Polysaccharide Conjugate Research Articles

Global Epidemiology of Meningococcal Disease-Causing Serogroups Before and After the COVID-19 Pandemic: A Narrative Review.

Invasive meningococcal disease (IMD) is associated with high morbidity and mortality and predominantly caused by five Neisseria meningitidis serogroups (A/B/C/W/Y). Polysaccharide conjugate vaccines induce T-cell-dependent immune responses, are immunogenic in infants and adults, and reduce carriage, and vaccination of age groups associated with high-carriage can provide indirect protection in the unvaccinated (herd immunity). Successful vaccination programs must be tailored to local epidemiology, which varies geographically, temporally, and by age and serogroup. Serogroup A IMD once predominated globally, but has largely disappeared following mass vaccination programs. Serogroup B was a predominant cause of IMD in many global regions from 2010 to 2018, typically affecting younger age groups. Spread of serogroup C clonal complex-11 IMD in the 1990s prompted implementation of MenC vaccine programs in many countries, resulting in declines in prevalence. Serogroup C still caused>20% of global IMD through the mid-2010s. Serogroup W became a significant contributor to global IMD after Hajj pilgrimage outbreaks in 2000; subsequent increases of endemic disease and outbreaks were reported pre-pandemic in many regions. Serogroup Y emerged in the 1990s as a significant cause of IMD throughout various regions and prevalence had increased or stabilized from 2010 to 2018. Serogroup X is uncommon outside the African meningitis belt, and its prevalence has declined since before the COVID-19 pandemic. Global IMD declines during the pandemic were followed by resurgences generally caused by serogroups that were prevalent pre-pandemic and affecting mainly unvaccinated age groups (particularly adolescents/young adults). Recent IMD epidemiology underscores the importance of vaccinating at-risk age groups against regionally prevalent serogroups; for example, the anti-serogroup X component of the recently prequalified MenACWXY vaccine is likely to provide limited protection outside the African meningitis belt. In other regions, comprehensive vaccination against MenB and MenACWY, which could be streamlined by the recently approved MenABCWY vaccine, seems more appropriate.

Oswald Avery: Pioneer of Bacterial Vaccines and the First to Discover the Function of DNA.

Dr. Oswald Theodore Avery (1877-1955), M.D., played an immense role in the biological and medical field because of his groundbreaking research. All his life, he worked on Streptococcus pneumoniae, the bacterium that causes pneumonia. He discovered the principle of polysaccharide conjugate vaccines, which now save the lives of millions of children and the elderly.He found that bacteria can transfer plasmids; most importantly, he identified that deoxyribonucleic acid (DNA) is the carrier of genetic information instead of the (at that time widely accepted) protein theory. Though he was never awarded the Nobel Prize, his work was the basis for countless achievementsbuilding on his foundation, ranging from effective vaccines to gene transfer technologies.

CRM197-scaffolded vaccines designed by epitope grafting ameliorate cognitive decline in an Alzheimer's disease model

Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Amyloid-beta (Aβ) plaque accumulation and tau neurofibrillary tangles (NFTs) formation in the brain are major neuropathological hallmarks of AD. Immunotherapies targeting Aβ and/or tau are deemed the most promising approaches for AD. Administrations with monoclonal antibodies against Aβ have yielded substantial breakthroughs clinically. Most vaccines tested clinically so far failed to prove efficacious in large part due to inappropriate design of vaccine antigens. In this study, a structure-guided approach was employed to design novel antigens targeting Aβ and/or tau by grafting multiple copies of Aβ and/or tau B-cell epitope peptide onto CRM197, which is the most widely used carrier protein in polysaccharide conjugate vaccines. The immunogenicity of the vaccines was evaluated in BALB/c mice and the efficacy was tested in a transgenic mouse model of human amyloidopathy. The antigens were highly immunogenic early vaccination substantially ameliorated cognitive decline in APP/PS1 mice and significantly reduced insoluble Aβ42/40 in the brains. These results demonstrate that the engineered antigens have protective effects on AD mice, offering a promising translatable strategy for the prevention and/or treatment of AD.

Economic evaluation on meningococcal vaccination strategies among children under nine years of age in Zhejiang province, China.

