Summary and Recommendations from the National Institute of Allergy and Infectious Diseases (NIAID) Workshop "Gonorrhea Vaccines: the Way Forward".

UNLABELLED: There is an urgent need for the development of an antigonococcal vaccine due to the increasing drug resistance found in this pathogen. The U.S. Centers for Disease Control (CDC) have identified multidrug-resistant gonococci (GC) as among 3 "urgent" hazard-level threats to the U.S. POPULATION: In light of this, on 29 to 30 June 2015, the National Institute for Allergy and Infectious Diseases (NIAID) sponsored a workshop entitled "Gonorrhea Vaccines: the Way Forward." The goal of the workshop was to gather leaders in the field to discuss several key questions on the current status of gonorrhea vaccine research and the path forward to a licensed gonorrhea vaccine. Representatives from academia, industry, U.S. Government agencies, and a state health department were in attendance. This review summarizes each of the 4 scientific sessions and a series of 4 breakout sessions that occurred during the one and a half days of the workshop. Topics raised as high priority for future development included (i) reinvigoration of basic research to understand gonococcal infection and immunity to allow intervention in processes essential for infection; (ii) clinical infection studies to establish parallels and distinctions between in vitro and animal infection models versus natural human genital and pharyngeal infection and to inform in silico modeling of vaccine impact; and (iii) development of an integrated pipeline for preclinical and early clinical evaluation and direct comparisons of potential vaccine antigens and adjuvants and routes of delivery.

Surveillance of antimicrobial susceptibilities of Neisseria gonorrhoeae in Nanning, China, 2000 to 2012.

OBJECTIVES: To monitor the frequency of antibiotic resistance of Neisseria gonorrhoeae (NG) in Nanning, China, between 2000 and 2012. METHODS: The production of ß-lactamase by NG isolates was determined using the paper acidometric testing method. Antimicrobial susceptibility testing was performed for tetracycline, ciprofloxacin, spectinomycin, and ceftriaxone using the agar dilution method. The χ(2) test, t test, and univariate and multivariate analyses were used to analyze the statistical difference of the results. RESULTS: A total of 923 NG isolates were collected in Nanning between 2000 and 2012. Among these, 131 (14.2%) were penicillinase-producing NG, 520 (56.3%) isolates were tetracycline-resistant NG, and 857 (92.9%) isolates were ciprofloxacin-resistant strains. One spectinomycin-resistant strain was identified in 2000. There were 304 (32.9%) isolates with decreased susceptibility to ceftriaxone; the proportion of such isolates increased from 22.8% in 2000 to 2002 to 48.9% in 2006 to 2008 (P < 0.001), followed by a fall to 32.2% in 2009 to 2012 (P = 0.001). Patients' age of 16 to 25 years and isolate collection period of 2008 to 2012 (except 2011) were demonstrated to be risk factors for infection with isolates with decreased susceptibility to ceftriaxone. CONCLUSIONS: Antimicrobial susceptibility of NG isolates obtained from patients in Nanning from 2000 to 2012 was characterized by high occurrence of penicillinase-producing NG, tetracycline-resistant NG, and ciprofloxacin-resistant strains. Spectinomycin and ceftriaxone can be considered drugs of choice for empirical treatment of NG infection in Nanning. Moreover, we recommend a combination of 500 mg or higher dose of intramuscular ceftriaxone and 1 g oral azithromycin be used for the treatment of NG infection in Nanning and possibly in China.

Vaccine research for gonococcal infections: where are we?

