Burden of diarrhea and antibiotic use among children in low-resource settings preventable byShigellavaccination: a simulation study

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Shigella is a leading cause of diarrhea and dysentery in children in low resource 21 settings, which is frequently treated with antibiotics. The primary goal of a Shigella vaccine 22 would be to reduce mortality and morbidity associated with Shigella diarrhea. However, 23 ancillary benefits could include reducing antibiotic use and antibiotic exposures for bystander 24 pathogens carried at the time of treatment, specifically for fluoroquinolones and macrolides 25 (F/M), which are the recommended drug classes to treat dysentery. 26 27

We used data from the Etiology, Risk Factors, and Interactions of Enteric Infections 28 and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to 29 estimate the impact of two one-dose (6 or 9 months) and three two-dose (6 & 9 months, 9 & 12 30 months, and 12 & 15 months) Shigella vaccines on diarrheal episodes, overall antibiotic use, and 31 F/M use. Further, we considered additional protection through indirect and boosting effects. To 32 estimate the absolute and relative reductions in the incidence of diarrhea and antibiotic use under 33 each vaccination scenario, Monte Carlo simulations with random sampling were performed. 34 35 Findings We analyzed 9392 diarrhea episodes and 15697 antibiotic courses among 1715 36 children in the MAL-ED birth cohort study. There were 273.8 diarrhea episodes, 30.6 shigellosis 37 episodes, and 457.6 antibiotic courses per 100-child years. A Shigella vaccine given at 9 & 12 38 months prevented 1.7 (95% CI: 1.3, 2.1) severe Shigella diarrhea episodes (46.5% reduction), 39 11.0 (95% CI: 10.0, 11.9) Shigella diarrhea episodes of any severity (35.9% reduction), 3.1 (95% 40 CI: 2.6, 3.7) F/M courses (2.9% reduction overall), 5.8 (95% CI: 5.2, 6.6) antibiotic courses 41 (1.0% reduction overall), and 6.3 (95% CI: 5.2, 7.5) F/M (3.2% reduction) and 11.2 (95% CI: 42 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 3 9.7, 12.9) antibiotic (1.2% reduction) exposures to bystander pathogens, respectively, per 100-43 child years. 44 45 Interpretation A Shigella vaccine could make substantial reductions in Shigella diarrhea, 46 antibiotic use to treat shigellosis, and bystander exposures due to shigellosis treatment. However, 47 the reductions in overall diarrhea episodes and antibiotic use would be modest. 48 49 Funding Wellcome Trust, Bill & Melinda Gates Foundation 50 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 4

51 Shigella is a leading cause of diarrhea and dysentery in children under the age of five in low- and 52 middle- income countries (LMICs)1. In the multisite Etiology, Risk Factors, and Interactions of 53 Enteric Infections and Malnutrition and the Consequences for Child Health and Development 54 (MAL-ED) cohort study, Shigella-attributed diarrhea was found to have an incidence of 26.1 55 episodes per 100 child years in the first two years of life.2 There are several Shigella vaccines in 56 the pipeline, of which three are in phase IIA and one in phase III trials.3 The World Health 57 Organization (WHO) recently published preferred product characteristics (PPC) for a Shigella 58 vaccine,1 and efforts are underway to define the full value proposition for such a vaccine. The 59 primary goal of a Shigella vaccine is to prevent mortality and moderate-to-severe episodes of 60 shigellosis with an efficacy target set by the WHO of 60% or more. Assuming this target can be 61 met in trials conducted in ideal settings, real world estimates of the reduction in diarrhea 62 episodes that would be expected after vaccine introduction are needed to predict population-level 63 vaccine impact. 64 65 Furthermore, a Shigella vaccine may produce ancillary benefits that need to be quantified, 66 specifically reductions in antibiotic exposures since diarrhea is a major cause of antibiotic use.4,5 67 Previous analyses have identified Shigella as a leading contributor to antibiotic consumption 68 among children in low-resource settings.5 In MAL-ED, Shigella was responsible for 14.8 69 antibiotic courses per 100-child years.4 Furthermore, 20.9% and 16.2% of all fluoroquinolone 70 and macrolide courses given for diarrhea, respectively, were to treat shigellosis.4 71 72 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 5 Vaccine impact on fluoroquinolone/macrolide (F/M) use is of particular interest as they are the 73 recommended treatment by the WHO for dysentery,6,7 and 34% of dysentery cases in children 74 under two years of age in the MAL-ED birth cohort were attributed to Shigella. Frequent use of 75 antibiotics drives selection for drug resistant pathogens,8 and drug-resistant shigellosis is of 76 concern.6 Azithromycin and fluoroquinolone resistant strains of Shigella are common in Asia 77 and are growing in prevalence elsewhere.9–11 78 79 In addition to preventing exposures to antibiotics for Shigella, a Shigella vaccine could further 80 reduce selective pressure on asymptomatic enteric