Haemophilus influenzae Type b Vaccine Immunogenicity in American Indian/Alaska Native Infants.

OBJECTIVES: American Indian and Alaska Native (AI/AN) infants historically experienced a disproportionate burden of invasive Haemophilus influenzae type b (Hib) disease, especially early in life. PedvaxHIB vaccine is preferentially recommended for AI/AN infants because it elicits protective antibody levels postdose 1. Vaxelis, a hexavalent vaccine that contains the same Hib conjugate as PedvaxHIB but at lower concentration, is recommended for US children, but postdose 1 Hib immunogenicity data are needed to inform whether a preferential recommendation should be made for AI/AN infants. METHODS: We conducted a phase IV randomized, open-label, noninferiority trial comparing postdose 1 immunogenicity of Vaxelis to PedvaxHIB in AI/AN infants. Participants were randomized to receive a primary series of PedvaxHIB or Vaxelis. Serum samples collected 30 days postdose 1 were tested for anti-Hib immunoglobulin G antibody by enzyme-linked immunosorbent assay. The anti-Hib immunoglobulin G geometric mean concentration (GMC) ratio (Vaxelis/PedvaxHIB) was estimated by constrained longitudinal data analysis. Noninferiority was defined a priori as the lower bound of the 95% confidence interval (CI) of the GMC ratio ≥0.67. RESULTS: A total of 327 of the 333 infants enrolled in the study were included in the per-protocol analysis. The postdose 1 anti-Hib GMC was 0.41 µg/mL (95% CI 0.33-0.52) in the Vaxelis group (n = 152) and 0.39 µg/mL (95% CI 0.31-0.50) in the PedvaxHIB group (n = 146). The constrained longitudinal data analysis GMC ratio was 1.03 (95% CI 0.76-1.39). CONCLUSIONS: Postdose 1 immunogenicity of Vaxelis was noninferior to PedvaxHIB. Our findings support the use of Vaxelis in AI/AN children, a population with elevated risk of Hib disease.

Use of Haemophilus influenzae Type b-Containing Vaccines Among American Indian and Alaska Native Infants: Updated Recommendations of the Advisory Committee on Immunization Practices - United States, 2024.

Invasive Haemophilus influenzae type b (Hib) disease is a serious bacterial infection that disproportionally affects American Indian and Alaska Native (AI/AN) populations. Hib vaccination with a monovalent Hib conjugate vaccine consisting of Hib capsular polysaccharide (polyribosylribitol phosphate [PRP]) conjugated to outer membrane protein complex of Neisseria meningitidis serogroup B, PRP-OMP (PedvaxHIB, Merck and Co., Inc.) has historically been preferred for AI/AN infants, who are at increased risk for invasive Hib disease, because it provides substantial protection after the first dose. On June 26, 2024, CDC's Advisory Committee on Immunization Practices (ACIP) recommended that a hexavalent, combined diphtheria and tetanus toxoids and acellular pertussis (DTaP), inactivated poliovirus (IPV), Hib conjugate, and hepatitis B (HepB) vaccine, DTaP-IPV-Hib-HepB (Vaxelis, MSP Vaccine Company) should be included with monovalent PRP-OMP in the preferential recommendation for AI/AN infants because of the PRP-OMP Hib component. A primary Hib vaccination series consisting of either 1) monovalent PRP-OMP (2-dose series at ages 2 and 4 months) or 2) DTaP-IPV-Hib-HepB (3-dose series at ages 2, 4, and 6 months) is preferred for AI/AN infants. DTaP-IPV-Hib-HepB is only indicated for use in infants at ages 2, 4, and 6 months and should not be used for the booster doses of Hib, DTaP, or IPV vaccines. For the booster dose of Hib vaccine, no vaccine formulation is preferred for AI/AN children; any Hib vaccine (except DTaP-IPV-Hib-HepB) should be used. This report summarizes evidence considered for these recommendations and provides clinical guidance for the use of Hib-containing vaccines among AI/AN infants and children.

Invasive Nontypeable Haemophilus influenzae Disease Outbreak at an Elementary School - Michigan, May 2023.

