Long-term complications and risk of other serious infections following invasive Haemophilus influenzae serotype b disease in vaccinated children

This study describes the long-term complications in children with Haemophilus influenzae serotype b (Hib) vaccine failure and to determine their risk of other serious infections. The families of 323 children with invasive Hib disease after appropriate vaccination (i.e. vaccine failure) were contacted to complete a questionnaire relating to their health and 260 (80.5%) completed the questionnaire. Of the 124 children with meningitis, 18.5% reported serious long-term sequelae and a further 12.1% of parents attributed other problems to Hib meningitis. Overall, 14% (32/231 cases) of otherwise healthy children and 59% (17/29 cases) of children with an underlying condition developed at least one other serious infection requiring hospital admission. In a Poisson regression model, the risk of another serious infection was independently associated with the presence of an underlying medical condition (incidence risk ratio (IRR) 7.6, 95% CI 4.8–12.1; p < 0.0001), both parents having had a serious infection (IRR 4.1, 95% CI 1.6–10.3; p = 0.003), requirement of more than two antibiotic courses per year (IRR 2.3, 95% CI 1.4–3.6; p = 0.001) and the presence of a long-term complication after Hib infection (IRR 1.8, 95% CI 1.1–3.1; p = 0.03). Thus, rates of long-term sequelae in children with vaccine failure who developed Hib meningitis are similar to those in unvaccinated children in the pre-vaccine era. One in seven otherwise healthy children (14%) with Hib vaccine failure will go on to suffer another serious infection requiring hospital admission in childhood, which is higher than would be expected for the UK paediatric population.     

Protection of rhesus macaques against inhalational anthrax with a Bacillus anthracis capsule conjugate vaccine

The efficacy of currently licensed anthrax vaccines is largely attributable to a single Bacillus anthracis immunogen, protective antigen. To broaden protection against possible strains resistant to protective antigen-based vaccines, we previously developed a vaccine in which the anthrax polyglutamic acid capsule was covalently conjugated to the outer membrane protein complex of Neisseria meningitidis serotype B and demonstrated that two doses of 2.5 μg of this vaccine conferred partial protection of rhesus macaques against inhalational anthrax . Here, we demonstrate complete protection of rhesus macaques against inhalational anthrax with a higher 50 μg dose of the same capsule conjugate vaccine. These results indicate that B. anthracis capsule is a highly effective vaccine component that should be considered for incorporation in future generation anthrax vaccines.     

Development of a conjugated gadolinium and cisplatin-gelatin possessing properties as an intravascular contrast agent for MR imaging

Purpose

The purpose of this study is to create a Gd-DTPA-Gel-Cis compound, which made from gadolinum (Gd), diethylenetriaminepentaacetic acid (DTPA)-dianhydride, cis-diamminedichloroplatinum (Cis) and bovine gelatin (Gel), that makes it possible to visualize Cis as intravascular agent under magnetic resonance imaging (MRI).

Materials and methods

The amount of DTPA, Gd, and Cis were titrated to determine the new compound's conjugation ratio with gelatin. Considering these functions, Gd-DTPA-Gel-Cis was synthesized, and its stability in bovine serum was evaluated. In addition, the signal intensity of the diluted sample was measured under 1.5 Tesla MRI.

Results

The synthesized 10 mg/ml of Gd-DTPA-Gel-Cis contained 42.84 μg/ml of Gd and 1.53 μg/ml of platinum. Gd-DTPA-Gel-Cis (100 mg/10 ml) enclosed into the cellulose dialysis tubing was placed in 90 ml of bovine serum and shaken reciprocally at 72 stroke/min at 37 °C. Partial release of free Pt was shown at 6 and 24 h, but no release of Gd occurred for a 24-h period. And high stability of Gd conjugated to DTPA-Gel-Cis. This result suggests possible anti-tumor effectiveness and high stability of Gd conjugated to DTPA-Gel-Cis. The diluted sample presented high signal intensity under 1.5 Tesla MRI.

Conclusion

Gd-DTPA-Gel-Cis has been developed successfully and we have proven its stability and contrast ability in MRI.     