pathogens (i.e., bystander pathogens) present 81 in the gut at the time of shigellosis treatment. Bystander pathogens are not the target of 82 treatment, but nonetheless are still exposed to antibiotics and are therefore at risk for 83 development of antimicrobial resistance (AMR). There were more than 7 antibiotic exposures 84 per child-year for bystander enteropathogenic bacteria in MAL-ED.5 85 86 To inform the vaccine value proposition, we aimed to quantify the potential impact of a Shigella 87 vaccine on the incidence of Shigella diarrhea (severe and non-severe), all diarrhea, and antibiotic 88 use in the first two years of life via various potential vaccination strategies. We considered 89 different vaccine efficacies, dosing schedules, and types, including leaky vaccines (i.e., 90 prevention of a fraction of episodes in all children) and all-or-nothing vaccines (i.e., prevention 91 of all episodes in a subset of children who are vaccine responders).12,13 We also quantified the 92 potential impact of indirect protection to children who were too young to be vaccinated and the 93 impact of a vaccine that performs better for children who have been previously exposed to 94 Shigella. 95 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 6 96

97 Study design and participants 98 The MAL-ED study design has been previously detailed.14 Briefly, this study was conducted at 99 eight sites (Dhaka, Bangladesh; Fortaleza, Brazil; Vellore, India; Bhaktapur, Nepal; Loreto, 100 Peru; Naushero Feroze, Pakistan; Venda, South Africa; and Haydom, Tanzania) from November 101 2009 to February 2014. Children were enrolled within 17 days of birth and followed for two 102 years. Fieldworkers conducted twice weekly home visits to collect information on daily 103 antibiotic use and presence of illness. Stool samples were collected monthly (non-diarrheal 104 surveillance samples) and during diarrheal episodes. Diarrhea episodes were defined as three or 105 more loose stools in a 24-hour period or the presence of blood in at least one stool. Diarrhea 106 severity was determined by the modified Vesikari score, previously outlined.15 107 108 Stool testing 109 The QIAamp Fast DNA Stool Mini Kit (Qiagen) was used to extract total nucleic acid from the 110 stool specimens.16 To detect the presence of 29 enteropathogens via quantitative polymerase 111 chain reaction (qPCR), TaqMan Array Cards (TAC) were run using AgPath One Step RT PCR 112 kit (Thermo-Fisher).2 The quantification cycle (Cq) to define pathogen detection was set to <35. 113 Shigella spp. were detected by the ipaH gene, as previously outlined.2 114 115 Modeled vaccine impacts 116 We estimated the impact of vaccines on the following outcomes. First, Shigella diarrhea was 117 defined as diarrhea episodes with an episode-specific attributable fraction for Shigella (AFe) 118 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 7 >0.5, regardless of other pathogens detected. AFes were calculated as 1 - (1/ORe), where ORe 119 was the pathogen-specific and quantity-specific odds ratio (OR) from a generalized linear mixed 120 model associating pathogen quantity with diarrhea.2 Second, severe Shigella diarrhea was 121 defined as Shigella diarrhea with a modified Vesikari score >6.15 Third, the number of severe 122 diarrhea episodes of any etiology was defined as diarrhea due to any cause with a modified 123 Vesikari score >6. Fourth, diarrhea episodes overall included any etiology and severity. 124 125 For vaccine impacts on antibiotic use, we focused on F/Ms as specific drug classes of interest 126 and additionally assessed any antibiotic use. Each diarrhea episode was considered treated with 127 antibiotics if antibiotics were taken during any day of the illness episode. Antibiotic courses 128 overall were defined by antibiotic courses given to the child for any reason, as previously 129 determined.5 Antibiotic courses were separated by two antibiotic-free days. Antibiotic exposures 130 to bystander pathogens (i.e., pathogens present at the time of antibiotic treatment, but that did not 131 cause the illness that was treated) were defined by linking each antibiotic course to the most 132 recent stool sample collected in the preceding 30 days. Any bacterial pathogens (atypical 133 enteropathogenic Escherichia coli (E.coli), Campylobacter, enteroaggregative E. coli, 134 enterotoxigenic E. coli, and typical enteropathogenic E. coli) detected in the linked stool were 135 assumed to be bystander pathogens during the antibiotic course.5 Antibiotic exposures to 136 bystander pathogens were attributed to the treatment of Shigella if the antibiotic course was 137 given during a diarrhea episode with a Shigella AFe > 0.5. 138 139 Vaccination scenarios 140 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 8 The characteristics of our simulated Shigella vaccine were modeled after those outlined in the 141 WHO’s PPC for a Shigella vaccine1 and those from vaccines currently in the pipeline. We 142 considered one- and two- dose Shigella vaccines with multiple potential vaccine dosing 143 schedules: a one-dose vaccine with administration at 6 months or 9 months, and two dose 144 vaccines with administration at 6 & 9 months, 9 & 12 months, and 12 & 15 months (Table 1). 