Feasibility of a Klebsiella pneumoniae vaccinea proposal for a first-in-human trial and future challenges.

Resumen

Klebsiella pneumoniae is an opportunistic bacteria causing 650.000 deaths worldwideassociated with antibiotic-resistance. K. pneumoniae causes a variety of infections, includinglower-respiratory, urinary-tract, abdominal, thoracic infections, and sepsis, which can leadrapidly to death due to the high level of antibiotic-resistance. The most vulnerable populationsare elderly people with chronic conditions and neonates1.The World-Health Organization and other international agencies are calling for thedevelopment of solutions alternative to antibiotics to combat the rising incidence of diseasecaused by K. pneumoniae worldwide. One type of the sought solutions are vaccines for risingimmunity able to contain the evolution of the infections to invasive disease in the vulnerablepopulation2. One of the vaccines under development is K-vax, a chimeric inactivated whole cellbacterial vaccine developed by Vaxdyn, currently in preclinical stage.Testing vaccines in human trials is a challenge due to the complexity in selecting the trialdesign and the trial population. One decisive step in the development of K-Vax is to design itsfuture clinical study. In this work, we have reviewed the state of the art regarding clinical trialsof vaccines with similarities to K-Vax. The designs have been crossed with available preclinicaldata to define the potential variables of the clinical trial.Thus, using both preclinical data and a database created through an exhaustive searching andanalysis of 34 studies with similar characteristics, our work led to the proposal of a feasible firstin human trial for K-Vax. In particular, after evaluating different scenarios, the most suitablestudy would include a group of at least 90 human volunteers, that could provide safety data toshow the lack of reactogenicity and immunogenicity data to establish a correlation of protectionand test strain coverage of the adjuvanted vaccine. We consider including a sentinel groupfirst, and the whole trial would be carried out in a randomized way, using placebo, doubleblinding, and with a dose escalation scheme, where 2 or 3 doses would be tested.In this work, we have also discussed how the information from the first in human trial couldlead to the design of feasible efficacy trials in subsequent clinical stages to overcome thebarriers for marketing the vaccine3 to prevent disease by K. pneumoniae and fulfill the currenturgent need.