The impact of human vaccines on bacterial antimicrobial resistance. A review.

At present, the dramatic rise in antimicrobial resistance (AMR) among important human bacterial pathogens is reaching a state of global crisis threatening a return to the pre-antibiotic era. AMR, already a significant burden on public health and economies, is anticipated to grow even more severe in the coming decades. Several licensed vaccines, targeting both bacterial (Haemophilus influenzae type b, Streptococcus pneumoniae, Salmonella enterica serovar Typhi) and viral (influenza virus, rotavirus) human pathogens, have already proven their anti-AMR benefits by reducing unwarranted antibiotic consumption and antibiotic-resistant bacterial strains and by promoting herd immunity. A number of new investigational vaccines, with a potential to reduce the spread of multidrug-resistant bacterial pathogens, are also in various stages of clinical development. Nevertheless, vaccines as a tool to combat AMR remain underappreciated and unfortunately underutilized. Global mobilization of public health and industry resources is key to maximizing the use of licensed vaccines, and the development of new prophylactic vaccines could have a profound impact on reducing AMR.

Evaluating the safety, tolerability, and immunogenicity of a 24-valent pneumococcal conjugate vaccine (VAX-24) in healthy adults aged 18 to 64 years: a phase 1/2, double-masked, dose-finding, active-controlled, randomised clinical trial.

BACKGROUND: Despite substantial reductions in pneumococcal disease with the availability of pneumococcal conjugate vaccines, a significant burden of pneumococcal disease remains due to the diversity of serotypes combined with serotype replacement. We developed a new vaccine candidate, VAX-24 (24-valent pneumococcal conjugate vaccine), using cell-free protein synthesis to produce a variant of cross-reactive material 197 (eCRM) as the carrier protein, increasing serotype coverage while minimising carrier suppression. The aim of this clinical trial was to assess the safety, tolerability, and immunogenicity of three different doses of VAX-24 compared to pneumococcal 20-valent conjugate vaccine (PCV20). METHODS: This was a phase 1/2, randomised, double-masked study of VAX-24 versus PCV20 conducted in the USA. Key inclusion criteria included being a male or female aged 18 to 64 years in good health; key exclusion criteria included previous history of pneumococcal disease, receipt of a licensed or investigational pneumococcal vaccine, or immunosuppressive therapy. Participants were randomly allocated in a 1:1:1:1 ratio by permuted block to receive one dose of VAX-24 (1·1 µg of each antigen, 2·2 µg of each antigen, or 2·2 µg of 17 antigens mixed with 4·4 µg of seven antigens), or PCV20. The safety population included all participants with safety data. The immunogenicity population was as per-treatment in phase 2. Primary outcome measures included solicited and unsolicited adverse events. Secondary outcomes included serotype-specific opsonophagocytic activity (OPA) geometric mean titres (GMT), and IgG geometric mean concentrations (GMC) were measured 1 month postvaccination. Traditional non-inferiority criteria included OPA geometric mean ratio (GMR), with a lower bound of the two sided 95% CI of greater than 0·5 for shared serotypes. This completed trial is registered at ClinicalTrials.gov, NCT05266456. FINDINGS: Safety profiles were comparable among the treatment groups, with 170 of 209 participants (81%, 95% CI 75·2-86·2) to 178 of 207 participants (86%, 80·5-90·4) reporting at least one solicited adverse event among the three VAX-24 groups. 24 of 207 participants (12%, 7·6-16·8) to 32 of 209 of participants (15%, 10·7-20·9) experiened an unsolicited treatment emergent adverse event within 1 month postvaccination. VAX-24 2·2 µg met traditional OPA GMR non-inferiority criteria for all 20 shared serotypes; 16 serotypes elicited GMR point estimates greater than 1·0, and four reached the lower bound of the two-sided 95% CI greater than 1·0. INTERPRETATION: VAX-24 had a safety profile similar to PCV20 at all doses, with the 2·2 µg dose showing increased serotype coverage with decreased carrier suppression. FUNDING: Vaxcyte.

Non-clinical immunological comparison of a Next-Generation 24-valent pneumococcal conjugate vaccine (VAX-24) using site-specific carrier protein conjugation to the current standard of care (PCV13 and PPV23).

