ngouri, Chad.
5. Estimate the cost-effectiveness of the OptiMAx intervention in Mirriah, Niger, and Ngouri, Chad.

Background Malnutrition and infectious disease form a vicious cycle, posing a double threat to vulnerable children in low- and middle-income countries. Malnutrition makes children more vulnerable to infectious diseases, while infectious diseases increase the risk of malnutrition. When caught in this cycle, children are far more likely to die or suffer adverse effects on their health and development. High rates of wasting and low immunization coverage also constitute a debilitating double burden for already fragile health systems. Every year, in these contexts, hundreds of thousands of children are treated for severe wasting, while suffering repeated and prolonged epidemics of vaccine-preventable diseases such as measles.

To reverse this dynamic, ALIMA (The Alliance for International Medical Action), a Dakar-based African medical alliance linking national Nongovernmental Organizations (NGOs) and international research institutes, has proposed a research program called OptiMAx to assess the potential impact of joint programming of monthly small-batch lipid-based nutritional supplementation (SQ-LNS) coupled with immunization services, with a particular focus on documenting the evolution of Pentavalent 3 and Measles 1 coverage in the 12-23 month age group.

Rural areas in Niger and Chad are at the center of this dynamic, recording some of the worst indicators of malnutrition, with recurrent epidemics of measles and sporadic outbreaks of diphtheria and whooping cough. Yet only 28.6% of children under the age of two in Ngouri (Chad) and 4% in Mirriah (Niger) have a minimum acceptable diet (1, 2).

Malnutrition indicators and immunization coverage rates in Chad and Niger are among the worst in the world. Stunting and wasting affect 28% and 8.6% of children respectively in Chad, and 47.0% and 12.2% in Niger. Stunting affects 35.7% of children under 5 (U5) in Ngouri, Chad, and 51.5% in Mirriah, Niger. Wasting affects 13.3% and 17.6% of children in Ngouri and Mirriah respectively. Vaccination coverage against measles 1 by card verification and recall of mothers/accompanying adults is 75.1% nationally in Chad and 83.5% in Niger. It is lower in Ngouri in Chad (67.3%) and Mirriah in Niger (74.3%) (1,2).

High rates of wasting and inadequate immunization coverage represent a debilitating double burden for fragile health systems, as in Chad and Niger, where hundreds of thousands of children are treated for severe wasting and repeated, prolonged epidemics of vaccine-preventable diseases such as measles occur.

1.2 Benefits of SQ-LNS supplementation Small-quantity lipid-based nutritional supplements (SQ-LNS) are food supplements designed to prevent malnutrition and improve child survival, growth and development. Lipid-based nutritional supplements are a category of ready-to-use, nutrient-rich food supplements fortified with milk powder, essential fatty acids, vitamins and minerals at levels designed to treat and prevent acute malnutrition.

They can be consumed straight from the package, do not require refrigeration and are safe from bacterial contamination. Ration size and level of enrichment vary according to their use in treating or preventing acute malnutrition. Ready-to-use therapeutic foods (RUTFs) or complementary foods come in 92 or 100 gram sachets, medium LNS in 50 gram sachets and SQ-LNS in 20 gram sachets.

SQ-LNS come in 20-gram sachets and are seen as a way of enriching the local diets of young children to better meet their specific nutrient needs. The recommended dose of one 20 grams sachet per day (at a cost of 0.09 USD per sachet) can be mixed with home-prepared foods or consumed directly from the sachet. SQ-LNS supplementation for children aged 6 to 23 (accompanied by messages to reinforce infant and young child feeding recommendations) is based on solid evidence. Feeding a child a single sachet of SQ-LNS per day for one year can reduce the risk of all-cause mortality by 27% (3), iron-deficiency anemia by 64% (4), severe wasting by 31% (5), and severe stunting by 17% (5). SQ LNS supplementation has also been shown to reduce the proportion of children in the lower range of cognitive development (language, social-emotional and motor scores) by 16-19% (6). Figure 2. The recent World Health Organization (WHO) guideline on complementary feeding of infants and young children aged 6 to 23 months recently recommended the use of SQ-LNS in food-insecure settings, the evidence being deemed "very safe" (7).

Another retrospective study showed that children who had received SQ-LNS supplementation and then been treated for an episode of acute malnutrition under a simplified protocol were associated with fewer hospitalizations than children who had not received SQ-LNS before being treated for cachexia (8, 9).

1.3 Study rationale: why use mass SQ-LNS supplementation as a vaccination incentive? ALIMA has already documented high vaccination coverage in health zones where SQ-LNS is distributed through health centers. Linking SQ-LNS distributions to child growth monitoring and Essential Program on Immunization (EPI) activities in a health center should have a significant impact on vaccination coverage at population level.