In May 2023, the Detroit Health Department was notified of four cases of invasive nontypeable Haemophilus influenzae (Hi) disease among students attending the same elementary school and grade, all with illness onsets within 7 days. Three patients were hospitalized, and one died. Most U.S. cases of invasive Hi disease are caused by nontypeable strains. No vaccines against nontypeable or non-type b Hi strains are currently available. Chemoprophylaxis is not typically recommended in response to nontypeable Hi cases; however, because of the high attack rate (four cases among 46 students; 8.7%), rifampin prophylaxis was recommended for household contacts of patients with confirmed cases and for all students and staff members in the school wing where confirmed cases occurred. Only 10.8% of students for whom chemoprophylaxis was recommended took it, highlighting gaps in understanding among caregivers and health care providers about persons for whom chemoprophylaxis was recommended. Public health authorities subsequently enhanced communication and education to the school community, improved coordination with health care partners, and established mass prophylaxis clinics at the school. This outbreak highlights the potential for nontypeable Hi to cause serious illness and outbreaks and the need for chemoprophylaxis guidance for nontypeable Hi disease. Achieving high chemoprophylaxis coverage requires education, communication, and coordination with community and health care partners.

Adverse events following immunization of co- and separate administration of DTaP-IPV/Hib vaccines: A real-world comparative study.

To fully understand the safety of DTaP-IPV/Hib vaccination, we evaluated the differences between DTaP-IPV/Hib co-administration and separate administration of the DTaP, IPV and Hib vaccines (DTaP+IPV+Hib) based on adverse events following immunization (AEFI). All AEFI reported in Hebei Province, China, between 2020 and 2022 were included in this study. The risk difference (RD%), relative risk (RR), and Chi-square value were used to compare the differences in reported rates of AEFI between the DTaP-IPV/Hib and DTaP+IPV+Hib groups. From 2020 to 2022, 130 AEFI cases were reported in Hebei Province after DTaP-IPV/Hib vaccination, corresponding to an AEFI reported rate of 66.9/million doses, which was significantly lower than that for DTaP+IPV+Hib (9836 AEFI with a reported rate of 637.8/million doses). The overall reported rate of non-severe AEFI for DTaP+IPV+Hib vaccines was 9.5 times that of DTaP-IPV/Hib vaccination [95% confidence interval (CI): 8.0, 11.3]. Meanwhile, the reported rate of AEFI among infants aged 0-1 y was 9.8 times higher for DTaP+IPV+Hib than for DTaP-IPV/Hib (95% CI: 8.2, 11.7). DTaP+IPV+Hib vaccination also resulted in higher risks of high fever, localized redness and swelling, localized induration, and allergic rash compared with DTaP-IPV/Hib vaccination. The risk of AEFI, which were mostly mild reaction, was higher after vaccination with DTaP+IPV+Hib than after DTaP-IPV/Hib vaccination.

Baicalin and probenecid protect against Glaesserella parasuis challenge in a piglet model.

Glaesserella parasuis (G. parasuis) induces vascular damage and systemic inflammation. However, the mechanism by which it causes vascular damage is currently unclear. Baicalin has important anti-inflammatory, antibacterial and immunomodulatory functions. In this study, we explored the ability of baicalin and probenecid to protect against G. parasuis challenge in a piglet model. Sixty piglets were randomly divided into a control group; an infection group; a probenecid group; and 25 mg/kg, 50 mg/kg and 100 mg/kg baicalin groups. The probenecid group and the 25 mg/kg, 50 mg/kg and 100 mg/kg baicalin groups were injected intramuscularly with 20 mg/kg body weight (BW) probenecid and 25 mg/kg BW, 50 mg/kg BW and 100 mg/kg BW baicalin, respectively. All piglets except those from the control group were injected intraperitoneally with 1 × 108 CFU of G. parasuis. The control group was injected intraperitoneally with TSB. The results showed baicalin and probenecid protected piglets against G. parasuis challenge, improved body weight and decreased temperature changes in piglets. Baicalin and probenecid attenuated IL-1ß, IL-10, IL-18, TNF-α and IFN-γ mRNA levels in the blood for 48 h, inhibited the production of the nucleosides ATP, ADP, AMP and UMP from 24 to 72 h, reduced Panx-1/P2Y6/P2X7 expression, weakened NF-kB, AP-1, NLRP3/Caspase-1 and ROCK/MLCK/MLC signalling activation, and upregulated VE-cadherin expression in the blood vessels of piglets challenged with G. parasuis. Baicalin and probenecid alleviated pathological tissue damage in piglets induced by G. parasuis. Our results might provide a promising strategy to control and treat G. parasuis infection in the clinical setting.

Non-pharmaceutical interventions for COVID-19 transiently reduced pneumococcal and Haemophilus influenzae carriage in a cross-sectional pediatric cohort in Southampton, UK.

