Molecular Characterization and Antimicrobial Resistance in Neisseria gonorrhoeae,Nunavut Region of Inuit Nunangat,Canada, 2018–2019

We assessed antimicrobial resistance (AMR) in Neisseria gonorrhoeae in Nunavut, Canada, using remnant gonorrhea nucleic acid amplification test–positive urine specimens. This study confirms the feasibility of conducting N. gonorrhoeae AMR surveillance and highlights the diversity of gonococcal sequence types and geographic variation of AMR patterns in the territory.     

Data and product needs for influenza immunization programs in low- and middle-income countries: Rationale and main conclusions of the WHO preferred product characteristics for next-generation influenza vaccines

In 2017, WHO convened a working group of global experts to develop the Preferred Product Characteristics (PPC) for Next-Generation Influenza Vaccines. PPCs are intended to encourage innovation in vaccine development. They describe WHO preferences for parameters of vaccines, in particular their indications, target groups, implementation strategies, and clinical data needed for assessment of safety and efficacy. PPCs are shaped by the global unmet public health need in a priority disease area for which WHO encourages vaccine development. These preferences reflect WHO’s mandate to promote the development of vaccines with high public health impact and suitability in Low- and Middle-Income Countries (LMIC). The target audience is all entities intending to develop or to achieve widespread adoption of a specific influenza vaccine product in these settings. The working group determined that existing influenza vaccines are not well suited for LMIC use. While many developed country manufactures and research funders prioritize influenza vaccine products for use in adults and the elderly, most LMICs do not have sufficiently strong health systems to deliver vaccines to these groups. Policy makers from LMICs are expected to place higher value on vaccines indicated for prevention of severe illness, however the clinical development of influenza vaccines focuses on demonstrating prevention of any influenza illness. Many influenza vaccine products do not meet WHO standards for programmatic suitability of vaccines, which introduces challenges when vaccines are used in low-resource settings. And finally, current vaccines do not integrate well with routine immunization programs in LMICs, given age of vaccine licensure, arbitrary expiration dates timed for temperate country markets, and the need for year-round immunization in countries with prolonged influenza seasonality. While all interested parties should refer to the full PPC document for details, in this article we highlight data needs for new influenza vaccines to better demonstrate the value proposition in LMICs.     

Biological feasibility and importance of a gonorrhea vaccine for global public health

There is a growing public health interest in controlling sexually transmitted infections (STIs) through vaccination due to increasing recognition of the global disease burden of STIs and the role of STIs in women’s reproductive health, adverse pregnancy outcomes, and the health and well-being of neonates. Neisseria gonorrhoeae has historically challenged vaccine development through the expression of phase and antigenically variable surface molecules and its capacity to cause repeated infections without inducing protective immunity. An estimated 78 million new N. gonorrhoeae infections occur annually and the greatest disease burden is carried by low- and middle-income countries (LMIC). Current control measures are clearly inadequate and threatened by the rapid emergence of antibiotic resistance. The gonococcus now holds the status of “super-bug” as there is currently no single reliable monotherapy for empirical treatment of gonorrhea. The problem of antibiotic resistance has elevated treatment costs and necessitated the establishment of large surveillance programs to track the spread of resistant strains. Here we review the need for a gonorrhea vaccine with respect to global disease burden and related socioeconomic and treatment costs, with an emphasis on the impact of gonorrhea on women and newborns. We also highlight the challenge of estimating the impact of a gonorrhea vaccine due to the need for more data on the burden of gonococcal pelvic inflammatory disease and related sequelae and of gonorrhea-associated adverse pregnancy outcomes and the problem of empirical diagnosis and treatment of STIs in LMIC. There is also a lack of clinical and basic science research in the area of gonococcal/chlamydia coinfection, which occurs in a high percentage of individuals with gonorrhea and should be considered when testing the efficacy of gonorrhea vaccines. Finally, we review recent research that suggests a gonorrhea vaccine is feasible and discuss challenges and research gaps in gonorrhea vaccine development.     

