Assessing the immunogenicity of the major outer membrane protein porin B of Neisseria gonorrhoeae as a vaccine candidate
Le, TuQuynh Khac
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Neisseria gonorrhoeae is a strict human pathogen and the causative agent of the sexually transmitted disease, gonorrhea. Gonococcal (GC) diseases remain one of the most reported sexually transmitted infections (STI) worldwide, representing a significant threat to reproductive health and burden on global health systems, accounting for 541,987 disability adjusted-life years in the year 2011. Infection by N. gonorrhoeae also increases the likelihood of patient acquisition and transmission of human immunodeficiency virus (HIV). Unfortunately, antibiotic treatment to gonococcal diseases is being threatened by the rapid spread of resistance to third-generation cephalosporins, the remaining treatment option used in clinics. The urgency of the situation is compounded by the relative lack of immunological protection conferred by previous infection by the bacterium. In response to the emergence of multidrug resistance, renewed energies are being directed towards the development of an effective, broadly protective vaccine. Difficulties in vaccine development arise from a lack of known correlates of protective immunity; there is no known broadly cross-protective immunity to GC and a truly reflective animal model has not been available. Nonetheless, previous studies have indicated that porins, neisserial major outer membrane proteins, are promising vaccine candidates. PorB makes up over 60% of the bacterium's outer membrane content and is involved in solute and ion exchange, invasion of target host cells, and evasion of host immunity. Porins from both the gonococcus and the meningococcus have been shown to have immunostimulatory activity, boosting B and dendritic (DC) cell proliferation and maturation in the absence of an exogenous adjuvant as mediated by TLR2 and MyD88. Importantly, as a potential vaccine candidate, PorB has relatively low antigenic variability, and can induce bactericidal antibodies. Gonococcal PorB was purified from a genetically modified strain, MS11delP3, which lacks another outer membrane protein, RMP, which is known to induce bactericidal blocking antibodies. PorB was formed into pure protein micelles, termed proteosomes, to protect the integrity of the native trimeric structure. Our study demonstrated that gonococcal PorB is able to stimulate both human embryonic kidney (HEK) cell line that overexpresses TLR2 and mouse primary macrophages (similar to the meningococcal PorB). To test PorB's immunogenicity, mice were immunized three times at two week intervals with PorB and porin specific IgG levels were measured. Unfortunately, PorB elicited lower levels of porin specific IgG than what was expected, which may be due to technical issues. We are currently investigating various possibilities. In addition, further immunization studies shall be carried out to better contextualize these results.