Meningococcal vaccination in Chinese national immunization program (NIP) includes polysaccharide vaccine against Neisseria meningitidis serogroup A (MPV-A) and polysaccharide vaccine against Neisseria meningitidis serogroup A and C(MPV-AC). This study aimed to assess the cost-effectiveness of an alternative strategy using polysaccharide conjugate vaccine against Neisseria meningitidis serogroup A,C,W,Y(MCV-ACWY) and polysaccharide vaccine against Neisseria meningitidis serogroup A,C,W,Y(MPV-ACWY). From a societal perspective, we constructed a decision tree-Markov model to simulate the economic and health consequences of meningococcal disease in a 2023 birth cohort with the current meningococcal vaccination strategy and the alternative. Parameters of epidemiology, vaccine efficacy, cost, and utility were extracted from database and previous literatures. The sensitivity analysis was implemented to evaluate the robustness of the model. Compared to the current practice, the alternative strategy could avoid 513 meningococcal disease cases, 53 sequelae and 47 deaths. The ICER was estimated at $16899.81 /QALY, under the threshold of one time of the GDP per capita of Zhejiang province in 2023. The incidence of meningococcemia, the incidence of meningococcal meningitis, the case fatality of meningococcemia, the vaccine efficacy of MCV-ACWY and the price of MCV-ACWY would influence the cost-effectiveness of the meningococcal vaccination strategies. At the threshold, the probability of cost-effectiveness was 14.76% for the current strategy and 55.98% for the alternative strategy, respectively. The current meningococcal vaccination strategy had effectively prevented meningococcal disease at a low cost, but with limited serogroup coverage. Strategy using MCV-ACWY and MPV-ACWY could increase health benefits at a substantial cost at a cost-effective manner.

Physicochemical characterization of emulsions stabilized with polysaccharide conjugates extracted from Pu'er tea and their protective effect on curcumin

This study aimed to investigate the influence of different storage periods on the emulsifying properties of polysaccharide-protein complexes (pTPC) in Pu 'er tea through structural analysis and macroscopic characterization, and further explore the stability of pTPC-stabilized nano-emulsions in various environmental conditions. Through determination of chemical composition, interfacial tension, and infrared spectroscopy, it was found that compared to pTPC-13, the higher amino acid content of pTPC-18 led to enhanced hydrogen bonding and electrostatic interactions between intramolecular polysaccharides and polyphenols, thereby increasing its adsorption rate and interfacial film thickness. Additionally, the stability of pTPC-18 stabilized nano-emulsions showed no significant changes in zeta potential and particle size over 0–90 days of storage, pH 2.0–9.0, 25–100 °C, Na+ and Ca2+, whereas pTPC-13 stabilized emulsions exhibited noticeable droplet aggregation and layering instability under the same stress conditions. Furthermore, for curcumin encapsulation, pTPC-18 nano-emulsions (60%) demonstrated stronger protection of curcumin compared to pTPC-13 nano-emulsions (39%). These results suggest that during long-term storage, the relative increase in protein and polyphenol content within pTPC-18 enhances its emulsifying properties, providing new insights into the development of lipid-active substance delivery systems.

Whey protein and maltodextrin conjugated foam-mat dried honey powder: Functional, physicochemical, structural, rheological and thermal characterization

Honey in its natural form possesses considerable challenges in mass production and transportation owing to its viscosity and stickiness, making it prone to crystallization over time. Dried honey powder makes it convenient for handling and processing. In this study, foam mat dried powder (FMDP) was obtained by foam mat drying technique in which whey protein isolate (WPI) and maltodextrin (MD) were used as foaming agent and foam stabilizer, respectively. The obtained FMDP was characterized in terms of physical, chemical, functional, phytochemical, rheological and structural properties to study the impact of foaming agents. WPI was found to improve the functionality, stability and glass transition temperature and on the other hand, MD was found to enhance the stability, crystallinity and the color of the FMDP. FTIR helped in understanding the changes in the functional groups attributed to the foaming agents. The crystallinity and the microstructural changes in the FMDP were observed from X-ray diffractograms and SEM micrographs, respectively. The rheological characterization confirmed the viscous nature of honey. The study confirmed the interaction between proteins and polysaccharides, which subsequently improved the heat stability, functional properties, solubility, emulsifying capacity, antioxidant properties, and solubility. The dried honey samples demonstrated minimal caking, low cohesiveness (Hausner ratio: 1.16 ± 0.027–1.29 ± 0.041), good and fair flowability (ranging between 14.25 ± 2.02–22.52 ± 2.25). Therefore, it can be concluded that during this study, protein and polysaccharide conjugate FMDP was obtained with better quality attributes, which can be further incorporated during various product development in food industries.

