Development of a New Type of Vaccine to Prevent Stomach Cancer
Abstract
This research proposal is relevant to the Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Area of stomach cancer. Our research will specifically address gaps in cancer prevention affecting mission readiness. We propose to prevent stomach cancer through the development of a vaccine against Helicobacter pylori infection, representing the major environmental exposure risk factor for stomach cancer. It is estimated that half of the world’s population have this bacterial infection. H. pylori lives in the stomach, where it causes inflammation of the stomach lining. Most individuals, however, do not know that they are infected. As a consequence, stomach cancer is often diagnosed once the disease is already advanced. For this reason, stomach cancer is referred to as a silent killer. Despite improvements in diagnosis and treatment, the 5-year survival rate for stomach cancer is still less than 30%. H. pylori infection is very common among United States (U.S.) military Veterans, particularly those of African-American, Hispanic, and Asian ethnicities. These Veterans are also most likely to suffer from stomach cancer and to be hospitalized due to the complications arising from this cancer. Furthermore, there is evidence that H. pylori transmission is facilitated by the conditions encountered by military personnel. The infection is mainly transmitted by oral-to-oral contact and, to a lesser extent, via the oral-fecal route. Within families, H. pylori infection is generally acquired before the age of 5 years, and so is likely to spread among Veterans’ family members, some of whom will go on to develop severe disease later in life. Although antibiotic therapies are available to eliminate H. pylori infection, these are not always effective. Therefore, new approaches are needed to better manage the infection and associated disease. It was suggested that a vaccine against H. pylori infection would be the most cost-effective means of preventing stomach cancer in the U.S. Although vaccine trials in animals reported promising results, subsequent findings from clinical studies have generally been disappointing. Most of the H. pylori vaccines tested so far have been of the subunit type in which one or more H. pylori proteins were administered together with an agent used to enhance immune responses to the vaccine, known as an adjuvant. We suggest that, in order for an H. pylori vaccine to be developed, new approaches need to be tried. The proposed research program is directed at developing an entirely new type of H. pylori vaccine based on membrane blebs that bud off growing bacteria. These blebs, known as membrane vesicles (MVs), are nanosized particles, less than 1/250,000th of an inch, that are non-infectious, non-replicative, and contain many components of the live bacteria from which they originate. Furthermore, bacterial MVs are able to induce immune responses in the host without the need for an adjuvant and are relatively safe, thus making them ideal vaccine candidates. One MV-based vaccine (BEXSERO) has already been licensed for use against certain types of meningococcal disease in humans, while other MV vaccines are in various stages of development. We propose to genetically modify H. pylori bacteria so as to generate MVs that are more immunogenic than those naturally produced by the bacterium. The ability of these genetically modified MVs to protect against H. pylori infection will be tested in a pre-clinical model. The proposed research is basic in nature but, in the first instance, is expected to provide a proof-of-concept for the use of MVs in a vaccine against H. pylori infection. MVs have many advantages over existing vaccines, and we expect that the research will show how MVs can overcome some of the current roadblocks in the field; notably, the absence of a truly effective adjuvant that is capable of inducing immune responses in the stomach, yet is not toxic for humans. There is also the possibilit
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110953
Entities
People
- Richard L. Ferrero
Organizations
- United States Army