Gonorrhoea continues to seriously impact human society with an estimated 106 million new infections occurring annually. The consequence of gonorrhoea on reproductive and neonatal health is especially concerning as is its role in the spread of HIV. Current control measures rely on the identification and treatment of infected individuals and their sexual contacts. The success of this strategy, which is already inadequate, is lessened by poor diagnostic capabilities in many parts of the world and challenged by the rapid emergence of antibiotic-resistant strains. The potential of untreatable gonorrhoea is now real, and a gonorrhoea vaccine is seriously needed. Historically, gonorrhoea vaccine research has been hampered by the antigenic variability of the gonococcal surface, a lack of known protective mechanisms, and the absence of a small laboratory animal model for testing candidate vaccines and manipulating host responses. Here we discuss recent advances that have rekindled research efforts towards a gonorrhoea vaccine. Several conserved and semiconserved vaccine antigens have been identified that elicit bactericidal antibodies or inhibit target function. A mouse genital tract infection model is available for systematic testing of vaccines, and transgenic mice have been developed to relieve host restrictions. Additionally, several immunological advances have been made including the identification of mechanisms by which Neisseria gonorrhoeae suppresses the adaptive response and the demonstration that Th1 responses clear experimental infection in mice and induce a protective memory response. We also discuss important issues with respect to product development that must be considered when entering the vaccine pipeline.

Low prevalence of ciprofloxacin-resistant Neisseria gonorrhoeae in Nuuk, Greenland.

During a 35-day period, 32 isolates of Neisseria gonorrhoeae strains were collected by culture from patients with positive nucleic acid amplification test results in Nuuk, Greenland, where ciprofloxacin is the preferred treatment. All isolates were quinolone susceptible, suggesting that resistance is rare. Sampling patients for culture before treatment may prove useful in reestablishing surveillance.

The possible roles of vitamin D and curcumin in treating gonorrhea.

Drug-resistant gonorrhea, Neisseria gonorrhoeae (N. gonorrhoeae), is an emerging concern, especially because the risk of bladder cancer is associated with this infection. N. gonorrhoeae suppresses T-helper 1(Th1) and Th2 responses and enhances Th17 responses via a mechanism involving transforming growth factor-beta (TGF-ß) and regulatory T cells. Blockade of TGF-ß alleviates the suppression of specific anti-gonococcal responses and allows Th1 and Th2 responses to emerge with concomitant boosting of immune memory and protective immunity. Gonorrhea activates nuclear factor kappaB (NF-kappaB), which plays a critical role in signal-transduction pathways involved in inflammation. The innate immune system can eventually clear gonorrhea. Vitamin D is emerging as a potential, powerful, anti-microbial agent with these effects: it supports the innate immune system in combating bacterial infections; it decreases levels of TGF-ß and NF-kappaB activation; and it induces production of LL-37 (cathelicidin), which has antimicrobial and antiendotoxin properties. In addition, via an independent vitamin D receptor pathway, curcumin also induces LL-37 production, inhibiting N. gonorrhoeae-induced NF-kappaB signaling and inducing autophagy. Therefore, vitamin D and curcumin taken together may be useful in combating both normal and drug-resistant gonorrhea. Moreover, the possible synergy between these two agents in improving outcomes is worthy of additional investigation.

[The combined therapy of patients with gonorrheal-chlamydial urogenital infections by leukinferon immunocorrection]. / Kompleksnaia terapiia bol'nykh s gonoreino-khlamidiinoi urogenital'noi infektsiei s immunokorrektsiei leikinferonom.

The adjuvant injection of wide-spectrum immunocorrector leukinferon to 45 males with gonorrheal-chlamydial urogenital infection receiving tarivid and doxicicline made the treatment shorter and the number of inflammatory complications and recurrences less numerous. Leukocyte and lymphocyte counts returned to normal values 6 days earlier and so did immunological indices. In control subjects (20 patients) on immunocorrection with tactivin inflammation persisted longer, urogenital complications were not cured, chlamydial recurrences occurred in 10% of the patients, immunological normalization was not reached.

Gonococcal endocarditis in a patient with mitral valve prolapse: study of host immunology and organism characteristics.

The first case of gonococcal endocarditis on a prolapsing mitral valve is reported. The organism was found to be highly sensitive to penicillin G, Arg- Hyp- Ura-, and sensitive to the bactericidal action of normal serum. This combination of characteristics in a strain of Neisseria gonorrheae causing systemic disease is distinctly unusual. With high dose penicillin therapy the immunologic parameters returned to normal and the patient made an uneventful recovery. High levels of circulating immune complexes were detected in the patient's serum.