Despite widespread utilization of pneumococcal conjugate vaccines (PCVs) and the resultant disease reduction, the development of PCVs containing additional serotypes remains a public health priority due to serotype replacement and the resultant shift to non-vaccine containing serotypes. However, incorporating additional serotypes to existing PCVs using conventional technologies has proven problematic. Immune responses to individual serotypes have consistently decreased as more polysaccharide-conjugates are added due to carrier suppression. Using our proprietary cell-free protein synthesis (CFPS) platform, we have successfully produced eCRM® based on the CRM197 sequence for use as an enhanced carrier protein to develop a 24-valent PCV. The eCRM carrier protein contains multiple non-native amino acids (nnAAs) located outside of the primary T-cell epitope regions, thereby enabling site-specific covalent conjugation of the pneumococcal polysaccharides to the nnAAs to consistently expose the critical T-cell epitopes. eCRM also serves to reduce structural heterogeneity associated with classic reductive-amination conjugation while promoting formation of the conjugate matrix structures, the hallmark of PCVs. This process serves to increase the overall polysaccharide:protein ratio, enabling the inclusion of more serotypes while minimizing carrier-mediated immunological interference. The aim of this non-clinical study was to construct a 24-valent PCV and evaluate its immunogenicity. Using the XPressCF® CFPS platform, the eCRM carrier protein was separately conjugated through nnAAs to each of the 24 pneumococcal polysaccharides through click chemistry and mixed with aluminum phosphate to produce VAX-24, Vaxcyte's proprietary PCV preclinical candidate. VAX-24, Prevnar13® and Pneumovax®23 were administered to New Zealand White rabbits to compare the resulting opsonophagocytic activity (OPA) and anti-capsular IgG antibodies. VAX-24 showed conjugate-like immune responses to all 24 serotypes based on comparable OPA and IgG responses to Prevnar13 and higher responses than Pneumovax 23. This study demonstrates the utility of site-specific conjugation technology in a preclinical setting and the potential for a PCV with improved serotype coverage.

MATS: Global coverage estimates for 4CMenB, a novel multicomponent meningococcal B vaccine.

Recently approved in the EU, US, Australia, and Canada, 4CMenB (Bexsero(®), GSK Vaccines) is a multi-component meningococcal B (MenB) vaccine containing 3 surface exposed recombinant proteins (fHbp, NadA, and NHBA) and New Zealand strain outer membrane vesicles (NZ OMV) containing PorA 1.4. The accepted correlate of protection to assess response to MenB vaccines, the serum bactericidal assay with human complement, is impractical for large panels of strains with diverse antigenic profile and expression. Therefore, the Meningococcal Antigen Typing System (MATS) was developed to identify MenB strains with a high likelihood of being covered by 4CMenB. MATS is used to assess MenB strain coverage without requiring sera, an advantage for testing large panels of bacterial isolates. MATS provides an accurate, conservative estimate of 4CMenB coverage. In a public-private partnership, 10 reference laboratories around the world were established and standardized to facilitate the timely collection and analysis of regional data. MATS has global public health implications for informing local policy makers of the predicted effect of the implementation of the 4CMenB vaccine. Coverage estimates are similar to or better than other recently approved vaccines, ranging from 66% to 91%. The use of MATS in post-vaccine implementation surveillance could provide data regarding vaccine effectiveness in the field and duration of protection on a global scale that will aid in the development of vaccine booster schedules, if necessary. This MATS approach could potentially be applied rapidly to assess epidemiology of other bacterial pathogens and coverage by other protein-based vaccines.

Vaccination with a multicomponent meningococcal B vaccine in prevention of disease in adolescents and young adults.