Polysaccharide Conjugates' contribution to mellow and thick taste of Pu-erh ripe tea, besides Theabrownin

Mellow and thick taste (MTT) is considered to be a typical taste characteristic of high-quality Pu-erh ripe tea. However, the role of polysaccharide conjugates remains unclear. In this study, the infusion of different grades of Pu-erh ripe tea was isolated to fractions by sensory-guided ultrafiltration technology and the key taste substances of MTT in Pu-erh ripe tea were identified and confirmed in the sensory reconstruction experiment. Further separation, purification and structural identification of the polysaccharide conjugates were carried out. Involving in aggregation morphology, the ultrafiltration fraction exhibited obvious MTT than other fractions. The main MTT compound (PRTPS-5), mainly composed of the rhamnose, galactose, arabinose and mannose, had a molecular weight of 22.93 kDa. The main chain of PRTPS-5 comprised α-L-Araf-(1→, →2,4)-α-L-Rhap-(1→, →2)-α-L-Rhap-(1→, α-D-Galp-(1→, →4)-α-D-GalpA-6-OMe-(1→, →4)-α-D-Manp-(1→, →3,6)-β-D-Galp-(1 → and →5)-α-L-Araf-(1 → and contained multiple pectic characteristic peaks. This result had scientific guiding significance for the quality enhancement of Pu-erh ripe tea.

Characterization of Turbo, a TLR Ligand-based Adjuvant for Glycoconjugate Vaccines.

Many bacterial polysaccharide vaccines, including the typhoid Vi polysaccharide (ViPS) and tetravalent meningococcal polysaccharide conjugate (MCV4) vaccines, do not incorporate adjuvants and are not highly immunogenic, particularly in infants. I found that endotoxin, a TLR4 ligand in ViPS, contributes to the immunogenicity of typhoid vaccines. Because endotoxin is pyrogenic, and its levels are highly variable in vaccines, I developed monophosphoryl lipid A, a nontoxic TLR4 ligand-based adjuvant named Turbo. Admixing Turbo with ViPS and MCV4 vaccines improved their immunogenicity across all ages and eliminated booster requirement. To understand the characteristics of this adjuvanticity, I compared Turbo with alum. Unlike alum, which polarizes the response toward the IgG1 isotype, Turbo promoted Ab class switching to all IgG isotypes with affinity maturation; the magnitude of this IgG response is durable and accompanied by the presence of long-lived plasma cells in the mouse bone marrow. In striking contrast with the pathways employed by alum, Turbo adjuvanticity is independent of NLPR3, pyroptotic cell death effector Gasdermin D, and canonical and noncanonical inflammasome activation mediated by Caspase-1 and Caspase-11, respectively. Turbo adjuvanticity is primarily dependent on the MyD88 axis and is lost in mice deficient in costimulatory molecules CD86 and CD40, indicating that Turbo adjuvanticity includes activation of these pathways. Because Turbo formulations containing either monophosphoryl lipid A or TLR2 ligands, Pam2CysSerLys4, and Pam3CysSerLys4 help generate Ab response of all IgG isotypes, as an adjuvant Turbo can improve the immunogenicity of glycoconjugate vaccines against a wide range of bacterial pathogens whose elimination requires appropriate IgG isotypes.

Characterization, stability, and curcumin bioaccessibility of buckwheat flower polysaccharide conjugate emulsion.

