{"paper_id":"4b270e59-7464-43d5-839e-86f1ca62b67d","body_text":"1 \n \nBurden of diarrhea and antibiotic use among children in low-resource settings preventable by 1 \nShigella vaccination: a simulation study 2 \n 3 \nStephanie A Brennhofer1, James A Platts-Mills1, Joseph A Lewnard2, Jie Liu3, Eric R Houpt1, 4 \nElizabeth T Rogawski McQuade4* 5 \n 6 \n1Division of Infectious Diseases & International Health, University of Virginia, Charlottesville, 7 \nVA, USA   8 \n 9 \n2Division of Epidemiology, School of Public Health, University of California, Berkeley, 10 \nCalifornia, USA  11 \n 12 \n3School of Public Health, Qingdao University, Qingdao, Shandong, China  13 \n 14 \n4Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 15 \nUSA  16 \n 17 \n* Corresponding author:  18 \nE-mail: erogaws@emory.edu 19 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n2 \n \nABSTRACT 20 \nBackground Shigella is a leading cause of diarrhea and dysentery in children in low resource 21 \nsettings, which is frequently treated with antibiotics. The primary goal of a Shigella vaccine 22 \nwould be to reduce mortality and morbidity associated with Shigella diarrhea. However, 23 \nancillary benefits could include reducing antibiotic use and antibiotic exposures for bystander 24 \npathogens carried at the time of treatment, specifically for fluoroquinolones and macrolides 25 \n(F/M), which are the recommended drug classes to treat dysentery. 26 \n 27 \nMethods We used data from the Etiology, Risk Factors, and Interactions of Enteric Infections 28 \nand Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to 29 \nestimate the impact of two one-dose (6 or 9 months) and three two-dose (6 & 9 months, 9 & 12 30 \nmonths, and 12 & 15 months) Shigella vaccines on diarrheal episodes, overall antibiotic use, and 31 \nF/M use. Further, we considered additional protection through indirect and boosting effects. To 32 \nestimate the absolute and relative reductions in the incidence of diarrhea and antibiotic use under 33 \neach vaccination scenario, Monte Carlo simulations with random sampling were performed.  34 \n 35 \nFindings We analyzed 9392 diarrhea episodes and 15697 antibiotic courses among 1715 36 \nchildren in the MAL-ED birth cohort study. There were 273.8 diarrhea episodes, 30.6 shigellosis 37 \nepisodes, and 457.6 antibiotic courses per 100-child years. A Shigella vaccine given at 9 & 12 38 \nmonths prevented 1.7 (95% CI: 1.3, 2.1) severe Shigella diarrhea episodes (46.5% reduction), 39 \n11.0 (95% CI: 10.0, 11.9) Shigella diarrhea episodes of any severity (35.9% reduction), 3.1 (95% 40 \nCI: 2.6, 3.7) F/M courses (2.9% reduction overall), 5.8 (95% CI: 5.2, 6.6) antibiotic courses 41 \n(1.0% reduction overall), and 6.3 (95% CI: 5.2, 7.5) F/M (3.2% reduction) and 11.2 (95% CI: 42 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n3 \n \n9.7, 12.9) antibiotic (1.2% reduction) exposures to bystander pathogens, respectively, per 100-43 \nchild years. 44 \n 45 \nInterpretation A Shigella vaccine could make substantial reductions in Shigella diarrhea, 46 \nantibiotic use to treat shigellosis, and bystander exposures due to shigellosis treatment. However, 47 \nthe reductions in overall diarrhea episodes and antibiotic use would be modest.  48 \n 49 \nFunding Wellcome Trust, Bill & Melinda Gates Foundation  50 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n4 \n \nINTRODUCTION  51 \nShigella is a leading cause of diarrhea and dysentery in children under the age of five in low- and 52 \nmiddle- income countries (LMICs)1. In the multisite Etiology, Risk Factors, and Interactions of 53 \nEnteric Infections and Malnutrition and the Consequences for Child Health and Development 54 \n(MAL-ED) cohort study, Shigella-attributed diarrhea was found to have an incidence of 26.1 55 \nepisodes per 100 child years in the first two years of life.2 There are several Shigella vaccines in 56 \nthe pipeline, of which three are in phase IIA and one in phase III trials.3 The World Health 57 \nOrganization (WHO) recently published preferred product characteristics (PPC) for a Shigella 58 \nvaccine,1 and efforts are underway to define the full value proposition for such a vaccine. The 59 \nprimary goal of a Shigella vaccine is to prevent mortality and moderate-to-severe episodes of 60 \nshigellosis with an efficacy target set by the WHO of 60% or more. Assuming this target can be 61 \nmet in trials conducted in ideal settings, real world estimates of the reduction in diarrhea 62 \nepisodes that would be expected after vaccine introduction are needed to predict population-level 63 \nvaccine impact. 64 \n 65 \nFurthermore, a Shigella vaccine may produce ancillary benefits that need to be quantified, 66 \nspecifically reductions in antibiotic exposures since diarrhea is a major cause of antibiotic use.4,5 67 \nPrevious analyses have identified Shigella as a leading contributor to antibiotic consumption 68 \namong children in low-resource settings.5 In MAL-ED, Shigella was responsible for 14.8 69 \nantibiotic courses per 100-child years.4 Furthermore, 20.9% and 16.2% of all fluoroquinolone 70 \nand macrolide courses given for diarrhea, respectively, were to treat shigellosis.4  71 \n 72 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n5 \n \nVaccine impact on fluoroquinolone/macrolide (F/M) use is of particular interest as they are the 73 \nrecommended treatment by the WHO for dysentery,6,7 and 34% of dysentery cases in children 74 \nunder two years of age in the MAL-ED birth cohort were attributed to Shigella. Frequent use of 75 \nantibiotics drives selection for drug resistant pathogens,8 and drug-resistant shigellosis is of 76 \nconcern.6 Azithromycin and fluoroquinolone resistant strains of Shigella are common in Asia 77 \nand are growing in prevalence elsewhere.9–11   78 \n 79 \nIn addition to preventing exposures to antibiotics for Shigella, a Shigella vaccine could further 80 \nreduce selective pressure on