The Southampton pneumococcal carriage study of children under 5 years old continued during the coronavirus disease 2019 (COVID-19) pandemic. Here, we present data from October 2018 to March 2023 describing prevalence of pneumococci and other pathobionts during the winter seasons before, during, and after the introduction of non-pharmaceutical interventions (NPIs) to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Nasopharyngeal swabs were collected from children attending outpatient clinics at a secondary care hospital and community healthcare sites. Pre-NPIs, in 2019/2020, the carriage prevalence of pneumococci at the hospital site was 32% (n = 161 positive/499 participants). During NPIs, this fell to 19% (n = 12/64), although based on fewer participants compared to previous years due to COVID-19 restrictions on health-care attendance. In 2021/2022, after NPIs had eased, prevalence rebounded to 33% (n = 15/46) [compared to NPIs period, χ2 (1, N = 110) =2.78, P = 0.09]. Carriage prevalence at community healthcare sites fell significantly from 27% (n = 127/470) in 2019/2020 to 19% during the NPI period (n = 44/228) in 2020/2021 [χ2 (1, N = 698) =4.95, P = 0.026]. No rebound was observed in 2021/2022 [19% (n = 56/288)]. However, in a multivariate logistic regression model, neither site had a significantly lower carriage prevalence during the NPI period compared to the post NPI period. A reduction in serotype diversity was observed in 2020/2021. Carriage of Haemophilus influenzae was particularly affected by NPIs with a significant reduction observed. In conclusion, among children under 5 years of age, transient, modest, and statistically non-significant alterations in carriage of both Streptococcus pneumoniae and H. influenzae were associated with SARS-CoV-2 NPIs.IMPORTANCEStreptococcus pneumoniae (the pneumococcus) continues to be a major contributor to global morbidity and mortality. Using our long-running pediatric study, we examined changes in pneumococcal carriage prevalence in nearly 3,000 children under the age of 5 years between the winters of 2018/2019 and 2022/2023. This period coincided with the severe acute respiratory syndrome coronavirus 2 pandemic and, in particular, the implementation of national strategies to limit disease transmission in the UK. We observed a transient reduction of both Streptococcus pneumoniae and Haemophilus influenzae in these populations during this period of non-pharmaceutical interventions. This aligned with the reduction in invasive pneumococcal disease seen in the UK and is therefore a likely contributor to this phenomenon.

HbpA from Glaesserella parasuis induces an inflammatory response in 3D4/21 cells by activating the MAPK and NF-κB signalling pathways and protects mice against G. parasuis when used as an immunogen.

Glaesserella parasuis is usually a benign swine commensal in the upper respiratory tract, but virulent strains can cause systemic infection characterized by pneumonia, meningitis, and fibrinous polyserositis. The intensive pulmonary inflammatory response following G. parasuis infection is the main cause of lung injury and death in pigs. Vaccination has failed to control the disease due to the lack of extended cross-protection. Accumulating evidence indicates that the heme-binding protein A (HbpA) is a potential virulence determinant and a promising antigen candidate for the development of a broader range of vaccines. However, it is not yet known whether HbpA contributes to G. parasuis virulence or has any potential immune protective effects against G. parasuis. Here, we show that HbpA can induce the transcription and secretion of proinflammatory cytokines (IL-6, TNF-α, and MCP-1) in porcine alveolar macrophages (PAM, 3D4/31). The HbpA protein is recognized by Toll-like receptors 2 and 4 on 3D4/21 macrophages, resulting in the activation of MAP kinase and NF-κB signalling cascades and the transcription and secretion of proinflammatory cytokines. HbpA contributes to virulence and bacterial pulmonary colonization in C57BL/6 mice and plays a role in adhesion to host cells and evasion of the bactericidal effect of pulmonary macrophages. In addition, mice immunized with HbpA were partially protected against challenge by G. parasuis SC1401. The results suggest that HbpA plays an important role in the pathogenesis of disease caused by G. parasuis and lay a foundation for the development of a subunit or chimeric anti-G. parasuis vaccine.

Semisynthetic Glycoconjugates as Potential Vaccine Candidates Against Haemophilus influenzae Type a.