In this study, buckwheat flower polysaccharide conjugates (BFPCs) were synthesized and evaluated for their emulsification properties. The stability of BFPC-stabilized emulsions was assessed through particle size analysis, zeta potential measurements, microscopic observations, and rheological tests. Gum Arabic served as a control to compare BFPC's emulsifying efficacy across varying storage conditions, including exposure to metal ions, pH variations, and different heat treatment temperatures. Results showed that BFPC significantly lowered interfacial tension (16.2mN/m) and effectively stabilized emulsions containing 60wt% medium-chain triglycerides at a concentration of 1.0wt%. Over a 20-day storage period, BFPC emulsions demonstrated robust resistance to heat (60-90°C), acidic conditions (pH 2.0-9.0), and ion concentrations (Na+, Ca2+). Moreover, in a high oil phase emulsion, BFPC enhanced the bioavailability of curcumin to 27.05%, markedly higher than the 7.10% observed without emulsification, underscoring its potential in nutrient delivery applications. PRACTICAL APPLICATION: Due to its excellent resistance, long-time emulsifying stability under different conditions, and its good effect in curcumin embedding, BFPC has a broad prospect and can be widely used under various conditions in food industry.

Effect of glycation with three polysaccharides on the structural and emulsifying properties of ovalbumin

Herein, three types of ovalbumin (OA)-polysaccharide conjugates were prepared with three polysaccharides (XG: xanthan gum; GG: guar gum; KGM: konjac glucomannan) for the fish oil emulsion stabilization. The glycation did not change the spectra bands and secondary structure percentages of OA, whereas it decreased the molecular surface hydrophobicity of OA. The initial emulsion droplet sizes were dependent on the polysaccharide types, OA preparation concentrations, polysaccharide: OA mass ratios, and glycation pH. The emulsion stability was mainly dependent on the polysaccharide types, polysaccharide: OA mass ratios, and glycation pH. However, it was minorly dependent on the OA preparation concentrations. The emulsions stabilized by conjugates with high polysaccharide: OA mass ratios (e.g., ≥3:5 for OA-GG) or appropriate glycation pH (e.g., 5.0–6.1 for OA-XG) showed no obvious creaming during the room temperature storage. This work provided basic knowledge on the structural modification and functional application of a protein.

Modeling 1-Cyano-4-Dimethylaminopyridine Tetrafluoroborate (CDAP) Chemistry to Design Glycoconjugate Vaccines with Desired Structural and Immunological Characteristics.

Glycoconjugation is a well-established technology for vaccine development: linkage of the polysaccharide (PS) antigen to an appropriate carrier protein overcomes the limitations of PS T-independent antigens, making them effective in infants and providing immunological memory. Glycoconjugate vaccines have been successful in reducing the burden of different diseases globally. However, many pathogens still require a vaccine, and many of them display a variety of glycans on their surface that have been proposed as key antigens for the development of high-valency glycoconjugate vaccines. CDAP chemistry represents a generic conjugation strategy that is easily applied to PS with different structures. This chemistry utilizes common groups to a large range of PS and proteins, e.g., hydroxyl groups on the PS and amino groups on the protein. Here, new fast analytical tools to study CDAP reaction have been developed, and reaction conditions for PS activation and conjugation have been extensively investigated. Mathematical models have been built to identify reaction conditions to generate conjugates with wanted characteristics and successfully applied to a large number of bacterial PSs from different pathogens, e.g., Klebsiella pneumoniae, Salmonella Paratyphi A, Salmonella Enteritidis, Salmonella Typhimurium, Shighella sonnei and Shigella flexneri. Furthermore, using Salmonella Paratyphi A O-antigen and CRM197 as models, a design of experiment approach has been used to study the impact of conjugation conditions and conjugate features on immunogenicity in rabbits. The approach used can be rapidly extended to other PSs and accelerate the development of high-valency glycoconjugate vaccines.

Cover Image

The cover image is based on the Research Article Theabrownins in dark tea form complexes with tea polysaccharide conjugates by Xiaoqiang Chen et al., https://doi.org/10.1002/jsfa.13431.image

Using Surface Immunogenic Protein as a Carrier Protein to Elicit Protective Antibody to Multiple Serotypes for Candidate Group B Streptococcal Glycan Conjugate Vaccines.

