Pneumococcal carriage following PCV13 delivered as one primary and one booster dose (1 + 1) compared to two primary doses and a booster (2 + 1) in UK infants

In January 2020 the UK changed from a 2 + 1 schedule for 13-valent pneumococcal conjugate vaccine (PCV13) to a 1 + 1 schedule (doses at 3 and 12 months) based on a randomized immunogenicity trial comparing the two schedules. Carriage prevalence measured at the time of booster and 6 months later in 191 of the 213 study infants was 57 % (109/191) and 60 % (114/190) respectively. There were eight episodes of vaccine-type (VT) or vaccine-related 6C carriage in the 2 + 1 and six in the 1 + 1 group; ≥4-fold rises in serotype-specific IgG in 71 children with paired post-booster and follow up blood samples at 21–33 months of age were found in 20 % (7/35) of the 2 + 1 and 15 % (6/41) of the 1 + 1 group. VTs identified in carriage and inferred from serology were similar comprising 3, 19A and 19F. Dropping a priming dose from the 2 + 1 PCV 13 schedule did not increase VT carriage in the study cohort. Ongoing population level carriage studies will be important to confirm this

Genomics Reveals the Worldwide Distribution of Multidrug-Resistant Serotype 6E Pneumococci.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The pneumococcus is a leading pathogen infecting children and adults. Safe, effective vaccines exist, and they work by inducing antibodies to the polysaccharide capsule (unique for each serotype) that surrounds the cell; however, current vaccines are limited by the fact that only a few of the nearly 100 antigenically distinct serotypes are included in the formulations. Within the serotypes, serogroup 6 pneumococci are a frequent cause of serious disease and common colonizers of the nasopharynx in children. Serotype 6E was first reported in 2004 but was thought to be rare; however, we and others have detected serotype 6E among recent pneumococcal collections. Therefore, we analyzed a diverse data set of ∼1,000 serogroup 6 genomes, assessed the prevalence and distribution of serotype 6E, analyzed the genetic diversity among serogroup 6 pneumococci, and investigated whether pneumococcal conjugate vaccine-induced serotype 6A and 6B antibodies mediate the killing of serotype 6E pneumococci. We found that 43% of all genomes were of serotype 6E, and they were recovered worldwide from healthy children and patients of all ages with pneumococcal disease. Four genetic lineages, three of which were multidrug resistant, described ∼90% of the serotype 6E pneumococci. Serological assays demonstrated that vaccine-induced serotype 6B antibodies were able to elicit killing of serotype 6E pneumococci. We also revealed three major genetic clusters of serotype 6A capsular sequences, discovered a new hybrid 6C/6E serotype, and identified 44 examples of serotype switching. Therefore, while vaccines appear to offer protection against serotype 6E, genetic variants may reduce vaccine efficacy in the longer term because of the emergence of serotypes that can evade vaccine-induced immunity

The antibody response following a booster with either a 10- or 13-valent pneumococcal conjugate vaccine in toddlers primed with a 13-valent pneumococcal conjugate vaccine in early infancy

BACKGROUND Both the 13- and 10-valent pneumococcal conjugate vaccines (PCV-13; PCV-10) are immunogenic and effective against vaccine-type pneumococcal disease when given to young children. However, limited data are available regarding the interchangeability of these 2 vaccines. METHODS UK children (n = 178) who had previously been vaccinated with PCV-13 at 2 and 4 months were randomized to receive either a PCV-13 or a PCV-10 booster at 12 months of age. PCV-13 vaccine-type antipolysaccharide serum immunoglobulin G (IgG) concentrations and opsonophagocytic assay titers were measured before and at 1 and 12 months following vaccination. The primary objective was to assess noninferiority of PCV-10 compared with PCV-13. RESULTS For 8 of the PCV-10 serotypes at least 97% of participants in both groups had IgG concentrations ≥0.35 µg/mL at 1 month after vaccination; inferior responses were seen for serotypes 5 and 9V following the PCV-10 compared with the PCV-13 booster. Post booster geometric mean IgG concentrations and opsonophagocytic assay titers were significantly superior for most serotypes in PCV-13 compared with PCV-10 recipients, whereas similar or inferior responses were seen for serotypes 4, 18C, and 19F. Although some increase in antibody was seen in PCV-10 recipients against the serotypes 6A and 19A (serotypes that cross-react with 6B and 19F in PCV-10, respectively) at 1-month post booster, these responses were significantly lower than in the PCV-13 group. CONCLUSIONS In PCV-13 primed infants, a PCV-10 booster is generally less immunogenic than a PCV-13 booster. For the 3 serotypes in PCV-10 with higher antigen content and/or conjugation to diphtheria or tetanus toxoid carrier proteins, higher or similar booster responses were seen in PCV-10 recipients. Although these findings suggest that responses are generally better with a PCV-13 booster among PCV-13 primed children, the clinical significance of these differences in immunogenicity is unclear

