Reticulocyte-binding protein homolog 5 (RH5) is a leading Plasmodium falciparum blood-stage vaccine candidate. Another possible candidate, apical membrane antigen 1 (AMA1), was not efficacious in ...malaria-endemic populations, likely due to pre-existing antimalarial antibodies that interfered with the activity of vaccine-induced AMA1 antibodies, as judged by in vitro growth inhibition assay (GIA). To determine how pre-existing antibodies interact with vaccine-induced RH5 antibodies, we purify total and RH5-specific immunoglobulin Gs (IgGs) from malaria-exposed Malians and malaria-naive RH5 vaccinees. Infection-induced RH5 antibody titers are much lower than those induced by vaccination, and RH5-specific IgGs show differences in the binding site between the two populations. In GIA, Malian polyclonal IgGs show additive or synergistic interactions with RH5 human monoclonal antibodies and overall additive interactions with vaccine-induced polyclonal RH5 IgGs. These results suggest that pre-existing antibodies will interact favorably with vaccine-induced RH5 antibodies, in contrast to AMA1 antibodies. This study supports RH5 vaccine trials in malaria-endemic regions.
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RH5 IgG titers induced by infection are lower than those induced by RH5 vaccinationInfection- and vaccine-induced RH5 IgGs have different specificity and avidityInfection- and vaccine-induced RH5 IgGs interact differently with RH5 mAbsInfection-induced IgGs generally do not reduce the activity of vaccine-induced IgGs
Willcox et al. combine antibodies from malaria-exposed Malians and volunteers who received a reticulocyte-binding protein homolog 5 (RH5) vaccine. In P. falciparum growth inhibition assays, infection-induced IgGs generally do not reduce the neutralizing activity of vaccine-induced IgGs. These results suggest that RH5 vaccines will induce effective antibodies in malaria-endemic populations.
The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of ...malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.
A blood-stage Plasmodium falciparum malaria vaccine would provide a second line of defence to complement partially effective or waning immunity conferred by the approved pre-erythrocytic vaccines. ...RH5.1 is a soluble protein vaccine candidate for blood-stage P falciparum, formulated with Matrix-M adjuvant to assess safety and immunogenicity in a malaria-endemic adult and paediatric population for the first time.
We did a non-randomised, phase 1b, single-centre, dose-escalation, age de-escalation, first-in-human trial of RH5.1/Matrix-M in Bagamoyo, Tanzania. We recruited healthy adults (aged 18–45 years) and children (aged 5–17 months) to receive the RH5.1/Matrix-M vaccine candidate in the following three-dose regimens: 10 μg RH5.1 at 0, 1, and 2 months (Adults 10M), and the higher dose of 50 μg RH5.1 at 0 and 1 month and 10 μg RH5.1 at 6 months (delayed-fractional third dose regimen; Adults DFx). Children received either 10 μg RH5.1 at 0, 1, and 2 months (Children 10M) or 10 μg RH5.1 at 0, 1, and 6 months (delayed third dose regimen; Children 10D), and were recruited in parallel, followed by children who received the dose-escalation regimen (Children DFx) and children with higher malaria pre-exposure who also received the dose-escalation regimen (High Children DFx). All RH5.1 doses were formulated with 50 μg Matrix-M adjuvant. Primary outcomes for vaccine safety were solicited and unsolicited adverse events after each vaccination, along with any serious adverse events during the study period. The secondary outcome measures for immunogenicity were the concentration and avidity of anti-RH5.1 serum IgG antibodies and their percentage growth inhibition activity (GIA) in vitro, as well as cellular immunogenicity to RH5.1. All participants receiving at least one dose of vaccine were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT04318002, and is now complete.
Between Jan 25, 2021, and April 15, 2021, we recruited 12 adults (six 50% in the Adults 10M group and six 50% in the Adults DFx group) and 48 children (12 each in the Children 10M, Children 10D, Children DFx, and High Children DFx groups). 57 (95%) of 60 participants completed the vaccination series and 55 (92%) completed 22 months of follow-up following the third vaccination. Vaccinations were well-tolerated across both age groups. There were five serious adverse events involving four child participants during the trial, none of which were deemed related to vaccination. RH5-specific T cell and serum IgG antibody responses were induced by vaccination and purified total IgG showed in vitro GIA against P falciparum. We found similar functional quality (ie, GIA per μg RH5-specific IgG) across all age groups and dosing regimens at 14 days after the final vaccination; the concentration of RH5.1-specific polyclonal IgG required to give 50% GIA was 14·3 μg/mL (95% CI 13·4–15·2). 11 children were vaccinated with the delayed third dose regimen and showed the highest median anti-RH5 serum IgG concentration 14 days following the third vaccination (723 μg/mL IQR 511–1000), resulting in all 11 who received the full series showing greater than 60% GIA following dilution of total IgG to 2·5 mg/mL (median 88% IQR 81–94).