Group B Streptococcus (GBS) is a life-threatening opportunistic pathogen, particularly in pregnant women, infants, and the elderly. Currently, maternal vaccination is considered the most viable long-term option for preventing GBS mother-to-infant infection, and two polysaccharide conjugate vaccines utilizing CRM197 as a carrier protein have undergone clinical phase II trials. Surface immunogenic protein (Sip), present in all identified serotypes of GBS strains so far, is a protective surface protein of GBS. In this study, the type Ia capsular polysaccharide (CPS) of GBS was utilized as a model to develop candidate antigens for a polysaccharide conjugate vaccine by coupling it with the Sip of GBS and the traditional carrier protein CRM197. Serum analysis from immunized New Zealand rabbits and CD1 mice revealed that there was no significant difference in antibody titers between the Ia-Sip group and Ia-CRM197 group; however, both were significantly higher than those observed in the Ia polysaccharide group. Opsonophagocytosis and passive immune protection results using rabbit serum indicated no significant difference between the Ia-Sip and Ia-CRM197 groups, both outperforming the Ia polysaccharide group. Furthermore, serum from the Ia-Sip group had a cross-protective effect on multiple types of GBS strains. The challenge test results in CD1 mice demonstrated that the Ia-Sip group provided complete protection against lethal doses of bacteria and also showed cross-protection against type III strain. Our study demonstrates for the first time that Ia-Sip is immunogenic and provides serotype-independent protection in glycan conjugate vaccines, which also indicates Sip may serve as an excellent carrier protein for GBS glycan conjugate vaccines and provide cross-protection against multiple GBS strains.

Physicochemical characterization of the fraction components of the theabrownin isolates from Pu'er tea

This study focuses on the isolation of theabrownins (TBs) from Pu'er tea. This isolation process involves low temperature water extraction, membrane separation, and multi-stage extraction with organic solvents. Subsequently, purification was performed using column chromatography with macroporous adsorbent resin D-101 and ethanol aqueous solution with a concentration of 0–64.81 g/100g. Five purified fractions were obtained, namely TBs-D1, TBs-D2, TBs-D3, TBs-D4, and TBs-D5, collectively referred to as TBs-D(1–5). These fractions were found to contain TBs and polysaccharides but lacked catechins, caffeine, theaflavin, and free protein. The average molecular weights of these fraction components exceeded 104 Da. These results indicated that TBs-D(1–5) were not free, but combined with tea polysaccharide conjugates (TPC), that is, TBs-TPC complexes. Furthermore, ultraviolet–visible spectrophotometry and Flourier transformation infrared spectroscopy confirmed the nature of TBs-D(1–5) as TBs-TPC complexes. Fluorescence spectra revealed that polysaccharides exert a quenching effect on the intrinsic fluorescence of TBs. Atomic force microscopy indicated that the sample forms a spherical cluster due to the aggregation of theabrownin molecules. Additionally, measurements of interfacial tension and water contact angle demonstrated that TBs-D(1–5) exhibit some amphiphilic properties. This research provides a theoretical foundation for the industrial production and utilization of TBs.

Immunogenicity and safety of a 14-valent pneumococcal polysaccharide conjugate vaccine (PNEUBEVAX 14™) administered to 6–8 weeks old healthy Indian Infants: A single blind, randomized, active-controlled, Phase-III study

