Efforts to develop a gonococcal vaccine have continued for over three decades without notable progress. While the significant sequelae of infection in females and solid evidence that concurrent gonococcal (GC) infection can enhance HIV transmission have spurred these investigations, this goal has become more urgent given the recent increase in GC antibiotic resistance, especially to ceftriaxone. Two major issues associated with this absence of success have been 1) the lack of an animal model that appreciates the human specificity of gonococcal adhesins and other virulence factors, and 2) the lack of correlates of immunity that can inform vaccine design. The overall objective of this proposal is to evaluate potential gonococcal vaccine candidates in a recently developed GC both transcervical induced upper genital tract (UGT) and intravaginal induced lower genital tract (LGT) infection models utilizing humanized transgenic mice expressing CEACAM 1 or CEACAM5 respectively.
The aims of this grant are to 1) Evaluate the ability of high priority gonococcal vaccine candidates (porin, OMV and LOS derived mimotopes) to protect humanized TG mice from LGT or UGT GC infection, 2) Determine which immune defects may allow for enhanced infection in WT mice (to aid in discerning potential correlates of immunity) and 3) Examine pattern of in vivo expressed GC genes by RNAseq transcriptomics and Compare to similar data from humans. If the aims are fulfilled, a new model for gonococcal vaccine evaluation will be established and validated by comparison to human infection, correlates of gonococcal immunity will be discerned, and the relative utility of gonococcal vaccine candidates will be determined in order to prioritize and guide their future development towards their ultimate use in humans.
The development of an anti-gonococcal vaccine is of great public health importance and urgency for a number of reasons: 1) Gonococcal infection causes significant sequelae in females, leading to pelvic inflammatory disease, tubal fibrosis and increased incidence of ectopic pregnancies and infertility; 2) there is solid evidence that concurrent GC infection can also increase HIV replication, which also can enhance HIV transmission; and 3) most alarmingly, gonococci have developed significant antibiotic resistance to mainstays of treatment, including quinolones and, more recently, ceftriaxone. Moreover, when considering that recent estimates suggest that over 100 million new gonococcal infections occur in the world each year, the significant rise in GC infections and associated sequelae expected to be associated with the spread of untreatable gonococcal infections has important local and global implications necessitating the development of a vaccine to control this assiduous human pathogen.
|Islam, Epshita A; Anipindi, Varun C; Francis, Ian et al. (2018) Specific Binding to Differentially Expressed Human Carcinoembryonic Antigen-Related Cell Adhesion Molecules Determines the Outcome of Neisseria gonorrhoeae Infections along the Female Reproductive Tract. Infect Immun 86:|
|Francis, Ian P; Islam, Epshita A; Gower, Adam C et al. (2018) Murine host response to Neisseria gonorrhoeae upper genital tract infection reveals a common transcriptional signature, plus distinct inflammatory responses that vary between reproductive cycle phases. BMC Genomics 19:627|
|Wetzler, Lee M; Feavers, Ian M; Gray-Owen, Scott D et al. (2016) Summary and Recommendations from the National Institute of Allergy and Infectious Diseases (NIAID) Workshop ""Gonorrhea Vaccines: the Way Forward"". Clin Vaccine Immunol 23:656-63|
|Islam, E A; Shaik-Dasthagirisaheb, Y; Kaushic, C et al. (2016) The reproductive cycle is a pathogenic determinant during gonococcal pelvic inflammatory disease in mice. Mucosal Immunol 9:1051-64|