Immunogenicity, safety, and reactogenicity of a half- versus full-dose BNT162b2 (Pfizer-BioNTech) booster following a two-dose ChAdOx1 nCoV-19, BBIBP-CorV, or Gam-COVID-Vac priming schedule in Mongolia: a randomised, controlled, non-inferiority trial.

Background: COVID-19 vaccine booster doses restore vaccine effectiveness lost from waning immunity and emerging variants. Fractional dosing may improve COVID-19 booster acceptability and uptake and will reduce the per-dose cost of COVID-19 booster programmes. We sought to quantify the immunogenicity, reactogenicity, and safety of a half-dose BNT162b2 (Pfizer-BioNTech) booster relative to the standard formulation. Methods: This randomised, controlled, non-inferiority trial recruited adults in Mongolia primed with a two-dose homologous ChAdOx1 nCov-19 (Oxford-AstraZeneca, n = 129 participants), BBIBP-CorV (Sinopharm (Beijing), n = 399), or Gam-COVID-Vac (Gamaleya, n = 70) schedule. Participants were randomised (1:1) to receive a 15 µg (half-dose) or 30 µg (full-dose) BNT162b2 booster. Participants and study staff assessing reactogenicity were blinded up to day 28. Co-primary endpoints were Wuhan-Hu-1 anti-spike S1 IgG seroresponse 28 days post-boosting and reactogenicity within 7 days of boosting. The non-inferiority margin for the absolute difference in seroresponse was -10%. Differences in seroresponse were estimated from logistic regression with marginal standardisation. Geometric mean ratios of IgG were also estimated. ClinicalTrials.gov Identifier: NCT05265065. Findings: Between May 27th and September 30th, 2022, 601 participants were randomized to full-dose BNT162b2 (n = 300) or half-dose (n = 301). 598 were included in safety analyses, and 587 in immunological analyses. The frequency of grade 3-4 reactions was similar between arms (half-dose: 4/299 [1.3%]; full-dose: 6/299 [2.0%]). Across all severity grades, half-dose recipients reported fewer local and systemic reactions (60% versus 72% and 25% versus 32%, respectively). Seroresponse was 84.7% (250/295) and 86.6% (253/292) in the half-dose and full-dose arms, respectively (Difference: -2.8%; 95% CI -7.7, 2.1). Geometric mean IgG titres were similar in those receiving full and half-dose boosters for the ChAdOx1 and BBIBP-CorV primed groups, but lower in the half-dose arm in Gam-COVID-Vac-primed participants (GMR: 0.71; 95% CI 0.54, 0.93). Interpretation: Half-dose BNT162b2 boosting elicited an immune response that was non-inferior to a full-dose, with fewer reactions, in adults primed with ChAdOx1 nCov-19 or BBIBP-CorV. Half-dose boosting may not be suitable in adults primed with Gam-COVID-Vac. Half-dose BNT162b2 boosting may be considered in populations primed with ChAdOx1 nCov-19 or BBIBP-CorV. Funding: Coalition for Epidemic Preparedness Innovations (CEPI).

Vitamin D supplements for fracture prevention in schoolchildren in Mongolia: analysis of secondary outcomes from a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Vitamin D supplementation has been shown to increase total hip areal bone mineral density in healthy children and adolescents. We aimed to investigate whether supplementing schoolchildren living in Mongolia with weekly vitamin D3 for 3 years affected fracture risk. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled trial across 18 public schools in Ulaanbaatar, Mongolia. Schoolchildren were eligible if they were aged 6-13 years at screening, had a negative QuantiFERON-TB Gold In-tube assay (QFT) result, were not hypersensitive to vitamin D or immunocompromised, did not use vitamin D supplements, did not have clinical signs of rickets, and had no intention of leaving Ulaanbaatar within 3 years. Participants were randomly assigned (1:1) to receive either vitamin D (oral dose of 14 000 international units [IU] vitamin D3, once per week) or placebo for 3 years using permuted block randomisation stratified by school of attendance. Participants, care providers, and all trial staff were masked to group assignment during the intervention. Prespecified secondary outcomes were incidence of fractures and adverse events, ascertained using questionnaires. The fracture and safety analyses included participants who completed at least one follow-up fracture questionnaire. We estimated adjusted risk ratios (RRs) and 95% CIs using generalised linear models with binomial distribution and a log link function with adjustment for school of attendance. The trial is registered with ClinicalTrials.gov, NCT02276755, and the intervention ended in May, 2019. FINDINGS: Between Sept 2, 2015, and March 20, 2017, 11 475 children were invited to participate in the study and 8851 were recruited and randomly assigned to receive either vitamin D (n=4418) or placebo (n=4433). 8348 participants were included in the fracture and safety analyses (4176 [94·5%] in the vitamin D group and 4172 [94·1%] in the placebo group). Of these, 4125 (49·4%) were female, 4223 (50·6%) were male, and 7701 (92·2%) were of Khalkh ancestry. Median age was 9·2 years (IQR 8·0-10·7) and 7975 (95·5%) participants had baseline serum 25-hydroxyvitamin D concentrations less than 50 nmol/L. During a median follow-up of 3·0 years (IQR 2·9-3·1), 268 (6·4%) participants in the vitamin D group and 253 (6·1%) in the placebo group reported one or more fractures (adjusted RR 1·10, 95% CI 0·93-1·29; p=0·27). Incidence of adverse events did not differ between study groups. INTERPRETATION: Oral vitamin D supplementation at a dose of 14 000 IU/week for 3 years was safe, but did not influence fracture risk in schoolchildren living in Mongolia who had a high baseline prevalence of vitamin D deficiency. FUNDING: US National Institutes of Health.

