Urgent Need to Understand and Prevent Gonococcal Infection: From the Laboratory to Real-World Context.

Neisseria gonorrhoeae is widespread globally. Primary prevention is unsuccessful and antimicrobial resistance threatens optimal management. There is no specific vaccine and natural infection studies show that N. gonorrhoeae can avoid and suppress immune responses. In addition to extensive variation in expression and specificity of many gonococcal surface antigens, it induces a robust inflammatory response through the Th17 pathway with a large influx of neutrophils and inflammatory cytokines but evades macrophages. The Th1- and Th2-mediated response is suppressed, resulting in low, short-lived antibody titers. Real-world evidence suggests that gonorrhea cases are reduced among recipients of N. meningitidis group B vaccines containing outer membrane vesicles (OMV). Although the first randomized trial of an OMV-containing MenB vaccine against N. gonorrhoeae infection did not show statistically significant vaccine efficacy, ongoing trials might shed further light. Several candidate vaccine antigens for a gonococcal-specific vaccine are being evaluated preclinically but only one has reached clinical trials.

Range of invasive meningococcal disease sequelae and health economic application - a systematic and clinical review.

BACKGROUND: Invasive meningococcal disease (IMD) is uncommon, life-threatening, with many diverse sequelae. The aims were to: 1) comprehensively characterise the sequelae; 2) have a systematic application for sequelae impact in economic evaluation (EE). METHODS: Sequelae categorised as physical/neurological or psychological/behavioural were identified from a systematic review of IMD observational studies (OS) and EEs in high-income countries (published 2001-2020). A comprehensive map and EE-relevant list, respectively, included physical/neurological sequelae reported in ≥2OS and ≥ 2OS + 2EE (≥1OS and ≥ 1OS + 1EE for psychological/behavioural). Sequelae proportions were selected from the highest quality studies reporting most sequelae. Three medical experts independently evaluated the clinical impact of findings. RESULTS: Sixty-Six OS and 34 EE reported IMD sequelae. The comprehensive map included 44 sequelae (30 physical/neurological, 14 psychological/behavioural), of which 18 (14 physical/neurological and 4 psychological/behavioural) were EE-relevant. Experts validated the study and identified gaps due to limited evidence, underreporting of psychological/behavioural sequelae in survivors/their families, and occurrence of multiple sequelae in the acute phase and long-term. CONCLUSIONS: The considerable burden of IMD sequelae on survivors and their families is potentially underestimated in EE, due to underreporting and poorly-defined subtle sequelae. When assessing IMD burden and potential interventions e.g., vaccination, sequelae range and duration, underreporting, and indirect burden on dependents should be considered.

Untapped Opportunities of Resin-to-Resin Transfer Reactions (RRTR) for the Convergent Assembly of Multivalent Peptide Conjugates.

Handling of the individual fragments remains a bottleneck in the convergent assembly of peptides. Overlooked since the emergence of ligation chemistries during the past two decades, so-called resin-to-resin transfer reactions (RRTR) are here described as a strategic shortcut in this context. Condensation of the involved moieties at an acceptor resin is facilitated by shuttling peptide segments directly from a donor resin in a one-pot fashion. The straightforward synthesis of a sterically constrained 13-mer peptidosteroid model illustrates the utility of this approach, presenting the first successful application of the RRTR methodology in the field of multivalent design and bioconjugation. Relying on established procedures to generate, monitor and isolate intermediates and products, the solid-phase nature of the entire strategy allows for the fast construction of polypeptide adducts and libraries thereof. As such, a rejuvenated use and new opportunities for RRTR are reported.

Stapling monomeric GCN4 peptides allows for DNA binding and enhanced cellular uptake.

The basic DNA recognition region of the GCN4 protein comprising 23 amino acids has been modified to contain two optimally positioned cysteines which have been linked and stapled using cross-linkers of suitable lengths. This results in stapled peptides with a stabilized α-helical conformation which allows for DNA binding and concurrent enhancement of cellular uptake.

Cyclodextrin-peptide conjugates for sequence specific DNA binding.

