Gonorrhea Vaccine Research Articles

Proteomics-driven Antigen Discovery for Development of Vaccines Against Gonorrhea

Expanding efforts to develop preventive gonorrhea vaccines is critical because of the dire possibility of untreatable gonococcal infections. Reverse vaccinology, which includes genome and proteome mining, has proven very successful in the discovery of vaccine candidates against many pathogenic bacteria. However, progress with this approach for a gonorrhea vaccine remains in its infancy. Accordingly, we applied a comprehensive proteomic platform-isobaric tagging for absolute quantification coupled with two-dimensional liquid chromatography and mass spectrometry-to identify potential gonococcal vaccine antigens. Our previous analyses focused on cell envelopes and naturally released membrane vesicles derived from four different Neisseria gonorrhoeae strains. Here, we extended these studies to identify cell envelope proteins of N. gonorrhoeae that are ubiquitously expressed and specifically induced by physiologically relevant environmental stimuli: oxygen availability, iron deprivation, and the presence of human serum. Together, these studies enabled the identification of numerous potential gonorrhea vaccine targets. Initial characterization of five novel vaccine candidate antigens that were ubiquitously expressed under these different growth conditions demonstrated that homologs of BamA (NGO1801), LptD (NGO1715), and TamA (NGO1956), and two uncharacterized proteins, NGO2054 and NGO2139, were surface exposed, secreted via naturally released membrane vesicles, and elicited bactericidal antibodies that cross-reacted with a panel of temporally and geographically diverse isolates. In addition, analysis of polymorphisms at the nucleotide and amino acid levels showed that these vaccine candidates are highly conserved among N. gonorrhoeae strains. Finally, depletion of BamA caused a loss of N. gonorrhoeae viability, suggesting it may be an essential target. Together, our data strongly support the use of proteomics-driven discovery of potential vaccine targets as a sound approach for identifying promising gonococcal antigens.

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

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. 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.

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...

Vaccines against gonorrhea: Current status and future challenges

Gonorrhea occurs at high incidence throughout the world and significantly impacts reproductive health and the spread of human immunodeficiency virus. Current control measures are inadequate and seriously threatened by the rapid emergence of antibiotic resistance. Progress on gonorrhea vaccines has been slow; however, recent advances justify significant effort in this area. Conserved vaccine antigens have been identified that elicit bactericidal antibodies and, or play key roles in pathogenesis that could be targeted by a vaccine-induced response. A murine genital tract infection model is available for systematic testing of antigens, immunization routes and adjuvants, and transgenic mice exist to relieve some host restrictions. Furthermore, mechanisms by which Neisseria gonorrhoeae avoids inducing a protective adaptive response are being elucidated using human cells and the mouse model. Induction of a Th1 response in mice clears infection and induces a memory response, which suggests Th1-inducing adjuvants may be key in vaccine-induced protection. Continued research in this area should include human testing and clinical studies to confirm or negate findings from experimental systems and to define protective host factors.

In Silico Identification of Dual Ability of N. gonorrhoeae ddl for Developing Drug and Vaccine Against Pathogenic Neisseria and Other Human Pathogens

The transmission and prevention of gonococcal infection is a global health problem and an effective drug or vaccine against the pathogen is yet to be developed. In our previous studies by analyzing metabolic pathways and membrane proteome of N. gonorrhoeae we found that four membrane associated targets could be better option in developing anti- gonorrhoeae drugs and vaccine. Here we showed that among these putative targets, D-alanine—D-alanine ligase (ddl) is the best candidate for development of both drug and vac- cine against N. gonorrhoeae and various other human bac- terial pathogens. Using in silico approaches, we developed the 3-D model of the enzyme and potential epitopes are also identified that may be helpful in peptide vaccine develop- ment against multiple pathogens including pathogenic Neis- seria . Epitopes require experimental validation for their ef- fectiveness as peptide vaccines against these pathogens.

