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Background: Additional safe and effective vaccines are needed to control the COVID-19 pandemic. Methods: HERALD is an ongoing phase 2b/3 randomised, observer-blinded, placebo-controlled clinical trial in ten countries in Europe and Latin America. SARS-CoV-2 naive adults were randomised 1:1 to receive two doses of CVnCoV mRNA vaccine candidate or placebo 28 days apart. Primary efficacy analysis included symptomatic COVID-19 more than 14 days after second dose. Solicited adverse events (AEs) were assessed in phase 2b participants and unsolicited AEs in all participants. The study is registered at ClinicalTrials.gov (NCT04652102). Findings: Between 11 December 2020 and 12 April 2021, 39 680 participants were randomised and 39 529 received CVnCoV (19 783) or placebo (19 746). Overall VE was 48·2% (95% CI: 31·0–61·4; 83/12 851 vs. 145/12 221 in CVnCoV and placebo recipients, respectively). Overall VE against moderate-to-severe COVID-19 was 70·7% (95% CI: 42·5–86·1; 12/12 851 vs. 37/12 211, respectively). In participants aged 18–60 years VE was 52·5% (95% CI: 36·2–64·8; 71/11 532 vs. 136/11 031, respectively). Too few cases occurred in participants aged ≥61 years (CVnCoV: 12, placebo: 9) precluding VE evaluation. Wild type SARS-CoV-2 was detected in 7/204 (3%) sequenced cases, with 14 variants being responsible for the other cases. Solicited adverse events, mostly systemic, were more common in CVnCoV recipients; 542/2002 CVnCoV recipients and 61/1980 placebo recipients reported grade 3 events. Unsolicited serious AEs were reported for 82/19 746 CVnCoV recipients and 66/19 746 placebo recipients; 8 and 2 SAEs, respectively were considered related to vaccination. Fatal SAEs were reported for 8 and 6 CVnCoV and placebo recipients. Interpretation: CVnCoV is efficacious in the prevention of COVID-19 of any severity and has an acceptable safety profile. Trial Registration: Study number: ClinicalTrials.gov Identifier: NCT04652102. Funding: This trial was funded by the German Federal Ministry of Education and Research (grant 01KI20703), and CureVac AG. Declaration of Interest: MB declares institutional funding from CureVac during the conduct of this study, from Janssen Vaccines, molecular partners, and Merck outside of the submitted work, and consulting fees from Janssen Vaccines. EJLDB, and MFMR, TO and XSL declare institutional funding from CureVac during the conduct of this study. LE, and LG declare institutional funding from CureVac during the conduct of this study and outside of the submitted work. CFL declares institutional funding from CureVac during the conduct of this study, and outside of the submitted work, and is a member of WHO Covid-19 Vaccine Effectiveness Working Group and WHO Product Development for Vaccines Advisory Committee (PDVAC). CL declares institutional funding from CureVac during the conduct of this study, and is a member of the of German Society of Infection board. ILR declares institutional funding from CureVac during the conduct of this study and from J &J, and OSE Immunotherapeutics outside of the submitted work. PGK declares institutional funding from CureVac during the conduct of this study, and is a member of the scientific advisory board for the HERALD clinical trial. VVRH declares institutional funding from CureVac during the conduct of this study, and speakers fees from Gilead outside of the submitted work. HJ declares consultant fees from CureVac, is the Medical Responsible Person for the HERALD clinical trial, and is co-chair of DSMB for the HERALD clinical trial. AK and PM are employed by CureVac, and hold stock options. OSK declares consultant fees from CureVac during the conduct of this study, and is a member of the DSMB for a CVnCoV phase 1 trial. TV declares consultant fees from CureVac during the conduct of this study, and consultant fees from CureVac, AstraZeneca, Pfizer, Johnson&Johnson, and Moderna outside of the submitted work. LO is employed by CureVac, and holds stock options, and is the holder of a pending patent. The other authors declare no competing interests. Ethical Approval: The trial protocol and amendments have been approved by the appropriate independent ethics committee or institutional review board at each study centre

Purpose To investigate the natural history and genetic associations of drusenoid pigment epithelial detachment (DPED) associated with age-related macular degeneration (AMD). Design Retrospective analysis of a prospective cohort study. Participants Of the 4203 Age-Related Eye Disease Study 2 (AREDS2) participants, 391 eyes (325 participants) had DPED without late AMD at the time of DPED detection. Genetic analyses included 120 white AREDS2 participants and 145 Age-Related Eye Disease Study (AREDS) participants with DPED. Methods Baseline and annual stereoscopic fundus photographs were graded centrally to detect DPED, a well-defined yellow elevated mound of confluent drusen ≥433 μm in diameter, and to evaluate progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD. Five single nucleotide polymorphisms (CFH [rs10611670], C3 [rs2230199], CFI [rs10033900], C2/CFB [rs114254831], ARMS2 [rs10490924]) and genetic risk score (GRS) group were investigated for association with DPED development. Kaplan–Meier analyses and multivariable proportional hazard regressions were performed. Main Outcome Measures Progression rates to late AMD and decrease of ≥3 lines in visual acuity (VA) from the time of DPED detection; association of rate of DPED development with genotype. Results Mean (standard deviation [SD]) follow-up time from DPED detection was 4.7 (0.9) years. DPED was associated with increased risk of progression to late AMD (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.98–2.82; P Conclusions This study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression.

