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Background: Longitudinal changes in vaccination-induced immune response remain inadequately characterized in adolescents. We present long-term safety, immunogenicity, and COVID-19 incidence following a 2-dose mRNA-1273 100-µg primary series, and immunogenicity following a single dose of mRNA-1273 50 µg in vaccine-naïve adolescents. Methods: TeenCOVE (NCT04649151) Part 1 randomized adolescents (12-17 years) to 2-dose mRNA-1273 100 µg (n = 2490) or placebo (n = 1243) 28 days apart. Subsequently, placebo recipients (n = 91) could receive open-label mRNA-1273. Primary objectives included prespecified adverse events through 12 months; secondary objectives were COVID-19 incidence and neutralizing and spike-binding antibodies (nAbs/bAbs) against SARS-CoV-2 (ancestral/variants) through 12 months (study period: December 2020-January 2022). In Part 2, vaccine-naïve adolescents (n = 52) received up to 2 doses of mRNA-1273 50 µg; interim analysis included Day 28 (D28) nAbs post-injection 1 in SARS-CoV-2-baseline-positive participants (serologic/virologic evidence of prior infection). Findings: In SARS-CoV-2-baseline-negative adolescents (N = 369), mRNA-1273 induced robust nAb responses versus baseline (geometric mean concentration [GMC] = 11; 95% CI, 11-12) at D28 (1868 [1759-1985]), 6 months (625 [583-670]) and 12 months (550 [490-618]) post-injection 2. Similar bAb responses were observed to alpha/beta/delta/gamma variants; nAb/bAb responses were similar in SARS-CoV-2-baseline-positive adolescents. The 2-dose mRNA-1273 100-µg primary series was generally well-tolerated; one case of nonserious, moderate, probable acute myocarditis resolved by 8 days from symptom onset. A single dose of mRNA-1273 50 µg in SARS-CoV-2-baseline-positive adolescents induced higher D28 nAb GMCs against ancestral SARS-CoV-2 than 2-dose mRNA-1273 100 µg in young adults (geometric mean ratio = 4.322 [3.274-5.707]). Interpretation: The overall risk-benefit profile of mRNA-1273 remains favorable in adolescents, with durable 12-month immune responses against SARS-CoV-2 (ancestral/variants). A single mRNA-1273 50-µg injection in vaccine-naïve adolescents elicited robust immune responses against SARS-CoV-2. Funding: This project has been funded in whole or in part with federal funds by the Department of Health and Human Services, United States; Administration for Strategic Preparedness and Response, United States; Biomedical Advanced Research and Development Authority, United States, under Contract No. 75A50120C00034. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Department of Health and Human Services or its components.
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BACKGROUND: The mRNA-1345 vaccine demonstrated efficacy against RSV disease with acceptable safety in adults ≥60 years in the ConquerRSV trial. Here, humoral immunogenicity results from the trial are presented. METHODS: This phase 2/3 trial randomly assigned adults (≥60 years) to mRNA-1345 50-µg encoding prefusion F (preF) glycoprotein (n = 17,793) vaccine or placebo (n = 17,748). RSV-A and RSV-B neutralizing antibody (nAb) and preF binding antibody (bAb) levels at baseline and day 29 post-vaccination were assessed in a per-protocol immunogenicity subset ([PPIS]; mRNA-1345, n = 1515; placebo, n = 333). RESULTS: Day 29 nAb geometric mean titers (GMTs) increased 8.4-fold against RSV-A and 5.1-fold against RSV-B from baseline. Seroresponses (4-fold rise from baseline) in the mRNA-1345 groups were 74.2% and 56.5% for RSV-A and RSV-B, respectively. Baseline GMTs were lower among participants who met the seroresponse criteria than those who did not. mRNA-1345 induced preF bAbs at day 29, with a pattern similar to nAbs. Day 29 antibody responses across demographic and risk subgroups were generally consistent with the overall PPIS. CONCLUSION: mRNA-1345 enhanced RSV-A and RSV-B nAbs and preF bAbs in adults (≥60 years) across various subgroups, including those at risk for severe disease, consistent with its demonstrated efficacy in the prevention of RSV disease.
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JN.1, the dominating SARS-CoV-2 variant, is antigenically distinct from ancestral BA.1, BA.5 and XBB.1.5 variants, raising concern about effectiveness of updated COVID-19 vaccines. Here, we compared the neutralizing antibody response against JN.1, 1-month after receipt of the three available Moderna mRNA vaccines. Sera obtained from 37, 30 and 30 XBB.1.5, BA.1 and BA.4-5 -vaccine recipients, respectively, were tested for anti-RBD IgG and for JN-1 specific neutralizing antibody levels. Geometric mean fold rise (GMFR) in JN.1 specific neutralizing titers was 27 (95 % CI: 17-43.1), 10.1 (95 % CI: 6.48-15.7) and 8.77 (95 % CI: 5.69-13.5) following XBB.1.5, BA.1 and BA.4-5 vaccines, respectively, translating into a 64 % lower adjusted response (geometric mean ratio [GMR] = 0.36, 95 % CI: 0.21-0.6) in the BA.1 arm, and a 75 % lower response (GMR = 0.25, 95 % CI: 0.15-0.43) in the BA.4-5 arm. This suggests that XBB.1.5 vaccination will most likely, result in improved effectiveness against JN.1 compared with other COVID-19 vaccines.