asymptomatic enteric pathogens (i.e., bystander pathogens) present 81 \nin the gut at the time of shigellosis treatment. Bystander pathogens are not the target of 82 \ntreatment, but nonetheless are still exposed to antibiotics and are therefore at risk for 83 \ndevelopment of antimicrobial resistance (AMR). There were more than 7 antibiotic exposures 84 \nper child-year for bystander enteropathogenic bacteria in MAL-ED.5  85 \n 86 \nTo inform the vaccine value proposition, we aimed to quantify the potential impact of a Shigella 87 \nvaccine on the incidence of Shigella diarrhea (severe and non-severe), all diarrhea, and antibiotic 88 \nuse in the first two years of life via various potential vaccination strategies. We considered 89 \ndifferent vaccine efficacies, dosing schedules, and types, including leaky vaccines (i.e., 90 \nprevention of a fraction of episodes in all children) and all-or-nothing vaccines (i.e., prevention 91 \nof all episodes in a subset of children who are vaccine responders).12,13 We also quantified the 92 \npotential impact of indirect protection to children who were too young to be vaccinated and the 93 \nimpact of a vaccine that performs better for children who have been previously exposed to 94 \nShigella.  95 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n6 \n \n 96 \nMETHODS 97 \nStudy design and participants 98 \nThe MAL-ED study design has been previously detailed.14 Briefly, this study was conducted at 99 \neight sites (Dhaka, Bangladesh; Fortaleza, Brazil; Vellore, India; Bhaktapur, Nepal; Loreto, 100 \nPeru; Naushero Feroze, Pakistan; Venda, South Africa; and Haydom, Tanzania) from November 101 \n2009 to February 2014. Children were enrolled within 17 days of birth and followed for two 102 \nyears. Fieldworkers conducted twice weekly home visits to collect information on daily 103 \nantibiotic use and presence of illness. Stool samples were collected monthly (non-diarrheal 104 \nsurveillance samples) and during diarrheal episodes. Diarrhea episodes were defined as three or 105 \nmore loose stools in a 24-hour period or the presence of blood in at least one stool. Diarrhea 106 \nseverity was determined by the modified Vesikari score, previously outlined.15 107 \n 108 \nStool testing 109 \nThe QIAamp Fast DNA Stool Mini Kit (Qiagen) was used to extract total nucleic acid from the 110 \nstool specimens.16 To detect the presence of 29 enteropathogens via quantitative polymerase 111 \nchain reaction (qPCR), TaqMan Array Cards (TAC) were run using AgPath One Step RT PCR 112 \nkit (Thermo-Fisher).2 The quantification cycle (Cq) to define pathogen detection was set to <35. 113 \nShigella spp. were detected by the ipaH gene, as previously outlined.2 114 \n 115 \nModeled vaccine impacts 116 \nWe estimated the impact of vaccines on the following outcomes. First, Shigella diarrhea was 117 \ndefined as diarrhea episodes with an episode-specific attributable fraction for Shigella (AFe) 118 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n7 \n \n>0.5, regardless of other pathogens detected. AFes were calculated as 1 - (1/ORe), where ORe 119 \nwas the pathogen-specific and quantity-specific odds ratio (OR) from a generalized linear mixed 120 \nmodel associating pathogen quantity with diarrhea.2 Second, severe Shigella diarrhea was 121 \ndefined as Shigella diarrhea with a modified Vesikari score >6.15 Third, the number of severe 122 \ndiarrhea episodes of any etiology was defined as diarrhea due to any cause with a modified 123 \nVesikari score >6. Fourth, diarrhea episodes overall included any etiology and severity.  124 \n 125 \nFor vaccine impacts on antibiotic use, we focused on F/Ms as specific drug classes of interest 126 \nand additionally assessed any antibiotic use. Each diarrhea episode was considered treated with 127 \nantibiotics if antibiotics were taken during any day of the illness episode. Antibiotic courses 128 \noverall were defined by antibiotic courses given to the child for any reason, as previously 129 \ndetermined.5 Antibiotic courses were separated by two antibiotic-free days. Antibiotic exposures 130 \nto bystander pathogens (i.e., pathogens present at the time of antibiotic treatment, but that did not 131 \ncause the illness that was treated) were defined by linking each antibiotic course to the most 132 \nrecent stool sample collected in the preceding 30 days. Any bacterial pathogens (atypical 133 \nenteropathogenic Escherichia coli (E.coli),  Campylobacter, enteroaggregative E. coli, 134 \nenterotoxigenic E. coli, and typical enteropathogenic E. coli) detected in the linked stool were 135 \nassumed to be bystander pathogens during the antibiotic course.5 Antibiotic exposures to 136 \nbystander pathogens were attributed to the treatment of Shigella if the antibiotic course was 137 \ngiven during a diarrhea episode with a Shigella AFe > 0.5. 138 \n 139 \nVaccination scenarios 140 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n8 \n \nThe characteristics of our simulated Shigella vaccine were modeled after those outlined in the 141 \nWHO’s PPC for a Shigella vaccine1 and those from vaccines currently in the pipeline. We 142 \nconsidered one- and two- dose Shigella vaccines with multiple potential vaccine dosing 143 \nschedules: a one-dose vaccine with administration at 6 months or 9 months, and two dose 144 \nvaccines with administration at 6 & 9 months, 9 & 12 months, and 12 & 15 months (Table 1). 145 \nVaccine efficacy 14 days after the second dose against severe Shigella diarrhea was simulated at 146 \n60% or 80% in separate scenarios. Efficacy against non-severe episodes was 40% and 60%, 147 \nrespectively. Vaccine efficacy between the first dose up to 14 days after the second dose was half 148 \nthat which was applied 14 days after the second dose. (Table 1).  