The potential impact of vaccination on the prevalence of gonorrhea

Gonorrhea, one of the most common sexually transmitted infections worldwide, can lead to serious sequelae, including infertility and increased HIV transmission. Recently, untreatable, multidrug-resistant Neisseria gonorrhoeae strains have been reported. In the absence of new antibiotics, and given the speed with which resistance has emerged to all previously used antibiotics, development of a vaccine would be the ideal solution to this public health emergency. Understanding the desired characteristics, target population, and expected impact of an anti-gonococcal vaccine is essential to facilitate vaccine design, assessment and implementation. The modeling presented herein aims to fill these conceptual gaps, and inform future gonococcal vaccine development. Using an individual-based, epidemiological simulation model, gonococcal prevalence was simulated in a heterosexual population of 100,000 individuals after the introduction of vaccines with varied efficacy (10–100%) and duration of protection (2.5–20 years). Model simulations predict that gonococcal prevalence could be reduced by at least 90% after 20 years, if all 13-year-olds were given a non-waning vaccine with 50% efficacy, or a vaccine with 100% efficacy that wanes after 7.5 years. A 40% reduction in prevalence is achievable with a non-waning vaccine of only 20% efficacy. We conclude that a vaccine of moderate efficacy and duration could have a substantive impact on gonococcal prevalence, and disease sequelae, if coverage is high and protection lasts over the highest risk period (i.e., most sexual partner change) among young people.     

The global roadmap for advancing development of vaccines against sexually transmitted infections: Update and next steps

In 2014, the World Health Organization, the US National Institutes of Health, and global technical partners published a comprehensive roadmap for development of new vaccines against sexually transmitted infections (STIs). Since its publication, progress has been made in several roadmap activities: obtaining better epidemiologic data to establish the public health rationale for STI vaccines, modeling the theoretical impact of future vaccines, advancing basic science research, defining preferred product characteristics for first-generation vaccines, and encouraging investment in STI vaccine development. This article reviews these overarching roadmap activities, provides updates on research and development of individual vaccines against herpes simplex virus, Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum, and discusses important next steps to advance the global roadmap for STI vaccine development.     

Report on eighth WHO meeting on development of influenza vaccines that induce broadly protective and long-lasting immune responses: Chicago,USA, 23–24 August 2016

In August 2016, the World Health Organization (WHO) convened the “Eighth meeting on development of influenza vaccines that induce broadly protective and long-lasting immune responses” to discuss the regulatory requirements and pathways for licensure of next-generation influenza vaccines, and to identify areas where WHO can promote the development of such vaccines. Participants included approximately 120 representatives of academia, the vaccine industry, research and development funders, and regulatory and public health agencies. They reviewed the draft WHO preferred product characteristics (PPCs) of vaccines that could address prioritized unmet public health needs and discussed the challenges facing the development of such vaccines, especially for low- and middle-income countries (LMIC). They defined the data desired by public-health decision makers globally and explored how to support the progression of promising candidates into late-stage clinical trials and for all countries. This report highlights the major discussions of the meeting.     

Understanding the public health value and defining preferred product characteristics for therapeutic human papillomavirus (HPV) vaccines: World Health Organization consultations,October 2021—March 2022

The World Health Organization (WHO) global strategy to eliminate cervical cancer (CxCa) could result in >62 million lives saved by 2120 if strategy targets are reached and maintained: 90% of adolescent girls receiving prophylactic human papillomavirus (HPV) vaccine, 70% of women receiving twice-lifetime cervical cancer screening, and 90% of cervical pre-cancer lesions and invasive CxCa treated. However, the cost and complexity of CxCa screening and treatment approaches has hampered scale-up, particularly in low- and middle-income countries (LMICs), and new approaches are needed. Therapeutic HPV vaccines (TxV), which could clear persistent high-risk HPV infection and/or cause regression of pre-cancerous lesions, are in early clinical development and might offer one such approach. During October 2021 to March 2022, WHO, in collaboration with the Bill and Melinda Gates Foundation, convened a series of global expert consultations to lay the groundwork for understanding the potential value of TxV in the context of current CxCa prevention efforts and for defining WHO preferred product characteristics (PPCs) for TxV. WHO PPCs describe preferences for vaccine attributes that would help optimize vaccine value and use in meeting the global public health need. This paper reports on the main discussion points and findings from the expert consultations. Experts identified several ways in which TxV might address challenges in current CxCa prevention programmes, but emphasized that the potential value of TxV will depend on their degree of efficacy and how quickly they can be developed and implemented relative to ongoing scale-up of existing interventions. Consultation participants also discussed potential use-cases for TxV, important PPC considerations (e.g., vaccine indications, target populations, and delivery strategies), and critical modelling needs for predicting TxV impact and cost-effectiveness.     