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BACKGROUND: Variant-containing mRNA vaccines for COVID-19 to broaden protection against SARS-CoV-2 variants are recommended based on findings in adults. We report interim safety and immunogenicity of an omicron BA.1 variant-containing (mRNA-1273.214) primary vaccination series and booster dose in paediatric populations. METHODS: This open-label, two-part, non-randomised phase 3 trial enrolled participants aged 6 months to 5 years at 24 US study sites. Eligible participants were generally healthy or had stable chronic conditions, without known SARS-CoV-2 infection in the previous 90 days. Individuals who were acutely ill or febrile 1 day before or at the screening visit or those who previously received other COVID-19 vaccines (except mRNA-1273 for part 2) were excluded. In part 1, SARS-CoV-2-vaccine-naive participants received two-dose mRNA-1273.214 (25 µg; omicron BA.1 and ancestral Wuhan-Hu-1 mRNA) primary series. In part 2, participants who previously completed the two-dose mRNA-1273 (25 µg) primary series in KidCOVE (NCT04796896) received a mRNA-1273.214 (10 µg) booster dose. Primary study outcomes were safety and reactogenicity of the mRNA-1273.214 primary series (part 1) or booster dose (part 2) as well as the inferred effectiveness of mRNA-1273.214 based on immune responses against ancestral SARS-CoV-2 (D614G) and omicron BA.1 variant at 28 days post-primary series (part 1) or post-booster dose (part 2). The safety set included participants who received at least one dose of the study vaccine; the immunogenicity set included those who provided immunogenicity samples. Interim safety and immunogenicity are summarised in this analysis as of the data cutoff date (Dec 5, 2022). This trial is registered with ClinicalTrials.gov, NCT05436834. FINDINGS: Between June 21, 2022, and Dec 5, 2022, 179 participants received one or more doses of mRNA-1273.214 primary series (part 1) and 539 received a mRNA-1273.214 booster dose (part 2). The safety profile within 28 days after either dose of the mRNA-1273.214 primary series and the booster dose was consistent with that of the mRNA-1273 primary series in this age group, with no new safety concerns or vaccine-related serious adverse events observed. At 28 days after primary series dose 2 and the booster dose, both mRNA-1273.214 primary series (day 57, including all participants with or without evidence of prior SARS-CoV-2 infection at baseline) and booster (day 29, including participants without evidence of prior SARS-CoV-2 infection at baseline) elicited responses that were superior against omicron-BA.1 (geometric mean ratio part 1: 25·4 [95% CI 20·1-32·1] and part 2: 12·5 [11·0-14·3]) and non-inferior against D614G (part 1: 0·8 [0·7-1·0] and part 2: 3·1 [2·8-3·5]), compared with neutralising antibody responses induced by the mRNA-1273 primary series (in a historical comparator group). INTERPRETATION: mRNA-1273.214 was immunogenic against BA.1 and D614G in children aged 6 months to 5 years, with a comparable safety profile to mRNA-1273, when given as a two-dose primary series or a booster dose. These results are aligned with the US Centers for Disease Control and Prevention recommendations for the use of variant-containing vaccines for continued protection against the emerging variants of SARS-CoV-2. FUNDING: Moderna.
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Vacuna nCoV-2019 mRNA-1273 , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunización Secundaria , Inmunogenicidad Vacunal , SARS-CoV-2 , Humanos , COVID-19/prevención & control , COVID-19/inmunología , Masculino , Femenino , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Preescolar , Lactante , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/administración & dosificación , Vacuna nCoV-2019 mRNA-1273/inmunología , Anticuerpos Antivirales/sangre , Estados Unidos , Anticuerpos Neutralizantes/sangre , Vacunación/métodosRESUMEN
BACKGROUND: Immunosuppressed individuals, including solid organ transplant recipients (SOTRs), are at high risk for severe COVID-19. METHODS: This open-label, phase 3b trial evaluated mRNA-1273 in 137 adult kidney and 77 liver SOTRs and 20 immunocompetent participants. In Part A, SOTRs received three 100-µg doses of mRNA-1273; immunocompetent participants received 2 doses. In Part B, an additional 100-µg dose was offered ≥4 months post-primary series. Here, we report interim trial results. RESULTS: mRNA-1273 was well-tolerated in SOTRs. Four serious adverse events were considered vaccine-related by the investigator in 3 SOTRs with pre-existing comorbidities. No vaccine-related biopsy-proven organ rejection events or deaths were reported. mRNA-1273 elicited modest neutralizing antibody (nAb) responses after dose 2 and improved responses after dose 3 in SOTRs. Post-dose 3 responses among liver SOTRs were comparable to post-dose 2 responses in immunocompetent participants. Post-additional dose responses were increased in SOTRs regardless of the primary series vaccination. In liver SOTRs, post-additional dose responses were â¼3-fold higher versus post-dose 2 but were lower than immunocompetent participant responses. Most kidney SOTRs received multiple immunosuppressants and had reduced antibody responses versus liver SOTRs. CONCLUSIONS: mRNA-1273 (100â µg) was well-tolerated and dose 3 and the additional dose improved antibody responses among SOTRs.
