To comprehensively analyze the quality of the antibody response between children with Multisystem inflammatory syndrome (MIS-C) and age-matched controls at one month after SARS-CoV-2 exposure, and ...infected in the same time-period.
Serum from 20 MIS-C children at admission, and 14 control children were analyzed. Antigen specific antibody isotypes and subclasses directed against various antigens of SARS-CoV-2 as well as against human common coronavirus (HCoVs) and commensal or pathogenic microorganisms were assessed by a bead-based multiplexed serological assay and by ELISA. The functionality of these antibodies was also assessed using a plaque reduction neutralization test, a RBD-specific avidity assay, a complement deposition assay and an antibody-dependent neutrophil phagocytosis (ADNP) assay.
Children with MIS-C developed a stronger IgA antibody response in comparison to children with uncomplicated COVID-19, while IgG and IgM responses are largely similar in both groups. We found a typical class-switched antibody profile with high level of IgG and IgA titers and a measurable low IgM due to relatively recent SARS-CoV-2 infection (one month). SARS-CoV-2-specific IgG antibodies of MIS-C children had higher functional properties (higher neutralization activity, avidity and complement binding) as compared to children with uncomplicated COVID-19. There was no difference in the response to common endemic coronaviruses between both groups. However, MIS-C children had a moderate increase against mucosal commensal and pathogenic strains, reflecting a potential association between a disruption of the mucosal barrier with the disease.
Even if it is still unclear why some children develop a MIS-C, we show here that MIS-C children produce higher titers of IgA antibodies, and IgG antibodies with higher functionality, which could reflect the local gastro-intestinal mucosal inflammation potentially induced by a sustained SARS-CoV-2 gut infection leading to continuous release of SARS-CoV-2 antigens.
AS03 is an Adjuvant System composed of α-tocopherol, squalene and polysorbate 80 in an oil-in-water emulsion. In various nonclinical and clinical studies, high levels of antigen-specific antibodies ...were obtained after administration of an AS03-adjuvanted vaccine, permitting antigen-sparing strategies. AS03 has been shown to enhance the vaccine antigen-specific adaptive response by activating the innate immune system locally and by increasing antigen uptake and presentation in draining lymph nodes, a process that is modulated by the presence of α-tocopherol in AS03. In nonclinical models of the AS03-adjuvanted prepandemic H5N1 influenza vaccine, increased levels of anti-influenza antibody afforded protection against disease and against virus replication of influenza strains homologous and heterologous to the vaccine strain. By incorporating AS03 in the pandemic H1N1/2009 vaccine, vaccine immunogenicity was increased compared with nonadjuvanted H1N1 vaccines. High H1N1/2009/AS03 vaccine effectiveness was demonstrated in several assessments in multiple populations. Altogether, the nonclinical and clinical data illustrate the ability of AS03 to induce superior adaptive responses against the vaccine antigen, principally in terms of antibody levels and immune memory. In general, these results support the concept of Adjuvant Systems as a plausible approach to develop new effective vaccines.
Adjuvant System 04 (AS04) combines the TLR4 agonist MPL (3-O-desacyl-4'-monophosphoryl lipid A) and aluminum salt. It is a new generation TLR-based adjuvant licensed for use in human vaccines. One of ...these vaccines, the human papillomavirus (HPV) vaccine Cervarix, is used in this study to elucidate the mechanism of action of AS04 in human cells and in mice. The adjuvant activity of AS04 was found to be strictly dependent on AS04 and the HPV Ags being injected at the same i.m. site within 24 h of each other. During this period, AS04 transiently induced local NF-kappaB activity and cytokine production. This led to an increased number of activated Ag-loaded dendritic cells and monocytes in the lymph node draining the injection site, which further increased the activation of Ag-specific T cells. AS04 was also found to directly stimulate those APCs in vitro but not directly stimulate CD4(+) T or B lymphocytes. These AS04-induced innate responses were primarily due to MPL. Aluminum salt appeared not to synergize with or inhibit MPL, but rather it prolonged the cytokine responses to MPL at the injection site. Altogether these results support a model in which the addition of MPL to aluminum salt enhances the vaccine response by rapidly triggering a local cytokine response leading to an optimal activation of APCs. The transient and confined nature of these responses provides further supporting evidence for the favorable safety profile of AS04 adjuvanted vaccines.
To elucidate the role of innate responses in vaccine immunogenicity, we compared early responses to hepatitis B virus (HBV) surface antigen (HBsAg) combined with different Adjuvant Systems (AS) in ...healthy HBV-naïve adults, and included these parameters in multi-parametric models of adaptive responses. A total of 291 participants aged 18-45 years were randomized 1:1:1:1:1 to receive HBsAg with AS01
, AS01
, AS03, AS04, or Alum/Al(OH)
at days 0 and 30 (ClinicalTrials.gov: NCT00805389). Blood protein, cellular, and mRNA innate responses were assessed at early time-points and up to 7 days after vaccination, and used with reactogenicity symptoms in linear regression analyses evaluating their correlation with HBs-specific CD4
T-cell and antibody responses at day 44. All AS induced transient innate responses, including interleukin (IL)-6 and C-reactive protein (CRP), mostly peaking at 24 h post-vaccination and subsiding to baseline within 1-3 days. After the second but not the first injection, median interferon (IFN)-γ levels were increased in the AS01
group, and IFN-γ-inducible protein-10 levels and IFN-inducible genes upregulated in the AS01 and AS03 groups. No distinct marker or signature was specific to one particular AS. Innate profiles were comparable between AS01
, AS01
, and AS03 groups, and between AS04 and Alum groups. AS group rankings within adaptive and innate response levels and reactogenicity prevalence were similar (AS01
≥ AS01
> AS03 > AS04 > Alum), suggesting an association between magnitudes of inflammatory and vaccine responses. Modeling revealed associations between adaptive responses and specific traits of the innate response post-dose 2 (activation of the IFN-signaling pathway, CRP and IL-6 responses). In conclusion, the ability of AS01 and AS03 to enhance adaptive responses to co-administered HBsAg is likely linked to their capacity to activate innate immunity, particularly the IFN-signaling pathway.
