Stabilising effects of competition and diversity determine vaccine impact on antibiotic resistance evolution

Abstract

One sentence summary: Competition and diversity are key to antibiotic resistance 17 evolution and determine whether vaccines will prevent or increase resistant infections. 18Bacterial vaccines can protect recipients from contracting potentially antibiotic-19 resistant infections. But by altering the selective balance between sensitive and 20 resistant strains, vaccines may also help suppress-or spread-antibiotic 21 resistance among unvaccinated individuals. Predicting the outcome requires 22 knowing the drivers of resistance evolution. Using mathematical modelling, we 23 identify competition and diversity as key mediators of resistance evolution. 24Specifically, we show that the frequency of penicillin resistance in Streptococcus 25 pneumoniae (pneumococcus) across 27 European countries can be explained by 26 between-host diversity in antibiotic use, heritable diversity in pneumococcal 27 carriage duration, or within-host competition. We use our calibrated model to 28 predict the impact of universal pneumococcal vaccination upon the prevalence of 29 carriage, incidence of disease, and frequency of resistance for S. pneumoniae. The 30 relative strength and directionality of competition between resistant and 31 sensitive pneumococcal strains determines whether vaccination promotes, 32 inhibits, or has little effect on the evolution of antibiotic resistance. Finally, we 33 find that differences in overall bacterial transmission and carriage alter 34 predictions, suggesting that evidence-based policies for managing resistance with 35 vaccines must be tailored to both pathogen and setting. 36 37In an age of widespread antibiotic resistance, there is growing interest in using vaccines 38 to prevent bacterial infections that would otherwise call for treatment with antibiotics 39(1-4). This interest arises for two main reasons: first, vaccines are effective against both 40 antibiotic-resistant and antibiotic-sensitive bacteria; and second, successful prophylaxis 41 removes the need for a course of antibiotic therapy that might promote more resistance 42(2-5). Over the past two decades, the use of pneumococcal conjugate vaccines (PCVs) 43 has seemingly borne out these advantages. Administering PCVs to young children has 44 substantially reduced disease caused by S. pneumoniae (5-8)-a common asymptomatic 45 coloniser of the nasopharynx which can cause pneumonia, meningitis and other 46 infections when invasive-and has decreased demand for antibiotic therapy, largely by 47 reducing cases of otitis media (5, 9). But because PCV formulations target only a fraction 48 of the ~100 known pneumococcal serotypes, the niche vacated by PCV-targeted 49 serotypes has been filled by non-vaccine serotypes, and overall pneumococcal carriage 50 has rebounded to pre-vaccine levels (10, 11). Concomitantly, the incidence of infections 51 attributed to non-vaccine serotypes (12) and the proportion of non-vaccine-type 52 infections exhibiting antibiotic resistance (5, 13) have risen in many settings. Concern 53 over serotype replacement-along ...