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BACKGROUND: Monovalent Omicron XBB.1.5-containing vaccines were approved for coronavirus disease 2019 (COVID-19) 2023-2024 immunizations. METHODS: This ongoing, open-label, phase 2/3 study evaluated messenger RNA (mRNA)-1273.815 monovalent (50-µg Omicron XBB.1.5 spike mRNA) and mRNA-1273.231 bivalent (25-µg each Omicron XBB.1.5 and BA.4/BA.5 spike mRNAs) vaccines, administered as fifth doses to adults who previously received primary series, third doses of an original mRNA COVID-19 vaccine, and fourth doses of an Omicron BA.4/BA.5 bivalent vaccine. Interim safety and immunogenicity 29 days after vaccination are reported. RESULTS: Participants (randomized 1:1) received 50-µg of mRNA-1273.815 (n = 50) or mRNA-1273.231 (n = 51); median intervals (interquartile range) from prior BA.4/BA.5 bivalent doses were 8.2 (8.1-8.3) and 8.3 (8.1-8.4) months, respectively. Fold increases in neutralizing antibody (nAb) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants from prebooster nAb levels were numerically higher against XBB.1.5, XBB.1.16, EG.5.1, BA.2.86, and JN.1 than BA.4/BA.5, BQ.1.1, or D614G on day 29. Monovalent vaccine also cross-neutralized FL.1.5.1, EG.5.1, BA.2.86, HK.3.1, HV.1, and JN.1 variants in a participant subset (n = 20) 15 days after vaccination. Reactogenicity was similar to that of mRNA-1273 vaccines. CONCLUSIONS: XBB.1.5-containing mRNA-1273 vaccines elicit robust, diverse nAb responses against more recent SARS-CoV-2 variants, including JN.1, supporting the XBB.1.5-spike update for COVID-19 vaccines.
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Vacuna nCoV-2019 mRNA-1273 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunogenicidad Vacunal , SARS-CoV-2 , Humanos , COVID-19/prevención & control , COVID-19/inmunología , Adulto , Femenino , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Vacuna nCoV-2019 mRNA-1273/inmunología , Anticuerpos Antivirales/sangre , Masculino , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Persona de Mediana Edad , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/administración & dosificación , Vacunación , Adulto Joven , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , AncianoRESUMEN
BACKGROUND: An mRNA-based RSV vaccine, mRNA-1345, is under clinical investigation to address RSV disease burden in older adults. METHODS: This phase 1, randomized, observer-blind, placebo-controlled, dose-ranging study evaluated safety, reactogenicity, and immunogenicity of mRNA-1345 in adults 65-79 years (NCT04528719). Participants were randomized to receive 1-dose of mRNA-1345 (12.5, 25, 50, 100, or 200-µg) or placebo and matched mRNA-1345 booster or placebo at 12-months. RESULTS: Overall, 298 participants received the first injection; 247 received the 12-month booster injection. mRNA-1345 was generally well-tolerated after both injections, with the most frequently reported solicited adverse reactions being injection-site pain, fatigue, headache, arthralgia, and myalgia. Reactogenicity was higher after the booster injection than the first injection but similar severity, time-to-onset, and duration. A single mRNA-1345 injection boosted RSV-A and RSV-B neutralizing antibody titers (nAb) and prefusion-F-binding antibody (preF-bAb) concentrations at 1-month (geometric mean-fold rises: RSV-A, 10.2-16.5; RSV-B, 5.3-12.5; preF-bAb, 7.2-12.1). RSV antibody levels remained above baseline through 12-months, indicating immune persistence. A 12-month booster injection also increased RSV-A and RSV-B nAb titers and preF-bAb concentrations; titers post-booster injection were numerically lower compared to titers after the first-dose, with overlapping 95% CIs. CONCLUSIONS: mRNA-1345 was well-tolerated and immunogenic following a single injection and a 12-month booster. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04528719.