Influence of vitamin D supplementation on fracture risk, bone mineral density and bone biochemistry in Mongolian schoolchildren: multicenter double-blind randomized placebo-controlled trial.

Background: Randomized controlled trials (RCT) of vitamin D supplementation to reduce fracture risk in children are lacking. Methods: We conducted a Phase 3 RCT of weekly oral supplementation with 14,000 IU vitamin D3 for 3 years in Mongolian schoolchildren aged 6-13 years. Serum 25-hydroxyvitamin D (25[OH]D) concentrations and the proportion of participants reporting ≥1 fracture were secondary outcomes for the main trial. Radial bone mineral density (BMD) was assessed in a nested sub-study, with serum concentrations of parathyroid hormone (PTH) and bone-specific alkaline phosphatase (BALP) determined in a subset of participants. Findings: 8851 children were enrolled in the main trial, of whom 1465 also participated in the sub-study. Vitamin D deficiency was prevalent at baseline (25[OH]D <20 ng/mL in 90.1%). The intervention elevated 25(OH)D concentrations (adjusted inter-arm mean difference [aMD] 20.3 ng/mL, 95% CI 19.9 to 20.6) and suppressed PTH concentrations (aMD -13.6 pmol/L, 95% CI -23.5 to -3.7), but it did not influence fracture risk (adjusted risk ratio 1.10, 95% CI 0.93 to 1.29, P=0.27) or radial BMD z-score (aMD -0.06, 95% CI -0.18 to 0.07, P=0.36). Vitamin D suppressed serum BALP concentrations more among participants with baseline 25(OH)D concentrations <10 vs. ≥10 ng/mL (Pinteraction=0.04). However, effects of the intervention on fracture risk and radial BMD were not modified by baseline vitamin D status (Pinteraction≥0.67). Interpretation: Weekly oral vitamin D supplementation elevated serum 25(OH)D concentrations and suppressed PTH concentrations in vitamin D-deficient schoolchildren in Mongolia. However, this was not associated with reduced fracture risk or increased radial BMD. Funding: National Institutes of Health.

Learning from the Implementation of the Child Nutrition Program: A Mixed Methods Evaluation of Process.

Nutrition and feeding interventions are important for children's growth and development. Holt International's Child Nutrition Program (CNP) is a child nutrition and feeding intervention. This study aims to describe and explore the implementation of CNP in Mongolia and the Philippines using mixed methods including qualitative and quantitative data analysis. The analysis framework was guided by the WHO's Monitoring the Building Blocks of Health Systems. Key informant interviews (KIIs) were conducted, transcribed, translated and coded. Knowledge, Attitude and Practice Surveys (KAPS) and pre-/post-tests from routine program audit data were analyzed. Analysis of nutrition (Mongolia: 95% CI: 7.5-16.6 (p = < 0.0001), Philippines: 95% CI: 7.6-15.7 (p= < 0.0001)) and feeding (Mongolia: 95% CI: 11.7-23.9 (p = < 0.0001), Philippines: 95% CI: 6.6-16.9 (p = < 0.0001)) tests indicate improvement post-training in both countries. KAPS indicate changes in desired practices from pre-training to post-training. Thematic analysis of KIIs highlight essential components for program implementation and effectiveness, including strong leadership, buy-in, secure funding, reliable supply chains, training and adequate staffing. This evaluation of program implementation highlights successful strategies and challenges in implementing CNP to improve the health of children in Mongolia and the Philippines. Lessons learned from the implementation of CNP can inform growth of the program, scaling strategies and provide insights for similar interventions.