Glycoconjugate vaccines are based on chemical conjugation of pathogen-associated carbohydrates with immunogenic carrier proteins and are considered a very cost-effective way to prevent infections. Most of the licensed glycoconjugate vaccines are composed of saccharide antigens extracted from bacterial sources. However, synthetic oligosaccharide antigens have become a promising alternative to natural polysaccharides with the advantage of being well-defined structures providing homogeneous conjugates. Haemophilus influenzae (Hi) is responsible for a number of severe diseases. In recent years, an increasing rate of invasive infections caused by Hi serotype a (Hia) raised some concern, because no vaccine targeting Hia is currently available. The capsular polysaccharide (CPS) of Hia is constituted by phosphodiester-linked 4-ß-d-glucose-(1→4)-d-ribitol-5-(PO4→) repeating units and is the antigen for protein-conjugated polysaccharide vaccines. To investigate the antigenic potential of the CPS from Hia, we synthesized related saccharide fragments containing up to five repeating units. Following the synthetic optimization of the needed disaccharide building blocks, they were assembled using the phosphoramidite approach for the installation of the phosphodiester linkages. The resulting CPS-based Hia oligomers were conjugated to CRM197 carrier protein and evaluated in vivo for their immunogenic potential, showing that all glycoconjugates were capable of raising antibodies recognizing Hia synthetic fragments.

Evaluation of immunoregulation and immunoprotective efficacy of Glaesserella parasuis histidine kinase QseC.

QseC is a membrane sensor kinase that enables bacteria to perceive autoinducers -3, adrenaline, and norepinephrine to initiate downstream gene transcription. In this study, we found that the QseC protein of Glaesserella parasuis can serve as an effective antigen to activate the host's immune response. Therefore, we investigated the immunogenicity and host protective effect of this protein. ELISA and indirect immunofluorescence results showed that QseC protein can induce high titer levels of humoral immunity in mice and regularly generate specific serum antibodies. We used MTS reagents to detect lymphocyte proliferation levels and found that QseC protein can cause splenic lymphocyte proliferation with memory and specificity. Further immunological analysis of the spleen cell supernatant revealed significant upregulation of levels of IL-1ß, IL-4 and IFN-γ in the QseC + adjuvant group. In the mouse challenge experiment, it was found that QseC + adjuvant can provide effective protection. The results of this study demonstrate that QseC protein provides effective protection in a mouse model and has the potential to serve as a candidate antigen for a novel subunit vaccine for further research.

Antibody persistence to diphtheria toxoid, tetanus toxoid, Bordetella pertussis antigens, and Haemophilus influenzae type b following primary and first booster with pentavalent versus hexavalent vaccines.

Thailand has incorporated the whole-cell (wP) pertussis vaccine into the expanded program on immunization since 1977 and has offered the acellular pertussis (aP) vaccine as an optional vaccine for infants since 2001. We followed healthy children from a clinical trial (ClinicalTrials.gov NCT02408926) in which children were randomly assigned to receive either pentavalent (DTwP-HB-Hib) or hexavalent (DTaP-IPV-HB-Hib) vaccines for their primary series (administered at 2, 4, and 6 months) and first booster vaccination (18 months). Both groups received Tdap-IPV as a second booster at the age of 4 y. Blood samples were collected for evaluation of antibody persistence to diphtheria toxoid (DT), tetanus toxoid (TT), and Bordetella pertussis (B. pertussis) between 2 and 6 y of age annually, and for the immunogenicity study of Tdap-IPV at 1 month after the second booster. Antibody persistence to Haemophilus influenzae type b (Hib) was followed until 3 y of age. A total of 105 hexavalent-vaccinated children and 91 pentavalent-vaccinated children completed this study. Both pentavalent and hexavalent groups demonstrated increased antibody levels against DT, TT, and B. pertussis antigens following the second booster with Tdap-IPV. All children achieved a seroprotective concentration for anti-DT and anti-TT IgG at 1 month post booster. The hexavalent group possessed significantly higher anti-pertactin IgG (adjusted p = .023), whereas the pentavalent group possessed significantly higher anti-pertussis toxin IgG (adjusted p < .001) after the second booster. Despite declining levels post-second booster, a greater number of children sustained protective levels of anti-DT and anti-TT IgG compared to those after the first booster.

Designing of a multi-epitopes based vaccine against Haemophilius parainfluenzae and its validation through integrated computational approaches.