Vaccination programs employing capsular-based meningococcal vaccines have proved successful in a variety of settings globally since first introduced over 40 years ago. Similar successes have been demonstrated using meningococcal vaccines for use against serogroup B (MenB) outbreak strains but the diversity of MenB strains has limited vaccine use outside targeted geographic regions. MenB continues to be a significant cause of outbreaks in adolescents and young adults, as recently demonstrated in university settings in the US (Princeton, New Jersey and Santa Barbara, California) and has the potential for hyperendemic disease levels such as currently experienced in Québec and the United Kingdom. In adolescents, increased endemic disease rates and outbreak potential are likely associated with social behaviors putting individuals at risk for carriage acquisition and may explain regional and temporal variations in epidemiology. A protein-based, multi-component MenB vaccine (4CMenB) is currently licensed for use in 37 countries including EU/EEA countries, Australia, Canada, Chile, Colombia, Uruguay, and the US. In this article we review the most recent clinical trial data with 4CMenB with a focus on adolescents and young adults. The vaccine appears to have an acceptable safety profile and is well-tolerated in adolescents and young adults while providing robust, persistent levels of bactericidal antibodies considered protective for each of the four antigenic components of the vaccine. With the recent availability of this vaccine, health care providers have the first comprehensive opportunity to control meningococcal disease, a highly disruptive public health problem with a disproportionate impact on adolescents and young adults.

Prevention of rare diseases: how revolutionary techniques can help vulnerable individuals-the example of serogroup B meningococcal infection.

In countries with established programmes for vaccination of infants, toddlers and adolescents with meningococcal conjugate vaccines, serogroup B invasive meningococcal disease remains the major cause of septicaemia and meningitis in the paediatric and adolescent age groups. Novartis has developed a serogroup B meningococcal vaccine, 4CMenB, to meet this need. We reviewed all 4CMenB studies. The studies found 4CMenB to be highly immunogenic when administered in all schedules, with protective antibody levels (serum bactericidal antibody titres ≥4 or ≥5 with human complement, hSBA) against serogroup B strains expressing vaccine antigens in >95% of vaccinated cohorts. When antibody levels waned, all tested groups demonstrated booster responses. Although possibly an underestimation, the Meningococcal Antigen Typing System (MATS) technique predicts that global coverage of 4CMenB against all serogroup B strains is in the range 66% (Canada) to 91% (USA). The vaccine was found to be generally well tolerated, although local and systemic reactions, notably fever in infants, typical of many vaccines, were increased following concomitant administration of 4CMenB with routine vaccines. When tested, prophylactic paracetamol significantly decreased the frequency and severity of reactions in infants, with no clinically significant impact on immunogenicity of 4CMenB or concomitant routine vaccines. The vaccine is approved for use in the following age groups in the European Union (2 months+), Canada (2 months through 17 years), Australia (2 months+) and Chile (2 months+), following clinical evaluation in 4843 infants and toddlers, and 1712 adolescents and adults, in schedules including a three-dose (2, 3, 4 or 2, 4, 6 months) and a two-dose (6-11 months) infant series with a booster in the second year of life, a two-dose series in toddlers (12-23 months) and children (2-10 years) given 2 months apart (with a booster at least in the EU), and a two-dose series in adolescents (11-17 years) given 1-6 months apart. 4CMenB presents a solution to the unmet medical need of offering protection against serogroup B invasive meningococcal disease in all age groups above 2 months.

A multi-component meningococcal serogroup B vaccine (4CMenB): the clinical development program.

Recently approved in Europe and Australia, the multi-component meningococcal B vaccine, 4CMenB (Bexsero®, Novartis Vaccines and Diagnostics), contains three surface-exposed recombinant proteins (fHbp, NadA, and NHBA) and New Zealand strain outer membrane vesicles (NZ OMV) with PorA 1.4 antigenicity. This comprehensive review of the 4CMenB clinical development program covers pivotal phase I/IIb/III studies in over 7,000 adults, adolescents, and infants. The immunological correlate for clinical protection used was human complement-mediated serum bactericidal activity titers ≥4 or 5 against indicator strains for individual antigens. Based on achievement of protective titers, a four-dose schedule (three primary doses and one booster dose) for infants and a two-dose schedule for adolescents provided the best results. Observed increases in injection site pain/tenderness and fever in infants, and injection site pain, malaise, and headache in adolescents compared with routine vaccines, were mostly mild to moderate; frequencies of rare events (Kawasaki disease, juvenile arthritis) were not significantly different from non-vaccinated individuals. 4CMenB is conservatively estimated to provide 66-91 % coverage against meningococcal serogroup B strains worldwide.