149 \n 150 \nFor scenarios that assumed the vaccine would produce indirect protection, we randomly selected 151 \n20% of Shigella diarrhea episodes that occurred in children under the age of the first dose of 152 \nvaccine administration to be prevented by the vaccine. These simulated levels of indirect 153 \nprotection were based on what was observed with the Vi-tetanus toxoid conjugate vaccine in 154 \nBangladesh.17 For instance, under a scenario with vaccine doses administered at 9 & 12 months, 155 \n20% of diarrhea episodes occurring in children under the age of 9 months were randomly 156 \nprevented. For scenarios that assumed the vaccine would perform better among children 157 \npreviously exposed to Shigella (i.e., boosting protection), efficacy was increased by an absolute 158 \n20% for Shigella diarrhea episodes that occurred in children who had a Shigella infection prior to 159 \nadministration of the first dose of the vaccine. For example, in the 9- & 12-month dosing vaccine 160 \nscenario with 60% efficacy with 20% boosting effects, if a child was infected with Shigella prior 161 \nto 9 months of age, their allocated efficacy went from 60% to 80%.  162 \n 163 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n9 \n \nOur primary simulated vaccine was a leaky vaccine,12,13 for which we applied a constant 164 \nproportional reduction (equal to the efficacy) across all diarrhea episodes and antibiotic courses 165 \n(i.e., the vaccine prevented 60% of all diarrhea episodes or antibiotic courses). In a sensitivity 166 \nanalysis, we simulated an all-or-nothing vaccine,12,13 for which we selected a subset of children 167 \nwho were vaccine responders at random, the size of which was defined by vaccine efficacy, and 168 \nprevented all diarrhea episodes and antibiotic courses in those children (i.e., all episodes among 169 \n60% of children were prevented).  170 \n 171 \nResults reported primarily in the text correspond to a leaky vaccine with two doses at 9 and 12 172 \nmonths with 60% efficacy since these characteristics may be the most realistic among the range 173 \nof acceptable parameters outlined in the WHO’s PPC.1 Results from all other vaccination 174 \nscenarios are described in the tables and figures. 175 \n 176 \nStatistical analysis  177 \nTo estimate the incidence of each diarrhea and antibiotic outcome defined above expected under 178 \neach vaccination scenario, we performed Monte Carlo simulations using random sampling with 179 \nreplacement of children to a sample size of 50,000. For each simulation, we randomly selected 180 \nShigella diarrhea episodes from these children to be prevented by a probability equal to vaccine 181 \nefficacy and calculated the incidence of each outcome excluding prevented episodes. In a no-182 \nvaccine scenario, no episodes were selected to be prevented. Estimates and confidence intervals 183 \nwere estimated by the median, 2.5th and 97.5th percentiles of 1,000 iterations of this procedure. 184 \nTo quantify the expected reductions in the outcomes listed above, we estimated absolute and 185 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n10 \n \nrelative differences and the percent change between each vaccine scenario and the no vaccine 186 \nscenario.  187 \n 188 \nAll statistical analyses were performed via R software, version 4.0.2 (Foundation for Statistical 189 \nComputing).   190 \n 191 \nEthics approvals and data availability 192 \nThis study involves human participants. For the parent study, ethical approval was obtained from 193 \nthe Institutional Review Boards at the University of Virginia School of Medicine 194 \n(Charlottesville, USA) (14595) and at each of the participating research sites: Ethical Review 195 \nCommittee, ICDDR,B (Bangladesh); Committee for Ethics in Research, Universidade Federal do 196 \nCeara; National Ethical Research Committee, Health Ministry, Council of National Health 197 \n(Brazil); Institutional Review Board, Christian Medical College, Vellore; Health Ministry 198 \nScreening Committee, Indian Council of Medical Research (India); Institutional Review Board, 199 \nInstitute of Medicine, Tribhuvan University; Ethical Review Board, Nepal Health Research 200 \nCouncil; Institutional Review Board, Walter Reed Army Institute of Research (Nepal); 201 \nInstitutional Review Board, Johns Hopkins University; PRISMA Ethics Committee; Health 202 \nMinistry, Loreto (Peru); Ethical Review Committee, Aga Khan University (Pakistan); Health, 203 \nSafety and Research Ethics Committee, University of Venda; Department of Health and Social 204 \nDevelopment, Limpopo Provincial Government (South Africa); Medical Research Coordinating 205 \nCommittee, National Institute for Medical Research; Chief Medical Officer, Ministry of Health 206 \nand Social Welfare (Tanzania). For the current study, we obtained ethical approval at the 207 \nUniversity of Virginia School of Medicine (Charlottesville, USA) (22398) and Emory University 208 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n11 \n \n(Atlanta, USA) (STUDY00003285). Participants gave informed consent to participate in the 209 \nstudy before taking part. The statistical analysis plan is available at osf.io/3asxh. Deidentified 210 \nparticipant data from the MAL-ED study is publicly available at ClinEpiDB.org. 211 \n 212 \nRole of the funding source 213 \nThe funders of this study did not have any role in the study design, collection, analysis, 214 \ninterpretation of the data, writing of the report, nor in the decision to submit the paper for 215 \npublication.  216 \n 217 \nRESULTS 218 \nThese analyses included 1715 children, of which 83% (n=1427) had at least one Shigella 219 \ninfection during their first two years of life (Table 2). There were 273.8 diarrhea episodes of any 220 \nseverity per 100 child-years (n=9392) and 30.6 Shigella diarrhea episodes per 100 child years 221 \n(n=754). Caregivers reported 457.6 courses per 100 child years of antibiotics (n=15697), 222 \namongst which 110.1 courses per 100 child years (n=3775) were to treat diarrhea episodes of any 223 \netiology and of which 16.3 courses per 100 child years were attributable to Shigella diarrhea 224 \n(n=427). Bystander pathogens had 646.1 (n=22161) and 32.9 (n=750) exposures to antibiotics 225 \nper 100 child years resulting from any antibiotic use and resulting from the treatment of Shigella, 226 \nrespectively. 