The RH5.1/Matrix-M vaccine candidate shows an acceptable safety and reactogenicity profile in both adults and 5–17-month-old children residing in a malaria-endemic area, with all children in the delayed third dose regimen reaching a level of GIA previously associated with protective outcome against blood-stage P falciparum challenge in non-human primates. These data support onward efficacy assessment of this vaccine candidate against clinical malaria in young African children.
The European and Developing Countries Clinical Trials Partnership; the UK Medical Research Council; the UK Department for International Development; the National Institute for Health and Care Research Oxford Biomedical Research Centre; the Division of Intramural Research, National Institute of Allergy and Infectious Diseases; the US Agency for International Development; and the Wellcome Trust.
The optical spectrograph and infrared imager system (OSIRIS) on board the Odin spacecraft is designed to retrieve altitude profiles of terrestrial atmospheric minor species by observing limb-radiance ...profiles. The grating optical spectrograph (OS) obtains spectra of scattered sunlight over the range 280800 nm with a spectral resolution of approximately 1 nm. The Odin spacecraft performs a repetitive vertical limb scan to sweep the OS 1 km vertical field of view over selected altitude ranges from approximately 10 to 100 km. The terrestrial absorption features that are superimposed on the scattered solar spectrum are monitored to derive the minor species altitude profiles. The spectrograph also detects the airglow, which can be used to study the mesosphere and lower thermosphere. The other part of OSIRIS is a three-channel infrared imager (IRI) that uses linear array detectors to image the vertical limb radiance over an altitude range of approximately 100 km. The IRI observes both scattered sunlight and the airglow emissions from the oxygen infrared atmospheric band at 1.27 µm and the OH (3-1) Meinel band at 1.53 µm. A tomographic inversion technique is used with a series of these vertical images to derive the two-dimensional distribution of the emissions within the orbit plane. PACS Nos.: 07.05.Pj, 07.60.Dq, 07.60.Rd, 07.87, 94.10.Dy, 94.10.Fa, 94.10.Gb, 94.10.Rk
ABSTRACT Antibodies acquired after vaccination or natural infection with Gram-negative bacteria, such as invasive Salmonella enterica serovar Typhimurium, can protect against disease. Immunization ...with naturally shed outer membrane vesicles from Gram-negative bacteria is being studied for its potential to protect against many infections, since antigens within vesicles maintain their natural conformation and orientation. Shedding can be enhanced through genetic modification, and the resulting particles, generalized modules for membrane antigens (GMMA), not only offer potential as vaccines but also can facilitate the study of B-cell responses to bacterial antigens. Here we show that the response to immunization with GMMA from S. Typhimurium (STmGMMA) provides B-cell-dependent protection and induces antibodies to two immunodominant antigens, lipopolysaccharide (LPS) and porins. Antibodies to LPS O antigen (O-Ag) markedly enhance protection in the spleen, but this effect is less marked in the liver. Strikingly, IgG responses to LPS and porins develop with distinct kinetics. In the first week after immunization, there is a dramatic T-cell-independent B1b-cell-associated induction of all IgG isotypes, except IgG1, to porins but not to LPS. In contrast, production of IgG1 to either antigen was delayed and T cell dependent. Nevertheless, after 1 month, cells in the bone marrow secreting IgG against porins or LPS were present at a similar frequency. Unexpectedly, immunization with O-Ag-deficient STmGMMA did not substantially enhance the anti-porin response. Therefore, IgG switching to all antigens does not develop synchronously within the same complex and so the rate of IgG switching to a single component does not necessarily reflect its frequency within the antigenic complex. IMPORTANCE Vaccines save millions of lives, yet for some infections there are none. This includes some types of Salmonella infections, killing hundreds of thousands of people annually. We show how a new type of vaccine, called GMMA, that is made from blebs shed from the Salmonella cell wall, works to protect against infection in mice by inducing host proteins (antibodies) specifically recognizing bacterial components (antigens). The rate of development of IgG antibody to antigens within GMMA occurred with different kinetics. However, the antibody response to GMMA persists and is likely to provide prolonged protection for those who need it. These results help show how antibody responses to bacterial antigens develop and how vaccines like GMMA can work and help prevent infection.
Background
It is common for patients with neurofibromatosis type 2 to develop bilateral profound hearing loss hearing loss, and this is one of the main determinants of quality of life in this patient ...group.
Objectives
The aim of this systematic review was to review the current literature regarding hearing outcomes of treatments for vestibular schwannomas in neurofibromatosis type 2 including conservative and medical management, radiotherapy, hearing preservation surgery and auditory implantation in order to determine the most effective way of preserving or rehabilitating hearing.
Search strategy
A MESH search in PubMed using search terms ((‘Neurofibromatosis 2’ Mesh) AND ‘Neuroma, Acoustic’Mesh) AND ‘Hearing Loss’ Mesh was performed. A search using keywords was also performed. Studies with adequate hearing outcome data were included. With the exception of the cochlear implant studies (cohort size was very small), case studies were excluded.
Evaluation method
The GRADE system was used to assess quality of publication. Formal statistical analysis of data was not performed because of very heterogenous data reporting.
