The role of immune correlates of protection on the pathway to licensure,policy decision and use of group B Streptococcus vaccines for maternal immunization: considerations from World Health Organization consultations

The development of a group B Streptococcus (GBS) vaccine for maternal immunization constitutes a global public health priority, to prevent GBS-associated early life invasive disease, stillbirth, premature birth, maternal sepsis, adverse neurodevelopmental consequences, and to reduce perinatal antibiotic use. Sample size requirements for the conduct of a randomized placebo-controlled trial to assess vaccine efficacy against the most relevant clinical endpoints, under conditions of appropriate ethical standards of care, constitute a significant obstacle on the pathway to vaccine availability. Alternatively, indirect evidence of protection based on immunologic data from vaccine and sero-epidemiological studies, complemented by data from opsonophagocytic in vitro assays and animal models, could be considered as pivotal data for licensure, with subsequent confirmation of effectiveness against disease outcomes in post-licensure evaluations. Based on discussions initiated by the World Health Organization we present key considerations about the potential role of correlates of protection towards an accelerated pathway for GBS vaccine licensure and wide scale use. Priority activities to support progress to regulatory and policy decision are outlined.     

Human native endocarditis caused by Streptococcus canis—a case report

We report a very rare case of Streptococcus canis native infective endocarditis in a 73‐year‐old woman living in close contact with her dog. Her echocardiography showed large calcifications in the mitral annulus, massive regurgitation below the posterior leaflet, and adjacent vegetation. Blood culture was positive for Streptococcus Lancefield group G. A coronary artery bypass and mitral valve replacement had to be done. Streptococcus canis was detected in a heart valve using a broad range PCR followed by 16S rRNA and confirmed by tuf gene sequencing, while tissue culture remained negative. The patient was not bitten by her dog nor did she have comorbidities or skin ulcers. She fully recovered.     

Cost-effectiveness of maternal immunization against neonatal invasive Group B Streptococcus in the Netherlands

BackgroundNeonatal invasive Group B Streptococcus (GBS) infection causes considerable disease burden in the Netherlands. Intrapartum antibiotic prophylaxis (IAP) prevents early-onset disease (EOD), but has no effect on late-onset disease (LOD). A potential maternal GBS vaccine could prevent both EOD and LOD by conferring immunity in neonates.ObjectiveExplore under which circumstances maternal vaccination against GBS would be cost-effective as an addition to, or replacement for the current risk factor-based IAP prevention strategy in the Netherlands.MethodsWe assessed the maximum cost-effective price per dose of a trivalent (serotypes Ia, Ib, and III) and hexavalent (additional serotypes II, IV, and V) GBS vaccine in addition to, or as a replacement for IAP. To project the prevented costs and disease burden, a decision tree model was developed to reflect neonatal GBS disease and long-term health outcomes among a cohort based on 169,836 live births in the Netherlands in 2017.ResultsUnder base-case conditions, maternal immunization with a trivalent vaccine would gain 186 QALYs and prevent more than €3.1 million in health care costs when implemented in addition to IAP. Immunization implemented as a replacement for IAP would gain 88 QALYs compared to the current prevention strategy, prevent €1.5 million in health care costs, and avoid potentially ~ 30,000 IAP administrations. The base-case results correspond to a maximum price of €58 per dose (vaccine + administration costs; using a threshold of €20,000/QALY). Expanding the serotype coverage to a hexavalent vaccine would only have a limited additional impact on the cost-effectiveness in the Netherlands.ConclusionsA maternal GBS vaccine could be cost-effective when implemented in addition to the current risk factor-based IAP prevention strategy in the Netherlands. Discontinuation of IAP would save costs and prevent antibiotic use, however, is projected to lead to a lower health gain compared to vaccination in addition to IAP.     