Synthetic models of bZIP transcription factors have been developed with the capability of specific DNA recognition. Our design is based on the CuAAC mediated conjugation of basic region Leucine Zipper peptides to different derivatives of α, ß and γ-cyclodextrins equipped with azide functionalities. Thorough optimization of reaction conditions allowed convergent and simultaneous conjugation of two long unprotected cationic peptides to cyclodextrin-bis azide derivatives. The resulting constructs were shown to specifically recognize their cognate DNA sequence with nM affinities. In comparison with previously developed TF models, the derivatives described here combine the enhanced DNA binding capabilities with an easy and convergent synthetic route.

Water-soluble NHC-Cu catalysts: applications in click chemistry, bioconjugation and mechanistic analysis.

Copper(I)-catalyzed 1,3-dipolar cycloaddition of azides and terminal alkynes (CuAAC), better known as "click" reaction, has triggered the use of 1,2,3-triazoles in bioconjugation, drug discovery, materials science and combinatorial chemistry. Here we report a new series of water-soluble catalysts based on N-heterocyclic carbene (NHC)-Cu complexes which are additionally functionalized with a sulfonate group. The complexes show superior activity towards CuAAC reactions and display a high versatility, enabling the production of triazoles with different substitution patterns. Additionally, successful application of these complexes in bioconjugation using unprotected peptides acting as DNA binding domains was achieved for the first time. Mechanistic insight into the reaction mechanism is obtained by means of state-of-the-art first principles calculations.

Reduced reactogenicity of primary vaccination with DT3aP-HBV-IPV/Hib compared with DT2aP-HBV-IPV-Hib among infants: Mathematical projections in six countries.

The hexavalent vaccines DT3aP-HBV-IPV/Hib and DT2aP-HBV-IPV-Hib are routinely used for primary immunization of infants against diphtheria, tetanus, pertussis, hepatitis B virus, poliomyelitis, and Haemophilus influenzae type b. A recent publication showed that after primary immunization with these vaccines, the odds ratios of adverse reactions (ARs) were significantly lower for DT3aP-HBV-IPV/Hib than for DT2aP-HBV-IPV-Hib. Our aim is to understand the impact of the various reactogenicity profiles at country level by comparing the ARs induced by one dose of DT3aP-HBV-IPV/Hib versus DT2aP-HBV-IPV-Hib in the primary infant immunization course. A mathematical projection tool was developed to simulate vaccination of infants with both vaccines in six countries: Austria, the Czech Republic, France, Jordan, Spain, and the Netherlands. Proportions of three local and five systemic ARs of interest for both vaccines were based on findings from a previous meta-analysis of ARs in infants. The absolute risk reductions calculated ranged from 3.0% (95% confidence interval [CI]: 2.8%-3.2%) for "Swelling at the injection site, any grade" to 10.0% (95% CI: 9.5%-10.5%) for "Fever, any grade." The difference in occurrence of the AR "Fever, any grade" between vaccines in 2020 ranged from over 7,000 in Austria to over 62,000 in France. Over 5 years, this would amount to a reduction of over 150,000 ARs in Austria and over 1.4 million ARs in France when using DT3aP-HBV-IPV/Hib instead of DT2aP-HBV-IPV-Hib. In conclusion, the estimated numbers of ARs following hexavalent vaccination in six countries showed that vaccination of infants with DT3aP-HBV-IPV/Hib could lead to fewer ARs than vaccination with DT2aP-HBV-IPV-Hib.

