Long term population impact of seven-valent pneumococcal conjugate vaccine with a “3 + 0″ schedule—How do “2 + 1″ and “3 + 1″ schedules compare?

IntroductionSignificant reductions in invasive pneumococcal disease (IPD) following 7-valent pneumococcal conjugate vaccine (7vPCV) are well documented, but population-level data comparing different schedules are sparse. We compared data from long-term stable surveillance in one Australian region (3 primary doses (3 + 0) schedule) with similar data from England and Wales (2 + 1 schedule) and the United States (3 + 1 schedule).MethodsIncidence rate ratios (IRRs) for all, vaccine type, and non-vaccine type IPD were calculated by age-group, using comparable case definitions and time periods post 7vPCV introduction.ResultsAt baseline, the % of IPD due to 7vPCV serotypes (VT) disease in children <5 years was 88% in Greater Sydney (GS), 83% in the United States (US), and 74% in England and Wales (E&W). IRR for VT IPD <5 years in GS was 0.05 (0.02–0.09), for ≥65 years was 0.15 (0.12–0.19) and for all ages 0.12 (0.10–0.13). In the US, IRR for VT IPD was lower in each age group, and for all ages the 95% CI of the IRR (0.06 (0.05–0.07)), did not overlap with GS or E&W (0.14 (0.11–0.18)). In contrast, the IRR for IPD due to any serotype did not differ between sites for any age group or overall.ConclusionsDifferences in direct and indirect reductions in VT IPD with a “3 + 0″ 7vPCV schedule versus “2 + 1″ or “3 + 1″ were small. All 3 countries moved to 13vPCV by 2011; data post 13vPCV will be important to assess IPD impact using more similar baseline incidence and comparison periods.     

Structural correlates of carrier protein recognition in tetanus toxoid-conjugated bacterial polysaccharide vaccines

An analysis of structure-antibody recognition relationships in nine licenced polysaccharide-tetanus toxoid (TT) conjugate vaccines was performed. The panel of conjugates used included vaccine components to protect against disease caused by Haemophilus influenzae type b, Neisseria meningitidis groups A, C, W and Y and Streptococcus pneumoniae serotype 18C. Conformation and structural analysis included size exclusion chromatography with multi-angle light scattering to determine size, and intrinsic fluorescence spectroscopy and fluorescence quenching to evaluate the protein folding and exposure of Trp residues. A capture ELISA measured the recognition of TT epitopes in the conjugates, using four rat monoclonal antibodies: 2 localised to the H_C domain, and 2 of which were holotoxoid conformation-dependent. The conjugates had a wide range of average molecular masses ranging from 1.8 × 10⁶ g/mol to larger than 20 × 10⁶ g/mol. The panel of conjugates were found to be well folded, and did not have spectral features typical of aggregated TT. A partial correlation was found between molecular mass and epitope recognition. Recognition of the epitopes either on the H_C domain or the whole toxoid was not necessarily hampered by the size of the molecule. Correlation was also found between the accessibility of Trp side chains and polysaccharide loading, suggesting also that a higher level of conjugated PS does not necessarily interfere with toxoid accessibility. There were different levels of carrier protein Trp side-chain and epitope accessibility that were localised to the H_C domain; these were related to the saccharide type, despite the conjugates being independently manufactured. These findings extend our understanding of the molecular basis for carrier protein recognition in TT conjugate vaccines.     

Vaccines for low-income countries

Low-income countries typically lag behind industrialised nations, where the introduction of new vaccines is commonly tailored to the pressures of the commercial market. Happily in recent years this paradigm has started to change with the introduction of a univalent meningococcal A conjugate vaccine that is specifically targeted for the prevention of epidemic meningitis in Africa. The declaration of the 2010s as a New Decade of Vaccines, together with Millennium Development Goals 4 and 5, provide a strong mandate for a new approach to the development of vaccines for low-income countries, so that there has never been a more exciting time to work in this field. This review considers the opportunities and challenges of developing these new vaccines in the context of innovations in vaccinology, the need to induce protective immunity in the populations at risk and the requirement for strong partnership between the countries that will use these vaccines and different elements of the vaccine industry.     

A cross-reacting material CRM197 conjugate vaccine induces diphtheria toxin neutralizing antibody response in children and adolescents infected or not with HIV

Anti-diphtheria antibody levels decrease with aging, and frequent booster vaccinations are required to maintain herd immunity. We analyzed the diphtheria toxin neutralizing antibody (DT-Nab) response induced by a conjugate vaccine (meningococcal C polysaccharide-CRM₁₉₇) in HIV-vertically infected (HI) children and adolescents and healthy controls (HC) with matched age. We report the association of DT-Nab with the bactericidal antibodies to serogroup C meningococcus (MenC). Before vaccination, 21 HI patients (50%) had no protection against diphtheria (≤0.01 IU/ml of antibody) and only 8 (19%) showed complete protection (≥0.1 IU/ml). About half of the HC (56%) had complete protection before immunization and 6 subjects (12%) had no protection against diphtheria. After one and two vaccine injections, 96% of HC and 64% of HI vaccinees, respectively, showed full protection against diphtheria. These data indicate that CRM₁₉₇ was able to induce primary and/or booster response in both groups of individuals.     

