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Chikungunya virus (CHIKV) infection causes acute disease characterized by fever, rash and arthralgia, which progresses to severe and chronic arthritis in up to 50% of patients. Moreover, CHIKV infection can be fatal in infants or immunocompromised individuals and has no approved therapy or prevention. This phase 1, first-in-human, randomized, placebo-controlled, proof-of-concept trial conducted from January 2019 to June 2020 evaluated the safety and pharmacology of mRNA-1944, a lipid nanoparticle-encapsulated messenger RNA encoding the heavy and light chains of a CHIKV-specific monoclonal neutralizing antibody, CHKV-24 (NCT03829384). The primary outcome was to evaluate the safety and tolerability of escalating doses of mRNA-1944 administered via intravenous infusion in healthy participants aged 18-50 years. The secondary objectives included determination of the pharmacokinetics of mRNA encoding for CHKV-24 immunoglobulin heavy and light chains and ionizable amino lipid component and the pharmacodynamics of mRNA-1944 as assessed by serum concentrations of mRNA encoding for CHKV-24 immunoglobulin G (IgG), plasma concentrations of ionizable amino lipid and serum concentrations of CHKV-24 IgG. Here we report the results of a prespecified interim analysis of 38 healthy participants who received intravenous single doses of mRNA-1944 or placebo at 0.1, 0.3 and 0.6 mg kg.sup.-1, or two weekly doses at 0.3 mg kg.sup.-1. At 12, 24 and 48 h after single infusions, dose-dependent levels of CHKV-24 IgG with neutralizing activity were observed at titers predicted to be therapeutically relevant concentrations ([greater than or equal to]1 [micro]g ml.sup.-1) across doses that persisted for [greater than or equal to]16 weeks at 0.3 and 0.6 mg kg.sup.-1 (mean t.sub.1/2 approximately 69 d). A second 0.3 mg kg.sup.-1 dose 1 week after the first increased CHKV-24 IgG levels 1.8-fold. Adverse effects were mild to moderate in severity, did not worsen with a second mRNA-1944 dose and none were serious. To our knowledge, mRNA-1944 is the first mRNA-encoded monoclonal antibody showing in vivo expression and detectable ex vivo neutralizing activity in a clinical trial and may offer a treatment option for CHIKV infection. Further evaluation of the potential therapeutic use of mRNA-1944 in clinical trials for the treatment of CHIKV infection is warranted. An mRNA-based therapeutic can drive expression of a functional antibody in humans at levels capable of neutralizing Chikungunya virus ex vivo., Author(s): Allison August [sup.1] , Husain Z. Attarwala [sup.1] , Sunny Himansu [sup.1] , Shiva Kalidindi [sup.1] , Sophia Lu [sup.1] , Rolando Pajon [sup.1] , Shu Han [sup.1] , [...]

Lactoferrin binding proteins A and B (LbpA and LbpB) compose the lactoferrin receptor of the obligate human pathogen Neisseria meningitidis. This receptor is thought to be important for colonization and initiation of invasive disease because of its role in acquiring host iron and providing protection from the cationic peptide, lactoferricin. By virtue of its function, the receptor is accessible to the host immune system and displays substantial sequence variation. In this study, we analyzed a broad collection of LbpAs (62) and LbpBs (101) to determine the distribution of sequence variation within each protein and to search for patterns between sequence similarity and strain typing. The sequence variation in LbpA was predominantly observed in 3 surface loops and, surprisingly, in the N-terminal region immediately upstream of the predicted TonB box. The analysis of LbpB revealed that the variability was distributed throughout the protein, particularly in the highly variable negatively charged regions in the C-lobe, but otherwise was greater in the N-lobe than the C-lobe. There was no readily identifiable correlation between the sequence variation within LbpA, LbpB, multi-locus sequence type, or serogroup. Key words: Neisseria meningitidis, lactoferrin, iron acquisition, sequence variation, lactoferrin binding. Les proteines de liaison de la lactoferrine A et B (LbpA et LbpB) constituent le recepteur de la lactoferrine du pathogene obligatoire humain Neisseria meningitidis. On croit que ce recepteur est important pour la colonisation et l'initiation de la phase invasive de la maladie a cause de son role dans l'acquisition du fer de l'hote et dans la protection contre la lactoferricine, un peptide cationique,. En vertu de sa fonction, le recepteur est accessible au systeme immunitaire de l'hote et montre une variation de sequence substantielle. Dans cette etude, nous avons analyse une vaste collection de LbpA (62) et de LbpB (101) afin de d' evaluer la distribution de la variation de sequence a l'interieur de la proteine, et chercher des patrons qui lient la similarite de sequence au type de souche. La variation de sequence a l'interieur de LbpA etait surtout observee dans les trois boucles de surface et, de maniere surprenante, dans la region N-terminale situee immediatement en amont de la boite TonB predite. L' analyse de LbpB a revele que la variabilite etait distribuee sur toute la proteine, particulierement dans les regions hautement variables chargees negativement du lobe C, mais qui, sinon, etait plus elevee dans le lobe N que dans le lobe C. Il n'y avait pas de correlation facilement identifiable entre la variation de sequence a l'interieur de LbpA et LbpB, le type de sequence multilocus ou le groupe serologique. Mots-cles: Neisseria meningitidis, lactoferrine, acquisition du fer, variation de sequence, liaison de la lactoferrine., Introduction Neisseria meningitidis is a Gram-negative diplococcus found solely in humans and is an important cause of meningitis and systemic infection (Stephens et al. 2007). The endemic rates of disease [...]

The molecular diversity of a novel Neisseria meningitidis antigen, encoded by the ORF NMB0088 of MC58 (FadL-like protein), was assessed in a panel of 64 diverse meningococcal strains. The panel consisted of strains belonging to different serogroups, serotypes, serosubtypes and MLST sequence types, of different clinical sources, years and countries of isolation. Based on the sequence variability of the protein, the FadL-like protein has been divided into four variant groups in this species. Antigen variants were associated with specific serogroups and MLST clonal complexes. Maximum-likelihood analyses were used to determine the relationships among sequences and to compare the selection pressures acting on the encoded protein. Furthermore, a model of population genetics and molecular evolution was used to detect natural selection in DNA sequences using the non-synonymous : synonymous substitution ([d.sub.N] : [d.sub.S]) ratio. The meningococcal sequences were also compared with those of the related surface protein in non-pathogenic commensal Neisseria species to investigate potential horizontal gene transfer. The N. meningitidis fadL gene was subject to only weak positive selection pressure and was less diverse than meningococcal major outer-membrane proteins. The majority of the variability in fadL was due to recombination among existing alleles from the same or related species that resulted in a discrete mosaic structure in the meningococcal population. In general, the population structuring observed based on the FadL-like membrane protein indicates that it is under intermediate immune selection. However, the emergence of a new subvariant within the hyperinvasive lineages demonstrates the phenotypic adaptability of N. meningitidis, probably in response to selective pressure. DOI 10.1099/mic.0.043182-0