Haemophilus parainfluenzae is a Gram-negative opportunist pathogen within the mucus of the nose and mouth without significant symptoms and has an ability to cause various infections ranging from ear, eye, and sinus to pneumonia. A concerning development is the increasing resistance of H. parainfluenzae to beta-lactam antibiotics, with the potential to cause dental infections or abscesses. The principal objective of this investigation is to utilize bioinformatics and immuno-informatic methodologies in the development of a candidate multi-epitope Vaccine. The investigation focuses on identifying potential epitopes for both B cells (B lymphocytes) and T cells (helper T lymphocytes and cytotoxic T lymphocytes) based on high non-toxic and non-allergenic characteristics. The selection process involves identifying human leukocyte antigen alleles demonstrating strong associations with recognized antigenic and overlapping epitopes. Notably, the chosen alleles aim to provide coverage for 90% of the global population. Multi-epitope constructs were designed by using suitable linker sequences. To enhance the immunological potential, an adjuvant sequence was incorporated using the EAAAK linker. The final vaccine construct, comprising 344 amino acids, was achieved after the addition of adjuvants and linkers. This multi-epitope Vaccine demonstrates notable antigenicity and possesses favorable physiochemical characteristics. The three-dimensional conformation underwent modeling and refinement, validated through in-silico methods. Additionally, a protein-protein molecular docking analysis was conducted to predict effective binding poses between the multi-epitope Vaccine and the Toll-like receptor 4 protein. The Molecular Dynamics (MD) investigation of the docked TLR4-vaccine complex demonstrated consistent stability over the simulation period, primarily attributed to electrostatic energy. The docked complex displayed minimal deformation and enhanced rigidity in the motion of residues during the dynamic simulation. Furthermore, codon translational optimization and computational cloning was performed to ensure the reliability and proper expression of the multi-Epitope Vaccine. It is crucial to emphasize that despite these computational validations, experimental research in the laboratory is imperative to demonstrate the immunogenicity and protective efficacy of the developed vaccine. This would involve practical assessments to ascertain the real-world effectiveness of the multi-epitope Vaccine.

Incidence of Bacteremia and Serious Bacterial Infections in Hyperpyrexic Infants Offered Universal Pneumococcal Conjugate Vaccine 13 and Haemophilus influenzae B Immunization.

BACKGROUND: High fevers, especially in young children, often alarm clinicians and prompt extensive evaluation based on perceptions of increased risk of serious bacterial infection (SBI), and even brain damage or seizure disorders. OBJECTIVE: The aim of this study was to determine the prevalence of SBI in infants aged 3-36 months with fever ≥40.5°C in a population of infants offered universal pneumococcal conjugate vaccine 13 and Haemophilus influenzae B immunization. METHODS: This study is a retrospective review of all infants aged 3-36 months with temperature ≥40.5°C presenting to a tertiary care pediatric emergency department over a 30-month period in an era of universal pneumococcal conjugate 13 and H. influenzae B immunization. RESULTS: SBI was recorded in 54 (21.8%) of 247 study infants, most commonly pneumonia 30 patients (12.1%) and urinary tract infection 16 patients (6.5%). Two patients had positive blood cultures, yielding a bacteremia rate of 0.8%. Patients with SBI had a significantly higher WBC count ( P < 0.0001) and C-reactive protein levels ( P < 0.0001), and were significantly more likely to be hospitalized ( P < 0.0001). DISCUSSION: Although SBI was common (21.8%) in our cohort of hyperpyrexic infants universally offered vaccination with pneumococcal conjugate 13 and H. influenzae B vaccines, bacteremia was a rare finding (0.8%).

Lung mucosal immunity to NTHi vaccine antigens: Antibodies in sputum of chronic obstructive pulmonary disease patients.

Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory illness in older adults. A major cause of COPD-related morbidity and mortality is acute exacerbation of COPD (AECOPD). Bacteria in the lungs play a role in exacerbation development, and the most common pathogen is non-typeable Haemophilus influenzae (NTHi). A vaccine to prevent AECOPD containing NTHi surface antigens was tested in a clinical trial. This study measured IgG and IgA against NTHi vaccine antigens in sputum. Sputum samples from 40 COPD patients vaccinated with the NTHi vaccine were collected at baseline and 30 days after the second dose. IgG and IgA antibodies against the target antigens and albumin were analyzed in the sputum. We compared antibody signals before and after vaccination, analyzed correlation with disease severity and between sputum and serum samples, and assessed transudation. Antigen-specific IgG were absent before vaccination and present with high titers after vaccination. Antigen-specific IgA before and after vaccination were low but significantly different for two antigens. IgG correlated between sputum and serum, and between sputum and disease severity. Sputum albumin was higher in patients with severe COPD than in those with moderate COPD, suggesting changes in transudation played a role. We demonstrated that immunization with the NTHi vaccine induces antigen-specific antibodies in sputum. The correlation between IgG from sputum and serum and the presence of albumin in the sputum of severe COPD patients suggested transudation of antibodies from the serum to the lungs, although local IgG production could not be excluded.Clinical Trial Registration: NCT02075541.

