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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
BACKGROUND: Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown. METHODS: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 µg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported. RESULTS: In part 1 of the trial, 751 children received 50-µg or 100-µg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-µg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 µg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-µg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-µg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant. CONCLUSIONS: Two 50-µg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).
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Vacuna nCoV-2019 mRNA-1273 , COVID-19 , Vacuna nCoV-2019 mRNA-1273/efectos adversos , Vacuna nCoV-2019 mRNA-1273/inmunología , Vacuna nCoV-2019 mRNA-1273/uso terapéutico , Adolescente , Adulto , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/sangre , COVID-19/complicaciones , COVID-19/inmunología , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/uso terapéutico , Niño , Método Doble Ciego , Humanos , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica , Eficacia de las Vacunas , Adulto JovenRESUMEN
BACKGROUND: The safety, reactogenicity, immunogenicity, and efficacy of the mRNA-1273 coronavirus disease 2019 (Covid-19) vaccine in young children are unknown. METHODS: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled evaluation of the selected dose. In part 2, we randomly assigned young children (6 months to 5 years of age) in a 3:1 ratio to receive two 25-µg injections of mRNA-1273 or placebo, administered 28 days apart. The primary objectives were to evaluate the safety and reactogenicity of the vaccine and to determine whether the immune response in these children was noninferior to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives were to determine the incidences of Covid-19 and severe acute respiratory syndrome coronavirus 2 infection after administration of mRNA-1273 or placebo. RESULTS: On the basis of safety and immunogenicity results in part 1 of the trial, the 25-µg dose was evaluated in part 2. In part 2, 3040 children 2 to 5 years of age and 1762 children 6 to 23 months of age were randomly assigned to receive two 25-µg injections of mRNA-1273; 1008 children 2 to 5 years of age and 593 children 6 to 23 months of age were randomly assigned to receive placebo. The median duration of follow-up after the second injection was 71 days in the 2-to-5-year-old cohort and 68 days in the 6-to-23-month-old cohort. Adverse events were mainly low-grade and transient, and no new safety concerns were identified. At day 57, neutralizing antibody geometric mean concentrations were 1410 (95% confidence interval [CI], 1272 to 1563) among 2-to-5-year-olds and 1781 (95% CI, 1616 to 1962) among 6-to-23-month-olds, as compared with 1391 (95% CI, 1263 to 1531) among young adults, who had received 100-µg injections of mRNA-1273, findings that met the noninferiority criteria for immune responses for both age cohorts. The estimated vaccine efficacy against Covid-19 was 36.8% (95% CI, 12.5 to 54.0) among 2-to-5-year-olds and 50.6% (95% CI, 21.4 to 68.6) among 6-to-23-month-olds, at a time when B.1.1.529 (omicron) was the predominant circulating variant. CONCLUSIONS: Two 25-µg doses of the mRNA-1273 vaccine were found to be safe in children 6 months to 5 years of age and elicited immune responses that were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).
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Vacuna nCoV-2019 mRNA-1273 , COVID-19 , Inmunogenicidad Vacunal , Niño , Preescolar , Humanos , Lactante , Adulto Joven , Vacuna nCoV-2019 mRNA-1273/inmunología , Vacuna nCoV-2019 mRNA-1273/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/epidemiología , COVID-19/inmunología , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Método Doble Ciego , Inmunogenicidad Vacunal/inmunología , Eficacia de las Vacunas , Resultado del Tratamiento , Adolescente , AdultoRESUMEN
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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BACKGROUND: A 2-dose mRNA-1273 primary series in children aged 6 months-5 years (25-µg) and 6-11 years (50-µg) had an acceptable safety profile and was immunogenic in the phase 2/3 KidCOVE study. We present data from KidCOVE participants who received an mRNA-1273 booster dose. METHODS: An mRNA-1273 booster dose (10-µg for children aged 6 months-5 years; 25-µg for children aged 6-11 years; age groups based on participant age at enrollment) was administered ≥6 months after primary series completion. The primary safety objective was the safety and reactogenicity of an mRNA-1273 booster dose. The primary immunogenicity objective was to infer efficacy of an mRNA-1273 booster dose by establishing noninferiority of neutralizing antibody (nAb) responses after a booster in children compared with nAb responses observed after the mRNA-1273 primary series in young adults (18-25 years) from the pivotal efficacy study. Data were collected from March 2022 to June 2023. RESULTS: Overall, 153 (6 months-5 years) and 2519 (6-11 years) participants received an mRNA-1273 booster dose (median age at receipt of booster: 2 and 10 years, respectively). The booster dose safety profile was generally consistent with that of the primary series in children; no new safety concerns were identified. An mRNA-1273 booster dose elicited robust nAb responses against ancestral SARS-CoV-2 among children and met prespecified noninferiority success criteria when compared with responses observed after the primary series in young adults. CONCLUSIONS: Safety and immunogenicity data support administration of a mRNA-1273 booster dose in children aged 6 months to 11 years. CLINICAL TRIALS REGISTRATION: NCT04796896.
