Development of Efficacious Vaccine Against UTI's

Duke University, Durham NC

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): UTIs is one of the most frequent bacterial infections of man with over 85% of the outpatient community acquired UTIs caused by E.coli. Since antibiotic resistance among uropathogenic E.coli is growing, prophylactic approaches are increasingly being sought. The virulence of E.coli is attributable to expression of fimbrial adhesion FimH that mediates bacterial adherence and subsequent bacterial invasion of the bladder uroepithelium. Vaccines comprising of FimH or FimH fragments have proven highly effective in protecting mice against UTIs. However, when these FimH vaccines were administered intramuscularly with alum as adjuvant in humans, the levels of FimH specific antibodies in the serum and mucosal surfaces were low and not sustainable. Currently, a major limitation in the use of FimH vaccine in the humans is the absence of effective and safe adjuvants capable of achieving high levels of specific antibodies in serum and mucosal secretions. Recently, we discovered that mast cells (MCs) play a hitherto unrecognized role at sites of infection in orchestrating the trafficking of dendritic cells and B and T cells, Key immune cells critical for the development of adaptive immune responses. These observations led us to investigate whether co-administering antigens along with MC activators would result in elevated antigen-specific immune response. Preliminary studies revealed administering different vaccine antigens along with compound 48/80 in the nasal regions of mice evoked a highly elevated IgG response in the serum as well as IgA responses in various mucosal fluids. These studies revealed that mast cell activators have the potential to serve as potent adjuvants. Here, we hypothesized that if FimH or FimH fragments were nasally co-administered into mice with a mast cell activator, we would evoke highly protective immunity against UTI. The goals of this study are to (1) ) Evaluate the immunogenicity and protective capacity against UTIs of a FimH1-25 peptide vaccine when co administered nasally with compound 48/80. (2) Compare the efficacy and safety of compound 48/80 as a vaccine adjuvant with other known MC activators (3) Confirm that the adjuvant activity demonstrated with mast cell activators acts through specific activation of resident MCs. PUBLIC HEALTH RELEVANCE: Vaccines comprising of Fim H or FimH fragments have proven highly effective in protecting mice against UTIs. However, when these FimH vaccines were administered intramuscularly with alum as adjuvant in humans, the levels of FimH antibodies in the serum and mucosal were low and not sustainable. Currently a major limitation in the use of Fim H vaccines in humans is the absence of effective and safe adjuvants capable of achieving high levels of specific antibodies in serum and mucosal secretion. Preliminary studies have revealed that administering different vaccine antigens along with a mast cell activator in the nasal regions of mice evoked a high level of IgG antibodies in the serum as well as IgA antibodies in various mucosal fluids. The primary goal of this study is therefore to evaluate the immunogenisity and protective capacity against UTIs of a FimH peptide vaccine when co-administered nasally with mast cell activator.