Purpose To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement. Design Prospective cohort study within a controlled clinical trial. Participants Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50–85 years. Methods Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype. Main Outcome Measures (1) Presence or development of GA; (2) change in the square root of GA area over time. Results At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27–0.30) and incident GA (0.28 mm/year; 0.27–0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P Conclusions Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a rare, multisystemic, progressive lysosomal storage disease caused by deficient activity of the iduronate-2-sulfatase (I2S) enzyme. Accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate results in a broad range of disease manifestations that are highly variable in presentation and severity; notably, approximately two-thirds of individuals are affected by progressive central nervous system involvement. Historically, management of this disease was palliative; however, during the 1990s, I2S was purified to homogeneity for the first time, leading to cloning of the corresponding gene and offering a means of addressing the underlying cause of MPS II using enzyme replacement therapy (ERT). Recombinant I2S (idursulfase) was produced for ERT using a human cell line and was shown to be indistinguishable from endogenous I2S. Preclinical studies utilizing the intravenous route of administration provided valuable insights that informed the design of the subsequent clinical studies. The pivotal Phase II/III clinical trial of intravenous idursulfase (Elaprase®; Shire, Lexington, MA, USA) demonstrated improvements in a range of clinical parameters; based on these findings, intravenous idursulfase was approved for use in patients with MPS II in the USA in 2006 and in Europe and Japan in 2007. Evidence gained from post-approval programs has helped to improve our knowledge and understanding of management of patients with the disease; as a result, idursulfase is now available to young pediatric patients, and in some countries patients have the option to receive their infusions at home. Although ERT with idursulfase has been shown to improve somatic signs and symptoms of MPS II, the drug does not cross the blood-brain barrier and so treatment of neurological aspects of the disease remains challenging. A number of novel approaches are being investigated, and these may help to improve the care of patients with MPS II in the future.

15th Annual Research Meeting of the WORLDSymposium(TM) -- FEB 04-07, 2019 -- Orlando, FL WOS: 000457351700338 … WORLDSymposium

Purpose: To report the clinical outcome after intravitreal dexamethasone implant in patients with retinitis pigmentosa and cystoid macular edema. Methods: Multicenter retrospective case series of eyes with retinitis pigmentosa and cystoid macular edema that underwent intravitreal dexamethasone implant. Primary outcome measures were best-corrected visual acuity in LogMAR and central macular thickness. Statistical analyses used two-tailed comparison with Wilcoxon signed-rank test. Results: There were a total of 45 eyes from 34 patients with a mean age of 32.7 years (range 16-57) and mean follow-up of 15.5 ± 13.0 months. At Month 3 after the first injection, mean initial best-corrected visual acuity improved from 0.61 ± 0.38 (20/81) to 0.37 ± 0.16 (20/47) (P = 0.012), whereas mean central macular thickness (m) decreased from 506 ± 288 m to 311.7 ± 71.6 m (P < 0.001) and mean intraocular pressure increased from 15.7 ± 2.3 mmHg to 19.8 ± 11.0 mmHg (P = 0.01). Fourteen eyes had multiple injections (1-7 reinjections) at a mean interval of 6 months. Treatment effect was durable with multiple injections, but with seven eyes developing visually significant cataracts. Conclusion: Best-corrected visual acuity improved up to 4 months in around half of the eyes. Eyes that benefited the most were pseudophakic, steroid nonresponsive, with large initial central macular thickness, and profuse fluorescein dye leakage. © Ophthalmic Communications Society, Inc.

The development of meningococcal serogroup B vaccines has been a worldwide public health priority based on continuing disease burden, combined with the scientific challenges associated with antigen identification. A new multicomponent vaccine, 4CMenB, is currently being evaluated for global licensure. The multicomponent strategy accounts for multiple surface antigens and, therefore, provides varied opportunities to induce bactericidal antibodies. 4CMenB contains four components: outer membrane vesicles from the New Zealand MenB outbreak strain, fHbp, NadA and NHBA. In early clinical studies protective antibody levels with acceptable tolerability outcomes were observed in persons who received 4CMenB starting at as young as 2 months of age. A meningococcal antigen-typing system has been developed to bridge clinical trial data with circulating strains. This article describes the early clinical development program and the rationale for Phase III study design and effectiveness evaluations.

Laboratory staff who work with meningococcal isolates are at increased risk for developing invasive disease relative to the general population. This was the first study of laboratory workers who received both a conjugate vaccine against meningococcal serogroups A, C, W-135, and Y (Men ACWY-CRM, Menveo) and an investigational multicomponent vaccine against serogroup B containing factor H binding protein, neisserial adhesin A, Neisseria heparin binding antigen, and New Zealand strain outer membrane vesicles (4CMenB). Healthy adults (18 to 50 years of age) received three doses of 4CMenB at baseline, 2 months, and 6 months followed by a single dose of MenACWY-CRM 1 month later. Immunogenicity was assessed via serum bactericidal assay using human complement (hSBA) at 1 month postvaccination; solicited reactogenicity and adverse events were monitored. Fifty-four participants enrolled. Bactericidal immune responses were evident after each dose of 4CMenB, as assessed by hSBA geometric mean titers and percentages of subjects with hSBA titers of ≥4 against the test strains or a 4-fold rise in titer over baseline. At 1 month postvaccination, most MenACWY-CRM recipients had hSBA titers of ≥8 against serogroups A, C, W-135, and Y. Few participants discontinued due to an adverse event or vaccine reaction. Rates of solicited reactions were lower after MenACWY-CRM than after 4CMenB administration. Sequential administration of 4CMenB and MenACWY-CRM provided robust evidence of an immune response against serogroups A, B, C, W-135, and Y in laboratory workers routinely exposed to meningococcal isolates.