145 Vaccine efficacy 14 days after the second dose against severe Shigella diarrhea was simulated at 146 60% or 80% in separate scenarios. Efficacy against non-severe episodes was 40% and 60%, 147 respectively. Vaccine efficacy between the first dose up to 14 days after the second dose was half 148 that which was applied 14 days after the second dose. (Table 1). 149 150 For scenarios that assumed the vaccine would produce indirect protection, we randomly selected 151 20% of Shigella diarrhea episodes that occurred in children under the age of the first dose of 152 vaccine administration to be prevented by the vaccine. These simulated levels of indirect 153 protection were based on what was observed with the Vi-tetanus toxoid conjugate vaccine in 154 Bangladesh.17 For instance, under a scenario with vaccine doses administered at 9 & 12 months, 155 20% of diarrhea episodes occurring in children under the age of 9 months were randomly 156 prevented. For scenarios that assumed the vaccine would perform better among children 157 previously exposed to Shigella (i.e., boosting protection), efficacy was increased by an absolute 158 20% for Shigella diarrhea episodes that occurred in children who had a Shigella infection prior to 159 administration of the first dose of the vaccine. For example, in the 9- & 12-month dosing vaccine 160 scenario with 60% efficacy with 20% boosting effects, if a child was infected with Shigella prior 161 to 9 months of age, their allocated efficacy went from 60% to 80%. 162 163 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 9 Our primary simulated vaccine was a leaky vaccine,12,13 for which we applied a constant 164 proportional reduction (equal to the efficacy) across all diarrhea episodes and antibiotic courses 165 (i.e., the vaccine prevented 60% of all diarrhea episodes or antibiotic courses). In a sensitivity 166 analysis, we simulated an all-or-nothing vaccine,12,13 for which we selected a subset of children 167 who were vaccine responders at random, the size of which was defined by vaccine efficacy, and 168 prevented all diarrhea episodes and antibiotic courses in those children (i.e., all episodes among 169 60% of children were prevented). 170 171

reported primarily in the text correspond to a leaky vaccine with two doses at 9 and 12 172 months with 60% efficacy since these characteristics may be the most realistic among the range 173 of acceptable parameters outlined in the WHO’s PPC.1 Results from all other vaccination 174 scenarios are described in the tables and figures. 175 176 Statistical analysis 177 To estimate the incidence of each diarrhea and antibiotic outcome defined above expected under 178 each vaccination scenario, we performed Monte Carlo simulations using random sampling with 179 replacement of children to a sample size of 50,000. For each simulation, we randomly selected 180 Shigella diarrhea episodes from these children to be prevented by a probability equal to vaccine 181 efficacy and calculated the incidence of each outcome excluding prevented episodes. In a no-182 vaccine scenario, no episodes were selected to be prevented. Estimates and confidence intervals 183 were estimated by the median, 2.5th and 97.5th percentiles of 1,000 iterations of this procedure. 184 To quantify the expected reductions in the outcomes listed above, we estimated absolute and 185 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 10 relative differences and the percent change between each vaccine scenario and the no vaccine 186 scenario. 187 188 All statistical analyses were performed via R software, version 4.0.2 (Foundation for Statistical 189 Computing). 190 191 Ethics approvals and data availability 192 This study involves human participants. For the parent study, ethical approval was obtained from 193 the Institutional Review Boards at the University of Virginia School of Medicine 194 (Charlottesville, USA) (14595) and at each of the participating research sites: Ethical Review 195 Committee, ICDDR,B (Bangladesh); Committee for Ethics in Research, Universidade Federal do 196 Ceara; National Ethical Research Committee, Health Ministry, Council of National Health 197 (Brazil); Institutional Review Board, Christian Medical College, Vellore; Health Ministry 198 Screening Committee, Indian Council of Medical Research (India); Institutional Review Board, 199 Institute of Medicine, Tribhuvan University; Ethical Review Board, Nepal Health Research 200 Council; Institutional Review Board, Walter Reed Army Institute of Research (Nepal); 201 Institutional Review Board, Johns Hopkins University; PRISMA Ethics Committee; Health 202 Ministry, Loreto (Peru); Ethical Review Committee, Aga Khan University (Pakistan); Health, 203 Safety and Research Ethics Committee, University of Venda; Department of Health and Social 204 Development, Limpopo Provincial Government (South Africa); Medical Research Coordinating 205 Committee, National Institute for