Overview of the development and current use of CRM197 conjugate vaccines for pediatric use

Glycoconjugate vaccines have been proven safe and effective against various diseases in children. Although these vaccines have a history of effectiveness, there are still many unanswered questions to be addressed, including conjugate interference when multiple vaccines are administered at one time, expansion of serotype coverage, effectiveness in special populations, and issues relating to conjugate vaccine use in the developing world. This paper focuses on the use of CRM₁₉₇ as a carrier protein, contrasting it to other carrier proteins used in single-antigen pediatric vaccines as well as identifying areas for future study.     

Can pneumococcal meningitis surveillance be used to assess the impact of pneumococcal conjugate vaccine on total invasive pneumococcal disease? A case-study from South Africa, 2005–2016

IntroductionSouth Africa introduced seven-valent pneumococcal conjugate vaccine (PCV7) in 2009 and PCV13 in 2011. We aimed to compare the estimated impact of PCV on pneumococcal meningitis (PM) to impact of PCV on total invasive pneumococcal disease (tIPD) based on risk reduction after PCV introduction.MethodsWe conducted national, laboratory-based surveillance for tIPD during 2005–2016. We estimated and compared rates of PCV13 and non-PCV13 serotype disease among tIPD and PM in individuals aged <5 years and ≥5 years, and compared these rates between the 2005–2008 pre-PCV introduction period and two time points after PCV introduction, 2012 and 2016.ResultsWe enrolled 45,853 tIPD cases; 17,251 (38%) were PM. By 2016, IPD caused by all serotypes decreased 55% (95%CI −57% to −53%) for tIPD, and 54% for PM (95%CI −58% to −51%), 0.7% difference between estimates (p = 0.7). No significant differences were observed between PCV7-serotype disease reduction in tIPD and PM in both age groups or the additional 6 serotypes included in PCV13 in <5 year olds in 2012 and 2016. In 2012 there was a significant difference between increases in non-PCV13 serotype disease in those ≥5 years for tIPD and PM (32% greater increase in PM, p < 0.001), but this difference was absent by 2016. There was a significant difference between the estimated decrease in additional PCV13 type disease in 2016 between tIPD and PM for those aged ≥5 years (28% greater reduction in PM, p = 0.008).ConclusionPM showed similar reductions to tIPD seven years after PCV introduction in vaccine serotype disease in those <5 years, and increases in non-vaccine serotype disease in all ages.     

测定盐酸盐类药物含量的线性滴定法——取代非水滴定的一种新方法

本文提出了测定有机碱盐酸盐类药物含量的线性滴定法,以取代传统的非水滴定法。根据Brnsted质子理论,导出了一个测定这类药物的线性滴定公式,由最优化一维搜素法使公式线性化,并用多元线性回归分析求解。该算法简便快速,适合于采用微电脑(Apple-Ⅱ型)计算,便于推广和应用。对于水难溶游离有机碱的盐酸盐可采用水—乙醇混合溶剂中的线性滴定法,因此,其共轭酸的稳定常数为10³～10¹⁰的大部分盐酸盐均可滴定。     

The impact of the changing pneumococcal national immunisation program among older Australians