Meeting report: Initial World Health Organization consultation on herpes simplex virus (HSV) vaccine preferred product characteristics,March 2017

The development of vaccines against herpes simplex virus (HSV) is an important global goal for sexual and reproductive health. A key priority to advance development of HSV vaccines is the definition of preferred product characteristics (PPCs), which provide strategic guidance on World Health Organization (WHO) preferences for new vaccines, specifically from a low- and middle-income country (LMIC) perspective. To start the PPC process for HSV vaccines, the WHO convened a global stakeholder consultation in March 2017, to define the priority public health needs that should be addressed by HSV vaccines and discuss the key considerations for HSV vaccine PPCs, particularly for LMICs. Meeting participants outlined an initial set of overarching public health goals for HSV vaccines in LMICs, which are: to reduce the acquisition of HIV associated with HSV-2 infection in high HIV-prevalence populations and to reduce the burden of HSV-associated disease, including mortality and morbidity due to neonatal herpes and impacts on sexual and reproductive health. Participants also considered the role of prophylactic versus therapeutic vaccines, whether both HSV-2 and HSV-1 should be targeted, important target populations, and infection and disease endpoints for clinical trials. This article summarizes the main discussions from the consultation.     

Genomic Epidemiology of Azithromycin-Nonsusceptible Neisseria gonorrhoeae,Argentina, 2005–2019

Azithromycin-nonsusceptible Neisseria gonorrhoeae strains are an emerging global public health threat. During 2015–2018, the prevalence of azithromycin-nonsusceptible gonococcal infection increased significantly in Argentina. To investigate the genomic epidemiology and resistance mechanisms of these strains, we sequenced 96 nonsusceptible isolates collected in Argentina during 2005–2019. Phylogenomic analysis revealed 2 main clades, which were characterized by a limited geographic distribution, circulating during January 2015–November 2019. These clades included the internationally spreading multilocus sequence types (STs) 1580 and 9363. The ST1580 isolates, which had MICs of 2–4 μg/mL, had mutations in the 23S rRNA. The ST9363 isolates, which had MICs of 2–4 or >256 μg/mL, had mutations in the 23S rRNA, a mosaic mtr locus, or both. Identifying the geographic dissemination and characteristics of these predominant clones will guide public health policies to control the spread of azithromycin-nonsusceptible N. gonorrhoeae in Argentina.     

Design and immune characterization of a novel Neisseria gonorrhoeae DNA vaccine using bacterial ghosts as vector and adjuvant

Gonorrhea, an important sexually transmitted disease, is becoming a growing public health problem around the globe. Vaccination is considered the best long-term approach for control of infection. In this study, we designed a novel Neisseria gonorrhoeae (N. gonorrhoeae) DNA vaccine delivered by bacterial ghosts and characterized its immune responses in vitro and in vivo. Our results demonstrate that bacterial ghosts greatly promoted BMDCs maturation and activation. Bacterial ghosts loaded with N. gonorrhoeae DNA vaccine were efficiently taken up by mouse macrophage RAW264.7 cells. Furthermore, oral immunization with the ghost vaccine candidate elicited greater CD4⁺ and CD8⁺ T cell responses and induced higher IgG responses than N. gonorrhoeae DNA vaccine alone. In addition, mice immunized with the vaccine candidate responded with a significant rise in bactericidal antibody titer. These results suggest that bacterial ghosts may function as a vaccine adjuvant by promoting BMDCs maturation, which in turn enhances the immune responses to the vaccine antigens. This study also highlights the potential of using bacterial ghosts as antigen delivery system in the development of an efficacious gonorrhea vaccine.     

