Impact of ivermectin on onchocerciasis transmission: assessing the empirical evidence that repeated ivermectin mass treatments may lead to elimination/eradication in West-Africa

BACKGROUND: The Onchocerciasis Control Program (OCP) in West Africa has been closed down at the end of 2002. All subsequent control will be transferred to the participating countries and will almost entirely be based on periodic mass treatment with ivermectin. This makes the question whether elimination of infection or eradication of onchocerciasis can be achieved using this strategy of critical importance. This study was undertaken to explore this issue. METHODS: An empirical approach was adopted in which a comprehensive analysis was undertaken of available data on the impact of more than a decade of ivermectin treatment on onchocerciasis infection and transmission. Relevant entomological and epidemiological data from 14 river basins in the OCP and one basin in Cameroon were reviewed. Areas were distinguished by frequency of treatment (6-monthly or annually), endemicity level and additional control measures such as vector control. Assessment of results were in terms of epidemiological and entomological parameters, and as a measure of inputs, therapeutic and geographical coverage rates were used. RESULTS: In all of the river basins studied, ivermectin treatment sharply reduced prevalence and intensity of infection. Significant transmission, however, is still ongoing in some basins after 10-12 years of ivermectin treatment. In other basins, transmission may have been interrupted, but this needs to be confirmed by in-depth evaluations. In one mesoendemic basin, where 20 rounds of four-monthly treatment reduced prevalence of infection to levels as low as 2-3%, there was significant recrudescence of infection within a few years after interruption of treatment. CONCLUSIONS: Ivermectin treatment has been very successful in eliminating onchocerciasis as a public health problem. However, the results presented in this paper make it almost certain that repeated ivermectin mass treatment will not lead to the elimination of transmission of onchocerciasis from West Africa. Data on 6-monthly treatments are not sufficient to draw definitive conclusions.     

Surface properties of aqueous solutions of L-leucine

The surface tension, sigma, of solutions of L-leucine (CH3)2CHCH2CH(NH2)COOH in water, as well as in aqueous solutions of NaOH and HCl were measured in the temperature range between 278 and 308 K using the Wilhelmy plate method. L-Leucine was found to be a very weak surfactant, which can be understood if assuming strong interactions of this solute with the water structure. Striking differences were observed in the surface entropy of L-leucine solutions in water, 0.5 M HCl and 0.5 M NaOH. Moreover, surface activity of the solute is much lower than that supposed taking into account the hydrophobicity of this amino acid. It was concluded that the observed phenomena are caused by the water structure changes close to the side chain of leucine, caused by enforced hydrophobic hydration, i.e. formation of clathrate-like hydrates.     

Production and characterization of a monoclonal antibody able to discriminate galectin-1 from galectin-2 and galectin-3

Antisera raised against galectin-1 exhibit crossreactivities with other galectins or related molecules. In order to overcome this problem, a monoclonal antibody to human brain galectin-1 was obtained by selecting clones without reactivity toward galectin-3. This mAb specifically bound galectin-1 of various animal origins but neither galectin-2 nor galectin-3. Western-blotting analysis of soluble human brain extracts after 2D gel electrophoresis revealed only the two most acidic isoforms of galectin-1. The ability of this mAb to bind galectin-1/asialofetuin complexes indicates that its epitope is not localized in the carbohydrate recognition domain of galectin-1. This particularity induces with efficiency its monospecificity.      

Blue Light Overrides Repression of Asexual Sporulation by Mating Type Genes in the Basidiomycete Coprinus cinereus

Monokaryotic mycelia of the homobasidiomycete Coprinus cinereus form asexual spores (oidia) constitutively in abundant numbers. Mycelia with mutations in both mating type loci (Amut Bmut homokaryons) also produce copious oidia but only when exposed to blue light. We used such an Amut Bmut homokaryon to define environmental and inherent factors that influence the light-induced oidiation process. We show that the Amut function causes repression of oidiation in the dark and that light overrides this effect. Similarly, compatible genes from different haplotypes of the A mating type locus repress sporulation in the dark and not in the light. Compatible products of the B mating type locus reduce the outcome of light on A-mediated repression but the mutated B function present in the Amut Bmut homokaryons is not effective. In dikaryons, the coordinated regulation of asexual sporulation by compatible A and B mating type genes results in moderate oidia production in light. Copyright 1998 Academic Press.     

An anchored restriction-mapping approach applied to the genetic analysis of the Anopheles gambiae malaria vector complex 1

We introduce here a simple approach for rapidly determining restriction maps for a number of regions of a genome; this involves "anchoring" a map with a rare restriction site (in this case the seldom-cutting EagI) followed by partial digestion of a frequent-cutting enzyme (e.g., Sau 3A). We applied this technology to five species of the Anopheles gambiae complex. In a single Southern blot we obtained about a 15-kb restriction map each for the mtDNA, rRNA gene, and a scnDNA region for each of five species. Phylogenetic analyses of these regions yield trees at odds with the more traditional chromosome inversion-based trees. The value of the approach for systematic purposes is the ease with which several large, independent regions of the genome can be quickly assayed for molecular variation.      