Background Neisserial surface protein A (NspA) is a highly conserved, surface-exposed outer membrane protein of Neisseria meningitidis that has been shown to induce a bactericidal immune response in animals against all pathogenic Neisserial serogroups. Methods Healthy 18–50-year-old adults were assigned to receive, in a dose escalating manner, 3 doses of 1 of 5 formulations of an experimental, unfolded, recombinant NspA (rNspA) vaccine or placebo, or 1 dose of commercially available quadravalent (A, C, Y, W-135) meningococcal polysaccharide vaccine (Menomune ® ). Adverse events were collected during the first week post-immunization, prior to the next dose and 1 month after the last dose. Serum for measurement of hematological and biochemical parameters and antibodies by enzyme immunoassay and bactericidal assay were measured before the first dose, prior to the second dose and 1 month after the last dose of vaccine. Results The rNspA vaccine was well tolerated by recipients. Injection-site pain was reported more frequently by recipients of the three highest doses of rNspA compared to placebo but at similar rates to the licensed meningococcal polysaccharide vaccine. Adverse events were reported less frequently after subsequent doses in the three-dose series. An antibody rise measured by enzyme immunoassay was elicited with a dose-related increase that reached a maximum with the 125 μg dose. Prolongation of the dosing interval between the second and third dose appeared to be associated with increased antibody levels. No bactericidal antibodies were detected after any of the rNspA formulations. Conclusions The unfolded rNspA meningococcal vaccine was well tolerated and immunogenic in healthy adult volunteers but did not elicit bactericidal antibodies.

Purpose: To evaluate the safety and efficacy of recombinant human iduronate-2-sulfatase (idursulfase) in the treatment of mucopolysaccharidosis II. Methods: Ninety-six mucopolysaccharidosis II patients between 5 and 31 years of age were enrolled in a double-blind, placebo-controlled trial. Patients were randomized to placebo infusions, weekly idursulfase (0.5 mg/kg) infusions or every-other-week infusions of idursulfase (0.5 mg/kg). Efficacy was evaluated using a composite endpoint consisting of distance walked in 6 minutes and the percentage of predicted forced vital capacity based on the sum of the ranks of change from baseline. Results: Patients in the weekly and every-other-week idursulfase groups exhibited significant improvement in the composite endpoint compared to placebo (P = 0.0049 for weekly and P = 0.0416 for every-other-week) after one year. The weekly dosing group experienced a 37-m increase in the 6-minute-walk distance (P = 0.013), a 2.7% increase in percentage of predicted forced vital capacity (P = 0.065), and a 160 mL increase in absolute forced vital capacity (P = 0.001) compared to placebo group at 53 weeks. Idursulfase was generally well tolerated, but infusion reactions did occur. Idursulfase antibodies were detected in 46.9% of patients during the study. Conclusion: This study supports the use of weekly infusions of idursulfase in the treatment of mucopolysaccharidosis II.

Purpose . To investigate the retinal survival time following central retinal artery occlusion (CRAO). Methods . In 38 elderly, atherosclerotic and hypertensive rhesus monkeys, transient CRAO (varying from 97 to 240 min) was produced by temporarily clamping the CRA at its site of entry into the optic nerve. Stereoscopic color fundus photography, fluorescein fundus angiography, electroretinography (ERG), and visual evoked potential (VEP) recording were performed before and during CRA clamping, after unclamping, and serially thereafter. After unclamping of the CRA, the animals were followed for variable lengths of time (median duration 8·14 weeks). Finally, the eyes and optic nerves were examined histologically. The data on ERG changes were analyzed in the following four time frames: (1) baseline before CRA clamping, (2) during CRA clamping, (3) immediately after unclamping, and (4) at the end of follow-up. Duration of CRAO was divided into four groups: 97, 105–120, 150–165, and ≥180 min. Results . A ‘negative ERG’ appeared during CRA clamping. With removal of the CRA clamp, there was b-wave recovery, with differential rates of recovery of ERG-eyes with shorter CRAO recovered sooner than those with longer occlusion. On removal of clamp, recovery was seen in scotopic 24 dB b-wave, photopic 0 dB single flash b-wave and 30 Hz flicker, with the b/a ratio of the combined rod and cone response and selective rod response showing statistically significant differences amongst the shorter and longer periods of CRAO. A delayed normalization of the depressed b/a ratio immediately after CRA reperfusion may indicate high-grade ischemic damage. At the final follow-up test session, no clear-cut derangement of any ERG parameter was seen for any group, with subtotal b-wave amplitude recovery for all groups. Longer CRAO produced incomplete VEP recovery. On histology, in the macular retina, eyes with CRAO for 97 min showed practically no damage, but duration of CRAO was found to be significantly associated with the amount of damage in the ganglion cell layer ( p =0·009) and inner nuclear layer ( p =0·017). Outer nuclear and plexiform layers and photoreceptors showed no damage at all with CRAO. There was no significant association of the ERG measures and histologic changes with any of the residual retinal circulation variables. Conclusions . Our electrophysiologic, histopathologic and morphometric studies showed that the retina of old, atherosclerotic, hypertensive rhesus monkeys suffers no detectable damage with CRAO of 97 min but above that level, the longer the CRAO, the more extensive the irreversible damage. The study suggests that CRAO lasting for about 240 min results in massive irreversible retinal damage.

The epidemiology of invasive Streptococcus agalactiae (GBS) disease was evaluated in South African children. Records of 208/220 children in whom GBS was isolated between January 1997 and December 1999 were reviewed. These included 63%, 31.7% and 5.3% children with early- (EOD,7 days of age), late- (LOD, age 7-90 days) and childhood-onset disease (COD, age90 days), respectively. The overall burden of EOD and LOD were 2.06 and 1/1000 live births, respectively. The overall mortality was 19.8% and 13.6% for infants with EOD and LOD, respectively. Risk factors for mortality in infants with EOD and LOD included septic shock (82.1% vs 1.9%), prematurity (35.2% vs 9.6%), low birthweight (29.2% vs 11.0%) and a leucocyte count5000/mm(3) (43.5% vs 18.6%). Eight (72.7%) of 11 children with COD had an immunosuppressive, predisposing cause for invasive bacterial disease. In infants with EOD and LOD, serotype III isolates caused 49.2% and 75.7% of disease, respectively, and, together with serotype Ia isolates, caused 78.9% and 100% of invasive disease, respectively. Invasive GBS disease is common in South African infants and current strategies aimed at reducing the burden of the disease should be reconsidered.

