Effect of biannual azithromycin distribution on antibody responses to malaria, bacterial, and protozoan pathogens in Niger

Abstract

The MORDOR trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality (NCT02048007). To help elucidate the mechanism for mortality reduction, we report IgG responses to 11 malaria, bacterial, and protozoan pathogens using a multiplex bead assay in pre-specified substudy of 30 communities in the rural Niger placebo-controlled trial over a three-year period (n = 5642 blood specimens, n = 3814 children ages 1-59 months). Mass azithromycin reduces Campylobacter spp. force of infection by 29% (hazard ratio = 0.71, 95% CI: 0.56, 0.89; P = 0.004) but serological measures show no significant differences between groups for other pathogens against a backdrop of high transmission. Results align with a recent microbiome study in the communities. Given significant sequelae of Campylobacter infection among preschool aged children, our results support an important mechanism through which biannual mass distribution of azithromycin likely reduces mortality in Niger.

Conflict of interest statement

The authors declare no competing interests. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the Public Health Service or by the U.S. Department of Health and Human Services.

© 2022. The Author(s).

Figures

Fig. 1. Study participant flow.

Thirty community clusters were randomly selected from a larger pool of clusters enrolled in the overall MORDOR Niger trial. A random sample of 40 children ages 1–59 months per community were selected for serological monitoring. Children https://osf.io/utxv3.

Fig. 2. Malarial IgG antibody responses by treatment group.

Estimates from 3860 children ages 12–59 months in the MORDOR Niger trial, 2015–2018. a Community-level seroprevalence to malarial antigens. Columns represent individual communities, which were stratified by treatment group and then sorted by overall mean seroprevalence. b Mean IgG seroprevalence to P. falciparum (positive to any measured antigen) by age and treatment group (lines), estimated with semiparametric splines. The shaded region from 12 to 59 months indicates the age range included in the primary analysis. c Antigen-specific IgG seroprevalence by treatment group and difference between groups. Points indicate group means and mean the difference between groups, error bars indicate 95% confidence intervals. d Antigen-specific force of infection estimated by the seroconversion rate, and hazard ratio for comparison between groups. Points indicate group means and the hazard ratio between groups, error bars indicate 95% confidence intervals. No between-group comparisons were statistically significant at the 95% confidence level after false discovery rate correction. Created with notebooks https://osf.io/b2v3r, https://osf.io/37ybm, https://osf.io/fwxn5, which include detailed point estimates and additional, consistent results based on geometric mean IgG levels.

Fig. 3. Bacterial and protozoan IgG antibody responses by treatment group.

Estimates from 4265 children ages 6–59 months in the MORDOR Niger trial, 2015–2018. a Community-level seroprevalence to bacterial and protozoan antigens. Columns represent individual communities, which were stratified by treatment group and then sorted by overall mean seroprevalence. b IgG seroprevalence to Campylobacter spp. p18 or p39 antigens by age and treatment group (lines), estimated with semiparametric splines. The shaded region from 6 to 24 months indicates the age range included in force of infection analyses, based on a pre-specified rule (n = 1496). c Pathogen-specific IgG seroprevalence by treatment group and the difference between groups (n = 4265 children ages 6–59). Points indicate group means and mean the difference between groups, error bars indicate 95% confidence intervals. d Pathogen-specific force of infection estimated by the seroconversion rate, and hazard ratio for comparison between groups. Antibody responses were measured from 1496 children ages 6–24 months (n = 4265 children ages 6–59 months for Salmonella and Streptococcus), based on pre-specified age restrictions. Points indicate group means and the hazard ratio between groups, error bars indicate 95% confidence intervals. The reduction in Campylobacter spp. seroconversion rate remained statistically significant after false-discovery rate correction. ETEC enterotoxigenic E. coli. Created with notebooks https://osf.io/b2v3r, https://osf.io/smwbn, https://osf.io/fwxn5, which include detailed point estimates and additional, consistent results based on geometric mean IgG levels.