A novel recombinant cross-protective vaccine against Shigellosis


Shigella belongs to the Enterobacteriaceae family and is a leading cause of severe bacterial dysentery in humans. Annually millions of cases occur globally with the majority in children in developing countries with more than 600,000 deaths. Shigellosis is a leading cause of morbidity and mortality in endemic countries such as sub-Saharan Africa and Southeast Asia. Treatment with antibiotics is failing with increasing levels of AMR including resistance to some newer drugs. AMR is thus driving the need for new and cost-effective vaccines. Following a USDA call for increased food safety against a high incidence of salmonellosis the PAL vaccine was developed for use in poultry. Pacific GeneTech (PGT) in-licensed the technology and associated patents from the University of Arkansas for both animal and human use. It has been used safely and effectively in poultry worldwide and USDA approval is anticipated in 2023. PGTx, PGT’s affiliated company, is focussing on its clinical development for use as a vaccine against bacterial dysentery. The vaccine has demonstrated both safety and good cross-protection against members of the Enterobacteriaceae family. These include virulent strains of Salmonella and ETEC in challenge studies in both mice and pigs. Shigella and E. coli are closely related and share the highly conserved PAL antigen constituent in the vaccine prompting interest in its potential to additionally protect against shigellosis. The vaccine is low cost, readily deployed in challenging field conditions and can be administered orally. All these are critical factors in the distribution and production of a vaccine in LMICS.

Project Outcomes

The study:  The study was designed to investigate the ability of the recombinant vectored PGTx PAL vaccine to protect against shigellosis. The challenge pathogens were Shigella flexneri 2a and Shigella sonnei, 2 of the main pathogens responsible for causing severe disease associated with high levels of morbidity and mortality in LMICs where bacterial dysentery is endemic. The aim was to compare the activity in BALB/c mice of the inactivated PGTx PAL vaccine with those of an inactivated S. flexneri 2a (wild type strain 2457T from WRAIR) and a S. sonnei 53G vaccine. All three vaccines consisted of 1x108 inactivated CFUs and were delivered intranasally in a total volume of 40 ml per mouse. A prime-boost-boost regimen was adopted with 14-day intervals between vaccinations over a 41-day study period. The PAL vaccine was given together with the company’s proprietary adjuvant mannosylated chitosan (MCA) at a concentration of 5%. The higher dose was selected after titration of MCA (1%, 2.5% and 5%) in a total volume of 40 ml per mouse. After a couple of days of discomfiture, all mice fully recovered irrespective of the dose of MCA received and so the higher dose was selected. Mice were anaesthetised during all vaccination and challenge procedures. Bloods were taken immediately prior to immunisations. Live challenge strains were delivered intranasally after the third immunisation at both high and low doses and consisted of S. flexneri 2a (4.46x107and 0.87x107 CFUs) and S. sonnei (1.15x107and 0.55x107 CFUs), respectively. Controls included PBS and inactivated Salmonella Enteritidis vector backbone. Survival and body weight of the mice were monitored for 15 days after challenge with daily observations and measurements. 

Results: Results showed that the survival rate after immunisation with the PAL vaccine was only 30% following the low dose challenge and no mice survived the high dose challenge. This was the case with both challenge strains tested.  By contrast the mice immunised with S. flexneri 2a showed a 50% survival in the high dose challenge and 100% survival following the low dose challenge against homologous S. flexneri 2a. All mice immunised with S. sonnei survived against challenge irrespective of challenge dose. In terms of serum antibody responses induced by the PAL vaccine after the 3rd immunisation there were increased anti-PAL IgG levels compared with the PBS negative control group. The same was reflected in IgG levels from bronchoalveolar lavage (BAL) fluid. Anti-PAL peptide IgA in BAL fluid showed a statistically significant increase in the PAL vaccinated and S. sonnei group. The conclusion from the study was that although the PAL vaccine did induce antibodies to both S. sonnei and S. flexneri antibody titres were not sufficient to protect against challenge with these pathogens in this model.

Comment: While PGTx has significant data on the ability of the PAL vaccine to protect against ETEC in chickens, mice and pigs this was the first investigation of the PAL vaccine against Shigella using a new model and a novel intranasal route of immunisation.


Dr Anna Obolensky
Director Translational Research
Pacific GeneTech (PGTx), UK


Dr Jae-Ouk Kim, Senior Research Scientist, International Vaccine Institute, South Korea

Prof Quentin Sattentau, Professor of Immunology, Sir William Dunn School of Pathology, University of Oxford, UK