Table 1.

Challenges in clinical trial design for vaccine development to prevent hospital-acquired infections.

Study parameter	Problem statement	Implications and potential solutions
Patient recruitment	It is difficult to define the patients at risk long beforehand. Hospital-acquired infections are typically associated with unplanned events such as cardiac surgery or ICU ventilation; adding to the difficulty, patients clearly at risk are often no longer able to sign informed consent	Since early involvement of future patients is key to success, multi-stakeholder cooperation is need and a fallback on nation-wide registries and cohorts could be very valuable
Diagnostics	Precise methodology for distinguishing infection from colonization and for detection of potential co-infections as important variables is frequently not in place and, thus, delays diagnosis or its accuracy. This further has impact on the precision of inclusion and exclusion criteria and clinical endpoints. Additionally, diagnosis of immune status and microbiome composition are not routinely collected	Diagnostic method development should be fostered to make rapid, comprehensive and precise diagnostics available. The value of immune status and microbiome assessment needs to be evaluated
Vaccination schedule	Late recruitment bears the risk that time between vaccination and disease manifestation is too short for establishment of stable immune memory and required booster vaccination	Vaccination schedules will vary depending on the proposed immunological mechanism of action. Boostering of an existing immune response is different from reshaping or de novo formation of an immune response. Induction of T cell immunity vs. antibody responses will require different approaches
Unpredictability of infection	Infection is unpredictable in regards to the time point of disease manifestation and the patients affected in the cohort. Manifestation of infection might not fall within the duration of the study. Examples highlighting this issue are bloodstream and prosthesis infections where infection rates vary strongly	Pre-established clinical trial networks with the flexibility to recruit patients from many different trial sites may have a great advantage to recruit a sufficiently high amount of subjects
Choice of clinical trial sites	Epidemiology is subject to change. Global spread of strains with antibiotic resistance and high transmission potential and environmental fitness changes the representation of strains over longer periods. Even more important for a clinical study, the local epidemiology varies. These changes are sometimes hard to track because they depend on multiple factors, e.g., regional representation of strains, infection control measures and antibiotic regimens. Consequently, hit rates at a study site can be unexpectedly low, thus diminishing the statistical power of the studies. One prominent example is that incidence of ventilator-associated pneumonia with P. aeruginosa on ICUs has declined, which might be attributed to the introduction of more rigorous infection control measures and standardized procedures	Pre-established clinical trial networks with well-characterized sites and information on local epidemiology and updates on changes in routine antibiotic regimens and infection control measures may be detrimental in commissioning of suitable sites and recruitment of study subjects. The network structure could facilitate and speed up the process
Clinical endpoints	Clinical endpoints such as survival or pneumonia on an ICU are often too broad and ambitious in their scope	Clinical endpoints should be based on the precise diagnosis and prevention of an infection with a specific target pathogen and co-infections excluded