Abstract
Background
Patients treated with anti-CD20 therapy are particularly at risk of developing severe coronavirus disease 2019 (COVID-19); however, little is known regarding COVID-19 vaccine ...effectiveness in this population.
Methods
This prospective observational cohort study assesses humoral and T-cell responses after vaccination with 2 doses of mRNA-based COVID-19 vaccines in patients treated with rituximab for rheumatic diseases or ocrelizumab for multiple sclerosis (n = 37), compared to immunocompetent individuals (n = 22).
Results
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies were detectable in only 69.4% of patients and at levels that were significantly lower compared to controls who all seroconverted. In contrast to antibodies, Spike (S)-specific CD4 T cells were equally detected in immunocompetent and anti-CD20 treated patients (85–90%) and mostly of a Th1 phenotype. Response rates of S-specific CD8 T cells were higher in ocrelizumab (96.2%) and rituximab-treated patients (81.8%) as compared to controls (66.7%). S-specific CD4 and CD8 T cells were polyfunctional but expressed more effector molecules in patients than in controls. During follow-up, 3 MS patients without SARS-CoV-2-specific antibody response had a mild breakthrough infection. One of them had no detectable S-specific T cells after vaccination.
Conclusions
Our study suggests that patients on anti-CD20 treatment are able to mount potent T-cell responses to mRNA COVID-19 vaccines, despite impaired humoral responses. This could play an important role in the reduction of complications of severe COVID-19.
Patients on anti-CD20 treatment who are at risk for severe coronavirus disease 2019 (COVID-19) are able to mount potent T -cell responses to mRNA COVID-19 vaccines, despite impaired humoral responses. This could play an important role in the reduction of complications of COVID-19.
•New adjuvants are typically a combination of delivery system and an immune potentiator.•A deeper understanding of innate immunity has helped the discovery of new adjuvants.•Adjuvant discovery and ...manufacture favor synthetic small molecule immune potentiators.•Aluminum salts (Alum) should remain the benchmark comparator for any new adjuvants.•Omics and systems biology will benefit the clinical development of adjuvanted vaccines.
In the last two decades, several vaccines formulated with a new generation of adjuvants have been licensed or approved to target diseases such as influenza, hepatitis B, cervical cancer, and malaria. These new generation adjuvants appear to work by delivering a localized activation signal to the innate immune system, which in turn promotes antigen-specific adaptive immunity. Advances in understanding of the innate immune system together with high-throughput discovery of synthetic immune potentiators are now expanding the portfolio of new generation adjuvants available for evaluation. Meanwhile, omics and systems biology are providing molecular benchmarks or signatures to assess vaccine safety and effectiveness. This accumulating knowledge and experience raises the prospect that the future selection of the right antigen/adjuvant combination can be more evidence based and can speed up the clinical development program for new adjuvanted vaccines.
Official protection of an exploited species sometimes precedes any quantitative understanding of its use, including any dependence of local residents on it for food and livelihood. Conservation ...initiatives could suffer without this information. The Goliath frog Conraua goliath is iconic globally because of its large size, and is categorized as Endangered on the IUCN Red List. The main threat to this species in Cameroon is overexploitation, but any associated socio-economic aspects of this have not been quantified. We provide insights into local perceptions of the Goliath frog and its consumption through structured interviews with 223 people living alongside this species. The Goliath frog is well known and hunted both for home consumption and the wild meat trade. We trailed seven collaborative Cameroonian Goliath frog hunters over two seasons to determine offtake. A total of 192 Goliath frogs were collected by these hunters, peaking in March. The hunters used nets, shotguns and spears. Their catch was eaten at home or sold fresh within the community or to travellers for XAF 1,500–5,000 (USD 3–10) each. We also studied the Goliath frog trade by examining the databases of the Cameroonian Ministry of Forestry and Wildlife, and CITES. CITES and hunters reported large exports of Goliath frogs but no trade was documented by the Ministry of Forestry and Wildlife. To support conservation planning, this study provides preliminary quantitative information on the extent of the threat of hunting to this Endangered frog.
Properties and Uses of Butanol reviews the different types of butanol along with its characteristics, methods of production and future trends observed in its applications as an alternative energy ...resource. The main aspects involved in the production of biobutanol are described, including raw materials, the transformation of biomass and the separation of the acetone-butanol-ethanol mixture. The most important areas of opportunity are determined, focusing on the enhancements required by the production process to increase reaction yields in the hydrolysis and fermentation steps. The closing study discusses the oxidation of butanol on Pt single crystal, the possible mechanisms of the butanol oxidation reaction, and the working principles of fuel cells.
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