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Open research questions in Bacterial Infections and Vaccines

52 unresolved questions extracted from the limitations and future-work sections of 325 Bacterial Infections and Vaccines papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Given the limited evidence base and the inherent risks of mechanical intervention in the setting of active infection, this approach should be reserved for highly selected cases in which alternative options have been exhausted. When intra-ar- terial vasodilators are insufficient and surgical interven- tion cannot be safely performed due to hemodynamic instability, retrievable stent angioplasty may restore cere- Retrievable stent angioplasty for infectious vasospasmwww.

    Novel application of the NeVa VS device in the management of severe vasospasm after meningitis · 2026 · DOI

  • Consequently, the associated factors identified herein should be regarded as preliminary evidence rather than definitive predictive indicators, and further large-scale, multicenter prospective studies and [ 25 biomedical regulation strategies ] are warranted to validate and extend our observations.

    Clinical characteristics and predictors of Mycoplasma pneumoniae pneumonia coinfection with Bordetella pertussis in children · 2026 · DOI

  • With limited data from Southwest China, this 7-year study aimed to characterize the pathogens and their AMR profiles to guide empirical therapy and infection control strategies.

    Bacterial spectrum and antimicrobial resistance of cerebrospinal fluid pathogens in pediatric bacterial meningitis: a 7-year study in Southwest China with emphasis on post-neurosurgical cases · 2026 · DOI

  • A limitation of this study is the lack of immune phenotyping of cellular components in NW samples, which precluded direct assessment of innate immune cell dynamics at the mucosal site of infection. Consequently, the cellular sources of soluble mediators and their roles in shaping the mucosal tissue microenvironment remain undefined. Future studies incorporating single-cell transcriptomic profiling of mucosal cellular components will be essential to delineate the host responses that promote sterilizing immunity versus those that drive immunopathology. ACKNOWLEDGEMENTS The authors sincerely thank all study participants for their time and commitment. We also acknowledge the contributions of the entire CHIM research team at the Canadian Center for Vaccinology and the Flow Cytometry Core Facility at Dalhousie University for their assistance. The CHIM study was 22 medRxiv preprint doi: https://doi.org/10.64898/2026.06.24.26356444; this version posted June 26, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. supported by CDC and NIH grants, whereas the work described in this manuscript was supported by the Canadian Institutes of Health Research (CIHR; grant PJT-159700 to JW) and the IWK Health Centre (grant PJ-1029189 to JW). SJ was supported by an IWK Graduate Studentship and a Nova Scotia Graduate Scholarship. HB was supported by a Dalhousie Microbiology and Immunology Graduate Studentship and a Nova Scotia Graduate Scholarship. AUTHOR CONTRIBUTIONS SJ: Data acquisition, Data analysis, Visualization, Writing - Original Draft. ME: CHIM Methodology, KLR: CHIM Methodology. HB: Data acquisition, Visualization. NX: Methodology, Data acquisition. EH: Data acquisition. CHM: Methodology. SH: CHIM Methodology, Supervision. JW: Study Design, Conceptualization, Data analysis, Visualization, Funding Acquisition, Supervision, Writing - Original Draft & Revision. All authors contributed towards the review and editing of the manuscript and agreed with the decision to submit for publication. DECLARATION OF INTERESTS We declare no competing interests. REFERENCES: 1. 2. 3. Kilgore, P.E., Salim, A.M., Zervos, M.J. & Schmitt, H.J. Pertussis: Microbiology, Disease, Treatment, and Prevention. Clinical microbiology reviews 29, 449-486 (2016). Domenech de Cellès, M. & Rohani, P. Pertussis vaccines, epidemiology and evolution. Nature reviews. Microbiology 22, 722-735 (2024). Duda-Madej, A., Łabaz, J., Topola, E., Bazan, H. & Viscardi, S. Pertussis-A Re-Emerging Threat Despite Immunization: An Analysis of Vaccine Effectiveness and Antibiotic Resistance. International journal of molecular sciences 26 (2025).

    Early Innate Immune Signatures Imprint Clinical Outcomes of Bordetella pertussis Challenge in a Controlled Human Infection Model · 2026 · DOI

  • In addition, this study was insufficient to reliably assess associations between specific antibiotic classes or exposure duration and particular severe AEs, including in patients with underlying 1 3Neurosurgical Review (2026) 49:402 hepatic, renal, or hematologic comorbidities. Prospective studies incorporating protocolized imaging are warranted to establish the reliabil- ity of 4-week MRI as a predictive biomarker.

    Feasibility of short-course antibiotic therapy for surgically treated brain abscess guided by 4-week MRI · 2026 · DOI

  • Further investigation of anti-PT IgG avidity should be pursued in natural pertussis outbreaks to determine whether it might be used to differentiate symptomatic from asymptomatic infections for epidemiologic purposes.