Medical Research; Chief Medical Officer, Ministry of Health 206 and Social Welfare (Tanzania). For the current study, we obtained ethical approval at the 207 University of Virginia School of Medicine (Charlottesville, USA) (22398) and Emory University 208 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 11 (Atlanta, USA) (STUDY00003285). Participants gave informed consent to participate in the 209 study before taking part. The statistical analysis plan is available at osf.io/3asxh. Deidentified 210 participant data from the MAL-ED study is publicly available at ClinEpiDB.org. 211 212 Role of the funding source 213 The funders of this study did not have any role in the study design, collection, analysis, 214 interpretation of the data, writing of the report, nor in the decision to submit the paper for 215 publication. 216 217

218 These analyses included 1715 children, of which 83% (n=1427) had at least one Shigella 219 infection during their first two years of life (Table 2). There were 273.8 diarrhea episodes of any 220 severity per 100 child-years (n=9392) and 30.6 Shigella diarrhea episodes per 100 child years 221 (n=754). Caregivers reported 457.6 courses per 100 child years of antibiotics (n=15697), 222 amongst which 110.1 courses per 100 child years (n=3775) were to treat diarrhea episodes of any 223 etiology and of which 16.3 courses per 100 child years were attributable to Shigella diarrhea 224 (n=427). Bystander pathogens had 646.1 (n=22161) and 32.9 (n=750) exposures to antibiotics 225 per 100 child years resulting from any antibiotic use and resulting from the treatment of Shigella, 226 respectively. 227 228 Prevention of diarrhea 229 A leaky Shigella vaccine given at 9 & 12 months with 60% efficacy would be expected to 230 prevent 1.7 (95% CI: 1.3, 2.1) severe Shigella diarrhea episodes and 11.0 (95% CI: 10.0, 11.9) 231 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 12 Shigella diarrhea episodes of any severity per 100 child years (Table 3), which corresponds to a 232 46.5% reduction in severe shigellosis episodes and a 35.9% reduction in shigellosis episodes of 233 any severity (Figure 1, Supp Table 1). While the vaccine would reduce the same number of 234 severe and all diarrhea episodes due to any etiology, the percent reductions would be smaller, at 235 3.7% for severe diarrhea episodes of any etiology and 4.0% for diarrhea episodes of any etiology 236 (Table 3, Figure 1, Supp Table 1). 237 238 The 11.0 (95% CI: 10.0, 11.9) prevented Shigella diarrhea episodes per 100 child years increased 239 slightly to 11.5 (95% CI: 10.6, 12.5) when analyses further allowed for 20% indirect protection 240 (Supp Table 2). This same vaccine with 20% boosting protection and no indirect protection 241 would prevent 12.8 (95% CI: 11.7, 14.0) Shigella diarrhea episodes (Supp Table 3). Together, a 242 vaccine with direct effects plus indirect and boosting protection effects would prevent 13.4 (95% 243 CI: 12.3, 14.5) Shigella diarrhea episodes per 100 child years (Supp Table 4), which equates to a 244 43.7% reduction in Shigella diarrhea episodes and a 54.5% reduction in severe Shigella diarrhea 245 episodes (Figure 2, Supp Table 5). 246 247 Prevention of antibiotic use 248 A two-dose Shigella vaccine given at 9 and 12 months with 60% vaccine efficacy could prevent 249 0.5 (95% CI: 0.2, 0.7) F/M treated severe Shigella diarrhea episodes (48.4% reduction), 3.1 (95% 250 CI: 2.6, 3.7) F/M treated Shigella episodes (37.3% reduction), and 6.3 (95% CI: 5.2, 7.5) F/M 251 exposures to bystander pathogens due to Shigella treatment (36.2% reduction) per 100 child 252 years (Table 4, Figure 3, Supp Table 6). However, this vaccine would reduce overall F/M uses 253 and overall F/M exposures to bystander pathogens by only 2.9% and 3.2%, respectively (Supp 254 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 13 Table 6). The 3.1 (95% CI: 2.6, 3.7) prevented F/M treated Shigella diarrhea episodes per 100 255 child years increased to 3.2 (95% CI: 2.7, 3.7) prevented episodes with added indirect protection 256 effects (Supp Table 7), to 3.6 (95% CI: 3.0, 4.3) with added boosting effects (Supp Table 8), and 257 to 3.7 (95% CI: 3.1, 4.4) when both indirect effects and boosting effects were added to the direct 258 effects (Supp Table 9). When indirect and boosting effects were added to the direct effects, there 259 were slight increases in percent reductions of all metrics: F/M treated Shigella diarrhea episodes 260 (37.3% to 45.1%), F/M courses overall (2.9% to 3.5%), F/M exposures to bystander pathogens 261 due to Shigella treatment (36.2% to 44.6%), and F/M exposures to bystander pathogens overall 262 (3.2% to 3.9%) (Figure 4, Supp Table 10). 