WHO working group meeting to develop WHO Recommendations to assure the quality,safety and efficacy of enterovirus 71 vaccines

Enterovirus A71 (EV71) is one of the major causative agents of hand, foot and mouth disease (HFMD), and is sometimes associated with severe central nervous system syndromes. Vaccines against EV71 infection have been developed or are in development in several countries and few have been licensed in China. In response to requests from some of these countries, WHO convened a working group meeting in Shanghai China from 11 to 12 September 2019 to develop WHO Recommendations to assure the quality, safety and efficacy of EV71 vaccines. Meeting participants included members of the drafting group, experts from vaccine developers, manufacturers, regulators and academia. The epidemiology of EV71, as well as the development, regulation and standardization of EV71 vaccines were reviewed in the meeting. Information on R&D, manufacturing, quality control and standardization of EV71 vaccines was presented by vaccine developers, manufacturers and regulators. Based on their experience, the working group discussed the main principles that would determine WHO’s position on quality, safety and efficacy of EV71 vaccines. The working group agreed to develop WHO Recommendations to assure the quality, safety and efficacy of inactivated EV71 vaccines with a scope covering only whole virus inactivated vaccines. Other type of vaccines, such as EV71 virus-like particles (VLPs) will not be covered as they are still at the developmental stage. The outline of the document was agreed and will follow the usual style of WHO recommendations. It was also agreed to submit the draft Recommendations for review and adoption to the WHO ECBS in 2020 following discussion at a WHO informal consultation, which will include NRAs and vaccine manufacturers.     

Design of a multi-epitope protein vaccine against herpes simplex virus,human papillomavirus and Chlamydia trachomatis as the main causes of sexually transmitted diseases

Sexually transmitted diseases (STDs) have a profound effect on reproductivity and sexual health worldwide. According to world health organization (WHO) 375 million new case of STD, including chlamydia trachomatis (chlamydia), Neisseria gonorrhoeae, HSV, HPV has been reported in 2016. More than 30 diverse pathogenesis have identified to be transmitted through sexual intercourse. Of these, viral infections (hepatitis B, herpes simplex virus (HSV or herpes), HIV, and human papillomavirus (HPV) are incurable. However, symptoms caused by the incurable viral infections can be alleviated through treatment. Antimicrobial resistance (AMR) of sexually transmitted infections (STIs) to antibiotics has increased recent years, in this regard, vaccination is proposed as an important strategy for prevention or treatment of STDs. Vaccine against HPV 16 and 18 suggests a new approach for controlling STDs but until now, there is no prophylactic or therapeutic vaccine have been approved for HSV-2 and Chlamydia trachomatis (CT); in this reason, developing an efficient vaccine is inevitable. Recently, different combinatorial forms of subunit vaccines against two or three type of bacteria have been designed.In this study, to design a combinatorial vaccine against HSV, CT, and HPV, the E7 and L2 from HPV, glycoprotein D from HSV-2 and ompA from CT were selected as final antigens. Afterward, the immunodominant helper T lymphocytes (HTLs) and cytolytic T lymphocytes (CTLs) epitopes were chosen from aforesaid antigens. P30 (tetanus toxoid epitope) as universal T-helper were also added to the vaccine. Moreover, flagellin D_1/D₀ as TLR5 agonist and the RS09 as a TLR4 ligand were incorporated to N and C-terminals of peptide vaccine, respectively. Finally, all selected parts were fused together by appropriate linkers to enhance vaccine efficiency. The physicochemical, structural, and immunological properties of the designed vaccine protein were assessed. To achieve the best 3D model of the protein vaccine, modeling, refinement, and validation of modeled structures were also done. Docking evaluation demonstrated suitable interaction between the vaccine and TLR5. Moreover, molecular dynamics (MD) studies showed an appropriate and stable structure of protein and TLR5. Based on immunoinformatic analysis, our vaccine candidate could potentially incite humoral and cellular immunities, which are critical for protection against HPV, HSV-2, and chlamydia trachomatis. It should be noted that, experimental studies are needed to confirm the efficacy of the designed vaccine.     