Vaccination of infants against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, and Haemophilus influenzae type b is often performed with combined vaccines against these six diseases. In many countries, these are the first vaccinations received by infants, and potential adverse reactions could affect compliance with future vaccinations. A previous study examined two of the combined vaccines, DT3aP-HBV-IPV/Hib and DT2aP-HBV-IPV-Hib, and showed that local adverse reactions at the injection site (pain, redness, and swelling) and general adverse reactions (fever, drowsiness, irritability, persistent crying, and lack of appetite) were less common after vaccination with DT3aP-HBV-IPV/Hib than with DT2aP-HBV-IPV-Hib.To understand the impact of this finding at a population level, we compared the adverse reactions caused by the hypothetical administration of the two vaccines under similar conditions. We simulated the vaccination of infants with both vaccines in six countries: Austria, the Czech Republic, France, Jordan, Spain, and the Netherlands.The simulation showed that the DT3aP-HBV-IPV/Hib vaccine could reduce cases of swelling at the injection site by 3% and fever by 10%. For the year 2020, the resulting reduction in the estimated number of fever occurrences would have ranged from over 7,000 in Austria to over 62,000 in France. In total, adverse reactions avoided could hypothetically have ranged from 30,781 in Austria to 269,025 in France. Over 5 years, this could have avoided an estimated number of adverse reactions of over 150,000 in Austria to over 1.4 million in France. In conclusion, such a switch of vaccine could substantially reduce adverse reactions.

Pandemic's influence on parents' attitudes and behaviors toward meningococcal vaccination.

Invasive meningococcal disease is a life-threatening infection preventable through vaccination. Pediatric vaccination rates have declined during the coronavirus disease 2019 (COVID-19) pandemic. This survey aimed to understand how parents' attitudes and behaviors have changed during the pandemic with regard to immunization and, more specifically, meningococcal vaccination. An online survey was emailed to parents of eligible children 0-4 years, following the selection process from UK, France, Germany, Italy, Brazil, Argentina, and Australia; and of adolescents 11-18 years from US. Data collection took place 19 January-16 February 2021. Quotas were set to ensure a representative sample. Eleven questions relating to general perceptions around vaccination and attitudes and behaviors toward meningitis vaccination were displayed. On 4,962 parents (average 35 years) participating in the survey, most (83%) believed important for their child to continue receiving recommended vaccines during the COVID-19 pandemic. Nearly half of routine vaccine appointments were delayed or canceled due to the pandemic, and 61% of respondents were likely to have their children catch up once COVID-19 restrictions were lifted. 30% of meningitidis vaccination appointments were canceled or delayed during the pandemic, and 21% of parents did not intend to reschedule them because of lockdown/stay at home regulations, and fear of catching COVID-19 in public places. It is crucial to communicate clear instructions to health workers and the general population and to provide appropriate safety precautions in vaccination centers. This will help to maintain vaccination rates and limit infections to prevent future outbreaks.

What is the context? Invasive meningococcal disease (IMD) is an uncommon infection that can lead to permanent disabilities and even death.Meningitis vaccination can prevent IMDs caused by Neisseria meningitidis.Vaccination rates have declined during the coronavirus (COVID-19) pandemic.What is new? We collected opinion of parents from the UK, France, Germany, Italy, Brazil, Argentina, Australia, and the US, to understand their attitudes and behaviors toward meningitis vaccination during the COVID-19 pandemic.Results were reviewed by health care professional experts as well as by patient authors (IMD survivors).Most (83%) of the 4,962 parents believed that it is important for their child to continue receiving recommended vaccines during the COVID-19 pandemic.Half of the scheduled appointments for meningitis vaccination were canceled or delayed during the COVID-19 pandemic, mainly due to lockdown regulations and fear of catching COVID-19.Twenty-one percent of the parents who had their child's meningitis vaccination appointment canceled, did not intend to reschedule it.What is the impact? It is crucial that clear information is communicated by health care authorities and practitioners about the availability of vaccination during pandemic and the safety precautions that are taken.Collected opinions emphasize the importance of continuing vaccinations against infectious diseases during a pandemic.

A Decade of Fighting Invasive Meningococcal Disease: A Narrative Review of Clinical and Real-World Experience with the MenACWY-CRM Conjugate Vaccine.