Antibody persistence after serogroup C meningococcal conjugate vaccine in children with sickle cell disease

BackgroundA decline of protective antibody titers after MCC vaccine has been demonstrated in healthy children, this may be an issue of concern for risk groups. The aim of this study was to evaluate the persistence of bactericidal antibodies after MCC vaccine in sickle cell disease (SCD) patients. The type of vaccine used and booster response were also analyzed.MethodsSCD patients (n = 141) previously immunized with MCC vaccines had blood drawn 2–8 years after the last priming dose. They were distributed according to age at primary immunization into groups: <2 years and 2–13 years and evaluated by years since vaccination (2–3, 4–5 and 6–8). Serum bactericidal antibodies with baby rabbit complement (rSBA) and serogroup C-specific IgG concentrations were measured. The correlate of protection was rSBA titer ⩾8. Subjects with rSBA <8 received a booster dose and antibody levels re-evaluated after 4–6 weeks.ResultsFor children primed under 2 years of age rSBA titer ⩾8 was demonstrated in 53.3%, 21.7% and 35.0%, 2–3, 4–5, 6–8 years, respectively, after vaccination, compared with 70.0%, 45.0% and 53.5%, respectively, for individuals primed at ages 2–13 years. rSBA median titers and IgG median levels were higher in the older group. Six to eight years after vaccination the percentage of patients with rSBA titers ⩾8 was significantly higher in the group primed with MCC-TT (78.5%) compared with those primed with MCC-CRM₁₉₇ [Menjugate® (33.3%) or Meningitec® (35.7%)] (p = 0.033). After a booster, 98% achieved rSBA titer ⩾8.ConclusionImmunity to meningococcal serogroup C in SCD children declines rapidly after vaccination and is dependent on the age at priming. Booster doses are needed to maintain protection in SCD patients. Persistence of antibodies seems to be longer in individuals primed with MCC-TT vaccine comparing to those immunized with MCC-CRM₁₉₇.     

普萘洛尔或血管紧张素Ⅱ结合胃癌单克隆抗体与丝裂霉素交联物导向治疗的实验研究

观察了普萘洛尔和血管紧张素Ⅱ(AT-Ⅱ)对胃癌单克隆抗体3H11和丝裂霉素(MMC)交联物导向治疗的增强作用。在荷瘤裸鼠体内观察,交联物的抑瘤率达50%,联合应用普萘洛尔或AT-Ⅱ,可使抑瘤率分别提高到79%和60%。从¹³¹Ⅰ-3H11,在荷瘤裸鼠体内的生物学分布实验中也看到,普萘洛尔或AT-Ⅱ均能提高肿瘤组织对¹³¹Ⅰ-3H11的摄取量。此结果表明,血管活性物质确可通过改善肿瘤血管的血流灌注,增加肿瘤内交联物含量,增强导向治疗的疗效。     

A new iterative reconstruction technique for attenuation correction in high-resolution positron emission tomography

A new iterative reconstruction technique (NIRT) for positron emission computed tomography (PET), which uses transmission data for nonuniform attenuation correction, is described. Utilizing the general inverse problem theory, a cost functional which includes a noise term was derived. The cost functional was minimized using a weighted-least-square maximum a posteriori conjugate gradient (CG) method. The procedure involves a change in the Hessian of the cost function by adding an additional term. Two phantoms were used in a real data acquisition. The first was a cylinder phantom filled with uniformly distributed activity of 74 MBq of fluorine-18. Two different inserts were placed in the phantom. The second was a Hoffman brain phantom filled with uniformly distributed activity of 7.4 MBq of¹⁸F. Resulting reconstructed images were used to test and compare a new iterative reconstruction technique with a standard filtered backprojection (FBP) method. The results confirmed that NIRT, based on the conjugate gradient method, converges rapidly and provides good reconstructed images. In comparison with standard results obtained by the FBP method, the images reconstructed by NIRT showed better noise properties. The noise was measured as rms% noise and was less, by a factor of 1.75, in images reconstructed by NIRT than in the same images reconstructed by FBP. The distance between the Hoffman brain slice reconstructed by FBP and the perfect PET Hoffman brain slice created from the MRI image was 0.526, while the same distance for the Hoffman brain slice reconstructed by NIRT was 0.328. The NIRT method suppressed the propagation of the noise without visible loss of resolution in the reconstructed PET images.     

Cytokine-Stimulating (In Vitro) Effect on Human Monocytes of Conjugates of Soluble Curdlan and Albumin Microbeads

Four kinds of conjugates (BSA-M-SC-Ra, BSA-M-SC-Re, AP-M-SC-Ra, and AP-M-SC-Re) composed of soluble fragments of [β](1 ± 3)-D-glucan (SC) and bovine serum albumin (BSA) or amine-modifled polystyrene (AP) microbeads were prepared: the contents of SC on the microbeads were found to be 13.6, 8.0, 3.6, and 2.6 μg per 1 X 10⁸ microbeads, respectively. Unconjugated BSA and AP microbeads and SC did not show cytokine-stimulating activity. BSA-M-SC-Re, BSA-M-SC-Ra, and AP-M-SC-Re showed strong cytokine-stimulating activity in vitro, indicating that conjugates composed of inactive fragments of polysaccharides and microbeads are able to induce cytokine release from mononuclear phagocytes. Conjugates with the SC linked to BSA microbeads by the reducing terminal (BSA-M-SC-Re) showed a stronger effect than conjugates in which SC was linked with BSA microbeads at random positions (BSA-M-SC-Ra).