Search

mRNA-1647 is an investigational mRNA-based vaccine against cytomegalovirus (CMV) that contains sequences encoding the CMV proteins glycoprotein B and pentamer. Humoral and cellular immune responses were evaluated in blood samples collected from healthy CMV-seropositive and CMV-seronegative adults who participated in a phase 1 trial of a three-dose series of mRNA-1647 (NCT03382405). Neutralizing antibody (nAb) titers against fibroblast and epithelial cell infection in sera from CMV-seronegative mRNA-1647 recipients were higher than those in sera from control CMV-seropositive samples and remained elevated up to 12 months after dose 3. nAb responses elicited by mRNA-1647 were comparable across 14 human CMV (HCMV) strains. Frequencies of antigen-specific memory B cells increased in CMV-seropositive and CMV-seronegative participants after each mRNA-1647 dose and remained elevated for up to 6 months after dose 3. mRNA-1647 elicited robust increases in frequencies and polyfunctionality of CD4+ T helper type 1 and effector CD8+ T cells in samples from CMV-seronegative and CMV-seropositive participants after stimulation with HCMV-specific peptides. The administration of three doses of mRNA-1647 to healthy adults elicited high nAb titers with wide-breadth, long-lasting memory B cells, and strong polyfunctional T-cell responses. These findings support further clinical development of the mRNA-1647 vaccine against CMV. IMPORTANCE Cytomegalovirus (CMV), a common virus that can infect people of all ages, may lead to serious health problems in unborn babies and those with a weakened immune system. Currently, there is no approved vaccine available to prevent CMV infection; however, the investigational messenger RNA (mRNA)-based CMV vaccine, mRNA-1647, is undergoing evaluation in clinical trials. The current analysis examined samples from a phase 1 trial of mRNA-1647 in healthy adults to better understand how the immune system reacts to vaccination. Three doses of mRNA-1647 produced a long-lasting immune response, thus supporting further investigation of the vaccine in the prevention of CMV infection. [ABSTRACT FROM AUTHOR]

Background and Objectives: Cerebral amyloid angiopathy-related inflammation (CAA-RI) and biopsy-positive primary angiitis of the CNS (BP-PACNS) have overlapping clinicoradiologic presentations. It is unknown whether clinical and radiologic features can differentiate CAA-RI from BP-PACNS and whether both diseases have different relapse rates. The objectives of this study were to compare clinicoradiologic presentations and relapse rates in patients with CAA-RI vs BP-PACNS., Methods: Patients with CAA-RI and BP-PACNS were enrolled from 2 retrospective multicenter cohorts. Patients with CAA-RI were biopsy-positive or met probable clinicoradiologic criteria. Patients with BP-PACNS had histopathologic confirmation of CNS angiitis, with no secondary etiology. A neuroradiologist read brain MRIs, blinded to the diagnosis of CAA-RI or BP-PACNS. Clinicoradiologic features were compared using univariable logistic regression models. Relapse rates were compared using a univariable Fine-Gray subdistribution hazard model, with death as a competing risk., Results: This study enrolled 104 patients with CAA-RI (mean age 73 years, 48% female sex) and 52 patients with BP-PACNS (mean age 45 years, 48% female sex). Patients with CAA-RI more often had white matter hyperintense lesions meeting the probable CAA-RI criteria (93% vs 51%, p < 0.001), acute subarachnoid hemorrhage (15% vs 2%, p = 0.02), cortical superficial siderosis (27% vs 4%, p < 0.001), ≥1 lobar microbleed (94% vs 26%, p < 0.001), past intracerebral hemorrhage (17% vs 4%, p = 0.04), ≥21 visible centrum semiovale perivascular spaces (34% vs 4%, p < 0.01), and leptomeningeal enhancement (70% vs 27%, p < 0.001). Patients with BP-PACNS more often had headaches (56% vs 31%, p < 0.01), motor deficits (56% vs 36%, p = 0.02), and nonischemic parenchymal gadolinium enhancement (82% vs 16%, p < 0.001). The prevalence of acute ischemic lesions was 18% in CAA-RI and 22% in BP-PACNS ( p = 0.57). The features with the highest specificity for CAA-RI were acute subarachnoid hemorrhage (98%), cortical superficial siderosis (96%), past intracerebral hemorrhage (96%), and ≥21 visible centrum semiovale perivascular spaces (96%). The probable CAA-RI criteria had a 71% sensitivity (95% CI 44%-90%) and 91% specificity (95% CI 79%-98%) in differentiating biopsy-positive CAA-RI from BP-PACNS. The rate of relapse in the first 2 years after remission was lower in CAA-RI than in BP-PACNS (hazard ratio 0.46, 95% CI 0.22-0.96, p = 0.04)., Conclusion: Clinicoradiologic features differed between patients with CAA-RI and those with BP-PACNS. Specific markers for CAA-RI were hemorrhagic signs of subarachnoid involvement, past intracerebral hemorrhage, ≥21 visible centrum semiovale perivascular spaces, and the probable CAA-RI criteria. A biopsy remains necessary for diagnosis in some cases of CAA-RI. The rate of relapse in the first 2 years after disease remission was lower in CAA-RI than in BP-PACNS.