The quadrivalent A, C, W and Y meningococcal vaccine conjugated to nontoxic mutant of diphtheria toxin (MenACWY-CRM) has been licensed since 2010 for the prevention of invasive meningococcal disease (IMD), an uncommon but life-threatening condition. Here, we summarize the experience accrued with MenACWY-CRM during the first decade since its licensure, by providing an overview of clinical trials investigating the safety, immunogenicity and co-administration of MenACWY-CRM with other vaccines as well as presenting real-world evidence regarding the impact of MenACWY-CRM vaccination on carriage and IMD incidence. MenACWY-CRM has demonstrated an acceptable clinical safety profile across a wide range of age groups; no safety concerns have been reported in special populations, such as immunocompromised infants and toddlers, or pregnant women. MenACWY-CRM has also been proven to be immunogenic in various age groups and geographic settings, and a booster dose has been shown to elicit strong anamnestic responses in all studied populations, irrespective of the vaccine used for priming. With no clinically relevant vaccine interactions reported, MenACWY-CRM is being conveniently integrated into existing vaccination programs for various age and risk groups; this possibility of co-administration helps improving vaccine coverage and streamlining the healthcare process of fighting preventable infectious diseases. Vaccination of adolescents and adults has been proven to reduce nasopharyngeal carriage for serogroups C, W and Y, which is an important element in reducing transmission. Real-world evidence indicates that MenACWY-CRM can reduce IMD incidence even in high-exposure groups. When combined with vaccines against serogroup B meningococci, MenACWY-CRM can offer protection against five of the most common serogroups responsible for IMD, which is an important advantage in the continuously evolving landscape of meningococcal serogroup epidemiology.

Invasive meningococcal disease is an uncommon but life-threatening infection that appears as meningitis and/or sepsis. It is caused by Neisseria meningitidis, a bacteria commonly present in the throat or nose. Vaccination with MenACWY-CRM (Menveo, GSK) helps to prevent invasive meningococcal disease caused by four of the most common N. meningitidis serogroups (A, C, W and Y). This vaccine has been licensed for 10 years: we summarized here all available evidence gathered since the vaccine has been available in general practice, from clinical development to real-world experience. Information gained during clinical trials of MenACWY-CRM confirms that vaccination is well tolerated, has an acceptable safety profile and would induce significant protection when given to individuals of various ages such as infants, toddlers, children, adolescents and adults, and when administered at the same time as routine or traveler vaccinations as well as vaccines against serogroup B meningococci (4CMenB). Vaccination with MenACWY-CRM has been shown to decrease the number of serogroup C, W and Y meningococci found in the nose and throat in adolescents and adults as well as the occurrence of invasive meningococcal disease in a high-exposure population from a real-world setting. MenACWY-CRM can conveniently be integrated into most of the existing vaccination schedules for various age and risk groups. When combined with vaccination against serogroup B meningococci, MenACWY-CRM can contribute to providing protection against five of the most common serogroups responsible for invasive meningococcal disease.

CIRCULATING CLONAL COMPLEXES AND SEQUENCE TYPES OF STREPTOCOCCUS PNEUMONIAE SEROTYPE 19A WORLDWIDE: THE IMPORTANCE OF MULTIDRUG RESISTANCE: A SYSTEMATIC LITERATURE REVIEW.