Cancer immunotherapy: exploiting neoepitopes

The efficacy of cancer vaccines has long been hampered by insufficient definition of tumor-specific antigens. A recent study by Kreiter et al. published in Nature has provided a blueprint for a patient-tailored approach to develop individualized RNA vaccines.For the past two decades, the concept of vaccination against cancer has suffered from insufficient definition of relevant target antigens. Consequently, clinical vaccination trials, typically targeting tumor-associated self-antigens, have generally failed to elicit therapeutic immunity in spite of detection of vaccine-induced T-cell responses in blood. In hindsight, these failures can be readily explained by the finding that many of these self-antigens are expressed in the thymus, resulting in deletion of the highly reactive T-cell repertoire and development of suppressive T-regulatory cells¹. Moreover, circumvention of thymic tolerance by infusion of genetically engineered T cells targeting such antigens was found to be associated with severe toxicity in vital somatic tissues, vividly illustrating the physiological importance of immunological tolerance to many tumor-associated antigens².In an almost ironic twist of science, clinical trials employing the two main ''competing'' approaches for cancer immunotherapy, have shown us how to move forward with cancer vaccines. First, in-depth evaluation of the T-cell response in melanoma patients who responded to TIL-therapy, and infusion of ex vivo expanded tumor-infiltrating T cells, revealed that the T-cell clones driving therapeutic efficacy were not directed against lineage-specific and cancer testis antigens, but instead against neo-epitopes encoded by the tumor mutanome³. Essentially the same observation was subsequently made in patients responding to so-called checkpoint inhibitors, antibodies against cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) or the programmed cell death (PD)-1/PD-L1 axis, that can activate T cells by neutralizing inhibitory pathways in T cells⁴.Since checkpoint inhibitors are not uniformly effective in every patient and every cancer type, while durable clinical responses frequently occur in the absence of overt manifestations of autoimmunity, it was fair to postulate that T cells unleashed by checkpoint inhibitors recognize patient- and cancer-specific neoantigens derived from non-synonymous mutations rather than conserved self-antigens. Indeed, whole-exome sequencing of pre- and post-treatment tumor tissue has since revealed a strong association of the clinical response to checkpoint inhibition with the frequency of pre-treatment non-synonymous mutations in mouse models⁵ and in human melanoma⁴ and non-small cell lung cancer⁶, two types of cancer with a particularly high mutational load.These findings have set the stage for coordinated programs to identify patient-specific mutated antigens and target these through specific vaccines or transfer of antigen-specific T cells. Set aside the economic and regulatory challenges resulting from this highly individualized approach, several important questions have to be clarified: How can we predict which of the 50-500 mutations in a given tumor are immunogenic? How can we identify not only HLA class I-restricted epitopes, but also HLA class II-restricted CD4+ T-helper epitopes that are of critical importance to support the immune attack by CD8+ T cells and innate effector cells? How do we implement this information towards the design of patient-tailored vaccines?The recent study by Kreiter and coworkers provided a blueprint for such an approach in the context of syngeneic mouse tumor models⁷. After identification of non-synonymous mutations through RNA and DNA sequencing and prioritization of the mutations based on expression level and prediction of presentation on MHC, animals were vaccinated using synthetic RNA vaccines encoding long peptides. Interestingly, the majority of immunogenic epitopes where found to be MHC class II-restricted⁷. The fact that non-synonymous cancer mutations are preferentially recognized by CD4+ T cells may not be so surprising as the requirements for peptide processing and binding to MHC II are less restrictive than that for MHC I⁸. A downside of this flexibility is that prediction algorithms for MHC class II presentation suffers from inaccuracy compared to class I algorithms. Hence testing in pre-clinical models such as MHC-transgenic mice may be necessary to experimentally identify such epitopes, as exemplified by a recent study characterizing a class II neo-epitope of the glioma driver mutation IDH1R132H⁹. Complementary assays such as in situ proximity ligation assay¹⁰ may aid the selection of neo-epitopes presented on class II molecules by MHC class II+ tumor cells or tumor-infiltrating antigen-presenting cells.The efficacy of neoantigen-specific CD4+ T cells in controlling established tumors raises the question as to what their mechanism of action is. While direct cytotoxicity by CD4+ T cells¹¹ may play a role in tumors expressing MHC class II, more prominent effector mechanism probably include the orchestration of CD8+ T cells and innate effector cells, as well as the anti-tumor impact of cytokines such as interferon-γ or tumor necrosis factor¹². The study by Kreiter et al. suggests that a multimer vaccine targeting CD4 neoepitopes may act by unmasking CD8 epitopes previously not visible or not sufficiently visible to the immune system. The delineation of this complex process of antigen spreading to CD8 epitopes will be important in the future to help further tailor individualized (neo)antigen-specific cancer vaccines.