What is the context? Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory illness in older adults and the third leading cause of death worldwide.One bacterium in the lungs, non-typeable Haemophilus influenzae (NTHi), is responsible for acute exacerbation of the disease, characterized by an increase in airway wall inflammation and symptoms, leading to high morbidity and mortality.A vaccine targeting NTHi was previously developed but did not show efficacy in reducing exacerbations in COPD patients, probably because the vaccine did not elicit an immune response in the lung mucosae, where the bacteria are located.What is the impact? Parenteral immunization with new vaccines targeting NTHi is able to elicit immune defense at the level of lung mucosae.Now that antibodies can be measured in sputum, new vaccines against COPD exacerbations or other lung infections can be tested for efficacy in the actual target tissue.Also, lung immunity against specific pathogens can now be tested.What is new? We determined that antigen-specific antibodies were present in the lungs after vaccination; these were assessed in sputum after vaccination with NTHi surface antigens.NTHi-specific IgG were present in the lungs and appeared to have arrived there primarily by transudation, a type of leakage from the serum to the lung mucosae.Transudation appeared to be stronger in severe than in moderate COPD patients.

Disparate kinetics in immune response of two different Haemophilus influenzae type b conjugate vaccines: Immunogenicity and safety observations from a randomized controlled phase IV study in healthy infants and toddlers using a 2+1 schedule.

Since the introduction of Haemophilus Influenzae type b (Hib) conjugate vaccines, invasive Hib disease has strongly declined worldwide, yet continued control of Hib disease remains important. In Europe, currently three different hexavalent combination vaccines containing Hib conjugates are marketed. In this phase IV, single-blind, randomized, controlled, multi-country study (NCT04535037), we aimed to compare, in a 2 + 1 vaccination schedule, the immunogenicity and safety and show non-inferiority, as well as superiority, of DTPa-HBV-IPV/Hib (Ih group) versus DTaP5-HB-IPV-Hib (Va group) in terms of anti-polyribosylribitol phosphate (PRP) antibody geometric mean concentrations (GMCs) and proportion of participants reaching anti-PRP antibody concentrations greater than or equal to a threshold of 5 µg/mL. One month after the booster vaccination, the anti-PRP antibody GMC ratio (Ih group/Va group) was 0.917 (95% CI: 0.710-1.185), meeting the non-inferiority criteria. The difference in percentage of participants (Ih group - Va group) reaching GMCs ≥5 µg/mL was -6.3% (95% CI: -14.1% to 1.5%), not reaching the predefined non-inferiority threshold. Interestingly, a slightly higher post-booster antibody avidity was observed in the Ih group versus the Va group. Both vaccines were well tolerated, and no safety concerns were raised. This study illustrates the different kinetics of the anti-PRP antibody response post-primary and post-booster using the two vaccines containing different Hib conjugates and indicates a potential differential impact of concomitant vaccinations on the anti-PRP responses. The clinical implications of these differences should be further studied.

Vaccination against Haemophilus influenzae type b (Hib) is included in the majority of national immunization programs worldwide and has shown to be effective in preventing Hib disease. In Europe, different vaccines containing Hib components are marketed. We compared the immune response and safety of 2 of these (DTPa-HBV-IPV/Hib, Ih group) and DTaP5-HB-IPV-Hib, Va group) in infants and toddlers, when used in a 2 + 1 schedule, i.e. two primary vaccination doses (at 2 and 4 months of age of the infant), followed by one booster dose at the age of one year. One month after the booster vaccination, the antibody concentration ratio between both groups (Ih group/Va group) was 0.917 (95% CI: 0.710­1.185) showing the DTPa-HBV-IPV/Hib vaccine was non-inferior to the DTaP5-HB-IPV-Hib vaccine; the difference in percentage of participants (Ih group ­ Va group) with antibody concentrations above 5 µg/mL was -6.3% (95% CI: −14.1% to 1.5%), which did not meet the pre-defined criterion for non-inferiority. In the Ih group, the quality of antibodies produced was somewhat higher versus the Va group. Both vaccines were well tolerated, and no safety concerns were raised. The kinetics of the immune response are different between the 2 vaccines. Since both vaccines contain different additional components (conjugated proteins), a possible effect of concomitant (simultaneously administered) vaccines was studied. Further investigations to confirm our findings are needed.