227 \n 228 \nPrevention of diarrhea  229 \nA leaky Shigella vaccine given at 9 & 12 months with 60% efficacy would be expected to 230 \nprevent 1.7 (95% CI: 1.3, 2.1) severe Shigella diarrhea episodes and 11.0 (95% CI: 10.0, 11.9) 231 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n12 \n \nShigella diarrhea episodes of any severity per 100 child years (Table 3), which corresponds to a 232 \n46.5% reduction in severe shigellosis episodes and a 35.9% reduction in shigellosis episodes of 233 \nany severity (Figure 1, Supp Table 1). While the vaccine would reduce the same number of 234 \nsevere and all diarrhea episodes due to any etiology, the percent reductions would be smaller, at 235 \n3.7% for severe diarrhea episodes of any etiology and 4.0% for diarrhea episodes of any etiology 236 \n(Table 3, Figure 1, Supp Table 1).  237 \n 238 \nThe 11.0 (95% CI: 10.0, 11.9) prevented Shigella diarrhea episodes per 100 child years increased 239 \nslightly to 11.5 (95% CI: 10.6, 12.5) when analyses further allowed for 20% indirect protection 240 \n(Supp Table 2). This same vaccine with 20% boosting protection and no indirect protection 241 \nwould prevent 12.8 (95% CI: 11.7, 14.0) Shigella diarrhea episodes (Supp Table 3). Together, a 242 \nvaccine with direct effects plus indirect and boosting protection effects would prevent 13.4 (95% 243 \nCI: 12.3, 14.5) Shigella diarrhea episodes per 100 child years (Supp Table 4), which equates to a 244 \n43.7% reduction in Shigella diarrhea episodes and a 54.5% reduction in severe Shigella diarrhea 245 \nepisodes (Figure 2, Supp Table 5).  246 \n 247 \nPrevention of antibiotic use 248 \nA two-dose Shigella vaccine given at 9 and 12 months with 60% vaccine efficacy could prevent 249 \n0.5 (95% CI: 0.2, 0.7) F/M treated severe Shigella diarrhea episodes (48.4% reduction), 3.1 (95% 250 \nCI: 2.6, 3.7) F/M treated Shigella episodes (37.3% reduction), and 6.3 (95% CI: 5.2, 7.5) F/M 251 \nexposures to bystander pathogens due to Shigella treatment (36.2% reduction) per 100 child 252 \nyears (Table 4, Figure 3, Supp Table 6). However, this vaccine would reduce overall F/M uses 253 \nand overall F/M exposures to bystander pathogens by only 2.9% and 3.2%, respectively (Supp 254 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n13 \n \nTable 6). The 3.1 (95% CI: 2.6, 3.7) prevented F/M treated Shigella diarrhea episodes per 100 255 \nchild years increased to 3.2 (95% CI: 2.7, 3.7) prevented episodes with added indirect protection 256 \neffects (Supp Table 7), to 3.6 (95% CI: 3.0, 4.3) with added boosting effects (Supp Table 8), and 257 \nto 3.7 (95% CI: 3.1, 4.4) when both indirect effects and boosting effects were added to the direct 258 \neffects (Supp Table 9). When indirect and boosting effects were added to the direct effects, there 259 \nwere slight increases in percent reductions of all metrics: F/M treated Shigella diarrhea episodes 260 \n(37.3% to 45.1%), F/M courses overall (2.9% to 3.5%), F/M exposures to bystander pathogens 261 \ndue to Shigella treatment (36.2% to 44.6%), and F/M exposures to bystander pathogens overall 262 \n(3.2% to 3.9%) (Figure 4,  Supp Table 10).  263 \n 264 \nWhile a two-dose Shigella vaccine given at 9 and 12 months with 60% vaccine efficacy would 265 \nprevent more instances of antibiotic use overall than of F/M specifically, the percent reductions 266 \nin overall antibiotic use were smaller than what was observed with F/M use (Supp Table 11, 267 \nSupp Figure 1, Supp Table 12). In this scenario, 1.1 (95% CI: 0.7, 1.4) courses of antibiotic 268 \ntreated severe Shigella diarrhea episodes (41.3% reduction), 5.8 (95% CI: 5.2, 6.6) antibiotic 269 \ntreated Shigella diarrhea episodes (35.6% reduction), and 11.2 (95% CI: 9.7, 12.9) antibiotic 270 \nexposures to bystander pathogens due to Shigella treatment (35.0% reduction) per 100 child 271 \nyears were prevented (Supp Table 11, Supp Figure 2, Supp Table 12). However, there was only a 272 \n1.0% and 1.2% reduction in overall antibiotic uses and overall exposures to bystander pathogens, 273 \nrespectively (Supp Table 12). Similar to what was observed with F/M, the addition of indirect 274 \nand boosting effects onto the direct effects minimally increased the number of prevented 275 \noutcomes (Supp Table 13-16, Supp Figure 2).  276 \n 277 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n14 \n \nAll-or-nothing vaccine compared to leaky vaccine 278 \nA Shigella vaccine given at 9 & 12 months that fully protected 60% of children (i.e., an all-or-279 \nnothing vaccine) prevented the same number of severe Shigella diarrhea episodes (1.7 (95% CI: 280 \n1.3, 2.1) episodes per 100 child years) as the leaky vaccine (i.e., prevented 60% of episodes 281 \nacross children) (Table 3, Supp Table 17). However, the all-or-nothing vaccine prevented more 282 \nShigella diarrhea episodes of any severity compared to the leaky vaccine (15.6 (95% CI: 14.3, 283 \n17.0) vs. 11.0 (95% CI: 10.0, 11.9) episodes per 100 child years) (Table 3, Supp Table 17). 284 \nSimilar results were found for the antibiotic outcomes, such that an all-or-nothing vaccine would 285 \nbe expected to prevent more of all outcomes except the severe outcomes, for which it would 286 \nprevent the same number as a leaky vaccine (Supp Table 18, Supp Table 19). 287 \n 288 \nThe corresponding results for the other vaccine scenarios listed in Table 1 are displayed in 289 \nFigures 1-2, Tables 3-4, Supp Figure 2, Supp Tables 1-4, 6-9, 11-15, 17-19). In general, the 290 \nearlier the vaccine is given, the greater the expected reduction in diarrhea episodes and antibiotic 291 \nuse. Additionally, the single dose vaccines were more efficacious than the two-dose vaccines 292 \ninitiated at the same time (e.g., one-dose at 9 months vs. two-doses at 9 and 12 months) since the 293 \nfull efficacy was achieved at an earlier age with the single dose vaccines. 