Results
Conservative management offers the best chance of hearing preservation in stable tumours. The use of bevacizumab probably improves the likelihood of hearing preservation in growing tumours in the short term and is probably more effective than hearing preservation surgery and radiotherapy in preserving hearing. Of the hearing preservation interventions, hearing preservation surgery probably offers better hearing preservation rates than radiotherapy for small tumours but recurrence rates for hearing preservation surgery were high. For patients with profound hearing loss, cochlear implantation provides significantly better auditory outcomes than auditory brainstem implantation. Patients with untreated stable tumours are likely to achieve the best outcomes from cochlear implantation. Those who have had their tumours treated with surgery or radiotherapy do not gain as much benefit from cochlear implantation than those with untreated tumours.
Conclusions
This review summarises the current literature related to hearing preservation/rehabilitation in patients with NF2. Whilst it provides indicative data, the quality of the data was low and should be interpreted with care. It is also important to consider that the management of vestibular schwannomas in NF2 is complex and decision‐making is determined by many factors, not just the need to preserve hearing.
Abstract
Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes ...NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas present sporadically without identification of germline pathogenic variants.
To identify novel genetic associations with risk of vestibular schwannoma development, we conducted a genome-wide association study in a cohort of 911 sporadic vestibular schwannoma cases collated from the neurofibromatosis type 2 genetic testing service in the north-west of England, UK and 5500 control samples from the UK Biobank resource. One risk locus reached genome-wide significance in our association analysis (9p21.3, rs1556516, P = 1.47 × 10−13, odds ratio = 0.67, allele frequency = 0.52).
9p21.3 is a genome-wide association study association hotspot, and a number of genes are localized to this region, notably CDKN2B-AS1 and CDKN2A/B, also referred to as the INK4 locus. Dysregulation of gene products within the INK4 locus have been associated with multiple pathologies and the genes in this region have been observed to directly impact the expression of one another. Recurrent associations of the INK4 locus with components of well-described oncogenic pathways provides compelling evidence that the 9p21.3 region is truly associated with risk of vestibular schwannoma tumorigenesis.
Sadler et al. report the results of a genome-wide association study investigating genetic contributors to the risk of sporadic vestibular schwannoma development, and reveal a highly significant risk locus (9p21.3). With 911 cases and 5500 controls, this is the first comprehensive GWAS investigating sporadic vestibular schwannoma.
Although diabetic retinopathy (DR) and age-related macular degeneration (AMD) are the two most common sight-threatening conditions in the elderly population, our understanding of the associated risks ...for these diseases have not been studied. Thus, we examined the association between AMD and DR in people with type 1 and type 2 diabetes from the Joslin 50-Year Medalist Study, composed of individuals who have had insulin-dependent diabetes for 50 years or longer and Beetham Eye Institute. In Medalists, there was an inverse association between DR severity and the presence of AMD (N=1163, P=<0.0001, AMD: 23.4%, 18.6, 7.9% for no-mild, moderate-severe, and proliferative DR, respectively). Similarly, the presence of AMD was associated with milder DR in the BEI cohort (N=58, P=0.004). There were no eyes with neovascular (severe AMD). The presence of AMD was associated with older age (P=0.03), increased diabetes duration (P<0.0001), less severe DR (P<0.0001), and the absence of neuropathy (P=0.003). In contrast, younger age (P=0.02) and the presence of neuropathy (P<0.0001) were associated with the presence of proliferative DR. Higher vitreous retinol-binding protein 3 (RBP3) to vascular endothelial growth factor (VEGF) ratios were associated with AMD and less severe DR in both postmortem Medalist and surgical BEI samples (N=187, P<0.05, all). The presence of milder DR was associated with increased risk of AMD development (24.8%, 10.0%, 5.0% for no-mild, moderate-severe, and proliferative DR, respectively, P=0.047), and risk of DR progression was decreased in eyes with versus without AMD (P=0.04) in a subset of Medalists with longitudinal follow up (22.9%). These novel findings that the inverse risk of DR and AMD is not likely due to similar pathogenic mechanisms and ageing factors. Further studies are needed to clarify the interactions between AMD and DR, that may provide new pathways to target against their development.
Disclosure
W.Fickweiler: None. G.L.King: Research Support; Janssen Research & Development, LLC. C.Jacoba: None. S.Jangolla: None. J.Gauthier: None. N.A.Ziemniak: None. I.Wu: None. J.D.Cavallerano: None. L.P.Aiello: Consultant; KalVista Pharmaceuticals, Inc., Novo Nordisk, MantraBio, Ceramedix, Research Support; Optos plc., Stock/Shareholder; KalVista Pharmaceuticals, Inc. J.Sun: Research Support; Adaptive Sensory Technology, Boehringer Ingelheim Inc., Roche Pharmaceuticals, Janssen Pharmaceuticals, Inc., Physical Sciences, Inc, Novo Nordisk, Optovue, Incorporated.
Funding
American Diabetes Association (7-21-PDF-022 to W.F.); National Eye Institute (R01EYE26080-01); National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK09433301); JDRF (17-2013-310); Dianne Nunnally Hoppes Fund; Beatson Pledge Fund
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