Differentiation between Streptococcus pneumoniae and other viridans group streptococci by matrix-assisted laser desorption/ionization time of flight mass spectrometry

ObjectivesMatrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) is becoming the method of choice for bacterial identification. However, correct identification by MALDI-TOF of closely related microorganisms such as viridans streptococci is still cumbersome, especially in the identification of S. pneumoniae. By making use of additional spectra peaks for S. pneumoniae and other viridans group streptococci (VGS). We re-identified viridans streptococci that had been identified and characterized by molecular and phenotypic techniques by MALDI-TOF.MethodsVGS isolates (n = 579), 496 S. pneumoniae and 83 non-S. pneumoniae were analysed using MALDI-TOF MS and the sensitivity and specificity of MALDI-TOF MS was assessed. Hereafter, mass spectra analysis was performed. Presumptive identification of proteins represented by discriminatory peaks was performed by molecular weight matching and the corresponding nucleotides sequences against different protein databases.ResultsUsing the Bruker reference library, 495 of 496 S. pneumoniae isolates were identified as S. pneumoniae and one isolate was identified as non-S. pneumoniae. Of the 83 non-S. pneumoniae isolates, 37 were correctly identified as non-S. pneumoniae, and 46 isolates as S. pneumoniae. The sensitivity of the MALDI-TOF MS was 99.8% (95% confidence interval (CI) 98.9–100) and the specificity was 44.6% (95% CI 33.7–55.9). Eight spectra peaks were mostly present in one category (S. pneumoniae or other VGS) and absent in the other category and inversely. Two spectra peaks of these (m/z 3420 and 3436) were selected by logistic regression to generate three identification profiles. These profiles could differentiate between S. pneumoniae and other VGS with high sensitivity and specificity (99.4% and 98.8%, respectively).ConclusionsSpectral peaks analysis based identification is a powerful tool to differentiate S. pneumoniae from other VGS species with high specificity and sensitivity and is a useful method for pneumococcal identification in carriage studies. More research is needed to further confirm our findings. Extrapolation of these results to clinical strains need to be deeply investigated.     

New immunosuppressive agents in transplantation

Immunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival.Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection.The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials.Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38…) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology.     

Skipped vertebral spontaneous spondylodiscitis caused by Granulicatella adiacens: Case report and a systematic literature review

BackgroundGranulicatella adiacens is a nutritional variant of streptococcus (NVS), which has been rarely reported as an etiologic agent in spondylodiscitis (SD).Material and methodsWe report a case of a 51-year-old male with from chronic low-back pain associated with right sciatica and ipsilateral monoparesis. Spinal MRI showed radiological signs on L1-L2 and L5-S1 discs consistent with SD. We also performed a systematic review of the pertinent literature in order to retrieve all the key information regarding microbiological and clinical features.ResultsIncluding our patients, seven cases with a mean age 56 ± 10.2 years were reported in English literature. Six patients were conservatively managed with antibiotic therapy (66%), whereas three with surgery in combination with antibiotics (33%). An endocarditis was associated in three cases, and a pacemaker infection in one. All patients received targeted antibiotic therapy resulting in a quick improvement of clinical symptoms with favorable outcome. Our case is the only with a skip spontaneous SD, which needed a surgical decompression due to the associated neurological symptoms.ConclusionsThis incidence of SD sustained by Granulicatella adiances could be underestimated due to their particular microbiological conditions requested for their cultures. However, this infection should be suspected in cases of culture-negative SD, especially when associated with endocarditis.     

Cas9 function and host genome sampling in Type II-A CRISPR–Cas adaptation

To acquire the ability to recognize and destroy virus and plasmid invaders, prokaryotic CRISPR–Cas systems capture fragments of DNA within the host CRISPR locus. Our results indicate that the process of adaptation by a Type II-A CRISPR–Cas system in Streptococcus thermophilus requires Cas1, Cas2, and Csn2. Surprisingly, we found that Cas9, previously identified as the nuclease responsible for ultimate invader destruction, is also essential for adaptation. Cas9 nuclease activity is dispensable for adaptation. In addition, our studies revealed extensive, unbiased acquisition of the self-targeting host genome sequence by the CRISPR–Cas system that is masked in the presence of active target destruction.     