A December 2023 Cochrane meta-analysis (10) examined interventions to improve childhood immunization coverage in low- and middle-income countries. The majority of the 41 studies meeting the inclusion criteria were individual or cluster randomized trials examining the impact of health education, the use of patient reminders - particularly by SMS - monetary incentives for families or performance-based payments to health systems. Only one of these studies, by Banerjee et al (11), used food for families to encourage attendance at vaccination sites. The main limitations cited are either single studies with small numbers of participants, or inconsistent results between different studies. Overall, the level of certainty of the evidence is low, and more high-quality studies are needed to inform policy and practice.

In parallel with the Cochrane meta-analysis, Gavi and the Eleanor Crook Foundation (ECF) published "A literature review and proposed learning agenda on Immunization-Nutrition Integration (INI)" in November 2023 (12). The integration of child nutrition and immunization makes sense insofar as the services are provided by the same health personnel and target the same age groups (12). To date, the only established combined intervention is vitamin A supplementation as part of routine EPI or supplementary immunization activities (oral polio vaccination campaigns). The ECF report identifies the optimal conditions for integrating services: overlapping target populations, compatibility of timing and frequency of services, acceptability to families and health workers, similar logistical requirements and level of competence required for health service staff. The intervention identified by the Gavi/ECF report as potentially fitting within these constraints is supplementation with small-quantity lipid-based nutritional supplements (SQ-LNS) as part of routine EPI.

Given the persistent difficulties in achieving Penta3 and first dose of measles-containing vaccine (MCV1) vaccination coverage high enough to reduce the frequency of epidemics, the implementation of a project to encourage EPI adherence is particularly relevant for children in the 6-11 month age bracket, which is also the optimal age for the initiation of SQ-LNS supplementation. The hypothesis is that the inclusion of SQ-LNS distribution in the EPI for this age group will significantly increase Penta 3 and measles vaccination coverage in high-risk, high-burden and hard-to-reach areas in West and Central Africa.

1.4 Potential barriers to accessing vaccination or the SQ-LNS supplementation program A range of factors influence access to, or use of, preventive or curative healthcare services at primary level. In both Chad and Niger, barriers to access may include geographical distance or flooding problems, lack of knowledge of available services, or poor quality of the relationship between families and healthcare providers. Investigators consider it essential to study the barriers and facilitators to access to vaccination and participation in the SQ-LNS supplementation program in our study areas.

1.5 Theory of change Our theory of change is that by adding SQ-LNS distributions to routine immunization activities in health centers or even health huts, more children will be vaccinated, particularly against measles, while benefiting from other health services in a cost-effective way. In addition, the distribution of SQ-LNS to children aged 6 to 18 months will reduce the opportunity costs associated with travel to health centers; SQ-LNS will improve the health and development of young children - creating a positive feedback loop that will encourage families to continue to visit the SQ-LNS distribution site; and the inclusion of vaccine-related questions in mid-upper arm circumference (MUAC) family training will provide an additional opportunity to reinforce the importance of immunization for young children's health and well-being. Investigators believe that encouraging to provide quality nutrition to their young children will help overcome the obstacles that prevent them from reaching the health center and health huts (e.g. distance, lack of knowledge of the vaccination schedule, etc.), which contribute to the number of under-vaccinated children in Ngouri, Chad and Mirriah, Niger.

SQ-LNS distributions also provide repeated opportunities to educate caregivers on the importance of vaccinations and tackle vaccine hesitancy, thereby improving on-time or catch-up vaccination coverage. At the same time, SQ-LNS will address key nutrient deficiencies in children's diets, improving growth and development outcomes. In the short to medium term, this will deliver more effective services to more people, while reducing the burden of malnutrition and infectious disease, and the costs associated with responding to both. In the long term, fewer measles infections, cases of acute malnutrition, hospitalizations, anemia and growth/development will mean lives saved, lives improved and a less overwhelmed, more cost-effective healthcare system.

1.7 History of ALIMA's Optimizing treatment of malnutrion (OptiMA) projects In 2022, acute malnutrition (AM) affected 45 million children under the age of 5 worldwide, including 13.7 million children suffering from the most severe form. (13) Nearly half of all deaths in children under the age of 5 are linked to undernutrition, which is also the main risk factor for loss of disability-adjusted life years in low- and middle-income countries. (14, 15) An estimated 4.6 million children worldwide with AM reside in West Africa, including 275,000 in Chad and 560,000 in Niger. (13)

Although effective treatment exists, coverage of treatment for severe acute malnutrition (SAM) and moderate acute malnutrition (MAM) is low overall, partly because different protocols and products are used in separate programs. (16) New approaches are being studied that define MAM as MUAC<125 mm or edema, and treat severe and moderate cases with RUTFs at a reduced dosage as the child's condition improves.