The potential impact of a vaccine on Neisseria gonorrhoeae prevalence among heterosexuals living in a high prevalence setting

BackgroundTreatment of Neisseria gonorrhoeae is under threat with the emergence and spread of antimicrobial resistance. Thus, there is a growing interest in the development of a gonorrhoea vaccine. We used mathematical modelling to assess the impact of a hypothetical vaccine in controlling gonorrhoea among heterosexuals living in a setting of relatively high N. gonorrhoeae prevalence (∼3 %).MethodsWe developed a mathematical model of N. gonorrhoeae transmission among 15–49-year-old heterosexuals, stratified by age and sex, and calibrated to prevalence and sexual behaviour data from South Africa as an example of a high prevalence setting for which we have data available. Using this model, we assessed the potential impact of a vaccine on N. gonorrhoeae prevalence in the entire population. We considered gonorrhoea vaccines having differing impacts on N. gonorrhoeae infection and transmission and offered to different age-groups.ResultsThe model predicts that N. gonorrhoeae prevalence can be reduced by ∼50 % in 10 years following introduction of a vaccine if annual vaccination uptake is 10 %, vaccine efficacy against acquisition of infection is 25 % and duration of protection is 5 years, with vaccination available to the entire population of 15–49-year-olds. If only 15–24-year-olds are vaccinated, the predicted reduction in prevalence in the entire population is 25 % with equivalent vaccine characteristics and uptake. Although predicted reductions in prevalence for vaccination programmes targeting only high-activity individuals and the entire population are similar over the same period, vaccinating only high-activity individuals is more efficient as the cumulative number of vaccinations needed to reduce prevalence in the entire population by 50 % is ∼3 times lower for this programme.ConclusionProvision of a gonorrhoea vaccine could lead to substantial reductions in N. gonorrhoeae prevalence in a high prevalence heterosexual setting, even with moderate annual vaccination uptake of a vaccine with partial efficacy.     

Priorities in research and development of vaccines against Plasmodium vivax malaria

The WHO Initiative for Vaccine Research (IVR) Malaria Vaccine Advisory Committee (MALVAC) provides advice to WHO on priorities in malaria vaccine research and development (R&D). This document summarizes a MALVAC scientific consultation of leading vaccine scientists on priorities in Plasmodium vivax vaccine R&D. The meeting discussed recent advances and key challenges in addressing identified gaps in knowledge. Major areas of discussion included disease burden estimates, clinical disease spectrum definitions, potential target product profiles and immunological and clinical research needed to better inform antigen selection and vaccine design. The need for further development of the human challenge model for P. vivax vaccines and specific considerations for conduct of field trials with P. vivax vaccines was outlined. This report summarizes the discussion and conclusions of the consultation, with recommendations for priority targeted research.     

Prospects and challenges with introduction of a mono-valent meningococcal conjugate vaccine in Africa

Epidemic meningococcal meningitis is a priority disease for prevention and control in Africa. The current World Health Organization (WHO) approach to the control of meningitis epidemics is based on early detection of cases and emergency vaccination of the population at risk with meningococcal polysaccharide (PS) vaccines. But this is a tall order for the developing nations of Africa where experts operate from an ineffective health system. Although the widespread use of meningococal polysaccharide vaccines has had a major and much appreciated public health impact on the disease it has not prevented epidemics of this dreaded infection. The current partnership between WHO and the PATH aims to develop, evaluate and introduce an appropriate and affordable meningococcal conjugate vaccine that could potentially provide for a means of preventing epidemic meningitis caused by N. meningitidis group A. In this paper, we review the prospects and challenges facing the introduction of the mono-valent conjugate vaccine in Africa.     

Challenges and opportunities in developing a Shigella-containing combination vaccine for children in low- and middle-income countries: Report of an expert convening

The gram-negative bacterium Shigella is an enteric pathogen responsible for significant morbidity and mortality due primarily to severe diarrhea and dysentery, mainly among children younger than five years of age living in low- and middle-income countries (LMICs). Long considered a priority target for vaccine development, recent scientific advances have led to a number of promising Shigella vaccine candidates now entering advanced stages of clinical testing. Yet, there is no guarantee that even a highly efficacious Shigella vaccine will be recommended, prioritized, purchased, and widely adopted—especially if it requires additional doses in the immunization schedule and/or visits within the immunization program. This uncertainty is due to a variety of factors, including continuing declines in Shigella-specific and overall diarrheal disease mortality rates, the increasing complexity and cost of infant immunization programs in LMICs, and the recent availability of other high-priority vaccines. Since combining a Shigella vaccine with an existing infant vaccine would conceivably increase its attractiveness, there is a need to systematically consider the challenges determining the public health value, clinical development, manufacturing, licensure, policy recommendations, and financing for a Shigella-containing combination vaccine.The international non-governmental health organization PATH convened an independent panel of 34 subject matter experts across academic, industry, philanthropic, and global health sectors to discuss hypothetical combinations of a notional parenteral Shigella vaccine with three existing vaccines in order to begin exploring the challenges associated with their development. The resulting insights and recommendations from this meeting contribute to PATH’s broader effort to evaluate the public health value of potential Shigella vaccines. They may also help guide future combination vaccine development efforts more broadly.     