Risk factors for active tuberculosis in 938 QuantiFERON-positive schoolchildren in Mongolia: a community-based cross-sectional study.

BACKGROUND: There is controversy regarding the relative influence of 'exogenous' versus 'endogenous' factors on the risk of progression from latent tuberculosis infection to active tuberculosis (TB) disease in children. METHODS: We conducted a cross-sectional analysis to identify risk factors for active tuberculosis in QuantiFERON®-TB Gold (QFT-G)-positive children aged 6-13 years attending 18 schools in Ulaanbaatar, Mongolia. Children underwent clinical and radiological screening for active tuberculosis, and data relating to potential risk factors for disease progression were collected by questionnaire and determination of serum 25-hydroxyvitamin D (25[OH]D) concentrations. Risk ratios were calculated using generalized estimating equations with adjustment for potential confounders. RESULTS: 129/938 (13.8%) QFT-positive children were diagnosed with active tuberculosis. Risk of active tuberculosis was independently associated with household exposure to pulmonary TB (adjusted risk ratio [aRR] 2.40, 95% CI 1.74 to 3.30, P < 0.001), month of sampling (adjusted risk ratio [aRR] for March-May vs. June-November 3.31, 95% CI 1.63 to 6.74, P < 0.001; aRR for December-February vs. June-November 2.53, 95% CI 1.23 to 5.19, P = 0.01) and active smoking by the child (aRR 5.23, 95% CI 2.70 to 10.12, P < 0.001). No statistically significant independent association was seen for age, sex, socio-economic factors, presence of a Bacillus Calmette-Guérin (BCG) scar, tobacco exposure or vitamin D status. CONCLUSIONS: Household exposure to active TB, winter or spring season and active smoking were independently associated with risk of active tuberculosis in QFT-positive children. Our findings highlight the potentially high yield of screening child household contacts of infectious index cases for active tuberculosis in low- and middle-income countries.

Prevalence and Determinants of QuantiFERON-Diagnosed Tuberculosis Infection in 9810 Mongolian Schoolchildren.

BACKGROUND: There is controversy regarding the potential influence of vitamin D deficiency, exposure to environmental tobacco smoke, BCG vaccination, season, and body habitus on susceptibility to Mycobacterium tuberculosis (MTB) infection. METHODS: We conducted a cross-sectional analysis to identify determinants of a positive QuantiFERON-TB Gold (QFT) assay result in children aged 6-13 years attending 18 schools in Ulaanbaatar, Mongolia. Data relating to potential risk factors for MTB infection were collected by questionnaire, physical examination, and determination of serum 25-hydroxyvitamin D (25[OH]D) concentrations. Risk ratios (RRs) were calculated with adjustment for potential confounders, and population attributable fractions (PAFs) were calculated for modifiable risk factors identified. RESULTS: Nine hundred forty-six of 9810 (9.6%) participants had a positive QFT result. QFT positivity was independently associated with household exposure to pulmonary tuberculosis (adjusted RR [aRR], 4.75 [95% confidence interval {CI}, 4.13-5.46, P < .001]; PAF, 13.1% [95% CI, 11.1%-15.0%]), vitamin D deficiency (aRR, 1.23 [95% CI, 1.08-1.40], P = .002; PAF, 5.7% [95% CI, 1.9%-9.3%]), exposure to environmental tobacco smoke (1 indoor smoker, aRR, 1.19 [95% CI, 1.04-1.35]; ≥2 indoor smokers, aRR, 1.30 [95% CI, 1.02-1.64]; P for trend = .006; PAF, 7.2% [95% CI, 2.2%-12.0%]), and increasing age (aRR per additional year, 1.14 [95% CI, 1.10-1.19], P < .001). No statistically significant independent association was seen for presence of a BCG scar, season of sampling, or body mass index. CONCLUSIONS: Vitamin D deficiency and exposure to environmental tobacco smoke are potentially modifiable risk factors for MTB infection.