Biology subjects

Mamroud, E.

Publications and source records attributed to Mamroud, E..

4 recordsLinked to original sources

bioRxiv2022

An Effective mRNA-LNP Vaccine Against the Lethal Plague Bacterium

Plague is a rapidly deteriorating contagious disease that has killed millions of people during the history of mankind and is caused by the gram-negative bacterium Yersinia pestis. Currently, the disease is treated effectively with antibiotics. However, in the case of an outbreak caused by a multiple-antibiotic-resistant strain, alternative countermeasures are required. Despite the many efforts to develop a safe vaccine against the disease, there is still no vaccine approved for use in western countries. mRNA Lipid Nanoparticle (mRNA-LNP) vaccines have been demonstrated during the Covid-19 pandemic to be a versatile, clinically relevant, and rapidly manufactured vaccine platform. However, harnessing this platform for bacterial pathogens remains a formidable challenge. Here, we describe the design of several mRNA-LNP vaccine versions against Y. pestis, based on the F1 capsular antigen. We demonstrate that mRNA-LNP vaccines encoding the F1 antigen with either no signal sequences or conjugated to human Fc, provide substantial cellular and humoral responses. Most importantly, these vaccine candidates fully protect animals against Y. pestis infection. The results of this study suggest that mRNA-LNPs can be effective as anti-bacterial vaccines, and further developed to combat other bacterial pathogens, which are urgently needed, given the looming threat of antibiotic resistance. One-Sentence SummaryA novel mRNA-LNP vaccine against Y. pestis, the etiological agent of plague and the first documented mRNA-LNP vaccine to protect against a lethal bacterial pathogen infection.

microbiology↗

bioRxiv2022

Phage therapy potentiates second-line antibiotic treatment against pneumonic plague

Plague pandemics and outbreaks have killed millions of people during the history of humankind. The disease, caused by Yersinia pestis bacteria, can currently be treated efficiently with antibiotics. However, in the case of multidrug-resistant (MDR) bacteria, alternative treatments are required. Bacteriophage (phage) therapy has shown efficient antibacterial activity in various experimental animal models and in human patients infected with different MDR pathogens. Herein, we evaluated the efficiency of {phi}A1122 and PST phage therapy, alone or in combination with second-line antibiotics, using a well-established mouse model of pneumonic plague. Phage treatment significantly delayed mortality and limited bacterial proliferation in the lungs. However, the treatment did not prevent bacteremia, suggesting that phage efficiency may decrease in circulation. Indeed, in vitro phage proliferation assays indicated that blood has inhibitory effects on lytic activity, which may be the major cause of treatment inefficiency. Combining phage therapy and second-line ceftriaxone treatment, which are individually insufficient, provided protection that led to survival of all infected animals, presenting a synergistic protective effect that represents a proof of concept for efficient combinatorial therapy in an emergency event of a plague outbreak involving MDR Y. pestis strains. Author summaryPlague, caused by Yersinia pestis bacteria, can be efficiently treated with antibiotics. However, alternative therapies for the case of natively evolved or maliciously generated antibiotic-resistant Y. pestis must be developed. Due to the global increase in antibiotic resistance, there is renewed interest in examining the effectiveness of bacteriophage-based alternative therapies. Here, using a mouse model of pneumonic plague, we demonstrate that phage treatment significantly delayed mortality. By monitoring bioluminescence of engineered Y. pestis strain and live bacterial counts, we show that phage therapy effectively inhibited bacterial proliferation in the lung but not in blood. In vitro analyses showed decreased phage activity in the presence of blood, which probably explains the low efficacy of phage treatment alone. Because combination therapies will be used in an emergency situation, we tested the efficacy of Y. pestis-lysing phages as adjunctive therapy with a second-line antibiotic, ceftriaxone. Whereas each individual treatment was insufficient, the combination provided effective protection and rescued all infected animals. These results clearly demonstrated the synergistic effect of combined phage and antibiotic therapy and represent a proof of concept for this alternative therapy against multidrug-resistant Y. pestis strains.

microbiology↗

bioRxiv2021

Monitoring group activity of hamsters and mice as a novel tool to evaluate COVID-19 progression, convalescence and rVSV-ΔG-spike vaccination efficacy

COVID-19 pandemic initiated a worldwide race toward the development of treatments and vaccines. Small animal models were the Syrian golden hamster and the K18-hACE2 mice infected with SARS-CoV-2 to display a disease state with some aspects of the human COVID-19. Group activity of animals in their home cage continuously monitored by the HCMS100 was used as a sensitive marker of disease, successfully detecting morbidity symptoms of SARS-CoV-2 infection in hamsters and in K18-hACE2 mice. COVID-19 convalescent hamsters re-challenged with SARS-CoV-2, exhibited minor reduction in group activity compared to naive hamsters. To evaluate rVSV-{Delta}G-spike vaccination efficacy against SARS-CoV-2, we used the HCMS100 to monitor group activity of hamsters in their home cage. Single-dose rVSV-{Delta}G-spike vaccination of immunized group showed a faster recovery compared to the non-immunized infected hamsters, substantiating the efficacy of rVSV-{Delta}G-spike vaccine. HCMS100 offers non-intrusive, hands-free monitoring of a number of home cages of hamsters or mice modeling COVID-19.

immunology↗

bioRxiv2020

A single dose of recombinant VSV-{triangleup}G-spike vaccine provides protection against SARS-CoV-2 challenge

The COVID-19 pandemic caused by SARS-CoV-2 that emerged in December 2019 in China resulted in over 7.8 million infections and over 430,000 deaths worldwide, imposing an urgent need for rapid development of an efficient and cost-effective vaccine, suitable for mass immunization. Here, we generated a replication competent recombinant VSV-{Delta}G-spike vaccine, in which the glycoprotein of VSV was replaced by the spike protein of the SARS-CoV-2. In vitro characterization of the recombinant VSV-{Delta}G-spike indicated expression and presentation of the spike protein on the viral membrane with antigenic similarity to SARS-CoV-2. A golden Syrian hamster in vivo model for COVID-19 was implemented. We show that vaccination of hamsters with recombinant VSV-{Delta}G-spike results in rapid and potent induction of neutralizing antibodies against SARS-CoV-2. Importantly, single-dose vaccination was able to protect hamsters against SARS-CoV-2 challenge, as demonstrated by the abrogation of body weight loss of the immunized hamsters compared to unvaccinated hamsters. Furthermore, whereas lungs of infected hamsters displayed extensive tissue damage and high viral titers, immunized hamsters lungs showed only minor lung pathology, and no viral load. Taken together, we suggest recombinant VSV-{Delta}G-spike as a safe, efficacious and protective vaccine against SARS-CoV-2 infection.

microbiology↗