Nasal Delivery of Haemophilus haemolyticus Is Safe, Reduces Influenza Severity, and Prevents Development of Otitis Media in Mice.

BACKGROUND: Despite vaccination, influenza and otitis media (OM) remain leading causes of illness. We previously found that the human respiratory commensal Haemophilus haemolyticus prevents bacterial infection in vitro and that the related murine commensal Muribacter muris delays OM development in mice. The observation that M muris pretreatment reduced lung influenza titer and inflammation suggests that these bacteria could be exploited for protection against influenza/OM. METHODS: Safety and efficacy of intranasal H haemolyticus at 5 × 107 colony-forming units (CFU) was tested in female BALB/cARC mice using an influenza model and influenza-driven nontypeable Haemophilus influenzae (NTHi) OM model. Weight, symptoms, viral/bacterial levels, and immune responses were measured. RESULTS: Intranasal delivery of H haemolyticus was safe and reduced severity of influenza, with quicker recovery, reduced inflammation, and lower lung influenza virus titers (up to 8-fold decrease vs placebo; P ≤ .01). Haemophilus haemolyticus reduced NTHi colonization density (day 5 median NTHi CFU/mL = 1.79 × 103 in treatment group vs 4.04 × 104 in placebo, P = .041; day 7 median NTHi CFU/mL = 28.18 vs 1.03 × 104; P = .028) and prevented OM (17% OM in treatment group, 83% in placebo group; P = .015). CONCLUSIONS: Haemophilus haemolyticus has potential as a live biotherapeutic for prevention or early treatment of influenza and influenza-driven NTHi OM. Additional studies will deem whether these findings translate to humans and other respiratory infections.

Preparation and immunogenicity evaluation of C-HapS-P6 fusion protein vaccine against nontypeable Haemophilus influenzae in mice.

Nontypeable Haemophilus influenzae (NTHi) is the dominant pathogen in several infectious diseases. Currently the use of antibiotics is the main intervention to prevent NTHi infections, however with the emergence of drug resistant strains, it has compromised the treatment of respiratory infections with antibiotics. Therefore there is an urgent need to develop a safe and effective vaccine to prevent NTHi infections. We investigate the potential of C-HapS-P6 fusion protein as a vaccine for treating NTHi in murine models. PGEX-6P2/C-HapS-P6 fusion gene was constructed using overlap extension polymerase chain reaction. The recombined plasmid was transformed into Escherichia coli for protein expression. The mice were subjected to intraperitoneal immunization using purified antigens. Immunoglobulin (Ig) G in serum samples and IgA in nasal and lung lavage fluids were analyzed using enzyme-linked immunosorbent assay. Cytokine release and proliferation capacity of splenic lymphocytes in response to antigens were measured in vitro. The protective effect of the C-HapS-P6 protein against NTHi infection was evaluated by NTHi count and histological examination. The data showed that the C-HapS-P6 fusion protein increased significantly the levels of serum IgG and nasal and lung IgA, and promoted the release of interleukin (IL)-2, interferon-ϒ, IL-4, IL-5, and IL-17 and the proliferation of splenic lymphocytes compared with C-HapS or P6 protein treatment alone. Moreover, C-HapS-P6 effectively reduced the NTHi colonization in the nasopharynx and lungs of mice. In conclusion, our results demonstrated that the C-HapS-P6 fusion protein vaccine can significantly enhance humoral and cell immune responses and effectively prevent against NTHi infection in the respiratory tract in murine models.

High Prevalence of Non-typeable Haemophilus influenzae and Haemophilus haemolyticus Among Vaccinated Children with Community-Acquired Pneumonia in Vietnam.

Among 467 children under five hospitalized with community-acquired pneumonia, the prevalence of Haemophilus influenzae or Haemophilus haemolyticus was 60.8%, all cases were non-typable H. influenzae (NTHi) or H. haemolyticus. NTHi/H. haemolyticus PCR detection was associated with about twice the risk for severe disease. The results highlight the need for increased awareness and research efforts to investigate the role of NTHi/H. haemolyticus in severe CAP among children.

Efficacy and Prolonged Safety of Haemophilus influenzae Type b Conjugate Vaccines.