263 264 While a two-dose Shigella vaccine given at 9 and 12 months with 60% vaccine efficacy would 265 prevent more instances of antibiotic use overall than of F/M specifically, the percent reductions 266 in overall antibiotic use were smaller than what was observed with F/M use (Supp Table 11, 267 Supp Figure 1, Supp Table 12). In this scenario, 1.1 (95% CI: 0.7, 1.4) courses of antibiotic 268 treated severe Shigella diarrhea episodes (41.3% reduction), 5.8 (95% CI: 5.2, 6.6) antibiotic 269 treated Shigella diarrhea episodes (35.6% reduction), and 11.2 (95% CI: 9.7, 12.9) antibiotic 270 exposures to bystander pathogens due to Shigella treatment (35.0% reduction) per 100 child 271 years were prevented (Supp Table 11, Supp Figure 2, Supp Table 12). However, there was only a 272 1.0% and 1.2% reduction in overall antibiotic uses and overall exposures to bystander pathogens, 273 respectively (Supp Table 12). Similar to what was observed with F/M, the addition of indirect 274 and boosting effects onto the direct effects minimally increased the number of prevented 275 outcomes (Supp Table 13-16, Supp Figure 2). 276 277 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 14 All-or-nothing vaccine compared to leaky vaccine 278 A Shigella vaccine given at 9 & 12 months that fully protected 60% of children (i.e., an all-or-279 nothing vaccine) prevented the same number of severe Shigella diarrhea episodes (1.7 (95% CI: 280 1.3, 2.1) episodes per 100 child years) as the leaky vaccine (i.e., prevented 60% of episodes 281 across children) (Table 3, Supp Table 17). However, the all-or-nothing vaccine prevented more 282 Shigella diarrhea episodes of any severity compared to the leaky vaccine (15.6 (95% CI: 14.3, 283 17.0) vs. 11.0 (95% CI: 10.0, 11.9) episodes per 100 child years) (Table 3, Supp Table 17). 284 Similar results were found for the antibiotic outcomes, such that an all-or-nothing vaccine would 285 be expected to prevent more of all outcomes except the severe outcomes, for which it would 286 prevent the same number as a leaky vaccine (Supp Table 18, Supp Table 19). 287 288 The corresponding results for the other vaccine scenarios listed in Table 1 are displayed in 289 Figures 1-2, Tables 3-4, Supp Figure 2, Supp Tables 1-4, 6-9, 11-15, 17-19). In general, the 290 earlier the vaccine is given, the greater the expected reduction in diarrhea episodes and antibiotic 291 use. Additionally, the single dose vaccines were more efficacious than the two-dose vaccines 292 initiated at the same time (e.g., one-dose at 9 months vs. two-doses at 9 and 12 months) since the 293 full efficacy was achieved at an earlier age with the single dose vaccines. 294 295

296 A leaky Shigella vaccine administered at 9 and 12 months with 60% vaccine efficacy could 297 provide a substantial reduction in severe Shigella diarrhea episodes, Shigella diarrhea episodes of 298 any severity, and F/M treated Shigella diarrhea episodes. However, given the multitude of causes 299 of diarrhea and antibiotic use in this population, the expected reductions in all-cause diarrhea and 300 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 15 antibiotic use overall were modest (<5%). While single-dose vaccines and vaccines given at 301 younger ages would prevent more diarrhea and antibiotic use, none of the vaccine candidates in 302 clinical development meet those criteria. 303 304 Incorporation of indirect protection and boosting only slightly increased the number of diarrhea 305 episodes and antibiotic courses expected to be preventable, suggesting these nuances will not be 306 major determinants of vaccine success. A Shigella vaccine will likely fall somewhere on the 307 continuum between a leaky (i.e., prevention of a fraction of episodes in all children) and all-or-308 nothing (i.e., prevention of all episodes in a subset of children who are vaccine responders) 309 vaccine.12,13 As expected, the all-or-nothing vaccine effects were larger than the leaky vaccine 310 effects for outcomes that were not limited to severe diarrhea because an all-or-nothing vaccine 311 would provide complete protection in a subset of individuals regardless of disease severity. 312 However, our analysis was limited by assuming that vaccine responders were a random subset of 313 the population. It may be more likely that vaccine responders would be expected to be at lower 314 risk of shigellosis even in the absence of vaccine. Furthermore, while our results estimate the 315 upper limit of the potential benefit of a Shigella vaccine since we assumed 100% vaccine 316 coverage, it is likely that vaccine coverage would be lower in a real-world setting. 317 318 The absolute reductions in F/M use achieved by a Shigella vaccine accounted for roughly half 319 the achievable reduction of all antibiotic use. However, there were greater percent reductions in 320 F/M use compared to all antibiotic use since F/Ms are often targeted for diarrhea treatment, and 321 specifically for dysentery presumed to be shigellosis. F/M use has been associated with 322 resistance in these drug classes,5,8,18 suggesting reductions in use achievable by a Shigella 323 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 16 vaccine could limit drug-resistant shigellosis as well as the development of resistance in other 324 enteric bacteria through reductions in bystander exposure. Our predicted reductions in all 325 antibiotic and F/M use could be underestimates if suspicion of Shigella is the main reason for 326 treating diarrhea regardless of etiology, such that treatment rates also decline for other diarrhea 327 etiologies after Shigella incidence is known to have been substantially reduced by the vaccine. 