    Avidity of anti-pertussis toxin antibodies is associated with symptomatic Bordetella pertussis infection in a novel controlled human infection model · 2026 · DOI

  • FundingCDC Contract #75D30122C15467 and CDC IPA Agreement #24IPA2417512 Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSImmunological correlates of protection against pertussis infection remain elusive.

    Mucosal and Systemic Antibodies Associated with Clinical Protection in a Pertussis Controlled Human Infection Model · 2026 · DOI

  • MR: So, from a clinical perspective, there are some factors that need to be considered. The risk of invasive meningococcal disease has distinct peaks at certain ages. First, infants and young children, those who are typically younger than 1 or 2 years of age; this is the highest risk group overall. In many countries, serogroup B predominates in this age group. Then, the next peak is among adolescents and young adults who are between 15 and 25 years of age. The reason for this peak is that young adults live typically in close contact settings like dormitories or military barracks with increased transmission. Serogroups B, C, W, and Y are more common among this group. Then, the third peak is among older adults who are more than 50–60 years of age.

    Podcast: Immune Persistence After Primary Vaccination with MenQuadfi · 2026 · DOI

  • The cohort did not include patients with tuberculous meningitis, and lipid features specific to pediatric tuberculous meningitis remain to be addressed in future studies; for context, prior CSF amino-acid metabolomics in pediatric TBM has highlighted distinct host- derived metabolic perturbations (Mason et al. Paired acute- and recovery-phase CSF samples were available only for PM patients, whereas VM patients contributed only acute-phase CSF samples; therefore, recovery-phase VM lipid changes could not be assessed.

    Cerebrospinal fluid lipid profiles as exploratory biomarkers for pediatric meningitis: a proof-of-concept case series · 2026 · DOI

  • This study has several limitations. First, the analysis was based on ecological surveillance data; therefore, causal relationships between IMD incidence and societal factors such as population mobility or international travel can- not be determined. Second, temporal patterns between inbound travel and IMD cases may have been influ- enced by confounding factors, including the numbers of imported and epidemiologically unclassified cases, as well as the implementation and subsequent relaxation of COVID-19 preventive measures, which could jointly affect both population movement and disease transmis- sion patterns. Third, serogroup information was incomplete and was not analyzed in the present study. Because shifts in cir- culating serogroups or clonal complexes may affect IMD epidemiology, the absence of standardized serogroup data limited assessment of strain-level dynamics. Fourth, prefecture-level incidence rates may be sensitive to small fluctuations in case counts because IMD remains a rare disease in Japan, which may partly contribute to the observed geographic heterogeneity. Fifth, age-specific incidence rates were not calculated due to the small number of cases within individual age strata, limiting direct comparison of age-specific risks. Finally, the most recent data for 2024 and 2025 are pro- visional; however, substantial changes to the overall tem- poral patterns are unlikely. Future studies incorporating serogroup surveillance, carriage data, and individual- level linkage information would further strengthen the epidemiological understanding of IMD trends in Japan.

    Nationwide epidemiology of invasive meningococcal disease in Japan, 2017–2025: implications of post-COVID-19 mobility · 2026 · DOI

  • The comparative efficacy of monomeric versus multivalent (tetravalent) peptide inhibitors has only been partially explored (e.g., MMβA-mono vs. MMβA-tet for Stx1/Stx2). Systematic evaluation of oligomerization state, valency, and spacing on inhibitory potency across the full panel of AB-type toxins is lacking.

    Novel endogenous protein-based strategies to inhibit clinically relevant bacterial AB-type toxins including pertussis toxin · 2026 · DOI

  • The tetravalent peptide library screening approach identified multiple lead candidates with differential inhibitory mechanisms (e.g., MMβA-tet for Stx1/Stx2, TF-1 and WA-8 for Stx2), but structure-activity relationship (SAR) analysis and optimization of these sequences to enhance binding affinity and therapeutic index have not been systematically performed.

    Novel endogenous protein-based strategies to inhibit clinically relevant bacterial AB-type toxins including pertussis toxin · 2026 · DOI

  • Several endogenous protein-based inhibitors identified in vitro (e.g., those targeting TcdB CROP domain or PA63 heptamer) lack corresponding in vivo validation studies in appropriate animal infection models. Translation from in vitro binding and inhibition assays to efficacy in living organisms for these candidates remains unexplored.

