Search

The COVE trial randomized participants to receive two doses of mRNA-1273 vaccine or placebo on Days 1 and 29 (D1, D29). Anti-SARS-CoV-2 Spike IgG binding antibodies (bAbs), anti-receptor binding domain IgG bAbs, 50% inhibitory dilution neutralizing antibody (nAb) titers, and 80% inhibitory dilution nAb titers were measured at D29 and D57. We assessed these markers as correlates of protection (CoPs) against COVID-19 using stochastic interventional vaccine efficacy (SVE) analysis and principal surrogate (PS) analysis, frameworks not used in our previous COVE immune correlates analyses. By SVE analysis, hypothetical shifts of the D57 Spike IgG distribution from a geometric mean concentration (GMC) of 2737 binding antibody units (BAU)/mL (estimated vaccine efficacy (VE): 92.9% (95% CI: 91.7%, 93.9%)) to 274 BAU/mL or to 27,368 BAU/mL resulted in an overall estimated VE of 84.2% (79.0%, 88.1%) and 97.6% (97.4%, 97.7%), respectively. By binary marker PS analysis of Low and High subgroups (cut-point: 2094 BAU/mL), the ignorance interval (IGI) and estimated uncertainty interval (EUI) for VE were [85%, 90%] and (78%, 93%) for Low compared to [95%, 96%] and (92%, 97%) for High. By continuous marker PS analysis, the IGI and 95% EUI for VE at the 2.5th percentile (519.4 BAU/mL) vs. at the 97.5th percentile (9262.9 BAU/mL) of D57 Spike IgG concentration were [92.6%, 93.4%] and (89.2%, 95.7%) vs. [94.3%, 94.6%] and (89.7%, 97.0%). Results were similar for other D29 and D57 markers. Thus, the SVE and PS analyses additionally support all four markers at both time points as CoPs.

BackgroundAt interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported.MethodsWe enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021.ResultsThe trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified.ConclusionsThe mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

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] , [...]

Background The reactogenicity and immunogenicity of coronavirus disease 2019 (COVID-19) vaccines are well studied. Little is known regarding the relationship between immunogenicity and reactogenicity of COVID-19 vaccines. Methods This study assessed the association between immunogenicity and reactogenicity after 2 mRNA-1273 (100 µg) injections in 1671 total adolescent and adult participants (≥12 years) from the primary immunogenicity sets of the blinded periods of the Coronavirus Efficacy (COVE) and TeenCOVE trials. Associations between immunogenicity through day 57 and solicited adverse reactions (ARs) after the first and second injections of mRNA-1273 were evaluated among participants with and without solicited ARs using linear mixed-effects models. Results mRNA-1273 reactogenicity in this combined analysis set was similar to that reported for these trials. The vaccine elicited high neutralizing antibody (nAb) geometric mean titers (GMTs) in evaluable participants. GMTs at day 57 were significantly higher in participants who experienced solicited systemic ARs after the second injection (1227.2 [1164.4–1293.5]) than those who did not (980.1 [886.8–1083.2], P =.001) and were associated with fever, chills, headache, fatigue, myalgia, and arthralgia. Significant associations with local ARs were not found. Conclusions These data show an association of systemic ARs with increased nAb titers following a second mRNA-1273 injection. While these data indicate systemic ARs are associated with increased antibody titers, high nAb titers were observed in participants after both injections, consistent with the immunogenicity and efficacy in these trials. These results add to the body of evidence regarding the relationship of immunogenicity and reactogenicity and can contribute toward the design of future mRNA vaccines. [ABSTRACT FROM AUTHOR]

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