328 As Shigella vaccines are evaluated in large Phase III trials, data on antibiotic treatment should be 329 carefully collected such that the impact of the vaccine on antibiotic use can be measured.1,19 To 330 quantify this impact, it will be important for vaccine effectiveness to be estimated against less-331 severe disease endpoints which account for the bulk of antibiotic use. 332 333 The vaccine scenarios modeled are in line with the WHO PPC guidance. However, some of the 334 current vaccines in the pipeline require more doses. There is one phase III Shigella vaccine 335 (ZF0901 (Beijing Zhifei Lvzhu Biopharmaceutical Co., Ltd.))20 and three phase IIA Shigella 336 vaccines (Shigella4V (Limmatech AG)21, altSonflex1-2-3 (GVGH),22 and GlycoShig3 (Institut 337 Pasteur)23) in the pipeline.3 ZF0901 is 3 doses for infants ages 3-6 months and 2 doses for those 338 aged 6-12 months. Shigella4V is 3 doses for infants (8 months +/- 1 month) and children (2-5 339 years). altSonflex1-2-3 is 3 doses for infants 9 months of age and changes to 2 doses for children 340 24-59 months. GlycoShig3 is 3 doses infants (9 months +/- 1 month) and children (2-5 years). 341 For our age group of interest (children under two years of age), the aforementioned vaccines 342 would all require 2-3 doses. Our estimates of the expected reductions in outcomes would apply 343 to a three-dose vaccine where the full efficacy is achieved after two doses. If full efficacy is not 344 achieved until a third dose, our expected reductions may be overestimated. 345 346 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 17 347 A Shigella vaccine will likely not be protective against all serotypes, but given the lack of 348 serotyping data, we were unable to simulate the prevention of episodes at the serotype level. 349 However, there is no need for a Shigella vaccine to contain all 49 serotypes for broad coverage. 350 Shigella flexneri (S. flexneri) is the leading cause of endemic diarrhea in LMICs while Shigella 351 sonnei (S. sonnei) is the leading cause in high income countries.6 While there are 15 serotypes 352 for S. flexneri, five (2a, 1b, 2b, 3a, 6) accounted for 89% of S. flexneri isolates from the Global 353 Enteric Multicenter Study (GEMS).24 On a yearly basis, there are minimal changes to the 354 dominant Shigella serotypes. Therefore, a quadrivalent vaccine with S. sonnei and S. flexneri 2a, 355 3a, and 6 could provide 64% protection against Shigella with coverage up to 88% via cross 356 protection.24 Our estimates assume 100% cross protection for subtypes not included in the 357 vaccine and therefore may be slightly overestimated depending on the true levels of cross 358 protection observed. 359 360 Finally, we did not consider the potential for waning immunity since we only observed outcomes 361 to two years of age. The effects of waning would likely occur more than 6 months after the last 362 vaccine dose, which was outside of our follow-up period for most vaccine scenarios. However, if 363 efficacy wanes substantially before two years of age, our expected reductions may also be 364 overestimated. Since waning may vary by endpoint (i.e., more pronounced waning for less 365 severe disease), this will be another important feature to monitor in trials. 366 367 It is important to note that while we targeted efficacies at 60% and 80%, those proportions of 368 outcomes were not prevented at the population level for two reasons: 1) targeted efficacies of 369 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 18 60% and 80% were for severe diarrhea only (as per the PPC) whereas efficacy was lower for 370 non-severe diarrhea and 2) episodes that occur prior to vaccination would not be expected to be 371 prevented. Because severe disease is more common in younger children, the expected relative 372 reductions in severe outcomes were particularly less for vaccine strategies with older ages of 373 administration. However, given the high burden of shigellosis and antibiotic treatment of 374 shigellosis, a Shigella vaccine could still make a substantial impact on Shigella diarrhea burden 375 in term of absolute reduction in episodes, and have ancillary benefits in the reduction of 376 antibiotic use. 377 378 Our estimates provide more realistic expectations for the reductions in diarrhea outcomes at the 379 population-level that could be achieved by Shigella vaccines under real world introduction 380 scenarios. A previous modeling study estimated similar absolute reductions in Shigella diarrhea 381 episodes under a more limited set of vaccine assumptions that did not account for partial 382 protection after a first dose, herd immunity, or effects on antibiotic use.25 Uniquely, we 383 demonstrate that Shigella vaccines could provide important reductions in antibiotic use for 384 severe and non-severe Shigella diarrheal episodes, and exposures to bystander pathogens due to 385 Shigella treatment. Given the high burden of enteric infections and antibiotic use among children 386 in LMICs, the value proposition of a Shigella vaccine in this population is strong and 387 substantially augmented by the projected impacts on antibiotic use. 388 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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389 This work was supported by Wellcome (219741/Z/19/Z to ETRM). The Etiology, Risk Factors 390 and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health 391 and Development Project (MAL-ED) was a collaborative project supported by the Bill & 392 Melinda Gates Foundation (OPP1131125), the Foundation for the NIH, the National Institutes of 393 Health, and the Fogarty International Center. 