Functional anti-polysaccharide IgG titres induced by unadjuvanted pneumococcal-conjugate vaccine when delivered by microprojection-based skin patch

Adequate access to effective and affordable vaccines is essential for the prevention of mortality due to infectious disease. Pneumonia – a consequence of Streptococcus pneumoniae infection – is the world's leading cause of death in children aged under 5 years. The development of a needle-free, thermostable pneumococcal-conjugate vaccine (PCV) could revolutionise the field by reducing cold-chain and delivery constraints. Skin patches have been used to deliver a range of vaccines, with some inducing significantly higher vaccine-specific immunogenicity than needle-injected controls in pre-clinical models, though they have yet to be used to deliver a PCV. We dry-coated a licensed PCV onto a microprojection-based patch (the Nanopatch) and delivered it to mouse skin. We analysed resulting anti-polysaccharide IgG responses. With and without adjuvant, anti-polysaccharide IgG titres induced by Nanopatch immunisation were significantly higher than dose-matched intramuscular controls. These improved responses were primarily obtained against pneumococcal serotypes 4 and 14. Importantly, capsule-specific IgG correlated with functionality in an opsonophagocytic killing assay. We demonstrate enhanced anti-PCV immunogenicity when delivered by Nanopatch over intramuscular injection. As the first study of a PCV delivered by a skin vaccination technology, this report indicates the potential for reduced costs and greater global distribution of such a vaccine

Anti-pneumococcal capsular polysaccharide antibody response and CD5 B lymphocyte subsets

The role of the CD19(+)CD5(+) and CD19(+)CD5(-) B-cell subpopulations in the antibody response to pneumococcal capsular polysaccharides (caps-PS) is controversial. In the present study we evaluated the role of the human CD19(+)CD5(+) and CD19(+)CD5(-) cell populations in the serotype-specific antibody response to caps-PS. After vaccination of 5 healthy human adults with Pneumovax® (PPV23), IgG anti-caps-PS serotype 4 antibody producing cells mainly resided in the CD19(+)CD5(-) B cell subset, as assessed by ELISpot analysis. Moreover, in a humanized SCID mice model, CD19(+)CD5(-) B cells were more effective than CD19(+)CD5(+) cells to produce IgG anti-cap-PS antibodies. Finally, an association was found between the level of IgG anti-caps-PS antibodies and the number of CD19(+)CD5(-) B cells in 33 humans vaccinated with PPV23. Taken together, our data suggest that CD5 defines a functionally distinct population of B cells in humans in the anti-caps-PS immune response.status: publishe

Tunneling and Suture of Thoracic Epidural Catheters Decrease the Incidence of Catheter Dislodgement

Background. Dislocation of epidural catheters (EC) is associated with early termination of regional analgesia and rare complications like epidural bleeding. We tested the hypothesis that maximum effort in fixation by tunneling and suture decreases the incidence of catheter dislocation. Methods. Patients scheduled for major surgery (n=121) were prospectively randomized in 2 groups. Thoracic EC were subcutaneously tunneled and sutured (tunneled) or fixed with adhesive tape (taped). The difference of EC length at skin surface level immediately after insertion and before removal was determined and the absolute values were averaged. Postoperative pain was evaluated by numeric rating scale twice daily and EC tips were screened microbiologically after removal. Results. Both groups did not differ with respect to treatment duration (tunneled: 109 hours ±46, taped: 97±37) and postoperative pain scores. Tunneling significantly reduced average extent (tunneled: 3 mm ±7, taped: 10±18) and incidence of clinically relevant EC dislocation (>20 mm, tunneled: 1/60, taped: 9/61). Bacterial contamination showed a tendency to be lower in patients with tunneled catheters (8/59, taped: 14/54, P=0.08). Conclusion. Thorough fixation of EC by tunneling and suturing decreases the incidence and extent of dislocation and potentially even that of bacterial contamination

Streptococcus pneumoniae serotype 1 burden in the African meningitis belt: Exploration of functionality in specific antibodies

