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

Resumen

Klebsiella pneumoniae is an opportunistic bacteria causing 650.000 deaths worldwide
associated with antibiotic-resistance. K. pneumoniae causes a variety of infections, including
lower-respiratory, urinary-tract, abdominal, thoracic infections, and sepsis, which can lead
rapidly to death due to the high level of antibiotic-resistance. The most vulnerable populations
are elderly people with chronic conditions and neonates1.
The World-Health Organization and other international agencies are calling for the
development of solutions alternative to antibiotics to combat the rising incidence of disease
caused by K. pneumoniae worldwide. One type of the sought solutions are vaccines for rising
immunity able to contain the evolution of the infections to invasive disease in the vulnerable
population2. One of the vaccines under development is K-vax, a chimeric inactivated whole cell
bacterial vaccine developed by Vaxdyn, currently in preclinical stage.
Testing vaccines in human trials is a challenge due to the complexity in selecting the trial
design and the trial population. One decisive step in the development of K-Vax is to design its
future clinical study. In this work, we have reviewed the state of the art regarding clinical trials
of vaccines with similarities to K-Vax. The designs have been crossed with available preclinical
data to define the potential variables of the clinical trial.
Thus, using both preclinical data and a database created through an exhaustive searching and
analysis of 34 studies with similar characteristics, our work led to the proposal of a feasible first
in human trial for K-Vax. In particular, after evaluating different scenarios, the most suitable
study would include a group of at least 90 human volunteers, that could provide safety data to
show the lack of reactogenicity and immunogenicity data to establish a correlation of protection
and test strain coverage of the adjuvanted vaccine. We consider including a sentinel group
first, and the whole trial would be carried out in a randomized way, using placebo, double
blinding, 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 could
lead to the design of feasible efficacy trials in subsequent clinical stages to overcome the
barriers for marketing the vaccine3 to prevent disease by K. pneumoniae and fulfill the current
urgent need.