394 395 DATA SHARING 396 De-identified participant data from the MAL-ED study is publicly available at ClinEpiDB.org 397 after approval of a proposal by the study PIs. 398 399 AUTHORS’ CONTIBUTIONS 400 SAB and ETRM led data analysis, visualization, interpretation, and writing of the report. JAP-M 401 contributed to data analysis, methodology, and visualization. JAP-M and JAL contributed to 402 interpretation. JL led the development of the laboratory assays. ERH led funding acquisition and 403 administration of the parent study. JAP-M, JAL, JL, and ERH contributed to reviewing/editing 404 the report. ETRM led conceptualization, methodology, and funding acquisition. 405 406 DECLARATION OF INTEREST 407 We declare no competing interests. 408 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 20

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Clinical Infectious Diseases. 492 2014;59(7):933-941. doi:10.1093/cid/ciu468 493 25. Anderson JD, Bagamian KH, Pecenka CJ, et al. Potential impact and cost-effectiveness 494 of Shigella vaccination in 102 low-income and middle-income countries in children aged 5 495 years or younger: a modelling study. The Lancet Global Health. 2023;11(6):e880-e891. 496 doi:10.1016/S2214-109X(23)00192-4 497 498 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 23 Table 1. Shigella vaccination scenarios simulated in the MAL-ED dataset, including dosing schedules, efficacies, and inclusion of indirect and boosting protection. Scenario Dosing schedule Shigella diarrhea Severity Efficacy 14 days after 1st dose Efficacy 14 days after 2nd dose Indirect effect Boosting effect after 1st dose, before 2nd dose Boosting effect after 2nd dose 0 No vaccine -- -- -- -- -- -- 1 1st: 6 months Severe 60% -- 20% +20% (80% VE) -- Non-severe 40% -- 20% +20% (60% VE) -- 2 1st: 9 months Severe 60% -- 20% +20% (80% VE) -- Non-severe 40% -- 20% +20% (60% VE) -- 3 1st: 6 months 2nd: 9 months Severe 30% 60% 20% +10% (40% VE) +20% (80% VE) Non-severe 20% 40% 20% +10% (30% VE) +20% (60% VE) 4 1st: 9 months 2nd: 12 months Severe 30% 60% 20% +10% (40% VE) +20% (80% VE) Non-severe 20% 40% 20% +10% (30% VE) +20% (60% VE) 5 1st: 12 months 2nd: 15 months Severe 30% 60% 20% +10% (40% VE) +20% (80% VE) Non-severe 20% 40% 20% +10% (30% VE) +20% (60% VE) 6 1st: 6 months Severe 80% -- 20% +20% (100% VE) -- Non-severe 60% -- 20% +20% (80% VE) -- 7 1st: 9 months Severe 80% -- 20% +20% (100% VE) -- Non-severe 60% -- 20% 20% (80% VE) -- 8 1st: 6 months 2nd: 9 months Severe 40% 80% 20% +10% (50% VE) +20% (100% VE) Non-severe 30% 60% 20% +10% (40% VE) +20% (80% VE) 9 1st: 9 months 2nd: 12 months Severe 40% 80% 20% +10% (50% VE) +20% (100% VE) Non-severe 30% 60% 20% +10% (40% VE) +20% (80% VE) 10 1st: 12 months 2nd: 15 months Severe 40% 80% 20% +10% (50% VE) +20% (100% VE) Non-severe 30% 60% 20% +10% (40% VE) +20% (80% VE) . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 24 Table 2. Diarrhea episodes, antibiotic use, and bystander pathogen exposures to antibiotics among 1715 children enrolled in the MAL-ED cohort. <6 months ≥ 6 months, <9 months ≥9 months, <12 months ≥12 months, <15 months ≥ 15 months No. 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) No. severe Shigella diarrhea episodes, n (rate) b,c,d 5 (0.8) 9 (2.9) 10 (3.2) 17 (5.5) 48 (5.2) No. 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) No. Shigella diarrhea episodes, n (rate) b,c,d 16 (2.6) 43 (14.0) 84 (27.3) 118 (38.3) 493 (53.3) No. diarrhea episodes of any etiology, n (rate) b,c, 2386 (278.3) 1498 (349.4) 1333 (310.9) 1236 (288.3) 2939 (228.5) No. 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) No. 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) No. antibiotic treated Shigella diarrhea episodes, n (rate) b,d 11 (1.6) 24 (6.9) 53 (15.2) 73 (21.0) 266 (25.5) No. 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) No. antibiotic courses overall, n (rate) b 3478 (405.6) 2283 (532.5) 2164 (504.7) 2105 (491.0) 5667 (440.6) No. 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) No. antibiotic exposures to bystander pathogens overall, n (rate) b 2736 (319.1) 3404 (793.9) 3641 (849.2) 3527 (822.6) 8853 (688.3) a 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 were collected with valid qPCR test results for Shigella; rates are extrapolated to all infections/episodes/exposures . