The selectivity of bacteriophages and the flexibility of phage-based preventative or curative treatments hold the promise to counteract the emerging antimicrobial resistant bacteria and other pathogens. An increasing understanding of the phage biology and recent scientific advancements in the field suggest that this might be possible.
Main Text
Bacteriophages (or phages) have been in the toolbox of medical treatments for almost a century. The use of phages to treat infection was mostly confined to eastern European countries, while in the Western world we abandoned their use a long time ago with the advent of antibiotics. However, the recent increasing threat of antimicrobial resistance led Western scientists to rediscover the phage therapy, and positive results were reported in several studies. Despite the attractiveness of developing a treatment that co-evolves with the pathogenic bacterium and counterattacks all its mechanisms of resistance, limitations were encountered. The selection of the bacteriophages cocktail necessitates a deep understanding of the bacterial strains causing disease. Moreover, information of efficacy in clinical trials is scarce, complicating the fulfillment of the regulatory requirements for new drug products. Furthermore, the cost of the treatment highly exceeded the one of conventional antibiotics, greatly limiting the use of phages in the clinical practice. While the use of bacteriophages as treatments lagged, these viruses promoted a massive leap forward in the biological sciences. Through studies of bacterial immunity to phages, there was also the discovery of the CRISPR-Cas system, which is revolutionizing the entire biology field. Technological improvements in genome editing, high-throughput sequencing, and synthetic biology allowed the use of phages as an easy and versatile tool to discover new vaccines and antigens, but also to engineer proteins and antibodies. In particular, phage display technology was extensively used to express recombinant proteins tethered to the bacteriophage capsid and to evolve in vitro antigens and antibodies. The basic principle of phage display was exploited in vaccinology, making the bacteriophage a delivery system for viral and bacterial proteins. These antigens, exposed on the surface of the phage, are highly localized and in the correct orientation, facilitating the activation of the immune cells. Moreover, the phage itself activates the immune system, providing a certain degree of adjuvanticity. Despite being versatile, the phage technology has not brought to licensure any vaccine yet. Nonetheless, the rise of new technological and scientific advances is opening new avenues for phage-based approaches. In a paper published in this issue of Med, Staquicini and colleagues introduced an interesting new concept in phage-based vaccination. They describe aerosol delivery of a phage display library expressing peptides and the discovery that the peptide CAKSMGDIVC increases pulmonary delivery of the phage. The peptide was found to bind the epithelial cell receptor a3b1. Following vaccination, CAKSMGDIVC-displaying phages induced higher titers against vaccine antigens compared to the insert-less ones. This proof-of-concept study opens an interesting translational application for enhanced targeted phage-guided delivery of vaccines or drugs to the airways and the blood stream. This is particularly relevant for airborne pathogens. In the current COVID-19 pandemics, mucosal immunity has thought to participate in prevention of SARS-CoV-2 infection. A recent study in mice described the protective effect of a single intranasal vaccination, which conferred sterilizing immunity against the virus. In this context, a vaccine platform like the one described by Staquicini et al. could bring an additional way to achieve targeted delivery in the lungs, with the upside of facilitating the systemic availability of the immunogen. Importantly, it is yet to be demonstrated that the CAKSMGDIVC-phage system can be coupled with a displayed or expressed exogenous antigen and that the strategy could confer enhanced immunity to the recombinant antigen.Other innovative approaches have demonstrated how to improve the range and effectiveness of phage-based approaches. Recent progress in genome engineering holds the promise to expand the phage therapy host range, fine-tune tissue specificity, and modify the immune response against the phage vector, therefore customizing even more the virus to its intended scope. Given the plasticity of this platform, the use of phages to overcome the AMR problem and to deliver vaccines is attractive (Figure 1), and some research data seem to indicate that this might be possible. However, innate response to phages in mammals are still not fully understood, and human trial data to demonstrate the benefit of phages in disease treatment and prevention are urgently needed.
Figure 1Applications of bacteriophages
(A) Bacteriophages can be engineered and applied in the medical field or in the lab, providing a possible solution to counteract the increasing antimicrobial resistance threat.
(B) Novel vaccine delivery of phages displaying the lung-targeting CAKSMGDIVC peptide described by Staquicini et al.
Leave a Reply