•Vaccines to prevent the global spread of SARS-CoV-2 infection are in development.•mRNA-1273 vaccine at 50 and 100 µg elicits robust immune responses in healthy adults.•Immunogenicity is generally ...similar in younger (18–55 yr) and older (≥55 yr) adults.•Safety profile of mRNA-1273 is acceptable; no serious adverse effects were observed.•Results support 2-dose regimens of 50 or 100 µg mRNA-1273 SARS-CoV-2 vaccine.
Vaccines are urgently needed to prevent the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We assessed the safety and immunogenicity of vaccine candidate mRNA-1273, encoding the prefusion-stabilized spike protein of SARS-CoV-2.
This phase 2, randomized, observer-blind, placebo-controlled trial was conducted at 8 sites in the USA, in healthy adults aged ≥18 years with no known history or risk of SARS-CoV-2 infection, and had not previously received an investigational CoV vaccine or treatment. Participants were stratified into two age cohorts (≥18-<55 and ≥55) and were randomly assigned (1:1:1) to either 50 or 100 µg of mRNA-1273, or placebo administered as two intramuscular injections 28 days apart. The primary outcomes were safety, reactogenicity, and immunogenicity assessed by anti-SARS-CoV-2-spike binding antibody level (bAb). Secondary outcome was immunogenicity assessed by SARS-CoV-2 neutralizing antibody (nAb) response.
Between 29 May and 8 July 2020, 600 participants were randomized, 300 per age cohort. The most common solicited adverse reactions were pain at injection site, headache, and fatigue following each vaccination in both age cohorts. One serious adverse event deemed unrelated by the site investigator occurred 33 days post-vaccination one. mRNA-1273 induced bAb and nAb by 28 days post-vaccination one that were higher at the 100 µg dose relative to the 50 µg dose; this difference was less apparent post-vaccination two. Binding antibodies and nAb increased substantially by 14 days following the second vaccination (day 43) to levels exceeding those of convalescent sera and remained elevated through day 57.
Vaccination with mRNA-1273 resulted in significant immune responses to SARS-CoV-2 in participants 18 years and older, with an acceptable safety profile, confirming the safety and immunogenicity of 50 and 100 µg mRNA-1273 given as a 2 dose-regimen.
ClinicalTrials.gov; NCT04405076.
Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine Baden, Lindsey R; El Sahly, Hana M; Essink, Brandon ...
New England journal of medicine/The New England journal of medicine,
02/2021, Letnik:
384, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based ...vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19.
This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. 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 SARS-CoV-2.
The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval CI, 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups.
The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).
The emergence of SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) with decreased susceptibility to neutralization has generated interest in assessments of booster doses and ...variant-specific vaccines. Clinical trial participants who received a two-dose primary series of the COVID-19 vaccine mRNA-1273 approximately 6 months earlier entered an open-label phase 2a study ( NCT04405076 ) to evaluate the primary objectives of safety and immunogenicity of a single booster dose of mRNA-1273 or variant-modified mRNAs, including multivalent mRNA-1273.211. As the trial is currently ongoing, this exploratory interim analysis includes preliminary descriptive results only of four booster groups (n = 20 per group). Immediately before the booster dose, neutralizing antibodies against wild-type D614G virus had waned (P < 0.0001) relative to peak titers against wild-type D614G measured 1 month after the primary series, and neutralization titers against B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) VOCs were either low or undetectable. Both the mRNA-1273 booster and variant-modified boosters were safe and well-tolerated. All boosters, including mRNA-1273, numerically increased neutralization titers against the wild-type D614G virus compared to peak titers against wild-type D614G measured 1 month after the primary series; significant increases were observed for mRNA-1273 and mRNA-1273.211 (P < 0.0001). In addition, all boosters increased neutralization titers against key VOCs and VOIs, including B.1.351, P.1. and B.1.617.2, that were statistically equivalent to peak titers measured after the primary vaccine series against wild-type D614G virus, with superior titers against some VOIs. This trial is ongoing.