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 25 Table 3. Absolute and relative differences in diarrhea outcomes among five vaccine scenarios with 60% and 80% full vaccine efficacies and no indirect or boosting protection. Vaccine scenario and efficacy outcome Absolute difference (cases per 100 child-years) Relative difference 60% VE (95% CI) 80% VE (95% CI) 60% VE (95% CI) 80% VE (95% CI) One dose - 6 months 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) 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) 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) 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) One dose - 9 months 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) 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) 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) 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) Two doses - 6 months & 9 months 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) 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) 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) 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) Two doses - 9 months & 12 months 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) 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) 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) 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) Two doses - 12 months & 15 months 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) 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) 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) 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) . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 26 Table 4. Absolute and relative differences in fluoroquinolone/macrolide (F/M) outcomes in among five vaccine scenarios with 60% and 80% full vaccine efficacies and no indirect or boosting protection. Vaccine scenario and efficacy outcome Absolute difference (cases per 100 child-years) Relative difference 60% VE (95% CI) 80% VE (95% CI) 60% VE (95% CI) 80% VE (95% CI) One dose - 6 months 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) 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) 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) 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) 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) 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) 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) One dose - 9 months 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) 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) 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) 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) 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) 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) 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) Two doses - 6 months & 9 months 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) 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) 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) 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) 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) 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) 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) Two doses - 9 months & 12 months 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) 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) 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) 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) 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) 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) 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) Two doses - 12 months & 15 months . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 27 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) 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) 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) 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) 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) 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) 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) . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint 28 Figure 1. Percent reductions in diarrhea outcomes among five vaccine scenarios with 60% (A) and 80% (B) full vaccine efficacies and no indirect or boosting protection. Figure 2. Percent reductions in diarrhea outcomes with the addition of indirect and boosting protection among the 9- and 12-month vaccine dosing scenario with 60% full vaccine efficacy. Figure 3. Percent reductions in fluroquinolone and macrolide (F/M) use outcomes among five vaccine scenarios with 60% (A) and 80% (B) full vaccine efficacies and no indirect or boosting protection. Figure 4. Percent reductions in fluroquinolone and macrolide (F/M) use outcomes with the addition of indirect and boosting protection among the 9- and 12-month vaccine dosing scenario with 60% full vaccine efficacy. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 3, 2023. ; https://doi.org/10.1101/2023.07.03.23292159doi: medRxiv preprint