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PhagoVax: Combining Vaccination with Phage Therapy

Research Project
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01.07.2021
 - 30.06.2023

PhagoVax: Proof of concept Oral inactivated vaccines induce secretory Immunoglobulin A (sIgA) with strong affinity for the surface of bacterial strains. sIgA trap growing bacteria in large clumps which neutralizes virulence (enchained growth). In naïve hosts, non-typhoidal Salmonella strains can outgrow the protective intestinal microbiota. In vaccinated hosts, sIgA trapped-pathogens have a reduced fitness. This provides a competitive advantage to the microbiota, which excludes Salmonella from the gut. Oral inactivated vaccines are cheap to produce, safe and simple to administer. We have established a streamlined procedure to construct such vaccines from any cultivable bacterial species. However, pathogens can modify their surface antigens and escape sIgA binding. So we have recently refined the inactivated vaccines and demonstrated that a rationally designed polyvalent oral vaccine reduces escape options. This works in mice exposed to mixtures of all inactivated escape variants that Salmonella Typhimurium is able to generate by mutations or epigenetic changes. The result is a robust production of high affinity sIgA able to neutralize all variants of the strain that we use to prepare the vaccine. We discovered that the sIgA in mice exposed to polyvalent vaccine either lead to exclusion of Salmonella from the gut (problem solved), or select for short O-antigen mutants. These mutants sporadically emerge because the immuno-dominant antigen is the long repetitive O-antigen polysaccharide chain that carpets the surface of the pathogen. The short O-antigen is advantageous in vaccinated mice since sIgA cannot bind efficiently. However, the short O-antigen renders Salmonella sensitive to a large diversity of bacteriophages normally inhibited by long O-antigens. We hypothesize that polyvalent oral vaccines should synergize with bacteriophages to block all evolutionary escape routes and reliably prevent non-typhoidal Salmonellosis. We named this original concept "PhagoVax". The specificity of the phage/vaccine "PhagoVax" approach is a substantial advantage compared to antibiotics which profoundly disrupt the host's microbiota, thus generating a favorable niche for opportunistic resistant pathogens. On the other hand, PhagoVax is designed to target different Salmonella strains and serotypes at once. First, we can easily modify the polyvalent vaccine composition in order to select for short O-antigen mutants in different serotypes. Second, a universal bacteriophage cocktail should be able to target several serotypes. Indeed, evolution of the short O-antigen exposes structures like membrane proteins (e.g. OmpC, BtuB) that are conserved among serotypes and serve as attachment sites for bacteriophages normally inhibited by long O-antigens. Moreover, the short O-antigen phenotype is due to the deletion of the wzyB gene via high frequency site-specific recombination. The unstable configuration of the wzyB locus is conserved among Salmonella enterica prevalent serotypes infecting humans and animals (e.g. Typhimurium, Enteritidis and Javiana). Loss of wzyB occurs at high-frequency and, as such, was already reported in natural isolates of Salmonella Enteritidis from broilers. By selecting for short O-antigen mutants, the polyvalent evolutionary trap vaccine erases what makes Salmonella serotypes difficult to target via one single bacteriophage cocktail i.e., the long, variable and modifiable O-antigen. Using vaccines or phages leads to escapers. Combining the two is synergistic because the respective escapers are more vulnerable to the other treatment: vaccination leads to loss of coating polysaccharides so that phages can attack more easily; bacteria protect themselves against phages by expressing these polysaccharides, which make them a better target for antibodies. In vaccinated animals treated with the right bacteriophage cocktail, there should be no way for Salmonella to escape eradication. Our ability to generate effective vaccines has been proven for non-typhoidal Salmonellosis in mice and is currently developed in pigs. In the murine model, we also have all the tools to follow the exact kinetics of bacteria growth, evolution, clearance and transmission to the next host. This sets the stage for efficient project development, and initial experiments will focus on the synergy between adaptive immunity and bacteriophage cocktails in generating evolutionary robust protection from non-typhoidal salmonellosis. We will challenge the approach by targeting different strains of non-typhoidal Salmonella expressing various serotypes and O-antigen modifying systems. We will determine clearance rates of the targeted bacteria and expansion of bacteriophages in the gut as well as optimal delivery and dosing of the bacteriophage cocktail.

Funding

PhagoVax: Combining Vaccination with Phage Therapy

Foundations / Associations (GrantsTool), 07.2021-06.2023 (24)
PI : Diard, Médéric.
CI : Scheiwiller, Marcel.

Members (2)

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Médéric Diard

Principal Investigator
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Nicolas Alexandre Wenner

Project Member