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BACKGROUND: Respiratory syncytial virus (RSV) can cause substantial morbidity and mortality among older adults. An mRNA-based RSV vaccine, mRNA-1345, encoding the stabilized RSV prefusion F glycoprotein, is under clinical investigation. METHODS: In this ongoing, randomized, double-blind, placebo-controlled, phase 2-3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive one dose of mRNA-1345 (50 µg) or placebo. The two primary efficacy end points were the prevention of RSV-associated lower respiratory tract disease with at least two signs or symptoms and with at least three signs or symptoms. A key secondary efficacy end point was the prevention of RSV-associated acute respiratory disease. Safety was also assessed. RESULTS: Overall, 35,541 participants were assigned to receive the mRNA-1345 vaccine (17,793 participants) or placebo (17,748). The median follow-up was 112 days (range, 1 to 379). The primary analyses were conducted when at least 50% of the anticipated cases of RSV-associated lower respiratory tract disease had occurred. Vaccine efficacy was 83.7% (95.88% confidence interval [CI], 66.0 to 92.2) against RSV-associated lower respiratory tract disease with at least two signs or symptoms and 82.4% (96.36% CI, 34.8 to 95.3) against the disease with at least three signs or symptoms. Vaccine efficacy was 68.4% (95% CI, 50.9 to 79.7) against RSV-associated acute respiratory disease. Protection was observed against both RSV subtypes (A and B) and was generally consistent across subgroups defined according to age and coexisting conditions. Participants in the mRNA-1345 group had a higher incidence than those in the placebo group of solicited local adverse reactions (58.7% vs. 16.2%) and of systemic adverse reactions (47.7% vs. 32.9%); most reactions were mild to moderate in severity and were transient. Serious adverse events occurred in 2.8% of the participants in each trial group. CONCLUSIONS: A single dose of the mRNA-1345 vaccine resulted in no evident safety concerns and led to a lower incidence of RSV-associated lower respiratory tract disease and of RSV-associated acute respiratory disease than placebo among adults 60 years of age or older. (Funded by Moderna; ConquerRSV ClinicalTrials.gov number, NCT05127434.).
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Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Vacunas de ARNm , Anciano , Humanos , Anticuerpos Antivirales , Método Doble Ciego , Infecciones por Virus Sincitial Respiratorio/epidemiología , Infecciones por Virus Sincitial Respiratorio/prevención & control , Virus Sincitial Respiratorio Humano/genética , Enfermedades Respiratorias/diagnóstico , Enfermedades Respiratorias/epidemiología , Enfermedades Respiratorias/prevención & control , Resultado del Tratamiento , Vacunas de ARNm/efectos adversos , Vacunas de ARNm/uso terapéutico , Vacunas contra Virus Sincitial Respiratorio/efectos adversos , Vacunas contra Virus Sincitial Respiratorio/uso terapéutico , Persona de Mediana EdadRESUMEN
We report femtosecond time-resolved measurements of the McLafferty rearrangement following the strong-field tunnel ionization of 2-pentanone, 4-methyl-2-pentanone, and 4,4-dimethyl-2-pentanone. The pump-probe-dependent yields of the McLafferty product ion are fit to a biexponential function with fast (â¼100 fs) and slow (â¼10 ps) time constants, the latter of which is faster for the latter two compounds. Following nearly instantaneous ionization, the fast time scale is associated with rotation of the molecule to a six-membered cyclic intermediate that facilitates transfer of the γ-hydrogen, while the â¼50-100 times longer time scale is associated with a π-bond rearrangement and bond cleavage between the α- and ß-carbons to produce the enol cation. These experimental measurements are supported by ab initio molecular dynamics trajectories, which further confirm the time scale of this important stepwise reaction in mass spectrometry.
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We examine the possibility that three hydrogen atoms in one plane of the cyclopropane dication come together in a concerted "ring-closing" mechanism to form H3+, a crucial cation in interstellar gas-phase chemistry. Ultrafast strong-field ionization followed by disruptive probing measurements indicates that the formation time of H3+ is 249 ± 16 fs. This time scale is not consistent with a concerted mechanism, but rather a process that is preceded by ring opening. Measurements on propene, an isomer of cyclopropane, reveal the H3+ formation time to be 225 ± 13 fs, a time scale similar to the H3+ formation time in cyclopropane. Ab initio molecular dynamics simulations and the fact that both dications share a common potential energy surface support the ring-opening mechanism. The reaction mechanism following double ionization of cyclopropane involves ring opening, then H-migration, and roaming of a neutral H2 molecule, which then abstracts a proton to form H3+. These results further our understanding of complex interstellar chemical reactions and gas-phase reaction dynamics relevant to electron ionization mass spectrometry.