Mucopolysaccharidosis II (MPS II), also known as Hunter syndrome, is a rare X-linked recessive lysosomal storage disorder with an incidence of 1 in 100 000 to 160 000 live births. The clinical disease is caused by a deficiency of iduronate-2-sulfatase, which results in a chronic and progressive accumulation of glycosaminoglycans or GAGs in nearly all cell types, tissues and organs of the body. Clinical manifestations of MPS II disease include airway obstruction and compromised lung capacity, cardiomyopathy and valvular heart disease, hepatosplenomegaly, severe skeletal deformities, and neurological decline in most patients. The lack of an effective treatment and the successes of enzyme replacement therapies (ERTs) for other lysosomal storage diseases motivated the development of an ERT for MPS II. Iduronate-2-sulfatase (idursulfase) was produced by recombinant DNA technology in a fully human protein production system which, importantly, resulted in the production of idursulfase with human glycosylation. The non-clinical development of idursulfase progressed from proof-of-principle pharmacodynamic studies, to dose and dose-frequency studies, to an analysis of tissue biodistribution of the enzyme, and finally to pharmacokinetic and toxicological assessments. The clinical development of the final drug product, called Elaprase® (Shire Human Genetic Therapies, Inc., Lexington, MA), consisted of an initial Phase I/II study, followed by a Phase II/III pivotal trial. The results of the Phase II/III showed that intravenous infusions of Elaprase were generally well tolerated, and that a weekly dosing regimen provided significant clinical benefit to MPS II patients as demonstrated by improvements in walking ability and pulmonary function. Elaprase received marketing authorisation in the USA in 2006 and in Europe in 2007. During this era, the development of Elaprase as an effective therapy for MPS II patients, was part of a continuum of many important scientific and medical advances in the field of rare genetic diseases.

The safety, immunogenicity, and impact on carriage of a nonvalent pneumococcal vaccine given at ages 6, 10, and 14 weeks were examined in a double-blind, randomized, placebo-controlled trial in 500 infants in Soweto, South Africa. No serious local or systemic side effects were recorded. Significant antibody responses to all pneumococcal serotypes were observed 4 weeks after the third dose. Haemophilus influenzae type b polyribosylribitol phosphate (geometric mean titer, 11.62 microg/mL) and diphtheria (1.39 IU/mL) antibodies were significantly higher in children receiving pneumococcal conjugate, compared with placebo recipients (4.58 microgram/mL and 0.98 IU/mL, respectively). Nasopharyngeal carriage of vaccine serotypes decreased in vaccinees at age 9 months (18% vs. 36%), whereas carriage of nonvaccine serotypes increased (36% vs. 25%). Carriage of penicillin-resistant pneumococci (21% vs. 41%) and cotrimoxazole-resistant pneumococci (23% vs. 35%) were significantly reduced 9 months after vaccination, compared with controls.

The objectives of this study were (1) to determine the safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate (PNCRM7) vaccine in infants and (2) to determine the effect of concurrent hepatitis B immunization during the primary series and the effect of concurrent diphtheria and tetanus toxoid and acellular pertussis [DTaP (ACEL-IMUNE)] and conjugate CRM197 Haemophilus influenzae type b [HbOC (HibTITER) immunization at time of the booster dose on the safety and immunogenicity of PNCRM7and these other concurrently administered vaccines.This was a randomized double-blinded study in 302 healthy infants in the Northern California Kaiser Permanente (NCKP) Health Plan. Infants received either PNCRM7 vaccine or meningococcal group C conjugate vaccine as a control at 2, 4 and 6 months of age and a booster at 12 to 15 months of age. Study design permitted the evaluation of immunology and safety of concurrent administration of routine vaccines. Antibody titers were determined on blood samples drawn before and 1 month after the primary series and the booster dose.After the third dose of PNCRM7 geometric mean concentrations (GMCs) ranged from 1.01 for serotype 9V to 3.72 microg/ml for serotype 14. More than 90% of all subjects had a post-third dose titer ofor =0.15 microg/ml for all serotypes, and the percentage of infants with a post-third dose titer ofor =1.0 microg/ml ranged from 51% for type 9V to 89% for type 14. After the PNCRM7 booster dose, the GMCs of all seven serotypes increased significantly over both post-Dose 3 and pre-Dose 4 antibody levels. In the primary series there were no significant differences in GMCs of pneumococcal antibodies between the subjects given PN-CRM7 alone or concurrently with hepatitis B vaccine. At the toddler dose concurrent administration of PNCRM7 and DTaP and HbOC resulted in a near conventional threshold for statistical significance of a post-Dose 4 GMC for serotype 23F [alone 6.75 mirog/ml vs. concurrent 4.11 microg/ml (P = 0.057)] as well as significantly lower antibody GMCs for H. influenza polyribosylribitol phosphate, diphtheria toxoid, pertussis toxin and filamentous hemagglutinin. For all antigens there were no differences between study groups in defined antibody titers that are considered protective.We conclude that PNCRM7 vaccine was safe and immunogenic. When this vaccine was administered concurrently at the booster dose with DTaP and HbOC vaccines, lower antibody titers were noted for some of the antigens when compared with the antibody response when PNCRM7 was given separately. Because the GMCs of the booster responses were all generally high and all subjects achieved similar percentages above predefined antibody titers, these differences are probably not clinically significant.

