Global, regional, and national estimates of the impact of a maternal Klebsiella pneumoniae vaccine: A Bayesian modeling analysis

BackgroundDespite significant global progress in reducing neonatal mortality, bacterial sepsis remains a major cause of neonatal deaths. Klebsiella pneumoniae (K. pneumoniae) is the leading pathogen globally underlying cases of neonatal sepsis and is frequently resistant to antibiotic treatment regimens recommended by the World Health Organization (WHO), including first-line therapy with ampicillin and gentamicin, second-line therapy with amikacin and ceftazidime, and meropenem. Maternal vaccination to prevent neonatal infection could reduce the burden of K. pneumoniae neonatal sepsis in low- and middle-income countries (LMICs) but the potential impact of vaccination remains poorly quantified. We estimated the potential impact of such vaccination on cases and deaths of K. pneumoniae neonatal sepsis and project the global effects of routine immunization of pregnant women with the K. pneumoniae vaccine as antimicrobial resistance (AMR) increases. Methods and findingsWe developed a Bayesian mixture-modeling framework to estimate the effects of a hypothetical K. pneumoniae maternal vaccine with 70% efficacy administered with coverage equivalent to that of the maternal tetanus vaccine on neonatal sepsis infections and mortality. To parameterize our model, we used data from 3 global studies of neonatal sepsis and/or mortality-with 2,330 neonates who died with sepsis surveilled from 2016 to 2020 undertaken in 18 mainly LMICs across all WHO regions (Ethiopia, Kenya, Mali, Mozambique, Nigeria, Rwanda, Sierra Leone, South Africa, Uganda, Brazil, Italy, Greece, Pakistan, Bangladesh, India, Thailand, China, and Vietnam). Within these studies, 26.95% of fatal neonatal sepsis cases were culture-positive for K. pneumoniae. We analyzed 9,070 K. pneumoniae genomes from human isolates gathered globally from 2001 to 2020 to quantify the temporal rate of acquisition of AMR genes in K. pneumoniae isolates to predict the future number of drug-resistant cases and deaths that could be averted by vaccination.Resistance rates to carbapenems are increasing most rapidly and 22.43% [95th percentile Bayesian credible interval (CrI): 5.24 to 41.42] of neonatal sepsis deaths are caused by meropenem-resistant K. pneumoniae. Globally, we estimate that maternal vaccination could avert 80,258 [CrI: 18,084 to 189,040] neonatal deaths and 399,015 [CrI: 334,523 to 485,442] neonatal sepsis cases yearly worldwide, accounting for more than 1.49% [CrI: 0.33 to 3.51] of all neonatal deaths. The largest relative benefits are in Africa (Sierra Leone, Mali, Niger) and South-East Asia (Bangladesh) where vaccination could avert over 5% of all neonatal deaths. Nevertheless, our modeling only considers country-level trends in K. pneumoniae neonatal sepsis deaths and is unable to consider within-country variability in bacterial prevalence that may impact the projected burden of sepsis. ConclusionsA K. pneumoniae maternal vaccine could have widespread, sustained global benefits as AMR in K. pneumoniae continues to increase. Author summary Why was this study done? Approximately 1 million newborns yearly die within the first 4 weeks of life due to bacteria infecting their bloodstream with (. ) as the leading cause of such infections.There have been numerous recent advancements in developing viable . vaccine and antibody-based treatments in preclinical models, with some treatments reaching Phase 1 clinical trials.The impacts of vaccination must be quantified and may prove useful to prioritizing vaccine distribution and better understanding the burden of sepsis. What did the researchers do and find? Using a Bayesian mixture-model based on clinical surveillance of neonatal sepsis, we present country-specific estimates for the number of deaths and cases of antimicrobial-resistant neonatal sepsis caused by . that would be averted if a vaccine with 70% efficacy were given to pregnant mothers.We find that most cases of . neonatal sepsis are resistant to first-line treatments, such as ampicillin and gentamicin.We estimate that a vaccine with 70% efficacy could prevent 399,015 [95th percentile credible interval (CrI): 334,523 to 485,442] cases and 80,258 [CrI: 18,084 to 189,040] neonatal deaths. What do these findings mean? A maternal vaccine that confers newborns with protection from . infection could reduce neonatal sepsis deaths in many low- and middle-income countries (LMICs) by nearly 15%.This would help to achieve targets set by the World Health Organization (WHO) for improved child health globally and to mitigate inequities in neonatal survival in low- and middle-income settings compared to high-income settings.Reducing cases of neonatal sepsis by vaccination could also contribute to reduced antibiotic use, subsequent improvements in antimicrobial resistance (AMR) rates, and a reduction in healthcare utilization and expenditure.