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Background & objectives: In India, lifestyle changes have contributed to increase in the number of people suffering from lipid profile abnormalities, which is a major risk factor for coronary artery diseases. The present study was aimed to estimate the prevalence of lipid profile abnormalities and 10 yr risk of cardiovascular disease (CVD) among the adult population in west Tripura district and to study the association of lipid profile abnormalities and increased CVD risk with sociodemography, body mass index (BMI), hypertension, random blood sugar (RBS) and haemoglobin level. Methods: This cross-sectional study was conducted amongst 445 adults of 20 to 60 yr of age from a randomly selected block in west Tripura district. The 10 yr risk of CVD was estimated using the Framingham Risk Assessment Tool. Results: The study revealed that overall 83.4 per cent adult population had lipid profile abnormalities, with 22.2, 42 and 70.3 per cent of participants having hypercholesterolaemia, hypertriglyceridaemia and low high-density lipoprotein level, respectively. Gender (P=0.02) and BMI (P<0.001) were the significant determinants of dyslipidaemia. Only 3.8 per cent of participants had intermediate or high risk of CVD, with all of them being males. Gender, age, occupation and RBS were significantly associated with increased CVD risk. Interpretation & conclusions: The study revealed a high burden of lipid profile abnormalities in the study population, with males having more risk of CVD. Hence, periodic screening of lipid profile abnormalities and risk of CVD should be incorporated at the primary care level to combat the CVD epidemic in India.
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Enfermedades Cardiovasculares , Hipertensión , Adulto , Femenino , Humanos , Masculino , Enfermedades Cardiovasculares/epidemiología , Estudios Transversales , Lípidos , Factores de Riesgo , Adulto Joven , Persona de Mediana EdadRESUMEN
BACKGROUND: A vaccine that prevents cytomegalovirus (CMV) infection in women could reduce the incidence of congenital CMV infection, a major cause of neurodevelopmental disability. We aimed to assess the safety and efficacy of a replication-defective investigational CMV vaccine, V160, in CMV-seronegative women. METHODS: This phase 2b, randomised, double-blind, placebo-controlled study was conducted at 90 sites in seven countries (USA, Finland, Canada, Israel, Spain, Russia, and Australia). Eligible participants were generally healthy, CMV-seronegative, non-pregnant, 16-35-year-old women of childbearing potential with exposure to children aged 5 years or younger. Participants were randomly assigned using central randomisation via an interactive response technology system 1:1:1 to one of three groups: V160 three-dose regimen (V160 at day 1, month 2, and month 6), V160 two-dose regimen (V160 on day 1, placebo at month 2, and V160 at month 6), or placebo (saline solution at day 1, month 2, and month 6). The primary outcomes were the efficacy of three doses of V160 in reducing the incidence of primary CMV infection during the follow-up period starting 30 days after the last dose of vaccine using a fixed event rate design, and the safety and tolerability of the two-dose and three-dose V160 regimens. We planned to test the efficacy of a two-dose regimen of V160 in reducing the incidence of primary CMV infection only if the primary efficacy hypothesis was met. Analyses for the primary efficacy endpoint were performed on the per-protocol efficacy population; safety analyses included all randomly assigned participants who received study vaccine. The primary efficacy hypothesis was tested at prespecified interim and final analyses. The study was ongoing and efficacy data continued to accrue at the time of final testing of the primary efficacy hypothesis. Vaccine efficacy was re-estimated after final testing of the primary efficacy hypothesis based on all available efficacy data at end of study. This trial is registered at ClinicalTrials.gov (NCT03486834) and EudraCT (2017-004233-86) and is complete. FINDINGS: Between April 30, 2018, and Aug 30, 2019, 7458 participants were screened, of whom 2220 were randomly assigned to the V160 three-dose group (n=733), V160 two-dose group (n=733), or placebo group (n=734). A total of 523 participants in the V160 three-dose group and 519 in the placebo group were included in the final hypothesis testing. Of these, there were 11 cases of CMV infection in the V160 three-dose group and 20 cases in the placebo group. The vaccine efficacy for the V160 three-dose group was 44·6% (95% CI -15·2 to 74·8) at the final testing of the primary efficacy hypothesis, a result corresponding to failure to demonstrate the primary efficacy hypothesis. On the basis of this result, the study was terminated for futility. The re-estimate of vaccine efficacy for the V160 three-dose group based on all available efficacy data at end of study (556 participants in the V160 three-dose group and 543 in the placebo group) was 42·4% (95% CI -13·5 to 71·1). A total of 728 participants in the V160 three-dose group, 729 in the V160 two-dose group, and 732 in the placebo group were included in the safety analyses. The most common solicited injection-site adverse event was injection-site pain (680 [93%] in the V160 three-dose group, 659 [90%] in the V160 two-dose group, and 232 [32%] in the placebo group). The most common solicited systemic adverse event was fatigue (457 [63%] in the V160 three-dose group, 461 [63%] in the V160 two-dose group, and 357 [49%] in the placebo group). No vaccine-related serious adverse events or deaths were reported. INTERPRETATION: V160 was generally well tolerated and immunogenic; however, three doses of the vaccine did not reduce the incidence of primary CMV infection in CMV-seronegative women compared with placebo. This study provides insights into the design of future CMV vaccine efficacy trials, particularly for the identification of CMV infection using molecular assays. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA (MSD).