An unreported case of Streptococcus cristatus septic arthritis of wrist in a neonate

Septic Arthritis of the wrist is rare in the paediatric population due to its extraarticular metaphysis. We report here a case of wrist septic arthritis in a neonate caused by an uncommon causative organism, Streptococcus cristatus.A 15 days old male child was referred with the complaint of swelling and decreased movement of the left wrist for 5 days. Local examination revealed warm, tender, erythematous and fluctuant swelling over the dorso-ulnar aspect of the left wrist. Ultrasonography of the affected region was suggestive of focal fluid collection in the wrist and periosteal elevation of the distal ulna. Aspiration followed by arthrotomy of the wrist joint was performed and multiple holes were made in the distal ulnar metaphysis using 0.8mm k-wire. The pus culture was positive for Streptococcus cristatus, sensitive to vancomycin, which was given for a total of 4 weeks. At one year follow up the child had a full, painless range of motion with no functional deficit. Final follow up x rays of the left wrist were normal.Streptococcus cristatus strains are described as Gram-positive, catalase-negative cocci, approximately 1 μm in diameter growing in chains and were originally isolated from the human throat and oral cavities. Its association with bone and joint infections has not been described in the literature. To our knowledge, this is the first case of isolated septic arthritis of wrist in a 15 days old child caused by Streptococcus cristatus.To conclude, wrist septic arthritis in a neonate is a rare entity. With the advanced diagnostics, species-level identification of rare organism like Streptococcus cristatus is possible along with antibiotic sensitivity for appropriate therapy. Early surgical decompression and intravenous culture-directed antibiotics are the mainstays of management.     

Safety and immunogenicity of a prototype recombinant alpha-like protein subunit vaccine (GBS-NN) against Group B Streptococcus in a randomised placebo-controlled double-blind phase 1 trial in healthy adult women

BackgroundGroup B Streptococcus (GBS) is the leading cause of life-threatening infections in new-borns and may cause invasive disease, stillbirth and preterm delivery during pregnancy. While no licensed vaccine exists, maternal immunization might protect against neonatal disease and adverse pregnancy outcomes. We assessed the safety and immunogenicity of a prototype vaccine consisting of the fused N-terminal domains of the AlphaC and Rib surface proteins of GBS (GBS-NN).MethodsGBS-NN was tested in a randomised, double-blind, placebo-controlled, parallel group, phase I study, in healthy non-pregnant women. A dose-escalation phase, with two doses, four weeks apart, of 10, 50 or 250 µg, administered with or without aluminium hydroxide, was initially assessed (n = 60). This was followed by a dose-confirmation study, where one dose of 100 µg adjuvanted GBS-NN was compared with two doses of either 50 or 100 µg adjuvanted GBS-NN, again administered with four weeks interval between the doses (n = 180). Safety and immunogenicity were monitored for one year.ResultsGBS-NN was well tolerated with some, mostly mild, injection site reactions observed. Adjuvant significantly increased antibody concentrations and the response was boosted by a second dose. The IgG GMCs remained strongly elevated during the whole one-year duration of the study. Maximal responses occurred after two 50 µg doses, resulting in IgG GMC of 16.9 µg/ml at the primary immunological endpoint, twelve weeks after the first dose. For this regimen, 100% and 89% of the subjects achieved antibody levels above the arbitrary thresholds of 1 and 4 µg/ml, respectively. The added beneficial effect of a second dose was most pronounced for subjects with pre-existing IgG levels below the median of the entire cohort.ConclusionThe prototype GBS-NN vaccine was found to be well tolerated and highly immunogenic with an optimal regimen of two doses of 50 µg in the presence of adjuvant. Further development of a maternal vaccine based on the N-terminal domains of the alpha-like protein family of GBS is warranted (NCT02459262).