Functional Characterization of Antibodies against Neisseria gonorrhoeae Opacity Protein Loops

BackgroundThe development of a gonorrhea vaccine is challenged by the lack of correlates of protection. The antigenically variable neisserial opacity (Opa) proteins are expressed during infection and have a semivariable (SV) and highly conserved (4L) loop that could be targeted in a vaccine. Here we compared antibodies to linear (Ablinear) and cyclic (Abcyclic) peptides that correspond to the SV and 4L loops and selected hypervariable (HV2) loops for surface-binding and protective activity in vitro and in vivo.Methods/FindingsAbSV cyclic bound a greater number of different Opa variants than AbSV linear, including variants that differed by seven amino acids. Antibodies to the 4L peptide did not bind Opa-expressing bacteria. AbSV cyclic and AbHV2 cyclic, but not AbSV linear or AbHV2 linear agglutinated homologous Opa variants, and AbHV2BD cyclic but not AbHV2BD linear blocked the association of OpaB variants with human endocervical cells. Only AbHV2BD linear were bactericidal against the serum resistant parent strain. Consistent with host restrictions in the complement cascade, the bactericidal activity of AbHV2BD linear was increased 8-fold when rabbit complement was used. None of the antibodies was protective when administered vaginally to mice. Antibody duration in the vagina was short-lived, however, with <50% of the antibodies recovered 3 hrs post-administration.ConclusionsWe conclude that an SV loop-specific cyclic peptide can be used to induce antibodies that recognize a broad spectrum of antigenically distinct Opa variants and have agglutination abilities. HV2 loop-specific cyclic peptides elicited antibodies with agglutination and adherence blocking abilities. The use of human complement when testing the bactericidal activity of vaccine-induced antibodies against serum resistant gonococci is also important.

Transgenic rice expresses an antigenic lipoprotein of Neisseria gonorrhoeae

AbstractBACKGROUND: The use of transgenic plants as new antigen‐delivery systems for subunit vaccines has been increasingly explored. We herein report progress toward a rice‐based vaccine against Neisseria gonorrhoeae.RESULTS: Two expression cassettes, pKrAgnH and pKcAgnH, containing the lipoprotein gene of N. gonorrhoeae (Ag473) under the control of the tobacco Rubisco small subunit (rbcS) promoter or the CaMV 35S promoter, respectively, were constructed and introduced into rice (Oryzy sativa L.) by Agrobacterium‐mediated transformation. Eleven independent transgenic lines were regenerated, integration of the Ag473 gene was confirmed by PCR and specific transcripts of the expected molecular size were detected by RT‐PCR. Expression of the putative polypeptide encoded by the Ag473 gene was detected by immunoassay with specific antibodies. ELISA and western blot revealed that the Ag473 protein was expressed and accumulated in both leaf and seed tissues of transgenic rice plants. Some transgenic lines expressed Ag473 up to 0.5% of the total soluble protein. Moreover, the immunogenicity of the expressed protein was tested in a mouse model and the results showed that specific antibodies were elicited in mice immunised intraperitoneally with protein extracts from transgenic rice plants.CONCLUSION: This study demonstrates the feasibility of using transgenic rice as a bioreactor for N. gonorrhoeae vaccine development. Copyright © 2008 Society of Chemical Industry

Correlates of Acceptance of a Hypothetical Gonorrhea Vaccine by Incarcerated Women

This study sought to identify correlates of acceptance of a hypothetical Neisseria gonorrhea (GC) vaccine in a high-risk sample of incarcerated women. The goal of this study was to inform efforts to promote acceptance of STI vaccines in development. This study consisted of a cross-sectional survey using a structured questionnaire. The majority (79%) of incarcerated women surveyed would accept GC vaccine. In multivariate analyses that controlled for demographics, significant health belief model psychosocial correlates of higher acceptance were perceived severity of infection (OR = 3.33) and vulnerability to infection (OR = 2.85). Fear of vaccination was significantly correlated with lower acceptance (OR = 0.42). Incarcerated women's willingness to accept a hypothetical GC vaccine is explained by components of the health belief model and a component of the theory of reasoned action.