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Infecciones por Citomegalovirus , Vacunas contra Citomegalovirus , Vacunas , Niño , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Citomegalovirus , Inmunización , Infecciones por Citomegalovirus/prevención & control , Método Doble Ciego , Inmunogenicidad VacunalRESUMEN
This ongoing, open-label, phase 2/3 trial compared the safety and immunogenicity of the Omicron BA.4/BA.5-containing bivalent mRNA-1273.222 vaccine with the ancestral Wuhan-Hu-1 mRNA-1273 as booster doses. Two groups of adults who previously received mRNA-1273 as primary vaccination series and booster doses were enrolled in a sequential, nonrandomized manner and received single-second boosters of mRNA-1273 (n = 376) or bivalent mRNA-1273.222 (n = 511). Primary objectives were safety and the noninferiority or superiority of neutralizing antibody (nAb) responses against Omicron BA.4/BA.5 and ancestral SARS-CoV-2 with the D614G mutation (ancestral SARS-CoV-2 (D614G)), 28 days post boost. Superiority and noninferiority were based on prespecified success criteria (lower bounds of 95% CI > 1 and < 0.677, respectively) of the mRNA-1273.222:mRNA-1273 geometric mean ratios. Bivalent Omicron BA.4/BA.5-containing mRNA-1273.222 elicited superior nAb responses against BA.4/BA.5 versus mRNA-1273 and noninferior responses against ancestral SARS-CoV-2 (D614G) at day 29 post boost in participants without detectable prior SARS-CoV-2 infection. Day 29 seroresponses against Omicron BA.4/BA.5 were higher for mRNA-1273.222 than for mRNA-1273 and similar against ancestral SARS-CoV-2 (D614G), both meeting noninferiority criterion. The safety profile of mRNA-1273.222 was similar to that previously reported for mRNA-1273 with no new safety concerns identified. Continued monitoring of neutralization and real-world vaccine effectiveness are needed as additional divergent-virus variants emerge. ClinicalTrials.gov registration: NCT04927065.
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Vacunas contra la COVID-19 , COVID-19 , Adulto , Humanos , Vacuna nCoV-2019 mRNA-1273 , Anticuerpos Neutralizantes , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Vacunas de ARNm , SARS-CoV-2/genéticaRESUMEN
We previously presented day 29 interim safety and immunogenicity results from a phase 2/3 study (NCT04927065) comparing the Omicron-BA.1-containing bivalent vaccine mRNA-1273.214 (50-µg) to the 50-µg mRNA-1273 booster in adults who previously received the mRNA-1273 primary series (100-µg) and mRNA-1273 first booster (50-µg) dose. Primary endpoints were safety, non-inferiority of the neutralizing antibody (nAb) and seroresponse against Omicron BA.1, superiority of the nAb response against Omicron-BA.1, and non-inferiority of the nAb response against ancestral SARS-CoV-2 for second boosters of mRNA-1273.214 versus mRNA-1273 at days 29 and 91. The key secondary endpoint was the seroresponse difference of mRNA-1273.214 versus mRNA-1273 against ancestral SARS-CoV-2 at days 29 and day 91. Participants were sequentially enrolled and dosed with 50-µg of mRNA-1273 (n = 376) or mRNA-1273.214 (n = 437) as second booster doses. Here we present day 91 post-booster results. In participants with no pre-booster, severe acute respiratory syndrome coronavirus 2-infection (SARS-CoV-2), mRNA-1273.214 elicited Omicron-BA.1-nAb titers (95% confidence interval [CI]) that were significantly higher (964.4 [834.4-1114.7]) than those of mRNA-1273 (624.2 [533.1-730.9]) and similar to those of mRNA-1273 against ancestral SARS-CoV-2 at day 91. mRNA-1273.214 also induced higher binding antibody responses against Omicron BA.1 and alpha, gamma and delta variants than mRNA-1273. Safety profiles were similar for both vaccines. The Omicron-BA.1 bivalent vaccine improved antibody responses compared to mRNA-1273 through 90 days post-booster.