BackgroundIntroduction of pneumococcal conjugate vaccines (PCVs) reduced the number of cases of pneumococcal disease (PD). However, there is an increase in clinical and economic burden of PD from serotypes that are not part of the existing pneumococcal vaccines, particularly impacting pediatric and elder population. In addition, the regions where the PCV is not available, the disease burden remains high. In this study, immunogenicity and safety of the BE’s 14-valent PCV (PNEUBEVAX 14™; BE-PCV-14) containing two additional epidemiologically important serotypes (22F and 33F) was evaluated in infants in comparison to licensed vaccine, Prevenar-13 (PCV-13). MethodsThis is a pivotal phase-3 single blind randomized active-controlled study conducted at 12 sites across India in 6–8 weeks old healthy infants at 6–10–14 weeks dosing schedule to assess immunogenic non-inferiority and safety of a candidate BE-PCV-14. In total, 1290 infants were equally randomized to receive either BE-PCV-14 or PCV-13. Solicited local reactions and systemic events, adverse events (AEs), serious AEs (SAEs), and medically attended AEs (MAAEs) were recorded. Immunogenicity was assessed by measuring anti-PnCPS (anti-pneumococcal capsular polysaccharide) IgG concentration and functional antibody titers through opsonophagocytic activity (OPA), one month after completing three dose schedule. Cross protection to serotype 6A offered by serotype 6B was also assessed in this study. FindingsThe safety profile of BE-PCV-14 was comparable to PCV-13 vaccine. Majority of reported AEs were mild in nature. No severe or serious AEs were reported in both the treatment groups. For the twelve common serotypes and for the additional serotypes (22F and 33F) in BE-PCV-14, NI criteria was demonstrated as defined by WHO TRS-977. Primary immunogenicity endpoint was met in terms of IgG immune responses for all 14 serotypesof BE-PCV-14. Moreover, a significant proportion of subjects (69%) seroconverted against serotype 6A, even though this antigen was not present in BE-PCV-14. This indicates that serotype 6B of BE-PCV-14 cross protects serotype 6A. BE-PCV-14 also elicited comparable serotype specific functional OPA immune responses to all the serotypes common to PCV-13. InterpretationsBE-PCV-14 was found to be safe and induced robust and functional serotype specific immune responses to all 14 serotypes. It also elicited cross protective immune response against serotype 6B.These findings suggest that BE-PCV-14 can be safely administered to infants and achieve protection against pneumococcal disease caused by serotypes covered in the vaccine.The study was prospectively registered with clinical trial registry of India – CTRI/2020/02/023129.

Development and validation of a 6-plex Luminex-based assay for measuring human serum antibodies to group B streptococcus capsular polysaccharides

ABSTRACT Six serotypes (Ia, Ib, II, III, IV, and V) cause nearly all group B streptococcal (GBS) disease globally. Capsular polysaccharide (CPS) conjugate vaccines aim to prevent GBS disease, however, licensure of a vaccine would depend on a standardized serological assay for measuring anti-CPS IgG responses. A multiplex direct Luminex-based immunoassay (dLIA) has been developed to simultaneously measure the concentration of serum IgG specific for the six prevalent GBS CPS serotypes. Assay validation was performed using serum samples obtained from human subjects vaccinated with an investigational 6-valent GBS CPS conjugate vaccine. Results for the assay are expressed as IgG concentrations (µg/mL) using a human serum reference standard composed of pooled sera from vaccinated subjects. The lower limits of quantitation (LLOQ) for all serotypes covered in the 6-plex GBS IgG dLIA fell within the range of 0.002-0.022 µg/mL IgG. Taken together, the 6-plex GBS IgG dLIA platform is specific for the six GBS serotypes included in Pfizer’s investigational vaccine, has a wide dilution adjusted assay range, and is precise (<18.5% relative standard deviation) for all serotypes, and, therefore, is suitable for quantitatively measuring vaccine-induced or naturally acquired serotype-specific anti-CPS IgG responses against GBS.

Molecular modification of low-dissolution soy protein isolates by anionic xanthan gum, neutral guar gum, or neutral konjac glucomannan to improve the protein dissolution and stabilize fish oil emulsion

Herein, the effects of anionic xanthan gum (XG), neutral guar gum (GG), and neutral konjac glucomannan (KGM) on the dissolution, physicochemical properties, and emulsion stabilization ability of soy protein isolate (SPI)-polysaccharide conjugates were studied. The SPI-polysaccharide conjugates had better water dissolution than the insoluble SPI. Compared with SPI, SPI-polysaccharide conjugates had lower β-sheet (39.6 %–56.4 % vs. 47.3 %) and α-helix (13.0 %–13.2 % vs. 22.6 %) percentages, and higher β-turn (23.8 %–26.5 % vs. 11.0 %) percentages. The creaming stability of SPI-polysaccharide conjugate-stabilized fish oil-loaded emulsions mainly depended on polysaccharide type: SPI-XG (Creaming index: 0) > SPI-GG (Creaming index: 8.1 %–21.2 %) > SPI-KGM (18.1 %–40.4 %). In addition, it also depended on the SPI preparation concentrations, glycation times, and glycation pH. The modification by anionic XG induced no obvious emulsion creaming even after 14-day storage, which suggested that anionic polysaccharide might be the best polysaccharide to modify SPI for emulsion stabilization. This work provided useful information to modify insoluble proteins by polysaccharides for potential application.