294 \n 295 \nDISCUSSION 296 \nA leaky Shigella vaccine administered at 9 and 12 months with 60% vaccine efficacy could 297 \nprovide a substantial reduction in severe Shigella diarrhea episodes, Shigella diarrhea episodes of 298 \nany severity, and F/M treated Shigella diarrhea episodes. However, given the multitude of causes 299 \nof diarrhea and antibiotic use in this population, the expected reductions in all-cause diarrhea and 300 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n15 \n \nantibiotic use overall were modest (<5%). While single-dose vaccines and vaccines given at 301 \nyounger ages would prevent more diarrhea and antibiotic use, none of the vaccine candidates in 302 \nclinical development meet those criteria.  303 \n 304 \nIncorporation of indirect protection and boosting only slightly increased the number of diarrhea 305 \nepisodes and antibiotic courses expected to be preventable, suggesting these nuances will not be 306 \nmajor determinants of vaccine success. A Shigella vaccine will likely fall somewhere on the 307 \ncontinuum between a leaky (i.e., prevention of a fraction of episodes in all children) and all-or-308 \nnothing (i.e., prevention of all episodes in a subset of children who are vaccine responders) 309 \nvaccine.12,13 As expected, the all-or-nothing vaccine effects were larger than the leaky vaccine 310 \neffects for outcomes that were not limited to severe diarrhea because an all-or-nothing vaccine 311 \nwould provide complete protection in a subset of individuals regardless of disease severity. 312 \nHowever, our analysis was limited by assuming that vaccine responders were a random subset of 313 \nthe population. It may be more likely that vaccine responders would be expected to be at lower 314 \nrisk of shigellosis even in the absence of vaccine.  Furthermore, while our results estimate the 315 \nupper limit of the potential benefit of a Shigella vaccine since we assumed 100% vaccine 316 \ncoverage, it is likely that vaccine coverage would be lower in a real-world setting. 317 \n 318 \nThe absolute reductions in F/M use achieved by a Shigella vaccine accounted for roughly half 319 \nthe achievable reduction of all antibiotic use. However, there were greater percent reductions in 320 \nF/M use compared to all antibiotic use since F/Ms are often targeted for diarrhea treatment, and 321 \nspecifically for dysentery presumed to be shigellosis. F/M use has been associated with 322 \nresistance in these drug classes,5,8,18 suggesting reductions in use achievable by a Shigella 323 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n16 \n \nvaccine could limit drug-resistant shigellosis as well as the development of resistance in other 324 \nenteric bacteria through reductions in bystander exposure. Our predicted reductions in all 325 \nantibiotic and F/M use could be underestimates if suspicion of Shigella is the main reason for 326 \ntreating diarrhea regardless of etiology, such that treatment rates also decline for other diarrhea 327 \netiologies after Shigella incidence is known to have been substantially reduced by the vaccine. 328 \nAs Shigella vaccines are evaluated in large Phase III trials, data on antibiotic treatment should be 329 \ncarefully collected such that the impact of the vaccine on antibiotic use can be measured.1,19 To 330 \nquantify this impact, it will be important for vaccine effectiveness to be estimated against less-331 \nsevere disease endpoints which account for the bulk of antibiotic use.  332 \n 333 \nThe vaccine scenarios modeled are in line with the WHO PPC guidance. However, some of the 334 \ncurrent vaccines in the pipeline require more doses. There is one phase III Shigella vaccine 335 \n(ZF0901 (Beijing Zhifei Lvzhu Biopharmaceutical Co., Ltd.))20 and three phase IIA Shigella 336 \nvaccines (Shigella4V (Limmatech AG)21, altSonflex1-2-3 (GVGH),22 and GlycoShig3 (Institut 337 \nPasteur)23) in the pipeline.3 ZF0901 is 3 doses for infants ages 3-6 months and 2 doses for those 338 \naged 6-12 months. Shigella4V is 3 doses for infants (8 months +/- 1 month) and children (2-5 339 \nyears). altSonflex1-2-3 is 3 doses for infants 9 months of age and changes to 2 doses for children 340 \n24-59 months. GlycoShig3 is 3 doses infants (9 months +/- 1 month) and children (2-5 years). 341 \nFor our age group of interest (children under two years of age), the aforementioned vaccines 342 \nwould all require 2-3 doses. Our estimates of the expected reductions in outcomes would apply 343 \nto a three-dose vaccine where the full efficacy is achieved after two doses. If full efficacy is not 344 \nachieved until a third dose, our expected reductions may be overestimated.  345 \n 346 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n17 \n \n 347 \nA Shigella vaccine will likely not be protective against all serotypes, but given the lack of 348 \nserotyping data, we were unable to simulate the prevention of episodes at the serotype level. 349 \nHowever, there is no need for a Shigella vaccine to contain all 49 serotypes for broad coverage. 350 \nShigella flexneri (S. flexneri) is the leading cause of endemic diarrhea in LMICs while Shigella 351 \nsonnei (S. sonnei) is the leading cause in high income countries.6 While there are 15 serotypes 352 \nfor S. flexneri, five (2a, 1b, 2b, 3a, 6) accounted for 89% of S. flexneri isolates from the Global 353 \nEnteric Multicenter Study (GEMS).24 On a yearly basis, there are minimal changes to the 354 \ndominant Shigella serotypes. Therefore, a quadrivalent vaccine with S. sonnei and S. flexneri 2a, 355 \n3a, and 6 could provide 64% protection against Shigella with coverage up to 88% via cross 356 \nprotection.24 Our estimates assume 100% cross protection for subtypes not included in the 357 \nvaccine and therefore may be slightly overestimated depending on the true levels of cross 358 \nprotection observed.  