Summary Background Meningococcal serogroup B disease disproportionately affects infants. We assessed lot-to-lot consistency, safety and immunogenicity, and the effect of concomitant vaccination on responses to routine vaccines of an investigational multicomponent vaccine (4CMenB) in this population. Methods We did primary and booster phase 3 studies between March 31, 2008, and Aug 16, 2010, in 70 sites in Europe. We used two series of sponsor-supplied, computer-generated randomisation envelopes to allocate healthy 2 month-old infants to receive routine vaccinations (diphtheria-tetanus-acellular pertussis, inactivated poliovirus, hepatitis B plus Haemophilus influenzae type b, and seven-valent pneumococcal vaccine) at 2, 4, and 6 months of age alone, or concomitantly with 4CMenB or serogroup C conjugate vaccine (MenC) in: 1) an open-label, lot-to-lot immunogenicity and safety substudy of three 4CMenB lots compared with routine vaccines alone (1:1:1:1, block size eight); or 2) an observer-blind, lot-to-lot safety substudy of three 4CMenB lots compared with MenC (1:1:1:3, block size six). At 12 months, 4CMenB-primed children from either substudy were randomised (1:1, block size two) to receive 4CMenB booster, with or without measles-mumps-rubella-varicella (MMRV) vaccine. Immunogenicity was assessed by serum bactericidal assay with human complement (hSBA) against serogroup B test strains, and on randomly selected subsets of serum samples for routine vaccines; laboratory personnel were masked to assignment. The first coprimary outcome was lot-to-lot consistency (hSBA geometric mean ratio of all lots between 0·5 and 2·0), and the second was an immune response (hSBA titre ≥5) for each of the three strains. The primary outcome for the booster study was immune response to booster dose. Immunogenicity data for 4CMenB were for the modified intention-to-treat population, including all infants from the open-label substudy who provided serum samples. The safety population included all participants who contributed safety data after at least one dose of study vaccine. These trials are registered with ClinicalTrials.gov, numbers NCT00657709 and NCT00847145. Findings We enrolled 2627 infants in the open-label phase, 1003 in the observer-blind phase, and 1555 in the booster study. Lot-to-lot consistency was shown for the three 4CMenB lots, with the lowest 95% lower confidence limit being 0·74 and the highest upper limit being 1·33. Of 1181–1184 infants tested 1 month after three 4CMenB doses (all lots pooled), 100% (95% CI 99–100) had hSBA titres of 5 or more against strains selective for factor H binding protein and neisserial adhesin A, and 84% (82–86) for New Zealand outer-membrane vesicle. In a subset (n=100), 84% (75–91) of infants had hSBA titres of 5 or more against neisseria heparin binding antigen. At 12 months of age, waning titres were boosted by a fourth dose, such that 95–100% of children had hSBA titres of 5 or more for all antigens, with or without concomitant MMRV. Immune responses to routine vaccines were much the same with or without concomitant 4CMenB, but concomitant vaccination was associated with increased reactogenicity. 77% (1912 of 2478) of infants had fever of 38·5°C or higher after any 4CMenB dose, compared with 45% (295 of 659) after routine vaccines alone and 47% (228 of 490) with MenC, but only two febrile seizures were deemed probably related to 4CMenB. Interpretation 4CMenB is immunogenic in infants and children aged 12 months with no clinically relevant interference with routine vaccines, but increases reactogenicity when administered concomitantly with routine vaccines. This breakthrough vaccine offers an innovative solution to the major remaining cause of bacterial meningitis in infant and toddlers. Funding Novartis Vaccines and Diagnostics.

The development of a broadly protective vaccine against meningococcal serogroup B is a well-recognized public health need. Whole-genome sequencing was used to identify meningococcal surface proteins that are conserved across strains. These proteins were incorporated into two investigational vaccines.Three randomized studies were performed to evaluate a three-component recombinant meningococcal serogroup B vaccine (rMenB) and rMenB plus outer membrane vesicles from the Norwegian outbreak strain 44/76 (rMenB+OMVNW). Participants were randomized to receive 3 or 4 doses of rMenB or rMenB+OMVNW or control vaccines and provided sera for exploratory immunogenicity testing against a panel of meningococcal serogroup B strains. A booster dose was administered 12 months after the initial primary series in one of the studies. The control cohort received a licensed quadrivalent meningococcal polysaccharide vaccine against serogroups A, C, W-135 and Y as well as hepatitis B vaccine as safety comparators. Solicited reactions within 7 days of any vaccination and adverse events throughout the studies were recorded.One hundred four participants enrolled into the clinical trials. Both rMenB and rMenB+OMVNW induced immune responses to multiple serogroup B strains in the majority of participants. Compared with rMenB, rMenB+OMVNW appeared somewhat more immunogenic and reactogenic; the study was not adequately powered for statistical assessment of these small differences. Both investigational vaccines were more reactogenic than the licensed vaccines. Few vaccinees discontinued any study due to reactogenicity to any study vaccine administered.Based on the immunogenicity and reactogenicity results in these participants, both rMenB and rMenB+OMVNW were promising candidates for further investigation.

Laboratory staff who work with meningococcal isolates are at increased risk for developing invasive disease relative to the general population. This was the first study of laboratory workers who received both a conjugate vaccine against meningococcal serogroups A, C, W-135, and Y (Men ACWY-CRM, Menveo) and an investigational multicomponent vaccine against serogroup B containing factor H binding protein, neisserial adhesin A, Neisseria heparin binding antigen, and New Zealand strain outer membrane vesicles (4CMenB). Healthy adults (18 to 50 years of age) received three doses of 4CMenB at baseline, 2 months, and 6 months followed by a single dose of MenACWY-CRM 1 month later. Immunogenicity was assessed via serum bactericidal assay using human complement (hSBA) at 1 month postvaccination; solicited reactogenicity and adverse events were monitored. Fifty-four participants enrolled. Bactericidal immune responses were evident after each dose of 4CMenB, as assessed by hSBA geometric mean titers and percentages of subjects with hSBA titers of ≥4 against the test strains or a 4-fold rise in titer over baseline. At 1 month postvaccination, most MenACWY-CRM recipients had hSBA titers of ≥8 against serogroups A, C, W-135, and Y. Few participants discontinued due to an adverse event or vaccine reaction. Rates of solicited reactions were lower after MenACWY-CRM than after 4CMenB administration. Sequential administration of 4CMenB and MenACWY-CRM provided robust evidence of an immune response against serogroups A, B, C, W-135, and Y in laboratory workers routinely exposed to meningococcal isolates.