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BACKGROUND: Maternal immunization against group B streptococcus (GBS) could protect infants from invasive GBS disease. Additional doses in subsequent pregnancies may be needed. We evaluated the safety and immunogenicity of a second dose of an investigational trivalent CRM197-glycoconjugate GBS vaccine (targeting serotypes Ia/Ib/III), administered to nonpregnant women 4-6 years postdose 1. METHODS: Healthy women either previously vaccinated with 1 dose of trivalent GBS vaccine 4-6 years before enrollment (n = 53) or never GBS vaccinated (n = 27) received a single trivalent GBS vaccine injection. Adverse events (AEs) were recorded. Serotype-specific (Ia/Ib/III) anti-GBS antibodies were measured by multiplex immunoassay prevaccination and 30/60 days postvaccination. RESULTS: AEs were reported with similar rates after a first or second dose; none were serious. Of previously GBS-vaccinated women, 92%-98% had anti-GBS concentrations that exceeded an arbitrary threshold (8 µg/mL) for each serotype 60 days postdose 2 vs 36%-56% postdose 1 in previously non-GBS-vaccinated women. Of previously GBS-vaccinated women with undetectable baseline (predose 1) anti-GBS levels, 90%-98% reached this threshold postdose 2. For each serotype, anti-GBS geometric mean concentrations (GMCs) 30/60 days postdose 2 in previously GBS-vaccinated women were ≥200-fold higher than baseline GMCs. Among women with undetectable baseline anti-GBS levels, postdose 2 GMCs in previously GBS-vaccinated women exceeded postdose 1 GMCs in previously non-GBS-vaccinated women (≥7-fold). CONCLUSIONS: A second trivalent GBS vaccine dose administered 4-6 years postdose 1 was immunogenic with a favorable safety profile. Women with undetectable preexisting anti-GBS concentrations may benefit from a sufficiently spaced second vaccine dose. CLINICAL TRIALS REGISTRATION: NCT02690181.
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Infecciones Estreptocócicas , Vacunas Estreptocócicas , Anticuerpos Antibacterianos , Femenino , Humanos , Inmunogenicidad Vacunal , Lactante , Embarazo , Infecciones Estreptocócicas/prevención & control , Streptococcus agalactiae , Vacunas ConjugadasRESUMEN
BACKGROUND: Maternal vaccination against group B Streptococcus (GBS) might provide protection against invasive GBS disease in infants. We investigated the kinetics of transplacentally transferred GBS serotype-specific capsular antibodies in the infants and their immune response to diphtheria toxoid and pneumococcal vaccination. METHODS: This phase 1b/2, observer-blind, single-center study (NCT01193920) enrolled infants born to women previously randomized (1:1:1:1) to receive either GBS vaccine at dosages of 0.5, 2.5, or 5.0 µg of each of 3 CRM197-glycoconjugates (serotypes Ia, Ib, and III), or placebo. Infants received routine immunization: combination diphtheria vaccine (diphtheria-tetanus-acellular pertussis-inactivated poliovirus/Haemophilus influenzae type b vaccine; age 6/10/ 14 weeks) and 13-valent pneumococcal CRM197-conjugate vaccine (PCV13; age 6/14 weeks and 9 months). Antibody levels were assessed at birth, day (D) 43, and D91 for GBS serotypes; 1 month postdose 3 (D127) for diphtheria; and 1 month postprimary (D127) and postbooster (D301) doses for pneumococcal serotypes. RESULTS: Of 317 infants enrolled, 295 completed the study. In infants of GBS vaccine recipients, GBS serotype-specific antibody geometric mean concentrations were significantly higher than in the placebo group at all timepoints and predictably decreased to 41%-61% and 26%-76% of birth levels by D43 and D91, respectively. Across all groups, ≥95% of infants were seroprotected against diphtheria at D127 and ≥91% of infants had seroprotective antibody levels against each PCV13 pneumococcal serotype at D301. CONCLUSIONS: Maternal vaccination with an investigational CRM197-glycoconjugate GBS vaccine elicited higher GBS serotype-specific antibody levels in infants until 90 days of age, compared with a placebo group, and did not affect infant immune responses to diphtheria toxoid and pneumococcal vaccination. CLINICAL TRIALS REGISTRATION: NCT01193920.