OBJECTIVE: The purpose of this study was to find data proving the influence of the Haemophilus influenzae type b (Hib) conjugate vaccination on the frequency of invasive Hib illness. METHODOLOGY: A systematic literature search was conducted on the PubMed database to identify peerreviewed publications pertaining to the epidemiology of Haemophilus influenzae meningitis, both before and after the introduction of Haemophilus influenzae type b (Hib) conjugate vaccines. The search query employed a combination of relevant keywords, including "invasive," "Haemophilus," "influenzae," "meningitis," and specific serotype b (Hib). Additionally, terms related to epidemiology, burden, risk factors, impact, Hib vaccine, Hib conjugate vaccine, combination vaccine, vaccine production, efficacy, immunisation coverage, surveillance, review, clinical aspects, outcomes, and various age groups (adults and children) were incorporated. RESULT: The search encompassed articles published till now. Subsequently, relevant research papers concerning Haemophilus influenzae meningitis were subjected to a comprehensive review and analysis. CONCLUSION: The Hib conjugate vaccination has shown to be extremely effective when administered to the entire population. However, changes to the immunisation protocol appear to be required in order to effectively manage invasive Hib illness.

SEROPROTECTION RATE OF HAEMOPHILUS INFLUENZAE TYPE B CONJUGATE VACCINE AND ASSOCIATED CLINICAL OUTCOMES AMONG NIGERIAN CHILDREN AGED 6 TO 23 MONTHS.

Introduction: Haemophilus influenzae type b (Hib) causes invasive infections almost exclusively in under- fives with those aged 6-23 months being the most vulnerable. In Nigeria, it is estimated to cause nearly 400,000 annual infections and another 30,000 under-five mortality attributable to pneumonia and meningitis alone. The Hib Conjugate Vaccine (HCV) is in widespread use to combat these devastating infections. Data on its impact in Nigeria is grossly scanty. This study evaluated the seroprotection rates (SPR) of HCV and associated clinical outcomes among children aged 6-23 months in Obi L.G.A. of Nasarawa State, Nigeria. Methods: A cross-sectional study of 267 children aged 6-23 months who had completed three doses of HCV. They were enrolled via a two-staged household-level cluster sampling. Relevant sociodemographic and clinical data were obtained using structured questionnaires and serum samples collected were analysed serologically for antipolyribosylribitol phosphate (anti-PRP) antibodies using ELISA. Results: The overall SPRs against invasive Hib disease and Hib nasopharyngeal colonization were 74.2% and 26.2%, respectively. The overall geometric mean titre (GMT) of anti-PRP was 1.85 µg/mL (95%CI: 1.60-2.14) and across age groups, GMTs were >1 µg/mL-the threshold for long-term protection against invasive Hib disease. Rates/duration of healthcare admissions and average episodes of probable Hib disease syndromes were lower in seroprotected but not statistically different from non-seroprotected children. Conclusion: The demonstrated anti-PRP titres and Seroprotection Rates infer a very good HCV efficacy in Nigerian children. The lack of significant difference in clinical outcomes may be attributable to nonspecificity.

Characterization of a highly virulent Avibacterium paragallinarum isolate.

Infectious coryza (IC) is an important respiratory infectious disease in chickens. In this study, an Avibacterium paragallinarum Page serovar C strain, named ZJ-C, was isolated from a local layer flock that was routinely vaccinated with an inactivated trivalent vaccine, using reference strain Modesto as the serovar C immunogen. The pathogenicity, immunogenicity, and genetic characteristics of ZJ-C were studied. The minimum pathogenic dose of the isolate was 100 CFU, which was 1/1,000 of the dose of the serovar C reference strain Modesto. The vaccination-challenge trial in specific pathogen-free (SPF) chickens showed that the ZJ-C bacterin could provide 100% protection against challenge from both ZJ-C and Modesto strains, whereas Modesto provided 100% protection against challenge from itself, but only 70% protection against ZJ-C. Sequence analysis of the HMTp210 hypervariable region (region 2) showed that the homology of region 2 between ZJ-C and Modesto was 96.14%, whereas the homology between ZJ-C and the Kume serovar C-4 reference strain HP60 was 99.83%. Phylogenetic analysis of region 2 showed that ZJ-C was most closely related to cluster C-4, represented by HP60. The experimental data obtained in this study will help the selection of optimal vaccine strains and assist serotyping studies of Av. paragallinarum.

Vaccination with inactivated multivalent vaccines is a primary strategy to control Infectious coryza. Avibacterium paragallinarum serotyping is important for effective protection as inactivated whole-cell vaccines provide protection against only the serogroup or serovar from which the vaccine was derived. In this study, a novel serovar within the serogroup C Avibacterium paragallinarum isolate ZJ-C has been characterized first time in China. It was highly virulent and induced 100% cross-protection to Modesto bacterin vaccinated chickens, but not the other way around.