359 \n 360 \nFinally, we did not consider the potential for waning immunity since we only observed outcomes 361 \nto two years of age. The effects of waning would likely occur more than 6 months after the last 362 \nvaccine dose, which was outside of our follow-up period for most vaccine scenarios. However, if 363 \nefficacy wanes substantially before two years of age, our expected reductions may also be 364 \noverestimated. Since waning may vary by endpoint (i.e., more pronounced waning for less 365 \nsevere disease), this will be another important feature to monitor in trials.  366 \n 367 \nIt is important to note that while we targeted efficacies at 60% and 80%, those proportions of 368 \noutcomes were not prevented at the population level for two reasons: 1) targeted efficacies of 369 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n18 \n \n60% and 80% were for severe diarrhea only (as per the PPC) whereas efficacy was lower for 370 \nnon-severe diarrhea and 2) episodes that occur prior to vaccination would not be expected to be 371 \nprevented. Because severe disease is more common in younger children, the expected relative 372 \nreductions in severe outcomes were particularly less for vaccine strategies with older ages of 373 \nadministration. However, given the high burden of shigellosis and antibiotic treatment of 374 \nshigellosis, a Shigella vaccine could still make a substantial impact on Shigella diarrhea burden 375 \nin term of absolute reduction in episodes, and have ancillary benefits in the reduction of 376 \nantibiotic use. 377 \n 378 \nOur estimates provide more realistic expectations for the reductions in diarrhea outcomes at the 379 \npopulation-level that could be achieved by Shigella vaccines under real world introduction 380 \nscenarios. A previous modeling study estimated similar absolute reductions in Shigella diarrhea 381 \nepisodes under a more limited set of vaccine assumptions that did not account for partial 382 \nprotection after a first dose, herd immunity, or effects on antibiotic use.25 Uniquely, we 383 \ndemonstrate that Shigella vaccines could provide important reductions in antibiotic use for 384 \nsevere and non-severe Shigella diarrheal episodes, and exposures to bystander pathogens due to 385 \nShigella treatment. Given the high burden of enteric infections and antibiotic use among children 386 \nin LMICs, the value proposition of a Shigella vaccine in this population is strong and 387 \nsubstantially augmented by the projected impacts on antibiotic use.  388 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n19 \n \nACKNOWLEDGEMENT 389 \nThis work was supported by Wellcome (219741/Z/19/Z to ETRM). The Etiology, Risk Factors 390 \nand Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health 391 \nand Development Project (MAL-ED) was a collaborative project supported by the Bill & 392 \nMelinda Gates Foundation (OPP1131125), the Foundation for the NIH, the National Institutes of 393 \nHealth, and the Fogarty International Center.  394 \n 395 \nDATA SHARING 396 \nDe-identified participant data from the MAL-ED study is publicly available at ClinEpiDB.org 397 \nafter approval of a proposal by the study PIs. 398 \n 399 \nAUTHORS’ CONTIBUTIONS 400 \nSAB and ETRM led data analysis, visualization, interpretation, and writing of the report. JAP-M 401 \ncontributed to data analysis, methodology, and visualization. JAP-M and JAL contributed to 402 \ninterpretation. JL led the development of the laboratory assays. ERH led funding acquisition and 403 \nadministration of the parent study. JAP-M, JAL, JL, and ERH contributed to reviewing/editing 404 \nthe report. ETRM led conceptualization, methodology, and funding acquisition.  405 \n 406 \nDECLARATION OF INTEREST  407 \nWe declare no competing interests.  408 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n20 \n \nREFERENCES  409 \n 410 \n1. WHO preferred product characteristics for vaccines against Shigella. 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(which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n22 \n \nin Europe (Stage 1) Followed by Age De-Escalation From Adults to Children and Infants, and 483 \nDose-Finding in Infants in Africa (Stage 2). clinicaltrials.gov; 2022. Accessed January 19, 484 \n2023. https://clinicaltrials.gov/ct2/show/NCT05073003 485 \n23. Institut Pasteur. A Phase 2a Age Descending Study to Investigate the Safety and 486 \nImmunogenicity of the SF2a-TT15 Synthetic Carbohydrate-Based Conjugate Vaccine Against 487 \nShigella Flexneri 2a in Adults, Children, and Infant Target Population in Endemic Countries. 488 \nclinicaltrials.gov; 2023. Accessed January 19, 2023. 489 \nhttps://clinicaltrials.gov/ct2/show/NCT04602975 490 \n24. Livio S, Strockbine NA, Panchalingam S, et al. Shigella Isolates From the Global Enteric 491 \nMulticenter Study Inform Vaccine Development. Clinical Infectious Diseases. 492 \n2014;59(7):933-941. doi:10.1093/cid/ciu468 493 \n25. Anderson JD, Bagamian KH, Pecenka CJ, et al. Potential impact and cost-effectiveness 494 \nof Shigella vaccination in 102 low-income and middle-income countries in children aged 5 495 \nyears or younger: a modelling study. The Lancet Global Health. 2023;11(6):e880-e891. 