Construction of a Neisseria gonorrhoeae vaccine by fusion of a peptide mimic of a lipooligosaccharide derived carbohydrate epitope with complement C3d

Construction of a Neisseria gonorrhoeae vaccine by fusion of a peptide mimic of a lipooligosaccharide derived carbohydrate epitope with complement C3d

Adverse Reactions to Vaccines

Table 8 lists an overview of adverse reactions to vaccines. In the past 5 years, active research has led to the licensing of several new vaccines and to clinical trials of several others. Hepatitis B subunit vaccine and the new human diploid rabies vaccine have been released for commercial use. An improved and unique live, attenuated oral Salmonella typhi vaccine is under active clinical trials in the Mideast and other areas and has shown great promise. Vaccines under development include a gonorrhea vaccine, an oral live H. influenzae type b vaccine, a Pseudomonas aeruginosa vaccine, and a group B streptococcal vaccine. Vaccines for varicella zoster, cytomegalovirus, herpes simplex, respiratory syncytical virus, and hepatitis A viruses are all undergoing clinical evaluations at the present time in an effort to speed these very useful materials to target populations. Adverse reactions to vaccinations will continue to occur and it is important for the allergist-immunologist to be aware of these potentially serious reactions as well as their clinical management.

The status of vaccines to meningococcal and gonococcal disease

Human beings are subject to infection by two species of Neisseria the meningococcus and the gonococcus. Vaccines effective against meningococcal infection are available and have been widely employed. Their effectiveness rests on the ability to induce antibodies which prevent invasion of the blood stream, but they have only minor effect on the mucosal infection in the nasopharynx, namely the carrier state. With the gonococcus it is the mucosal infection of the genitourinary tract which is, in fact, the disease, and hence a successful gonococcal vaccine must be able to prevent this infection as well as its local extension to the adnexa. The surface antigens of the meningococcus and gonococcus have been found to be remarkably homologous, and their biological properties are becoming clearer. The prospects for a gonorrhoea vaccine will be discussed.

Doubly resistant gonorrhea looms as future problem

While sexually transmitted herpesvirus infections and acquired immunodeficiency syndrome (AIDS) have been making headlines, there recently have been some equally dramatic developments in connection with the continuing gonorrhea pandemic. The latest concerns spectinomycin hydrochlorideresistant, penicillinase-producing<i>Neisseria gonorrhoeae</i>(PPNG), a double-trouble strain first seen clinically less than two years ago. For what is believed to be the first time, there is confirmation that this doubly resistant organism can be transmitted person-to-person. Such transmission occurred between prostitutes and eight American servicemen stationed in the Pacific (where, in a separate study, a gonorrhea vaccine trial began this year with US military volunteers). Until transmissability was documented, a key question was whether such multiply resistant gonorrhea strains somehow evolved in the already infected host or were transmitted as part of the gonococcal infection. The first time the doubly resistant infection was reported was in late spring of 1981. The patient was a 20-year-old man

Doubly resistant gonorrhea looms as future problem

While sexually transmitted herpesvirus infections and acquired immunodeficiency syndrome (AIDS) have been making headlines, there recently have been some equally dramatic developments in connection with the continuing gonorrhea pandemic. The latest concerns spectinomycin hydrochlorideresistant, penicillinase-producing Neisseria gonorrhoeae (PPNG), a double-trouble strain first seen clinically less than two years ago. For what is believed to be the first time, there is confirmation that this doubly resistant organism can be transmitted person-to-person. Such transmission occurred between prostitutes and eight American servicemen stationed in the Pacific (where, in a separate study, a gonorrhea vaccine trial began this year with US military volunteers). Until transmissability was documented, a key question was whether such multiply resistant gonorrhea strains somehow evolved in the already infected host or were transmitted as part of the gonococcal infection. The first time the doubly resistant infection was reported was in late spring of 1981. The patient was a 20-year-old man