INTRODUCTION: Streptococcus pneumoniae is a major cause of morbidity and mortality, especially amongst young children and the elderly. Childhood implementation of pneumococcal conjugate vaccines (PCVs) significantly reduced the incidence of invasive pneumococcal disease (IPD), while several nonvaccine serotypes remained substantial. Although there is evidence of the impact of higher-valent PCVs on serotype 19A, 19A IPD burden and antibiotic resistance remain a major concern post-vaccination. AREAS COVERED: We performed a systematic literature review to analyze the frequency and clonal distribution of serotype 19A isolates in the pre- and post-PCV era worldwide providing a scientific background on the factors that influence multidrug resistance in pneumococcal isolates. EXPERT COMMENTARY: Serotype 19A IPD incidence increased in all regions following the introduction of the 7-valent PCV. The higher-valent PCVs have reduced the rates of 19A IPD isolates, but several circulating strains with diverse antibiotic resistance prevailed. Heterogeneous clonal distribution in serotype 19A was observed within countries and regions, irrespective of higher-valent PCV used. An increase of 19A isolates from pre- to post-vaccination periods were associated with frequently occurring serotype switching events and with the prevalence of multidrug resistant strains. Rational antibiotic policies must be implemented to control the emergence of resistance.Plain Language SummaryWhat is the context?Streptococcus pneumoniae is a major cause of pneumococcal diseases especially amongst young children and the elderly. Vaccination with pneumococcal conjugate vaccines has significantly reduced the incidence of invasive pneumococcal disease worldwide. However, the invasive pneumococcal disease remains an important health problem due to the increase of nonvaccine serotypes. Serotype 19A is predominant in many countries worldwide. Factors contributing to its prevalence include serotype replacement, the emergence of clones with multidrug resistance due to antibiotic overuse, and potential bacteria adaptation in response to the vaccine.What is new?We performed a systematic literature review to 1) analyze the incidence and clonal distribution of serotype 19A isolates pre- and post-vaccination worldwide, and to collect data evaluating antimicrobial resistance patterns displayed by the clones of serotype 19A. We found that 1) clonal distribution in serotype 19A was heterogeneous within countries and regions, irrespective of the vaccine used; 2) the diversity of 19A isolates increased after vaccination. It was associated with frequent serotype switching events and with the prevalence of multidrug resistant strains.What is the impact?Implementation of policies to educate on sustainable antibiotic use and infectious prevention measures may help control the emergence of antibiotic resistance. High-quality active surveillance and future molecular epidemiology studies are needed to understand rapid genetic changes.

Looking beyond meningococcal B with the 4CMenB vaccine: the Neisseria effect.

Infections with Neisseria meningitidis and Neisseria gonorrhoeae have different clinical manifestations, but the bacteria share up to 80-90% genome sequence identity. The recombinant meningococcal serogroup B (MenB) vaccine 4CMenB consists of four antigenic components that can be present in non-B meningococcal and gonococcal strains. This comprehensive review summarizes scientific evidence on the genotypic and phenotypic similarities between vaccine antigens and their homologs expressed by non-B meningococcal and gonococcal strains. It also includes immune responses of 4CMenB-vaccinated individuals and effectiveness and impact of 4CMenB against these strains. Varying degrees of strain coverage were estimated depending on the non-B meningococcal serogroup and antigenic repertoire. 4CMenB elicits immune responses against non-B meningococcal serogroups and N. gonorrhoeae. Real-world evidence showed risk reductions of 69% for meningococcal serogroup W clonal complex 11 disease and 40% for gonorrhea after 4CMenB immunization. In conclusion, functional antibody activity and real-world evidence indicate that 4CMenB has the potential to provide some protection beyond MenB disease.

Specific dsDNA recognition by a mimic of the DNA binding domain of the c-Myc/Max transcription factor.

We here report on the synthesis of the first mimic of the DNA binding domain of the c-Myc/Max-bHLH-ZIP transcription factor able to selectively recognize its cognate E-box sequence 5'-CACGTG-3' through the major groove of the double-stranded DNA. The designed peptidosteroid conjugate was shown to be effective as DNA binder in the presence of excess competitor DNA.

Sequence-selective DNA recognition and enhanced cellular up-take by peptide-steroid conjugates.

Several GCN4 bZIP TF models have previously been designed and synthesized. However, the synthetic routes towards these constructs are typically tedious and difficult. We here describe the substitution of the Leucine zipper domain of the protein by a deoxycholic acid derivative appending the two GCN4 binding region peptides through an optimized double azide-alkyne cycloaddition click reaction. In addition to achieving sequence specific dsDNA binding, we have investigated the potential of these compounds to enter cells. Confocal microscopy and flow cytometry show the beneficial influence of the steroid on cell uptake. This unique synthetic model of the bZIP TF thus combines sequence specific dsDNA binding properties with enhanced cell-uptake. Given the unique properties of deoxycholic acid and the convergent nature of the synthesis, we believe this work represents a key achievement in the field of TF mimicry.