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Vacunas contra la COVID-19 , COVID-19 , Adulto , Humanos , Vacuna nCoV-2019 mRNA-1273 , Anticuerpos Neutralizantes , COVID-19/prevención & control , SARS-CoV-2 , Vacunas Combinadas , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
BACKGROUND: The omicron BA.1 bivalent booster is used globally. Previous open-label studies of the omicron BA.1 (Moderna mRNA-1273.214) booster showed superior neutralising antibody responses against omicron BA.1 and other variants compared with the original mRNA-1273 booster. We aimed to compare the safety and immunogenicity of omicron BA.1 monovalent and bivalent boosters with the original mRNA-1273 vaccine in a large, randomised controlled trial. METHODS: In this large, randomised, observer-blind, active-controlled, phase 3 trial in the UK (28 hospital and vaccination clinic sites), individuals aged 16 years or older who had previously received two injections of any authorised or approved COVID-19 vaccine, with or without an mRNA vaccine booster (third dose), were randomly allocated (1:1) using interactive response technology to receive 50 µg omicron BA.1 monovalent or bivalent vaccines or 50 µg mRNA-1273 administered as boosters via deltoid intramuscular injection. The primary outcomes were safety and immunogenicity at day 29, including prespecified non-inferiority and superiority of booster immune responses, based on the neutralising antibody geometric mean concentration (GMC) ratios of the monovalent and bivalent boosters compared with mRNA-1273. Safety was assessed in all participants who received first or second boosters, and primary immunogenicity outcomes were assessed in all participants who received the planned booster dose, had pre-booster and day 29 antibody data, had no major protocol deviations, and who were SARS-CoV-2-negative. The study is registered with EudraCT (2022-000063-51) and ClinicalTrials.gov (NCT05249829) and is ongoing. FINDINGS: Between Feb 16 and March 24, 2022, 724 participants were randomly allocated to receive omicron BA.1 monovalent (n=366) or mRNA-1273 (n=357), and between April 2 and June 17, 2022, 2824 participants were randomly allocated to receive omicron BA.1 bivalent (n=1418) or mRNA-1273 (n=1395) vaccines as second boosters. Median durations (months) between the most recent COVID-19 vaccine and study boosters were similar for omicron BA.1 monovalent (4·0 months [IQR 3·6-4·7]) and mRNA-1273 (4·1 [3·5-4·7]), and for the omicron BA.1 bivalent (5·5 [4·8-6·2]) and mRNA-1273 (5·4 [4·8-6·2]) boosters. The omicron BA.1 monovalent and bivalent boosters elicited superior neutralising GMCs against the omicron BA.1 variant compared with mRNA-1273, with GMC ratios of 1·68 (99% CI 1·45-1·95) and 1·53 (1·41-1·67) at day 29 post-booster doses in participants without previous SARS-CoV-2 infection. Both boosters induced non-inferior ancestral SARS-CoV-2 (Asp614Gly) immune responses with GMCs that were similar for the bivalent (2987·2 [95% CI 2814·9-3169·9]) versus mRNA-1273 (2911·3 [2750·9-3081·0]) and lower for the monovalent (2699·7 [2431·3-2997·7] vs 3020·6 [2776·5-3286·2]) boosters, with respective GMC ratios of 1·05 (99% CI 0·96-1·15) and 0·82 (95% CI 0·74-0·91). Results were comparable regardless of previous SARS-CoV-2 infection status. Incidences of solicited adverse reactions with the omicron BA.1 monovalent (335 [91·3%] of 367 participants) and omicron BA.1 bivalent (1285 [90·4%] of 1421 participants) boosters were similar to those observed previously for mRNA-1273, with no new safety concerns identified and no occurrences of fatal adverse events. INTERPRETATION: Omicron-containing booster vaccines generated superior immunogenicity against omicron BA.1 and comparable immunogenicity against the original strain with no new safety concerns. It remains important to continuously monitor the immune responses and real-world vaccine effectiveness as divergent SARS-CoV-2 variants emerge. FUNDING: Moderna.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Humanos , Vacuna nCoV-2019 mRNA-1273 , COVID-19/prevención & control , SARS-CoV-2/genética , Anticuerpos Neutralizantes , Reino Unido , Inmunogenicidad Vacunal , Anticuerpos AntiviralesRESUMEN
Proximity ligation assay (PLA) is an immunofluorescence assay, which determines in situ interaction of two biomolecules present within 40 nm close proximity. Here, we describe a modification of PLA for visual detection of in situ protein interactions with nascent RNA in a single cell (IPNR-PLA). In IPNR-PLA, nascent RNA is labeled by incorporating 5-fluorouridine (FU), a uridine nucleotide analogue, followed by covalent cross-linking of the interacting partners in proximity to newly synthesized RNA. By using combination of anti-BrdU antibody, which specifically binds to FU, and primary antibody against a protein of interest, the IPNR reaction results in fluorescent puncta as a positive signal, only if the candidate proteins are in proximity to nascent RNA. We have validated this method by demonstrating known CDK9 and elongating RNA pol II interaction with nascent RNA. Finally, we used this method to test for the presence of DNA double strand breaks as well as Poly (ADP-ribose) polymerase 1 (PARP1), an RNA binding protein, in the vicinity of nascent RNA in cancer cells. The capability of performing parallel IF labeling and quantifiable multiparameter measurements within heterogeneous cell populations makes IPNR-PLA very attractive for use in biological studies. Overall, we have developed the IPNR-PLA method for analysis of protein association with nascent RNA with single-cell resolution, which is highly sensitive, quantitative, efficient, and requires little starting experimental material.