Purpose: This study evaluated the safety and effectiveness of long-term enzyme replacement therapy with idursulfase (recombinant human iduronate-2-sulfatase) in patients with Hunter syndrome. Methods: All 94 patients who completed a 53-week double-blinded study of idursulfase enrolled in this open-labeled extension study and received intravenous idursulfase at a dose of 0.5 mg/kg weekly for 2 years, and clinical outcomes and safety were assessed. Results: No change in percent predicted forced vital capacity was seen, but absolute forced vital capacity demonstrated sustained improvement and was increased 25.1% at the end of the study. Statistically significant increases in 6-minute walking test distance were observed at most time points. Mean liver and spleen volumes remained reduced throughout the 2-year extension study. Mean joint range of motion improved for the shoulder and remained stable in other joints. Both the parent- and child-assessed Child Health Assessment Questionnaire Disability Index Score demonstrated significant improvement. Infusion-related adverse events occurred in 53% of patients and peaked at Month 3 of treatment and declined thereafter. Neutralizing IgG antibodies were detected in 23% of patients and seemed to attenuate the improvement in pulmonary function. Conclusions: Weekly infusions of idursulfase result in sustained clinical improvement during 3 years of treatment.

Background The use of angiotensin-converting enzyme inhibitors (ACEI) has been associated with the development of bradykinin-mediated angioedema. With ever-widening indications for ACEI in diseases including hypertension, congestive heart failure and diabetic nephropathy, a concomitant increase in ACEI-Angioedema (ACEI-A) has been reported. At present there is no validated severity scoring or discharge criteria for ACEI-A. We sought to develop and validate an investigator rating scale with corresponding discharge criteria using clinicians experienced in treating ACEI-A. Methods In-depth, 60-min qualitative telephone interviews were conducted with 12 US-based emergency physicians. Beforehand, clinicians were sent four case studies describing patients experiencing different severities of angioedema attacks. Clinicians were initially asked open-ended questions about their experience of patients’ symptoms, treatment and discharge decisions. Clinicians then rated each patient case study and discussed patient diagnoses, ratings of symptom severity and discharge evaluation. The ratings were used to assess inter-rater reliability of the scale using the intra-class correlation coefficient (ICC) using IBM SPSS analysis Version 19 software. Results The findings provide support focusing on four key symptoms of airway compromise scored on a 0–4 scale: 1) Difficulty Breathing, 2) Difficulty Swallowing, 3) Voice Changes and 4) Tongue Swelling and the corresponding discharge criteria of a score of 0 or ‘No symptoms’ for Difficulty Breathing and Difficulty Swallowing and a score of 0 or 1 indicating mild or absence of symptoms for Voice Change and Tongue Swelling. Eleven clinicians agreed the absence of standardized discharge criteria supported the use of this scale. All physicians concurred with the recommended discharge criteria. The clinician ratings provided evidence of strong inter-rater reliability for the rating scale (ICC > 0.80). Conclusion The investigator rating scale and discharge criteria are clinically valid, relevant and reliable. Moreover, both address the current unmet need for standardized ED discharge criteria.

To investigate the retinal survival time following central retinal artery occlusion (CRAO).In 38 elderly, atherosclerotic and hypertensive rhesus monkeys, transient CRAO (varying from 97 to 240 min) was produced by temporarily clamping the CRA at its site of entry into the optic nerve. Stereoscopic color fundus photography, fluorescein fundus angiography, electroretinography (ERG), and visual evoked potential (VEP) recording were performed before and during CRA clamping, after unclamping, and serially thereafter. After unclamping of the CRA, the animals were followed for variable lengths of time (median duration 8.14 weeks). Finally, the eyes and optic nerves were examined histologically. The data on ERG changes were analyzed in the following four time frames: (1) baseline before CRA clamping, (2) during CRA clamping, (3) immediately after unclamping, and (4) at the end of follow-up. Duration of CRAO was divided into four groups: 97, 105-120, 150-165, andor = 180 min.A 'negative ERG' appeared during CRA clamping. With removal of the CRA clamp, there was b-wave recovery, with differential rates of recovery of ERG-eyes with shorter CRAO recovered sooner than those with longer occlusion. On removal of clamp, recovery was seen in scotopic 24 dB b-wave, photopic 0 dB single flash b-wave and 30 Hz flicker, with the b/a ratio of the combined rod and cone response and selective rod response showing statistically significant differences amongst the shorter and longer periods of CRAO. A delayed normalization of the depressed b/a ratio immediately after CRA reperfusion may indicate high-grade ischemic damage. At the final follow-up test session, no clear-cut derangement of any ERG parameter was seen for any group, with subtotal b-wave amplitude recovery for all groups. Longer CRAO produced incomplete VEP recovery. On histology, in the macular retina, eyes with CRAO for 97 min showed practically no damage, but duration of CRAO was found to be significantly associated with the amount of damage in the ganglion cell layer (p = 0.009) and inner nuclear layer (p = 0.017). Outer nuclear and plexiform layers and photoreceptors showed no damage at all with CRAO. There was no significant association of the ERG measures and histologic changes with any of the residual retinal circulation variables.Our electrophysiologic, histopathologic and morphometric studies showed that the retina of old, atherosclerotic, hypertensive rhesus monkeys suffers no detectable damage with CRAO of 97 min but above that level, the longer the CRAO, the more extensive the irreversible damage. The study suggests that CRAO lasting for about 240 min results in massive irreversible retinal damage.