496 \ndoi:10.1016/S2214-109X(23)00192-4 497 \n498 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n23 \n \nTable 1. Shigella vaccination scenarios simulated in the MAL-ED dataset, including dosing schedules, efficacies, and inclusion of \nindirect and boosting protection. \nScenario  Dosing schedule \nShigella \ndiarrhea \nSeverity \nEfficacy 14 \ndays after \n1st dose \nEfficacy \n14 days \nafter 2nd \ndose \nIndirect \neffect \nBoosting effect after 1st \ndose, before 2nd dose \nBoosting effect \nafter 2nd dose \n \n0 No vaccine \n \n-- -- -- -- -- -- \n1 1st: 6 months \n \nSevere 60% -- 20% +20% (80% VE) -- \nNon-severe 40% -- 20% +20% (60% VE) -- \n2 1st: 9 months Severe 60% -- 20% +20% (80% VE) -- \n Non-severe 40% -- 20% +20% (60% VE) -- \n3 \n1st: 6 months \n2nd: 9 months \n \nSevere 30% 60% 20% +10% (40% VE) +20% (80% VE) \nNon-severe 20% 40% 20% +10% (30% VE) +20% (60% VE) \n4 \n1st: 9 months \n2nd: 12 months Severe 30% 60% 20% +10% (40% VE) +20% (80% VE) \n Non-severe 20% 40% 20% +10% (30% VE) +20% (60% VE) \n5 \n1st: 12 months \n2nd: 15 months Severe 30% 60% 20% +10% (40% VE) +20% (80% VE) \n Non-severe 20% 40% 20% +10% (30% VE) +20% (60% VE) \n        \n6 1st: 6 months Severe 80% -- 20% +20% (100% VE) -- \n Non-severe 60% -- 20% +20% (80% VE) -- \n7 1st: 9 months Severe 80% -- 20% +20% (100% VE) -- \n Non-severe 60% -- 20% 20% (80% VE) -- \n8 \n \n1st: 6 months \n2nd: 9 months Severe 40% 80% 20% +10% (50% VE) +20% (100% VE) \n Non-severe 30% 60% 20% +10% (40% VE) +20% (80% VE) \n9 \n \n1st: 9 months \n2nd: 12 months Severe 40% 80% 20% +10% (50% VE) +20% (100% VE) \n Non-severe 30% 60% 20% +10% (40% VE) +20% (80% VE) \n10 \n \n1st: 12 months \n2nd: 15 months Severe 40% 80% 20% +10% (50% VE) +20% (100% VE) \n Non-severe \n 30% 60% 20% +10% (40% VE) +20% (80% VE) \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n24 \n \nTable 2. Diarrhea episodes, antibiotic use, and bystander pathogen exposures to antibiotics among 1715 children enrolled in the MAL-ED cohort. \n <6 months ≥ 6 months,  \n<9 months \n≥9 months, <12 \nmonths \n≥12 months, \n<15 months \n≥ 15 months \nNo. children with their first instance of a Shigella infection, n (%) a,d 163 (9.5) 199 (11.6) 275 (16.0) 251 (14.6) 539 (31.4) \nNo. severe Shigella diarrhea episodes, n (rate) b,c,d 5 (0.8) 9 (2.9) 10 (3.2) 17 (5.5) 48 (5.2) \nNo. severe diarrhea episodes of any etiology, n (rate) b,c, 434 (50.6) 286 (66.7) 192 (44.8) 186 (43.4) 290 (22.5) \nNo. Shigella diarrhea episodes, n (rate) b,c,d 16 (2.6) 43 (14.0) 84 (27.3) 118 (38.3) 493 (53.3) \nNo. diarrhea episodes of any etiology, n (rate) b,c, 2386 (278.3) 1498 (349.4) 1333 (310.9) 1236 (288.3) 2939 (228.5) \nNo. antibiotic treated severe Shigella diarrhea episodes, n (rate) b,d 6 (0.9) 6 (1.7) 12 (3.5) 12 (3.5) 32 (3.1) \nNo. antibiotic treated severe diarrhea episodes of any etiology, n (rate) b 253 (29.5) 206 (48) 145 (33.8) 103 (24.0) 184 (14.3) \nNo. antibiotic treated Shigella diarrhea episodes, n (rate) b,d 11 (1.6) 24 (6.9) 53 (15.2) 73 (21.0) 266 (25.5) \nNo. antibiotic treated diarrhea episodes of any etiology, n (rate) b 804 (93.8) 629 (146.7) 588 (137.1) 480 (112.0) 1274 (99.0) \nNo. antibiotic courses overall, n (rate) b 3478 (405.6) 2283 (532.5) 2164 (504.7) 2105 (491.0) 5667 (440.6) \nNo. antibiotic exposures to bystander pathogens due to Shigella treatment, n (rate) b,d 25 (3.6) 39 (11.2) 102 (29.3) 133 (38.3) 451 (43.2) \nNo. antibiotic exposures to bystander pathogens overall, n (rate) b 2736 (319.1) 3404 (793.9) 3641 (849.2) 3527 (822.6) 8853 (688.3) \na denominator = 1715 kids; b Rate is per 100 child years; c Includes episodes that were and were not treated by antibiotics; d Counted among infections/episodes/exposures in which stools \nwere collected with valid qPCR test results for Shigella; rates are extrapolated to all infections/episodes/exposures \n \n \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n25 \n \nTable 3. Absolute and relative differences in diarrhea outcomes among five vaccine scenarios with 60% and 80% full \nvaccine efficacies and no indirect or boosting protection.  \nVaccine scenario and efficacy outcome \nAbsolute difference \n(cases per 100 child-years) \n Relative difference \n60% VE  \n(95% CI) \n80% VE  \n(95% CI) \n 60% VE  \n(95% CI) \n80% VE  \n(95% CI) \nOne dose - 6 months      \n     Severe Shigella diarrhea episodes 2.0 (1.6, 2.5) 2.7 (2.2, 3.4)  0.43 (0.40, 0.47) 0.24 (0.21, 0.29) \n     Severe diarrhea episodes of any etiology 2.0 (1.6, 2.5) 2.7 (2.2, 3.4)  0.96 (0.95, 0.96) 0.94 (0.93, 0.95) \n     Shigella diarrhea episodes 12.6 (11.6, 13.7) 18.6 (17.1, 20.2)  0.59 (0.58, 0.60) 0.39 (0.38, 0.40) \n     Diarrhea episodes of any etiology 12.6 (11.6, 13.7) 18.6 (17.1, 20.2)  0.95 (0.95, 0.96) 0.93 (0.93, 0.94) \nOne dose - 9 months      \n     Severe Shigella diarrhea episodes 1.8 (1.4, 2.3) 2.4 (1.8, 3.0)  0.50 (0.45, 0.55) 0.33 (0.27, 0.40) \n     Severe diarrhea episodes of any etiology 1.8 (1.4, 2.3) 2.4 (1.8, 3.0)  0.96 (0.95, 0.97) 0.95 (0.94, 0.96) \n     Shigella diarrhea episodes 11.8 (10.8, 12.7) 17.3 (15.9, 18.8)  0.62 (0.60, 0.63) 0.43 (0.42, 0.45) \n     Diarrhea episodes of any etiology 11.8 (10.8, 12.7) 17.3 (15.9, 18.8)  0.96 (0.95, 0.96) 0.94 (0.93, 0.94) \nTwo doses - 6 months & 9 months      \n     Severe Shigella diarrhea episodes 1.9 (1.5, 2.4) 2.6 (2.0, 3.2)  0.47 (0.43, 0.51) 0.29 (0.24, 0.34) \n     Severe diarrhea episodes of any etiology 1.9 (1.5, 2.4) 2.6 (2.0, 3.2)  0.96 (0.95, 0.97) 0.94 (0.93, 0.96) \n     Shigella diarrhea episodes 12.2 (11.2, 13.2) 17.9 (16.5, 19.4)  0.60 (0.59, 0.61) 0.41 (0.40, 0.43) \n     Diarrhea episodes of any etiology 12.2 (11.2, 13.2) 17.9 (16.5, 19.4)  0.96 (0.95, 0.96) 0.93 (0.93, 0.94) \nTwo doses - 9 months & 12 months      \n     Severe Shigella diarrhea episodes 1.7 (1.3, 2.1) 2.2 (1.7, 2.8)  0.53 (0.49, 0.59) 0.38 (0.32, 0.45) \n     Severe diarrhea episodes of any etiology 1.7 (1.3, 2.1) 2.2 (1.7, 2.8)  0.96 (0.95, 0.97) 0.95 (0.94, 0.96) \n     Shigella diarrhea episodes 11.0 (10.0, 11.9) 16.2 (14.8, 17.6)  0.64 (0.63, 0.65) 0.47 (0.45, 0.49) \n     Diarrhea episodes of any etiology 11.0 (10.0, 11.9) 16.2 (14.8, 17.6)  0.96 (0.96, 0.96) 0.94 (0.94, 0.95) \nTwo doses - 12 months & 15 months      \n     Severe Shigella diarrhea episodes 1.4 (1.0, 1.7) 1.8 (1.4, 2.3)  0.62 (0.56, 0.67) 0.49 (0.42, 0.57) \n     Severe diarrhea episodes of any etiology 1.4 (1.0, 1.7) 1.8 (1.4, 2.3)  0.97 (0.96, 0.98) 0.96 (0.95, 0.97) \n     Shigella diarrhea episodes 9.1 (8.3, 10.0) 13.4 (12.2, 14.7)  0.70 (0.69, 0.72) 0.56 (0.54, 0.58) \n     Diarrhea episodes of any etiology 9.1 (8.3, 10.0) 13.4 (12.2, 14.7)  0.97 (0.96, 0.97) 0.95 (0.95, 0.96) \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n26 \n \nTable 4. Absolute and relative differences in fluoroquinolone/macrolide (F/M) outcomes in among five vaccine scenarios with 60% and 80% full vaccine \nefficacies and no indirect or boosting protection.  \nVaccine scenario and efficacy outcome \nAbsolute difference \n(cases per 100 child-years) \n Relative difference \n60% VE (95% CI) 80% VE (95% CI)  60% VE (95% CI) 80% VE (95% CI) \nOne dose - 6 months      \n     F/M treated severe Shigella diarrhea episodes 0.5 (0.3, 0.8) 0.7 (0.4, 1.0)  0.45 (0.38, 0.56) 0.27 (0.19, 0.41) \n     F/M treated severe diarrhea episodes of any etiology 0.5 (0.3, 0.8) 0.7 (0.4, 1.0)  0.92 (0.89, 0.95) 0.90 (0.85, 0.94) \n     F/M treated Shigella diarrhea episodes 3.4 (2.9, 4.0) 5.1 (4.3, 5.9)  0.58 (0.57, 0.60) 0.39 (0.37, 0.41) \n     F/M treated diarrhea episodes of any etiology 3.4 (2.9, 4.0) 5.1 (4.3, 5.9)  0.91 (0.90, 0.92) 0.87 (0.85, 0.88) \n     F/M courses overall 3.4 (2.9, 4.0) 5.1 (4.3, 5.9)  0.97 (0.96, 0.97) 0.95 (0.95, 0.96) \n     F/M exposures to bystander pathogens due to Shigella treatment 7.2 (5.9, 8.4) 10.6 (8.8, 12.5)  0.59 (0.57, 0.61) 0.39 (0.37, 0.42) \n     F/M exposures to bystander pathogens overall 7.2 (5.9, 8.4) 10.6 (8.8, 12.5)  0.96 (0.96, 0.97) 0.95 (0.94, 0.95) \nOne dose - 9 months      \n     F/M treated severe Shigella diarrhea episodes 0.5 (0.3, 0.7) 0.6 (0.4, 1.0)  0.49 (0.41, 0.62) 0.33 (0.22, 0.49) \n     F/M treated severe diarrhea episodes of any etiology 0.5 (0.3, 0.7) 0.6 (0.4, 1.0)  0.93 (0.90, 0.96) 0.91 (0.86, 0.95) \n     F/M treated Shigella diarrhea episodes 3.2 (2.7, 3.8) 4.8 (4, 5.6)  0.61 (0.59, 0.63) 0.42 (0.40, 0.45) \n     F/M treated diarrhea episodes of any etiology 3.2 (2.7, 3.8) 4.8 (4, 5.6)  0.91 (0.90, 0.92) 0.87 (0.86, 0.89) \n     F/M courses overall 3.2 (2.7, 3.8) 4.8 (4, 5.6)  0.97 (0.97, 0.97) 0.96 (0.95, 0.96) \n     F/M exposures to bystander pathogens due to Shigella treatment 6.7 (5.6, 8.0) 9.9 (8.3, 11.7)  0.61 (0.59, 0.64) 0.43 (0.40, 0.46) \n     F/M exposures to bystander pathogens overall 6.7 (5.6, 8.0) 9.9 (8.3, 11.7)  0.97 (0.96, 0.97) 0.95 (0.94, 0.96) \nTwo doses - 6 months & 9 months      \n     F/M treated severe Shigella diarrhea episodes 0.5 (0.3, 0.8) 0.7 (0.4, 1.0)  0.48 (0.4, 0.58) 0.30 (0.21, 0.45) \n     F/M treated severe diarrhea episodes of any etiology 0.5 (0.3, 0.8) 0.7 (0.4, 1.0)  0.93 (0.89, 0.96) 0.90 (0.86, 0.94) \n     F/M treated Shigella diarrhea episodes 3.4 (2.8, 3.9) 4.9 (4.2, 5.8)  0.60 (0.58, 0.61) 0.40 (0.38, 0.43) \n     F/M treated diarrhea episodes of any etiology 3.4 (2.8, 3.9) 4.9 (4.2, 5.8)  0.91 (0.90, 0.92) 0.87 (0.85, 0.88) \n     F/M courses overall 3.4 (2.8, 3.9) 4.9 (4.2, 5.8)  0.97 (0.96, 0.97) 0.95 (0.95, 0.96) \n     F/M exposures to bystander pathogens due to Shigella treatment 6.9 (5.8, 8.2) 10.2 (8.6, 12.0)  0.60 (0.58, 0.62) 0.41 (0.39, 0.44) \n     F/M exposures to bystander pathogens overall 6.9 (5.8, 8.2) 10.2 (8.6, 12.0)  0.97 (0.96, 0.97) 0.95 (0.94, 0.96) \nTwo doses - 9 months & 12 months      \n     F/M treated severe Shigella diarrhea episodes 0.5 (0.2, 0.7) 0.6 (0.3, 0.9)  0.52 (0.42, 0.63) 0.35 (0.24, 0.50) \n     F/M treated severe diarrhea episodes of any etiology 0.5 (0.2, 0.7) 0.6 (0.3, 0.9)  0.93 (0.90, 0.96) 0.91 (0.86, 0.95) \n     F/M treated Shigella diarrhea episodes 3.1 (2.6, 3.7) 4.5 (3.8, 5.4)  0.63 (0.61, 0.65) 0.45 (0.42, 0.48) \n     F/M treated diarrhea episodes of any etiology 3.1 (2.6, 3.7) 4.5 (3.8, 5.4)  0.92 (0.91, 0.93) 0.88 (0.86, 0.89) \n     F/M courses overall 3.1 (2.6, 3.7) 4.5 (3.8, 5.4)  0.97 (0.97, 0.98) 0.96 (0.95, 0.96) \n     F/M exposures to bystander pathogens due to Shigella treatment 6.3 (5.2, 7.5) 9.3 (7.7, 11.1)  0.64 (0.61, 0.66) 0.47 (0.43, 0.50) \n     F/M exposures to bystander pathogens overall 6.3 (5.2, 7.5) 9.3 (7.7, 11.1)  0.97 (0.96, 0.97) 0.95 (0.95, 0.96) \nTwo doses - 12 months & 15 months      \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n27 \n \n     F/M treated severe Shigella diarrhea episodes 0.4 (0.2, 0.7) 0.5 (0.3, 0.9)  0.57 (0.47, 0.69) 0.42 (0.29, 0.58) \n     F/M treated severe diarrhea episodes of any etiology 0.4 (0.2, 0.7) 0.5 (0.3, 0.9)  0.94 (0.91, 0.97) 0.92 (0.87, 0.96) \n     F/M treated Shigella diarrhea episodes 2.6 (2.2, 3.1) 3.9 (3.2, 4.6)  0.68 (0.66, 0.71) 0.53 (0.50, 0.57) \n     F/M treated diarrhea episodes of any etiology 2.6 (2.2, 3.1) 3.9 (3.2, 4.6)  0.93 (0.92, 0.94) 0.90 (0.88, 0.91) \n     F/M courses overall 2.6 (2.2, 3.1) 3.9 (3.2, 4.6)  0.98 (0.97, 0.98) 0.96 (0.96, 0.97) \n     F/M exposures to bystander pathogens due to Shigella treatment 5.3 (4.3, 6.4) 7.8 (6.4, 9.4)  0.70 (0.67, 0.73) 0.55 (0.51, 0.59) \n     F/M exposures to bystander pathogens overall 5.3 (4.3, 6.4) 7.8 (6.4, 9.4)  0.97 (0.97, 0.98) 0.96 (0.95, 0.97) \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n28 \n \nFigure 1. Percent reductions in diarrhea outcomes among five vaccine scenarios with 60% (A) \nand 80% (B) full vaccine efficacies and no indirect or boosting protection. \n \nFigure 2. Percent reductions in diarrhea outcomes with the addition of indirect and boosting \nprotection among the 9- and 12-month vaccine dosing scenario with 60% full vaccine efficacy. \n \nFigure 3. Percent reductions in fluroquinolone and macrolide (F/M) use outcomes among five \nvaccine scenarios with 60% (A) and 80% (B) full vaccine efficacies and no indirect or boosting \nprotection. \n \nFigure 4. Percent reductions in fluroquinolone and macrolide (F/M) use outcomes with the \naddition of indirect and boosting protection among the 9- and 12-month vaccine dosing scenario \nwith 60% full vaccine efficacy. \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint","source_license":"CC-BY-4.0","license_restricted":false}