Objective
To develop a patient‐specific 3‐dimensional (3D) printed drill guide for placement of cervical transpedicular screws and to assess its accuracy.
Study design
Prospective case‐series.
Sample ...Population
Thirty‐two cervical pedicle screws (CPS) placed in 3 large breed dogs.
Methods
Computed tomographic (CT) data of the cervical vertebrae were exported to a medical image processing software and 3D virtual vertebral models were created for each vertebra. These models were processed in a computer aided design (CAD) software to determine the optimal trajectory and size of the CPS. Virtual drill guides were created for each patient, 3D‐printed, and used intraoperatively. Locking titanium screw heads were bonded with polymethylmethacrylate cement to stabilize affected vertebral segments. Postoperative CT was used to assess the radiological accuracy of CPS placement in each dog. For each screw, CAD files were analyzed to determine a screw‐diameter‐to‐pedicle‐width‐ratio (SDPWR) at the narrowest point of the pedicle.
Results
A total of 32 CPS were placed, measuring 3.5 mm (n = 20), 2.7 mm (n = 11), and 2.4 mm (n = 1) in diameter. The majority (29/32) of these screws were placed without evidence of vertebral canal breach (grade 0), whereas a vertebral canal breach <2 mm (grade 1) was detected in 3/32 screws. This outcome was achieved despite a mean SDPWR of 0.75 (range 0.58‐0.93).
Conclusion
The use of a 3D‐printed patient‐specific drill guide permitted accurate placement of 32 bicortical pedicle screws in the caudal cervical vertebrae of 3 dogs. This technique may improve clinical outcome through superior biomechanical properties of screws, reduced surgical time, and reduced morbidity. These results warrant evaluation of patient outcome in a larger population.
Objective
To describe the clinical presentation, magnetic resonance imaging features, and outcome of cats treated with hemilaminectomy for intervertebral disc extrusion (IVDE).
Study design
Short ...case series.
Animals
Six cats.
Methods
Medical records were reviewed for signalment, onset, duration, and severity of clinical signs, magnetic resonance imaging features, surgical findings, and clinical outcome with a minimum postoperative follow‐up of 4 weeks.
Results
Our population included 6 cats with a median age of 8.6 years, consisting predominantly of males (n = 5) and purebred cats (n = 4). An acute onset and short duration of progressive clinical signs of myelopathy was the most common presentation; spinal hyperesthesia was present in 3 cats. A large volume of extradural material was identified by MRI within the lumbar vertebral column of each cat, causing marked spinal cord compression. The most common sites affected were L2‐L3 (n = 2) and L6‐L7 (n = 2). Follow‐up after hemilaminectomy was available in 5 cats: 4 had normal voluntary motor function, and 1 had recurrence of acute paraplegia, compromised nociception, and an extensive T2w hyperintense intramedullary lesion according to MRI. All 4 cats with preoperative urinary incontinence remained incontinent for at least 1 week despite good voluntary motor function of pelvic limbs.
Conclusion
Intervertebral disc extrusion was diagnosed by MRI in all 6 cats, most commonly at L2‐3 and L6‐7. Hemilaminectomy resulted in a good to excellent outcome in 4 of 5 cats.
Clinical significance
Feline IVDE can be diagnosed by MRI and carry a good prognosis after surgical decompression, although urinary continence may be delayed despite good pelvic limb voluntary motor function.
Developing a safe and immunogenic vaccine against Zika virus remains an unmet medical need. We did two phase 1 studies that evaluated the safety and immunogenicity of two mRNA-based Zika virus ...vaccines (mRNA-1325 and mRNA-1893) in adults.