Background: Seasonal influenza remains a global public health concern. A messenger RNA (mRNA)-based quadrivalent seasonal influenza vaccine, mRNA-1010, was investigated in a 3-part, first-in-human, phase 1/2 clinical trial., Methods: In Parts 1-3 of this stratified, observer-blind study, adults aged ≥18 years old were randomly assigned to receive a single dose (6.25 µg to 200 µg) of mRNA-1010 or placebo (Part 1) or an active comparator (Afluria; Parts 2-3). Primary study objectives were assessment of safety, reactogenicity, and humoral immunogenicity of mRNA-1010, placebo (Part 1), or active comparator (Parts 2-3). Exploratory endpoints included assessment of cellular immunogenicity (Part 1) and antigenic breadth against vaccine heterologous (A/H3N2) strains (Parts 1-2)., Results: In all study parts, solicited adverse reactions were reported more frequently for mRNA-1010 than placebo or Afluria and most were grade 1 or 2 in severity. No vaccine-related serious adverse events or deaths were reported. In Parts 1-2, a single dose of mRNA-1010 (25 µg to 200 µg) elicited robust Day 29 hemagglutination inhibition (HAI) titers that persisted through 6 months. In Part 3, lower doses of mRNA-1010 (6.25 µg to 25 µg) elicited Day 29 HAI titers that were higher or comparable to Afluria for influenza A strains. Compared with Afluria, mRNA-1010 (50 µg) elicited broader A/H3N2 antibody responses (Part 2). mRNA-1010 induced greater T-cell responses than placebo at Day 8 that were sustained or stronger at Day 29 (Part 1)., Conclusions: Data support the continued development of mRNA-1010 as a seasonal influenza vaccine., Clinicaltrials.gov Identifier: NCT04956575 (https://clinicaltrials.gov/study/NCT04956575)., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

mRNA-1647 is an investigational mRNA-based vaccine against cytomegalovirus (CMV) that contains sequences encoding the CMV proteins glycoprotein B and pentamer. Humoral and cellular immune responses were evaluated in blood samples collected from healthy CMV-seropositive and CMV-seronegative adults who participated in a phase 1 trial of a three-dose series of mRNA-1647 (NCT03382405). Neutralizing antibody (nAb) titers against fibroblast and epithelial cell infection in sera from CMV-seronegative mRNA-1647 recipients were higher than those in sera from control CMV-seropositive samples and remained elevated up to 12 months after dose 3. nAb responses elicited by mRNA-1647 were comparable across 14 human CMV (HCMV) strains. Frequencies of antigen-specific memory B cells increased in CMV-seropositive and CMV-seronegative participants after each mRNA-1647 dose and remained elevated for up to 6 months after dose 3. mRNA-1647 elicited robust increases in frequencies and polyfunctionality of CD4 + T helper type 1 and effector CD8 + T cells in samples from CMV-seronegative and CMV-seropositive participants after stimulation with HCMV-specific peptides. The administration of three doses of mRNA-1647 to healthy adults elicited high nAb titers with wide-breadth, long-lasting memory B cells, and strong polyfunctional T-cell responses. These findings support further clinical development of the mRNA-1647 vaccine against CMV.IMPORTANCECytomegalovirus (CMV), a common virus that can infect people of all ages, may lead to serious health problems in unborn babies and those with a weakened immune system. Currently, there is no approved vaccine available to prevent CMV infection; however, the investigational messenger RNA (mRNA)-based CMV vaccine, mRNA-1647, is undergoing evaluation in clinical trials. The current analysis examined samples from a phase 1 trial of mRNA-1647 in healthy adults to better understand how the immune system reacts to vaccination. Three doses of mRNA-1647 produced a long-lasting immune response, thus supporting further investigation of the vaccine in the prevention of CMV infection.CLINICAL TRIALSRegistered at ClinicalTrials.gov (NCT03382405)., Competing Interests: All authors are employees of Moderna, Inc., and may hold stock/stock options in the company.