A new meningococcal group C-CRM197conjugate vaccine (MnCC; Meningitec) has been evaluated in multiple clinical trials in the United States and most recently has been approved for routine administration in the United Kingdom. Meningococcal serogroup C (MnC)-specific immunoglobulin G (IgG) antibodies in pre- and postimmunization sera obtained from healthy U.S. adults, toddlers, and infants were quantitated by enzyme-linked immunosorbent assay (ELISA) and by an antibody-dependent, complement-mediated serum bactericidal assay (SBA). Serogroup-specific IgG antibody (micrograms per milliliter) in adults immunized either with the quadrivalent polysaccharide (A, C, Y, and W-135) vaccine or with MnCC showed a strong correlation (r= 0.848 and 0.934, respectively) by linear regression analysis with SBA. Sera from infants immunized with the MnCC (n= 30) and an age-matched unimmunized control group (n= 15) were also analyzed. Linear regression analysis of serum bactericidal and IgG ELISA data from sera obtained at 2 months of age (preimmunization) showed no correlation; however, a high degree of correlation was observed at time points after two (r= 0.877) and three (r= 0.951) immunizations, where significant rises in anti-MnC polysaccharide antibodies occurred relative to the age-matched control group. Infants previously primed with 3 doses of MnCC were given a booster dose of conjugate vaccine at 12 to 15 months of age. The correlation coefficient of ELISA to SBA for combined pre- and postbooster data wasr= 0.836 (n= 48 pairs). In conclusion, increases in serum bactericidal activity in immunized adult, toddler, and infant populations were found to correlate very well with increases in serogroup-specific IgG concentrations, whereas the correlation between these two assays in nonimmunized 2-month-old infants was poor. Characterizing the relationship between these methods is important for understanding the significance of antigen-specific antibody concentrations relative to vaccine performance and protection from disease.

The objective of this study was to examine vaccine type-specific antibody titers eight months after a five-valent pneumococcal conjugate vaccine (PCV) in human immunodeficiency virus (HIV) and non-HIV-infected children under two years of age. Sixteen HIV-infected and 14 non-HIV-infected children under two years of age, and of similar age, race and sex distribution, received three doses (separated by two months each) of a five-valent oligosaccharide PCV (types 6B, 14, 18C, 19F, and 23F separately coupled to diphtheria CRM197). An additional 11 non-HIV-infected children, of similar demographic distribution to the PCV groups, received three doses of saline placebo. sera were collected just prior to, and at one and eight months after the three study drug doses. Serum vaccine type-specific pneumococcal IgG antibodies were measured by enzyme-linked immunoabsorbant assay (ELISA). There was an impressive rise in antibody titers pre- to one month post-third PCV in both the HIV (58-970-fold) and non-HIV-infected (19-553-fold) children. There was a rapid and similar drop in antibody titers eight months after the PCV series for both HIV (range 69-87% drop) and non-HIV-infected (range 57-79% drop) subjects respectively. However, 46% of the antibody titers from HIV-infected children and 62% of the titers from non-HIV-infected children were still1.0 microgram ml-1 compared to placebo recipients for whom only 5% of the titers were1.0 microgram ml-1 (p0.05). At the eight month post-PCV series blood draw, there were no significant differences in the GMTs, the percent drop in titers, or proportion of titers1.0 microgram ml-1 between the five HIV-infected children who had advanced (CDC class: N3, A3, B2-3, C1-3) compared to the 11 children with mild (CDC class: N1-2, A1-2, B1) HIV disease at the time of their first PCV dose. Eight months after the PCV series, the proportion of titers (combined all five serotypes)1.0 microgram ml-1 was slightly, but significantly, lower for HIV-infected subjects (46%) compared to non-HIV-infected subjects (62%) (p0.05). These data are helpful in describing the kinetics of antibody responses to pneumococcal conjugate vaccines in both HIV and non-HIV-infected young children.

Objective. To determine the safety and immunogenicity of heptavalent pneumococcal saccharide vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) individually conjugated to CRM197 (PNCRM7), administered at 2, 4, 6, and 12 to 15 months of age.Design. Two hundred twelve healthy 2-month-old infants were equally randomized to receive four consecutive doses of PNCRM7 or an investigational meningococcal group C conjugate vaccine, which served as a control. Concomitantly administered routine vaccines were oral polio vaccine and combined diphtheria toxoid, tetanus toxoid, and whole cell pertussis vaccine/Haemophilus influenzae type b vaccine consisting of capsular oligosaccharides conjugated to CRM197 (DTP/HbOC) at 2, 4, and 6 months, and either measles-mumps-rubella vaccine or HbOC at 12 to 15 months. Active safety surveillance was conducted for 3 days after each dose. Antibody concentrations to each of the 7 pneumococcal serotypes were measured by enzyme-linked immunosorbent assay prevaccination, after doses two and three, prebooster, and postbooster.Results. Significantly fewer children experienced local reactions at the PNCRM7 injection site than at the DTP/HbOC site. There was no increase in the incidence or severity of local reactions at the PNCRM7 site with increasing doses of vaccine. Mild to moderate postvaccination fever was common in both the PNCRM7 and control vaccine groups, however DTP/HbOC was administered concurrently. All 7 vaccine serotypes were immunogenic. The kinetics of the immune responses were serotype-specific. After three doses of PNCRM7, between 92% to 100% of children had ≥0.15 μg/mL of antibody, and 51% to 90% achieved a level of ≥1 μg/mL against specific serotypes. A booster dose of PNCRM7 resulted in a brisk anamnestic response to all 7 vaccine serotypes, demonstrating effective stimulation of T-cell memory by the primary series of vaccinations.Conclusion. Primary immunization followed by a booster dose of PNCRM7 seemed to be acceptably safe and resulted in significant rises in antibody to all 7 serotypes.Implications. Studies to assess vaccine efficacy of PNCRM7 for prevention of systemic disease, nasopharyngeal colonization, and acute otitis media are in progress. If PNCRM7 proves to be protective, there is the potential to prevent up to 85% of invasive pneumococcal disease occurring in US children.