OptiMA is one such strategy, which includes: training families to use MUAC tapes to detect early signs of malnutrition in their children; admitting children for treatment in cases of MUAC <125 mm or edema; and treating all children with SAM or MAM with a single product, RUTF, at a progressively reduced dose as the children's condition improves under treatment. OptiMA showed promise both in a randomized controlled trial in the DRC, which included a demonstration of non-inferiority among the subgroup of children admitted under the current WHO definition of SAM, and in prospective observational cohorts in Burkina Faso and Niger. (17-20)

Other simplified and combined protocols using the same admission and discharge criteria but a different reduced-dose regimen of RUTF have demonstrated non-inferiority in cluster-randomized control trials in Sierra Leone, South Sudan and Kenya (the ComPAS study), as well as in Mali (which also used community health worker (CHW)-led treatment). (21-23). More recently, ComPAS has published promising results from prospective observational cohorts in the Central African Republic (CAR) and Mali (24, 25)

In 2023, the World Health Organization (WHO) updated the normative guidelines for the management of MAM in children, including three new recommendations that are consistent with OptiMA and other simplified and combined protocols.(26) Firstly, the preferred treatment for children with MAM should be specialized food preparations (SFF) such as lipid-based nutritional supplements (e.g., ready-to-use complementary foods (ASPE) or RUTF). Secondly, children belonging to a new category of high-risk MAM should be treated as a priority (i.e. those whose MAM has additional risk factors such as a MUAC of 115-119 mm, an age below two years or a weight-for-age z-score (WAZ) <-3). Finally, in certain settings, the dose of RUTF may be reduced for children admitted for SAM but who no longer present with severe edema or emaciation. (The new guidelines also advocate the use of health care aides with appropriate levels of supervision for the management of SAM in children.)

The OptiMA protocol is currently being implemented on a large scale in seven districts in five West African countries to gather further evidence of the approach in both rural and urban routine settings. These prospective observational cohorts in Chad, Mali, Niger and Nigeria use annual coverage surveys to determine whether OptiMA leads to increased AD treatment coverage while meeting established standards for program outcomes. (27) Investigators maintain an individual database for all children treated with the OptiMA protocol. This individual database now includes almost 200,000 treated episodes of acute malnutrition, including multiple episodes for the same child due to relapse. The OptiMA database contains over 200 variables for each episode, covering anthropometric data, medication administration, vaccinations and other health data. The database is regularly monitored by the regional OptiMA team in collaboration with the data manager present in each project. This will enable us to assess the impact of SQ-LNS supplementation on OptiMA's performance indicators before the onset of acute malnutrition.

The decision to nest SQ-LNS/PEV activities in OptiMA sites was also made in part due to the results of a previous OptiMA pilot study conducted by ALIMA in Mirriah, Niger, where it was found that children receiving SQ-LNS supplementation prior to RUTF treatment had fewer hospitalizations and fewer non-responders than children who did not receive SQ-LNS prior to RUTF treatment (28, 29). Investigators hypothesize that SQ-LNS supplementation improved children's individual resilience so that they could better overcome an episode of acute malnutrition. A secondary aim of OptiMAx is to deepen our understanding of the possible benefits for children receiving SQ-LNS before being treated for an episode of acute malnutrition with RUTF.

2. Hypothesis The OptiMAx study will test the hypothesis that SQ-LNS supplementation combined with the routine Expanded Program on Immunization (EPI), and distributed in health facilities that offer vaccination, could increase vaccination coverage overall. OptiMAx will also assess how SQ-LNS distribution could act on the barriers to vaccination faced by families, and how the cost and impact of SQ-LNS distribution compares with the costs of supplementary immunization activities (SIAs). In this way, it will be possible to determine whether it is possible to achieve a dual impact on increasing vaccination coverage and improving growth.

3. Proposed intervention 3.1 OptiMAx study design ALIMA and its national partners BEFEN (Mirriah, Niger) Alerte Sante (Ngouri, Chad ) have been operating in the 2 districts proposed for this study for over 10 years. Since 2022, they have been carrying out the OptiMA study in these 2 districts,which aims to increase coverage in the management of acute malnutrition. As part of the OptiMA study, ALIMA and BEFEN run an annual community training campaign on the use of the MUAC ribbon within the family. This training campaign aims to be exhaustive, enabling us to estimate the number of children aged 6-59 months in each village. It also provides an opportunity to ask questions about the receipt (or non-receipt) of certain vaccines for children aged 12-24 months.