Australia has a universal infant pneumococcal conjugate vaccination program and until recently a universal pneumococcal polysaccharide vaccine program for non-Indigenous adults aged ≥65 years and Indigenous adults aged ≥50 years. We documented the impacts of infant and adult vaccination programs on the epidemiology of invasive pneumococcal disease (IPD) in Indigenous and non-Indigenous adults.IPD notifications from the National Notifiable Disease Surveillance System were analysed from 2002 to 2017, grouped by age, vaccine serotype group and Indigenous status. Since the universal funding of infant and elderly pneumococcal vaccination programs in January 2005, total IPD decreased by 19% in non-Indigenous adults aged ≥65 years but doubled in Indigenous adults aged ≥50 years. Vaccine uptake was suboptimal in both groups but lower in Indigenous adults. IPD due to the serotypes contained in the pneumococcal conjugate vaccines (PCV) except for serotype 3 declined markedly over the study period but were replaced by non-PCV serotypes. Serotype 3 is currently the most common in older adults. In the populations eligible for the adult 23-valent pneumococcal polysaccharide vaccine (23vPPV) program, IPD rates due to its exclusive serotypes increased to a lower extent than non-vaccine types. In 2017, non-vaccine serotypes accounted for most IPD in the older population eligible for the 23vPPV program, while it's eleven exclusive serotypes accounted for the majority of IPD in younger adults.Infant and adult pneumococcal vaccination programs in Australia have shaped the serotype-specific epidemiology of IPD in older adults. IPD remains a significant health burden for the Indigenous population. Herd immunity impact is clear for PCV serotypes excluding serotype 3 and serotype replacement is evident for non-PCV serotypes. The adult 23vPPV immunisation program appears to have partially curbed replacement with IPD due to its eleven exclusive serotypes, highlighting a potential benefit of increasing adult 23vPPV coverage in Australia.     

Intracellular Metabolism and Cytotoxicity of Transferrin-Neocarzinostatin Conjugates of Differing Molar Ratios

Transferrin-neocarzinostatin (NCS) conjugates with differing molar ratios of drug to protein were synthesized and their intracellular metabolism was investigated. The conjugate mixtures of transferrin-NCS were separated by DEAE-Sephacel column chromatography. The separated molecular species were examined with respect to binding affinity to transferrin receptor, cytotoxicity and intracellular metabolism using the human leukemia cell line, K562. Transferrin-NCS conjugate is capable of binding to transferrin receptors specifically and its reactivity became weaker as the ratio of bound NCS to transferrin was increased. Transferrin-6NCS did not bind measurably to the receptor. On the other hand, the cytotoxicity was augmented when the number of NCS molecules bound per molecule of transferrin was increased to 4NCS/transferrin, while transferrin-5NCS and transferrin-6NCS species exhibited low activity. Examination of the kinetics of metabolism by pulse chase study using ¹²⁵I-labeled ligand indicated that unconjugated transferrin and transferrin-NCS conjugates were internalized in similar ways, although the degradation of internalized conjugate was more marked in the case of transferrin-4NCS than transferrin-1NCS. Thus, the molar ratio of transferrin-drug conjugate could be optimized with respect to both the binding activity to receptor and the intracellular metabolic pathway.     

Development of Shigella conjugate vaccines targeting Shigella flexneri 2a and S. flexneri 3a using a simple platform-approach conjugation by squaric acid chemistry

There is a need for vaccines effective against shigella infection in young children in resource-limited areas. Protective immunity against shigella infection targets the O-specific polysaccharide (OSP) component of lipopolysaccharide. Inducing immune responses to polysaccharides in young children can be problematic, but high level and durable responses can be induced by presenting polysaccharides conjugated to carrier proteins. An effective shigella vaccine will need to be multivalent, targeting the most common global species and serotypes such as Shigella flexneri 2a, S. flexneri 3a, S. flexneri 6, and S. sonnei. Here we report the development of shigella conjugate vaccines (SCV) targeting S. flexneri 2a (SCV-Sf2a) and 3a (SCV-Sf3a) using squaric acid chemistry to result in single point sun-burst type display of OSP from carrier protein rTTHc, a 52 kDa recombinant protein fragment of the heavy chain of tetanus toxoid. We confirmed structure and demonstrated that these conjugates were recognized by serotype-specific monoclonal antibodies and convalescent sera of humans recovering from shigellosis in Bangladesh, suggesting correct immunological display of OSP. We vaccinated mice and found induction of serotype-specific OSP and LPS IgG responses, as well as rTTHc-specific IgG responses. Vaccination induced serotype-specific bactericidal antibody responses against S. flexneri, and vaccinated animals were protected against keratoconjunctivitis (Sereny test) and intraperitoneal challenge with virulent S. flexneri 2a and 3a, respectively. Our results support further development of this platform conjugation technology in the development of shigella conjugate vaccines for use in resource-limited settings.