Redirecting an ineffective natural immune response to achieve biofilm eradication

Published in Microbiology

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Biofilms, the 3D sophisticated communities that are the preferred lifestyle of bacteria in nature, are also implicated in 65-80% of all chronic bacterial diseases.  Due to multiple unique properties of biofilms, the resident bacteria are highly recalcitrant to killing by both traditional antibiotics, as well as host immune effectors.  As a long-standing goal, we’ve been focused on trying to better understand the proteome of bacterial biofilms in an effort to identify a common antigenic target for the development of a novel vaccine antigen that had the potential to induce the formation of antibodies that would either prevent a biofilm from forming and/or disrupt one that had already formed.  During this collaborative pursuit, the members of the Goodman and Bakaletz laboratories made the intriguing discovery that bacterial DNA (or extracellular DNA, eDNA), which is a very common constituent of the biofilms formed by multiple pathogens, was arranged in a lattice-like formation wherein at the vertices of every crossed strand of eDNA was positioned a bacterial DNA-binding protein of the small two-member DNABII family.  These DNABII proteins were revealed to be linchpin proteins that provided structural integrity to the biofilm so that when biofilms formed by many diverse species of bacteria were incubated with antiserum to one of these two DNABII proteins, a rapid structural collapse of the biofilm occurred with release of the resident bacteria in a state that was now significantly more susceptible to the action of antimicrobials and host immune effectors. This result demonstrated the potential for development of a novel therapeutic vaccine that could be used to treat chronic and recurrent diseases of bacterial biofilm origin. 

In our new paper (, we attempt to leverage this new understanding to develop a therapeutic chimeric vaccine antigen that will accomplish several targeted goals.  First, this vaccine antigen was designed to mimic those specific domains of the DNABII protein that we had shown were immunoprotective, and thereby induce the formation of antibodies that could disrupt biofilms as well, or ideally, even perhaps better than had antibodies to the whole native protein (which also contains non-protective domains).  Second, this chimeric vaccine antigen needed to be able to induce the formation of antibodies that could demonstrate efficacy against not only biofilms formed in vitro, but also those that were formed in an intact mammalian host, during experimental disease.  An additional concern was focused on the principle of ‘original antigenic sin’, wherein immunization with the intact native DNABII protein was predicted to simply boost the natural, but ineffective, host immune response to these common biofilm structural constituents.  Thereby, lastly, our chimeric DNABII-derived and specific epitope-targeted vaccine candidate needed to be able to redirect the host immune response away from the non-protective domains, and instead now selectively boost the response to the immunoprotective domains.  We show data that provide support for both a powerful therapeutic approach for pathogenic biofilm resolution, and also for development of a DNABII-directed vaccine candidate that would avoid augmentation of any pre-existing natural, but non-protective, immune response.

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Next-generation vaccines for infectious diseases

This cross-journal Collection welcomes submissions that propose technological advancements in vaccine/antigen design, target combinations, delivery systems for any pathogen groups, as well as adjunctive therapies.

Publishing Model: Open Access

Deadline: Sep 01, 2024