Asunto(s)
Anticuerpos , ARN , Animales , ARN/metabolismo , Anticuerpos/química , Anticuerpos/metabolismo , Proteínas de Unión al ARN , Mamíferos/metabolismoRESUMEN
A-kinase anchoring protein (AKAP) comprises a family of scaffold proteins, which decides the subcellular localisation of a combination of signalling molecules. Spoonbill (Spoon) is a putative A-kinase anchoring protein in Drosophila. We have earlier reported that Spoon suppresses ribonuclear foci formed by trinucleotide repeat expanded transcripts associated with Spinocerebellar Ataxia 8 neurodegeneration in Drosophila. However, the role of Spoonbill in cellular signalling was unexplored. In this report, we have unravelled a novel function of Spoon protein in the regulation of the apoptotic pathway. The Drosophila TNFα homolog, Eiger, induces apoptosis via activation of the JNK pathway. We have shown here that Spoonbill is a positive regulator of the Eiger-induced JNK signalling. Further genetic interaction studies show that the spoon interacts with components of the JNK pathway, TGF-ß activated kinase 1 (Tak1 - JNKKK), hemipterous (hep - JNKK) and basket (bsk - JNK). Interestingly, Spoonbill alone can also induce ectopic activation of the JNK pathway in a context-specific manner. To understand the molecular mechanism underlying Spoonbill-mediated modulation of the JNK pathway, the interaction between Spoon and Drosophila JNK was assessed. basket encodes the only known JNK in Drosophila. This serine/threonine-protein kinase phosphorylates Jra/Kay, which transcriptionally regulate downstream targets like Matrix metalloproteinase 1 (Mmp1), puckered (puc), and proapoptotic genes hid, reaper and grim. Interestingly, we found that Spoonbill colocalises and co-immunoprecipitates with the Basket protein in the developing photoreceptor neurons. Hence, we propose that Spoon plays a vital role in JNK-induced apoptosis. Furthermore, stress-induced JNK activation underlying Parkinson's Disease was also examined. In the Parkinson's Drosophila model of neurodegeneration, depletion of Spoonbill leads to a partial reduction of JNK pathway activation, along with improvement in adult motor activity. These observations suggest that the putative scaffold protein Spoonbill is a functional and physical interacting partner of the Drosophila JNK protein, Basket. Spoon protein is localised on the outer mitochondrial membrane (OMM), which may perhaps provide a suitable subcellular niche for activation of Drosophila Basket protein by its kinases which induce apoptosis.
Asunto(s)
Proteínas de Drosophila , Drosophila melanogaster , Animales , Drosophila melanogaster/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas de Anclaje a la Quinasa A/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Apoptosis/genética , Fosfoproteínas Fosfatasas/metabolismoRESUMEN
The Development of reliable and field-compatible detection methods is essential to monitoring and controlling the spread of any global pandemic. We herein report a novel anti-RNA:DNA hybrid (anti-RDH) antibody-based biosensor for visual, colorimetric lateral flow assay, using gold nanoparticles, coupled with transcription-mediated-isothermal-RNA-amplification (TMIRA) for specific and sensitive detection of viral RNA. We have demonstrated its utility for SARS-CoV-2 RNA detection. This technique, which we have named RDH-LFA (anti-RNA:DNA hybrid antibody-based lateral flow assay), exploits anti-RDH antibody for immunocapture of viral RNA hybridized with specific DNA probes in lateral flow assay. This method uses biotinylated-oligonucleotides (DNAB) specific to SARS-CoV-2 RNA (vRNA) to generate a vRNA-DNAB hybrid. The biotin-tagged vRNA-DNAB hybrid molecules bind to streptavidin conjugated with gold nanoparticles. This hybrid complex is trapped by the anti-RDH antibody immobilized on the nitrocellulose membrane resulting in pink color signal leading to visual naked-eye detection in 1â minute. Combining RDH-LFA with isothermal RNA amplification (TMIRA) significantly improves the sensitivity (LOD:10â copies/µl) with a total turnaround time of an hour. More importantly, RDH-LFA coupled with the TMIRA method showed 96.6% sensitivity and 100% specificity for clinical samples when compared to a commercial gold standard reverse-transcription quantitative polymerase-chain-reaction assay. Thus, the present study reports a rapid, sensitive, specific, and simple method for visual detection of viral RNA, which can be used at the point-of-care without requiring sophisticated instrumentation.
RESUMEN
Messenger RNA (mRNA)-based vaccine platforms used for the development of mRNA-1273 and BNT162b2 have provided a robust adaptable approach to offer protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, as variants of concern (VoCs), such as omicron and associated sub-variants, emerge, boosting strategies must also adapt to keep pace with the changing landscape. Heterologous vaccination regimens involving the administration of booster vaccines different than the primary vaccination series offer a practical, effective, and safe approach to continue to reduce the global burden of coronavirus disease 2019 (COVID-19). To understand the immunogenicity, effectiveness, and safety of heterologous mRNA-based vaccination strategies, relevant clinical and real-world observational studies were identified and summarized. Overall, heterologous boosting strategies with mRNA-based vaccines that are currently available and those in development will play an important global role in protecting individuals from COVID-19 caused by emerging VoCs.