Monophosphoryl Lipid A-based Adjuvant to Promote the Immunogenicity of Multivalent Meningococcal Polysaccharide Conjugate Vaccines.

Activation of the adaptive immune system requires the engagement of costimulatory pathways in addition to B and T cell Ag receptor signaling, and adjuvants play a central role in this process. Many Gram-negative bacterial polysaccharide vaccines, including the tetravalent meningococcal conjugate vaccines (MCV4) and typhoid Vi polysaccharide vaccines, do not incorporate adjuvants. The immunogenicity of typhoid vaccines is due to the presence of associated TLR4 ligands in these vaccines. Because the immunogenicity of MCV4 is poor and requires boosters, I hypothesized that TLR4 ligands are absent in MCV4 and that incorporation of a TLR4 ligand-based adjuvant would improve their immunogenicity. Consistent with this hypothesis, two Food and Drug Administration-approved MCV4 vaccines, MENVEO and MenQuadfi, lack TLR4 ligands. Admixing monophosphoryl lipid A, a TLR4 ligand-based adjuvant formulation named "Turbo" with MCV4 induced significantly improved IgM and IgG responses to all four meningococcal serogroup polysaccharides in adult and aged mice after a single immunization. Furthermore, in infant mice, a single booster was sufficient to promote a robust IgG response and 100% seroconversion when MCV4 was adjuvanted with Turbo. Turbo upregulated the expression of the costimulatory molecules CD40 and CD86 on B cells, and Turbo-driven adjuvanticity is lost in mice deficient in CD40 and CD86. These data suggest that Turbo induces the required costimulatory molecules for its adjuvant activity and that incorporation of Turbo could make bacterial polysaccharide vaccines more immunogenic, minimize booster requirements, and be cost-effective, particularly for those individuals in low- and middle-income and disease-endemic countries.

Humoral and cellular immune responses induced by serogroup W135 meningococcal conjugate and polysaccharide vaccines

Investigating the mechanisms by which W135 meningococcal conjugate (PSW135-TT) activates adaptive immune responses in mice can provide a comprehensive understanding of the immune mechanisms of bacterial polysaccharide conjugate vaccines. We compared B-cell and T-cell immune responses immunized with W135 meningococcal capsular polysaccharides (PSW135), tetanus toxoid (TT) and PSW135-TT in mice. The results showed that PSW135-TT could induce higher PSW135-specific and TT-specific IgG antibodies with a significant enhancement after two doses. All serum antibodies immunized with PSW135- TT had strong bactericidal activity, whereas none of the serum antibodies immunized with PSW135 had bactericidal activity. Besides, IgM and IgG antibodies immunized with PSW135-TT after two doses were positively correlated with the titer of bactericidal antibodies. We also found Th cells favored Th2 humoral immune responses in PSW135-TT, PSW135, and TT-immunized mice, especially peripheral blood lymphocytes. Furthermore, PSW135-TT and TT could effectively activate bone marrow derived dendritic cells (BMDCs) and promote BMDCs to highly express major histocompatibility complex Ⅱ (MHCⅡ), CD86 and CD40 molecules in mice, whereas PSW135 couldn’t. These data verified the typical characteristics of PSW135-TT and TT as T cell dependent antigen (TD-Ag) and PSW135 as T cell independent antigen (TI-Ag), which will be very helpful for further exploration of the immune mechanism of polysaccharide-protein conjugate vaccines and improvement of the quality of bacterial polysaccharide conjugate vaccines in future.

Penbraya: A pentavalent meningococcal vaccine.

The FDA has licensed Penbraya (Pfizer), a pentavalent polysaccharide conjugate meningococcal vaccine, for prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroups A, B, C, W, or Y (MenABCWY) in persons 10-25 years old. Penbraya is the only meningococcal vaccine that contains all five of these serogroups. Two quadrivalent polysaccharide conjugate meningococcal vaccines containing serogroups A, C, W, and Y (MenACWY; Menveo, MenQuadfi) and two meningococcal serogroup B vaccines (MenB; Bexsero, Trumenba) are available in the US.