Two randomised, placebo-controlled, dose-ranging, multicentre, phase 1 trials, one of mRNA-1325 (mRNA-1325 trial) and one of mRNA-1893 (mRNA-1893 trial), were done. For both studies, eligible participants were healthy adults (aged 18–49 years) who were flavivirus seronegative or flavivirus seropositive at baseline. Participants in the mRNA-1325 trial, which was done at three centres in the USA, were randomly assigned centrally (1:4), using a randomisation table, to the placebo group or one of three mRNA-1325 dose groups (10, 25, or 100 μg). All participants received two doses. The mRNA-1325 vaccine encoded the premembrane and envelope E structural proteins (prME) from a Micronesia 2007 Zika virus isolate. Participants in the mRNA-1893 trial, which was done at three centres in the USA and one centre in Puerto Rico, were randomly assigned (1:4) to the placebo group or one of four mRNA-1893 dose groups (10, 30, 100, or 250 μg) using centralised interactive response technology. All participants in the mRNA-1893 trial received dose one on day 1 and then dose two on day 29. The mRNA-1893 vaccine encoded the prME from the RIO-U1 Zika virus isolate. Safety was the primary outcome of each study, which was evaluated in the respective safety populations (mRNA-1325 trial: participants who received at least one dose and provided safety data; mRNA-1893 trial: participants who received at least one dose) and the solicited safety population (mRNA-1893 trial only: received at least 1 dose and contributed solicited adverse reaction data). Endpoints in both trials included solicited adverse reactions within 7 days after vaccination and unsolicited adverse events within 28 days after vaccination. The secondary outcome of both trials was immunogenicity assessed by Zika virus-specific neutralising antibodies (nAbs) in the per-protocol populations in either trial (participants with no major protocol deviations received full doses of assigned dose level within the acceptable time window, had samples drawn within acceptable time window, and had prevaccination and corresponding post-vaccination serum samples for testing). These were descriptive studies, with no formal hypothesis testing in either trial. Both trials are registered with ClinicalTrials.gov, NCT03014089 (mRNA-1325 trial) and NCT04064905 (mRNA-1893 trial).
The mRNA-1325 trial was done from Dec 14, 2016, to Aug 16, 2018. 90 participants were enrolled: 53 (59%) participants were women and 37 (41%) were men; 84 (93%) were White; and 74 (82%) were not Hispanic or Latino. All three dose levels of mRNA-1325 (10, 25, and 100 μg) were generally well tolerated, but the vaccine elicited poor Zika virus-specific nAb responses. At 28 days after dose two, geometric mean titres (GMTs) were highest for mRNA-1325 10 μg (10·3 95% CI 5·9–18·2). The mRNA-1893 trial was done from July 23, 2019, to March 22, 2021. 120 participants (70 58% women and 50 42% men) were enrolled, most participants were White (89 74%), and not Hispanic or Latino (91 76%). In the mRNA-1893 trial, solicited adverse reactions in participants who received a vaccine were mostly grade 1 or 2 and occurred more frequently at higher dose levels and after dose two. No participants withdrew due to an unsolicited treatment-emergent adverse event and most of these events were not treatment related. On day 57, all evaluated mRNA-1893 dose levels induced robust Zika virus-specific nAb responses, independent of flavivirus serostatus, that persisted until month 13. At day 57 in participants who were flavivirus seronegative, plaque reduction neutralisation titre test nAb GMTs were highest for mRNA-1893 100 μg (454·2 330·0–619·6); in participants who were flavivirus seropositive, GMTs were highest for mRNA-1893 10 μg (224·1 43·5–1153·5) and mRNA-1893 100 μg (190·5 19·2–1887·2).
These findings support the continued development of mRNA-1893 against Zika virus, which was well tolerated at all evaluated dose levels and induced strong Zika virus-specific serum nAb responses after two doses, regardless of baseline flavivirus serostatus.
Biomedical Advanced Research and Development Authority and Moderna.
VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies ...provide support for the idea that VX-787 occupies the 7-methyl GTP (m(7)GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a KD (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection.
In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the ...cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay ( Wagaman P. C. ; Leong M. A. ; Simmen K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105−114 ) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.
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