CORRIGENDUM: Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome

Background Protecting infants against serogroup B meningococcal disease is a long-standing public health need. An investigational multicomponent vaccine (4CMenB) containing three recombinant proteins identified using whole-genome sequencing and outer membrane vesicles from the New Zealand outbreak strain was evaluated in healthy infants. Methods Healthy infants were randomised to receive routine infant vaccines alone, with one of three 4CMenB lots, or with serogroup C conjugate vaccine at 2, 4, 6 months of age. In an open-label cohort, 4CMenB was assessed via serum bactericidal assay using human complement (hSBA) against serogroup B test strains. Noninferiority criteria for seroresponse to routine vaccines were predefined. In open-label and observer-blind cohorts, prespecified solicited injection site and systemic reactions within 7 days of vaccination were evaluated. Adverse events were monitored. Results Overall 3630 infants enrolled. All lots of 4CMenB had consistent immunogenicity, and 100% of 4CMenB recipients had protective titers to at least two heterologous serogroup B strains. Responses to 4CMenB and routine vaccines were consistent with protection; no evidence of interference with co-administration of 4CMenB was noted for any antigen except Polio 2. Participants receiving 4CMenB and the routine vaccines showed evidence of increased reactogenicity compared with those receiving routine vaccines only or those receiving MenC and routine vaccines. Parents of infants in the observer-blind cohort were more likely to seek medical attention for fever than were those in the open-label cohort. Conclusion In this study, 4CMenB showed a very promising immunogenicity profile and acceptable reactogenicity in infants.

SAFETY AND IMMUNOGENICITY OF HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE(Wyeth-Lederle) IN INFANCY. 986

Demonstration of lysozyme by the immunoperoxidase method was used to determine whether ozone-induced defects in phagocytic killing of inhaled Staphylococcus aureus by rat alveolar macrophages were associated with absence of this important bactericidal enzyme. Rats were infected with aerosols of S. aureus and then exposed for 5 hr to 2.5 ppm of ozone. Left lungs were cultured for staphylococci; right lungs were stained for lysozyme and bacteria. Compared with control animals, rats exposed to ozone showed diminished rates of bacterial killing; a larger percentage of extracellular, uningested bacteria; an increased number of intracellular staphylococcal clumps; and absence of lysozyme in macrophages permitting staphylococcal proliferation. These results, in which absence of enzyme activity occurred in macrophages subjected to the dual insults of ozone exposure and ingested bacteria, provide an explanation for the inability of phagocytes to kill ingested bacteria after exposure to ozone.

Rats were chronically infected with Pseudomonas aeruginosa by entrapping viable bacteria in agar beads and intratracheally inoculating the beads into the left lung. The infection was allowed to stabilize over a 10-d period and the animals were then placed in environmental chambers and exposed to either filtered air or 0.64 ppm ozone (23 h/d) for 14 or 28 d. Rats exposed to ozone had reduced body weight and increased lung sizes and lung weights when compared with animals breathing filtered air. Rats inoculated with beads containing live P. aeruginosa had increased lung weights when compared with rats inoculated with beads containing heat-killed P. aeruginosa or controls. Quantitation of total viable bacteria in rats exposed to ozone or to filtered air revealed no significant differences in bacterial numbers. Thus, in this model, chronic exposure to ozone produces increases in lung volume and weight but does not enhance a smoldering Pseudomonas infection.

We investigated the intravitreal toxicity of cotrimoxazole (trimethoprim 80 mg and sulfamethoxazole 400 mg/5 ml of injection fluid) in albino rabbits. Eyes injected intravitreally with 1600 µg/0.1 cc (reported in trimethoprim concentration) exhibited no histologic or abnormal electroretinographic responses after 14 days. A vitrectomy infusion solution containing 32 ug/ml (reported in trimethoprim concentration) produced no toxicity, as demonstrated either by electroretinography or histology. Cotrimoxazole appears to be well-tolerated in rabbit eyes when administered by both intravitreal injection and vitrectomy infusion solution.

Spontaneous antigenic and phenotypic variations in the lipooligosaccharide (LOS) of two strains of Haemophilus influenzae type b (Hib) were previously shown to be associated with changes in virulence (A. Kimura and E.J. Hansen, Infect. Immun. 51:69-79, 1986). The goal of the present study was to define further the stability of LOS expression by this pathogen and the role of Hib LOS in virulence. Variation in LOS antigenic reactivity, as detected with LOS-specific monoclonal antibodies, was observed in 3 of 30 Hib strains after single-colony passage. When large numbers of individual colonies from seven other Hib strains were screened, however, spontaneous LOS antigenic variation was detected in all of the strains. Antigenic variation was not consistently associated with an altered LOS phenotype, as determined by sodium dodecyl sulfate-polyacrylamide gradient gel electrophoresis and silver staining of LOS preparations. Changes in the LOS antigenic phenotype were correlated with altered virulence potential in two strains. In these strains, acquisition of reactivity with certain LOS-directed monoclonal antibodies was associated with the synthesis of a higher-molecular-weight LOS, enhanced virulence, and increased resistance to serum killing involving the classical complement pathway.

To clinically and surgically evaluate clot lysis in an animal model of subretinal hemorrhage after intravitreal injection of tissue plasminogen activator.Autologous subretinal hemorrhages were created via a transvitreal approach in 18 pigs. The next day (day 1) animals were randomly selected to receive either an intravitreal injection of 0.1 mL balanced salt solution or 0.1 mL tissue plasminogen activator (25 micrograms) followed by observation or vitrectomy a day later. On day 2, six pigs (all treated with tissue plasminogen activator) underwent a vitrectomy in which aspiration of the subretinal hemorrhage was attempted. The other eyes were evaluated for clot lysis by ophthalmoscopy at days 3, 10, and 30. All eyes were examined histopathologically.The eyes that had been treated with tissue plasminogen activator demonstrated a color change at the peripheral margin, which suggested that clot lysis had occurred. At the time of the vitrectomy, the clots were liquefied partially; removal by aspiration alone, however, was not possible. Photoreceptor damage was moderate to severe by day 10 in all eyes, whether they were treated with tissue plasminogen activator or balanced salt solution. All eyes that underwent vitrectomy had moderate to severe photoreceptor damage.In this animal model, intravitreal tissue plasminogen activator was associated with features that suggested partial clot lysis; tissue plasminogen activator did not produce sufficient lysis to allow surgical removal by aspiration alone, however.