Streptococcus pneumoniae serotype 1 (Sp1) constitutes an important cause of seasonal endemic meningitis in all age groups in the African meningitis belt. Despite a higher meningitis incidence, the Burkinabó population has an Sp1-specific antibody seroprevalence similar to that reported in the United Kingdom (UK). We aimed to establish whether the opsonophagocytic activity (OPA) of pneumococcal IgG naturally present in Burkina Faso differs from that seen in individuals in the UK and to compare the OPAs generated by natural and vaccine-induced immunity. Samples collected from pneumococcal vaccine-naive Burkinabó and UK subjects were matched for age (1 to 39 years) and anti-Sp1 IgG level, analyzed for OPA to 3 S. pneumoniae serotypes (1, 5, and 19A), and compared to postvaccine samples. Furthermore, the Burkinabó samples were assessed for IgG avidity and sero-type-specific IgM concentrations. One hundred sixty-nine matched serum samples from both populations were selected. A greater proportion of Burkinabó subjects aged 1 to 19 years had functional Sp1 activity (OPA ≥ 8) compared to UK subjects (12% versus 2%, P < 0.001); however, the proportions were similar among adults (9%). The correlation between Sp1 IgG concentration and OPA was good (P < 0.001), but many individuals had nonfunctional IgG, which was not related to avidity. While the Sp1 IgM concentrations correlated with OPA, not all of the function in serum samples with low IgG could be attributed to IgM. Finally, vaccine-induced Sp1-specific IgG was more functional than equivalent amounts of naturally occurring IgG. In conclusion, despite a substantially higher pneumococcal meningitis incidence, no decreased functional immunity to Sp1 could be evidenced in the Burkinabó population compared to that in the population from the UK. Furthermore, the naturally induced antibodies were less functional than vaccine-induced antibodies.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Pneumococcal conjugate vaccine 13 delivered as one primary and one booster dose (1 + 1) compared with two primary doses and a booster (2 + 1) in UK infants: a multicentre, parallel group randomised controlled trial.

BACKGROUND: Infants in the UK were first offered a pneumococcal conjugate vaccine (PCV7) in 2006, given at 2 and 4 months of age and a booster dose at 13 months (2 + 1 schedule). A 13-valent vaccine (PCV13) replaced PCV7 in 2010. We aimed to compare the post-booster antibody response in UK infants given a reduced priming schedule of PCV13 (ie, a 1 + 1 schedule) versus the current 2 + 1 schedule and to assess the potential effect on population protection. METHODS: In this multicentre, parallel group, randomised controlled trial, we recuited infants due to receive their primary immunisations aged up to 13 weeks on first vaccinations by information booklets mailed out via the NHS Child Health Information Service and the UK National Health Application and Infrastructure Services. Eligible infants were randomly assigned (1:1) to receive PCV13 at 2, 4, and 12 months (2 + 1 schedule) or 3 and 12 months of age (1 + 1 schedule) delivered with other routine vaccinations. Randomisation was done by computer-generated permuted block randomisation, with a block size of six. Participants and clinical trial staff were not masked to treatment allocation. The primary endpoint was serotype-specific immunoglobulin G concentrations values (geometric mean concentrations [GMC] in μg/mL) measured in blood samples collected at 13 months of age. Analysis was by modified intention to treat with all individuals included by randomised group if they had a laboratory result. This trial is registered on the EudraCT clinical trial database, number 2015-000817-32, and ClinicalTrials.gov, number NCT02482636. FINDINGS: Between September, 2015, and June, 2016, 376 infants were assessed for eligibility. 81 infants were excluded for not meeting the inclusion criteria (n=50) or for other reasons (n=31). 213 eligible infants were enrolled and randomly allocated to group 1 (n=106; 2 + 1 schedule) or to group 2 (n=107; 1 + 1 schedule). In group 1, 91 serum samples were available for analysis 1 month after booster immunisation versus 86 in group 2. At month 13, post-booster, GMCs were equivalent between schedules for serotypes 3 (0·61 μg/mL in group 1 vs 0·62 μg/mL in group 2), 5 (1·74 μg/mL vs 2·11 μg/mL), 7F (3·98 μg/mL vs 3·36 μg/mL), 9V (2·34 μg/mL vs 2·50 μg/mL), and 19A (8·38 μg/mL vs 8·83 μg/mL). Infants given the 1 + 1 schedule had significantly greater immunogenicity post-booster than those given the 2 + 1 schedule for serotypes 1 (8·92 μg/mL vs 3·07 μg/mL), 4 (3·43 μg/mL vs 2·55 μg/mL), 14 (16·9 μg/mL vs 10·49 μg/mL), and 19F (14·76 μg/mL vs 11·12 μg/mL; adjusted p value range <0·001 to 0·047). The 2 + 1 schedule was superior for serotypes 6A, 6B, 18C and 23F (adjusted p value range <0·0001 to 0·017). In a predefined numerical subset of all of the infants recruited to the study (n=40 [20%]), functional serotype-specific antibody was similar between schedules. 26 serious adverse events were recorded in 21 (10%) infants across the study period; 18 (n=13) were in the 2 + 1 group and eight (n=8) in the 1 + 1 group. Only one serious adverse event, a high temperature and refusal to feed after the first vaccination visit in a child on the 2+1 schedule was considered related to vaccine. INTERPRETATION: Our findings show that for nine of the 13 serotypes in PCV13, post-booster responses in infants primed with a single dose are equivalent or superior to those seen following the standard UK 2 + 1 schedule. Introducing a 1 + 1 schedule in countries with a mature PCV programme and established herd immunity is likely to maintain population control of vaccine-type pneumococcal disease. FUNDING: NIHR and the Bill & Melinda Gates Foundation

Correction for van Tonder et al., Genomics Reveals the Worldwide Distribution of Multidrug-Resistant Serotype 6E Pneumococci.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files