In preparation for the OptiMAx study, investigators identified 10 health zones (HZs) in Mirriah and 12 in Ngouri. The choice was determined by the quantity of SQ-LNS available and the number of children who could be supplemented for 24 months. Investigators conducted a MUAC-family training campaign in the HZs of each district, during which we exhaustively interviewed all children aged 6-59 months and asked about the number of doses of measles vaccine (MCV) and Pentavalent vaccine received by children aged 12-24 months. Investigators were thus able to estimate, village by village, MCV1 coverage and the proportion of children with zero-dose Pentavalent in the 12-24 month age group.

3.2 Study design for OptiMAx qualitative research and economic analysis (under the direction of LSHTM) The study will include primary data collection as part of an observational study (mixed methods process evaluation (30, 31) and gender sub-study) and analysis of secondary data collected by the ALIMA/Befen (Niger) and ALIMA/Alerte Santé (Chad) teams (household surveys, MUAC-family surveys and OptiMA data collection) as part of health impact modelling and economic analysis (32-35).

Data collection for the process evaluation will include qualitative interviews and focus group discussions (FGDs), as well as logbooks, documentary analysis of routine programmatic data collected by ALIMA, and the inclusion of selected survey questions in surveys conducted by ALIMA. As part of the qualitative data collection, investigators will also study gender-related facilitating factors and obstacles (36-39).

In total, up to 424 participants will be recruited for qualitative data collection in the two countries, including 168 interview participants (48 healthcare workers, 40 parents and 20 partners/spouses, 30 non-adopters and 30 partners/spouses) and 256 group discussion participants (32 focus groups with up to 8 participants each).

In each country, investigators will work closely with a local researcher, who will be selected and recruited by LSHTM and ALIMA in close collaboration. Researchers will be recruited from the regions where the OptiMAx project is being implemented, and will therefore contribute to understanding local factors such as language, cultural dynamics and geography, which may have an impact on participant sampling and data collection procedures. Wherever possible, investigators will try to recruit staff with experience and knowledge of gender issues. Managers will receive in-depth training and supervision from LSHTM, particularly with regard to gender mainstreaming in all components of the study, and will participate in the development of thematic guides, data collection, transcription and data analysis.

In addition to process evaluation, modeling studies and economic analyses will provide evidence on 1) the impact of routine SQ-LNS distribution, 2) referral for treatment in cases of wasting, and 3) updating vaccination status on nutrition and vaccine-preventable disease outcomes. This will include the direct health effects of OptiMAx, as well as the less directly measurable health effects (e.g. avoided cases of vaccine-preventable diseases and wasting, and avoided deaths from vaccine-preventable diseases and wasting) and the economic cost of these additional benefits. As a result, project data can be used to answer stakeholders' anticipated questions about OptiMAx and the feasibility of adopting the intervention post-project as part of routine programming. Modeling studies will include both dynamic and statistical modeling, reflecting the most recent data - from a literature review - on the role of undernutrition in increasing susceptibility to different infectious diseases by affecting natural and vaccine-induced immune potential, and on the impact of infectious diseases on nutritional status. These data will be combined with context-specific data from each of the study sites to generate results on the impact of the OptiMAx intervention on different health and program outcomes.

The results of the modeling studies feed into a series of economic analyses. A costing sub-study will be undertaken to better understand the costs of the OptiMAx program, as well as the costs of routine EPI activities and activities related to epidemics or catch-up campaigns. The economic costs associated with the health outcomes derived from the model will make it possible to compare different scenarios for implementing OptiMAx and/or EPI activities.

Inclusion Criteria:

• All non-malnourished children between 6 and 12 months of age will be eligible for SQ-LNS supplementation until they reach 18 months of age.

For the annual household surveys,

• Children aged 6 to 59 months will be surveyed on MUAC status and other malnutrition-related issues, while the immunization analysis will focus on children aged 12 to 23 months;
• With the informed oral consent of the parents or legal guardian ;
• Reside in the neighborhoods included in the study.

For the mixed-methods process evaluation and gender sub-study (to be carried out in the months following implementation).

Inclusion criteria

• OptiMAx intervention personnel (e.g. healthcare staff)
• A group of mothers of children benefiting from the intervention
• Male partners/spouses of parents
• Community members from the sites targeted by the intervention will be recruited for the focus groups.
• Non-adherents or parents who choose not to continue nutritional supplementation and/or vaccination despite their availability under the program will be recruited for interviews.
• Husbands/male partners of non-members will also be surveyed.

Exclusion Criteria:

• Age-eligible children with MUAC <125 or edema will first be treated for acute malnutrition with OptiMA and then resume supplementation with SQ-LNS.

There is no exclusion criteria for the annual household surveys

Exclusion criteria for the mixed-methods process evaluation

- Parents or guardians under 15 years of age.