    Novel endogenous protein-based strategies to inhibit clinically relevant bacterial AB-type toxins including pertussis toxin · 2026 · DOI

  • The screening and identification of endogenous protein/peptide inhibitors has been incomplete, with the authors noting that 'many potential inhibitors of bacterial toxins still need to be identified.' Systematic large-scale screening of the entire human proteome and peptidome against the panel of clinically relevant AB-type toxins (anthrax, cholera, Shiga toxins, C. difficile toxins) has not been comprehensively performed.

    Novel endogenous protein-based strategies to inhibit clinically relevant bacterial AB-type toxins including pertussis toxin · 2026 · DOI

  • While ABPs (Angiepeptides) demonstrate dual inhibitory activity against both C. difficile bacteria and their toxins (TcdA and TcdB), the mechanism underlying this dual mode of action has not been characterized at the molecular level. Direct comparison of antibacterial efficacy versus toxin inhibition potency in the same infection model is required.

    Novel endogenous protein-based strategies to inhibit clinically relevant bacterial AB-type toxins including pertussis toxin · 2026 · DOI

  • α1AT-containing drugs are already approved for α1AT deficiency treatment, but their therapeutic efficacy as off-label inhibitors of pertussis toxin has not been evaluated in clinical or preclinical in vivo studies. Systematic investigation of α1AT pharmacokinetics and toxin-neutralizing capacity specifically in pertussis toxin-mediated disease models is needed.

    Novel endogenous protein-based strategies to inhibit clinically relevant bacterial AB-type toxins including pertussis toxin · 2026 · DOI

  • The LPS quantification used the Purpald assay to measure KDO content in OMV, IM, and OM fractions, but the paper did not investigate how lipopolysaccharide composition or structural heterogeneity affects the efficiency of OMV budding in relation to periplasmic hydrostatic pressure and peptidoglycan degradation.

    Periplasmic crowding and peptidoglycan hydrolase activity as drivers of outer membrane vesiculation in Acinetobacter baumannii · 2026 · DOI

  • The study normalized OMV samples to 50 μg total protein prior to GlcNAc quantification, but did not establish whether periplasmic crowding reaches a quantifiable threshold that triggers OMV release, nor was the relationship between periplasmic protein concentration and vesiculation frequency directly measured.

    Periplasmic crowding and peptidoglycan hydrolase activity as drivers of outer membrane vesiculation in Acinetobacter baumannii · 2026 · DOI

  • While the paper demonstrates that DegP protease and other periplasmic proteases are involved in OMV formation, the quantitative relationship between specific hydrolase activity levels (measured in enzymatic units or kinetic parameters) and the rate of outer membrane vesiculation has not been systematically established across different A. baumannii strains or growth conditions.

    Periplasmic crowding and peptidoglycan hydrolase activity as drivers of outer membrane vesiculation in Acinetobacter baumannii · 2026 · DOI

  • The study quantified peptidoglycan fragments using the DNS colorimetric assay on GlcNAc content in OMV fractions, but did not characterize the specific types of peptidoglycan hydrolysis products (muropeptides, peptidoglycan fragments of varying cross-linking states) that accumulate in the periplasm during vesiculation in A. baumannii.

    Periplasmic crowding and peptidoglycan hydrolase activity as drivers of outer membrane vesiculation in Acinetobacter baumannii · 2026 · DOI

  • However, there is limited data comparing their efficacy in neonates or infants with CNS infections, especially when further complicated by seizures and pneumonia.

    Treatment approaches for MDR Acinetobacter baumannii CNS in an infant: a case report on external ventricular drain vs Ommaya reservoir · 2025 · DOI

  • Although many studies have been performed for determination of the ASO titer in our country, only a few studies have been conducted for specification the upper limit of normal for (ULN) ADB.

    Detection of anti- DNase B antibody upper normal values in children's age groups who were admitted to hospital with noninfectious reasons · 2015 · DOI

  • The interspecies diversity of Opc protein family has been identified in Neisseria polysaccharea and other Neisseria species, but functional analysis comparing adhesion efficiency and receptor binding specificity across these divergent Opc variants is absent.

    The Biology of Neisseria Adhesins · 2013 · DOI

  • Phase variation of opa genes is influenced by promoter strength, but the relationship between promoter poly-cytidine repeat length variation and Opc outer membrane protein expression levels in clinical meningococcal isolates from disease versus carriage has not been quantitatively characterized.

    The Biology of Neisseria Adhesins · 2013 · DOI

  • The two-partner secretion system's contribution to Neisseria meningitidis adhesion has been demonstrated, but systematic comparison of adhesion-promoting mechanisms between autotransporter pathways and two-partner secretion pathways in the same meningococcal strains is lacking.

    The Biology of Neisseria Adhesins · 2013 · DOI

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52 open questions have been extracted from the limitations and future-work passages of 325 Bacterial Infections and Vaccines papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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