Gonorrheal Infection,Pelvic Inflammatory Disease and Spinal Disability

Gonorrheal infection is an important sexually transmitted disease. Neisseria gonorrhoeae is responsible for about one-third to one-half of cases of acute pelvic inflammatory disease (PID). Spinal osteochondrosis is an important complication of chronic gonococcal PID. Rehabilitative intervention plays an important role for coping with this condition. In addition to gonococcal PID, congenital gonorrhea and gonococcal prostatitis are the other two important conditions that relate to spinal disability.     

Determinations of the sensitivity of Neisseria gonorrhoeae to penicillin performed on solid media of different composition

The increasing frequency of strains of Neisseria gonorrhoeae with reduced sensitivity to penicillin is making it more and more important to determine the sensitivity of individual strains before and after treatment with this antibiotic. It was recently demonstrated that the concentrations of penicillin inhibitory to Neisseria gonorrhoea depend upon the medium employed. This important observation made it desirable to have available for interlaboratory comparisons a non-commercial reproducible medium which would support the growth of the vast majority of the gonococcal strains in circulation. Using a plate dilution procedure, various modifications of the HYL medium described elsewhere were compared with the routine medium for carrying out sensitivity determinations. Both stock and fresh strains of Neisseria gonorrhoeae were used in the experiments. The 50% inhibitory concentrations observed on the two media did not differ to any great extent, being only about 40% higher on the routine medium than on the HYL medium. The difference between the HYL medium and the routine medium was somewhat greater for the less sensitive strains than for the more sensitive strains. The variations in the difference from strain to strain were larger for the more sensitive fresh strains than for the less sensitive strains and the stock strains. This observation limits the value of a correction method employing, for example, three reference strains as a means of ensuring comparability between the results of different laboratories.     

Vaccines against Neisseria meningitidis serogroup B strains – What does genomics reveal on the Portuguese strain’s coverage

In Portugal, Neisseria meningitidis serogroup B (MenB) is the most common serogroup causing invasive meningococcal disease. To protect against MenB disease two protein based MenB vaccines are available in Portugal, the 4CMenB that was licenced in 2014 and included in the routine immunization program in October 2020, and the bivalent rLP2086 vaccine licensed in 2017. The aim of this study was to predict the coverage of the 4CMenB and rLP2086 vaccines against Portuguese isolates of Neisseria meningitidis sampled between 2012 and 2019 and to evaluate the diversity of vaccine antigens based on genomic analysis.Whole-genome sequence data from 324 Portuguese Neisseria meningitidis isolates were analysed. To predict strain coverage by 4CMenB and rLP2086, vaccine antigen reactivity was assessed using the MenDeVar index available on the PubMLST Neisseria website.This study included 235 (75.6%) MenB isolates of all invasive MenB strains reported between 2012 and 2019. Moreover, 89 non MenB isolates sampled in the same period, enrolling 68 from invasive disease and 21 from healthy carriers, were also studied.The predicted strain coverage of MenB isolates was 73.5% (95% CI: 64.8%–81.2%) for 4CMenB and 100% for rLP2086. Predicted strain coverage by 4CMenB in the age group from 0 to 4 years old, was 73.9%. Most of MenB isolates were covered by a single antigen (85.4%), namely fHbp (30.3%), P1.4 (29.2%), and NHBA (24.7%).In Portugal, the most prevalent peptides in MenB isolates were: P1.4 (16.2%), NHBA peptide 2 (14.0%), and fHbp peptide 14 (7.2%), from 4CMenB and fHbp peptide 19 (10.6%) from rLP2086. No significant temporal trends were observed concerning the distribution and diversity of vaccine antigen variants.4CMenB and rLP2086 vaccines showed potential coverage for isolates regardless serogroup.The use of both vaccines should be considered to control possible outbreaks caused by serogroups with no vaccine available.