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Anticuerpos Antibacterianos/sangre , Proteínas Bacterianas/inmunología , Inmunidad Materno-Adquirida , Vacunas Neumococicas/inmunología , Streptococcus agalactiae/inmunología , Vacunas Combinadas/inmunología , Anticuerpos Antibacterianos/biosíntesis , Anticuerpos Antibacterianos/inmunología , Proteínas Bacterianas/administración & dosificación , Proteínas Bacterianas/química , Vacuna contra Difteria, Tétanos y Tos Ferina/administración & dosificación , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Femenino , Vacunas contra Haemophilus/administración & dosificación , Vacunas contra Haemophilus/inmunología , Humanos , Esquemas de Inmunización , Inmunización Secundaria , Inmunogenicidad Vacunal , Lactante , Cinética , Masculino , Madres , Vacunas Neumococicas/administración & dosificación , Vacunas Neumococicas/efectos adversos , Polisacáridos/administración & dosificación , Polisacáridos/inmunología , Embarazo , Streptococcus agalactiae/química , Vacunación , Vacunas Combinadas/administración & dosificación , Vacunas Conjugadas/administración & dosificación , Vacunas Conjugadas/efectos adversos , Vacunas Conjugadas/inmunologíaRESUMEN
The respiratory syncytial virus (RSV) is responsible for as many as 199000 annual deaths worldwide. Currently, there is no standard treatment for RSV disease and no vaccine. Sendai virus (SeV) is an attractive pediatric vaccine candidate because it elicits robust and long-lasting virus-specific B cell and T cell activities in systemic and mucosal tissues. The virus serves as a gene delivery system as well as a Jennerian vaccine against its close cousin, human parainfluenza virus type 1. Here we describe the testing of a recombinant SeV (SeVRSV-Fs) that expresses an unconstrained, secreted RSV-F protein as a vaccine against RSV in cotton rats. After a single intranasal immunization of cotton rats with SeVRSV-Fs, RSV-specific binding and neutralizing antibodies were generated. These antibodies exhibited cross-reactivity with both RSV A and B isolates. RSV-F-specific IFN-γ-producing T cells were also activated. The SeVRSV-Fs vaccine conferred protection against RSV challenge without enhanced immunopathology. In total, results showed that an SeV recombinant that expresses RSV F in an unconstrained, soluble form can induce humoral and cellular immunity that protects against infection with RSV.
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Infecciones por Virus Sincitial Respiratorio/prevención & control , Virus Sincitiales Respiratorios/metabolismo , Virus Sendai/inmunología , Linfocitos T/inmunología , Vacunas Virales/administración & dosificación , Administración Intranasal , Animales , Anticuerpos Antivirales/metabolismo , Modelos Animales de Enfermedad , Técnicas de Transferencia de Gen , Humanos , Inmunización , Interferón gamma/metabolismo , Activación de Linfocitos , Ratas , Proteínas Recombinantes de Fusión/genética , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/genética , Virus Sendai/genética , Sigmodontinae , Linfocitos T/virología , Proteínas Virales de Fusión/genética , Vacunas Virales/genéticaRESUMEN
BACKGROUND: Group B Streptococcus (GBS) is a leading cause of serious infection in very young infants. Robust incidence data from many geographic regions, including Latin America and Asia, are however lacking. METHODS: A multicenter, hospital-based observational study was performed in Panama, Dominican Republic, Hong Kong and Bangladesh. All represented urban, tertiary referral hospitals, except Bangladesh. GBS cases (microbiological isolation from normally sterile sites in infants aged 0-89 days) were collected over 12 months. RESULTS: At 2.35 (95% CI: 1.74-3.18) cases per 1000 live births, the incidence of early onset GBS disease (EOD) was highest in the Dominican Republic, compared with 0.76 (95% CI: 0.41-1.39) in Hong Kong and 0.77 (95% CI: 0.44-1.35) in Panama, while no cases were identified in Bangladesh. Over 90% of EOD cases occurred on the first day of life, with case fatality ratios ranging from 6.7% to 40%, varying by center, age of onset and clinical presentation. Overall, 90% of GBS (EOD and late onset disease) was due to serotypes Ia, Ib and III. CONCLUSIONS: The incidence rate of early onset GBS infection reported in Dominican Republic was not dissimilar from that described in the United States prior to screening and intrapartum antibiotic prophylaxis, while the incidence in Hong Kong was higher than previously reported in the Asian region. The failure to identify GBS cases in Bangladesh highlights a need to better understand the contribution of population, healthcare and surveillance practice to variation in reported incidence. Overall, the identified disease burden and serotype distribution support the need for effective prevention methods in these populations, and the need for community based surveillance studies in rural areas where access to healthcare may be challenging.
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Infecciones Estreptocócicas/epidemiología , Infecciones Estreptocócicas/microbiología , Streptococcus agalactiae , Profilaxis Antibiótica , Bangladesh/epidemiología , República Dominicana/epidemiología , Femenino , Hong Kong/epidemiología , Humanos , Incidencia , Lactante , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Masculino , Panamá/epidemiología , Embarazo , Complicaciones Infecciosas del Embarazo/prevención & control , Factores de Riesgo , Serogrupo , Infecciones Estreptocócicas/prevención & control , Infecciones Estreptocócicas/transmisión , Streptococcus agalactiae/clasificación , Streptococcus agalactiae/genéticaRESUMEN
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: 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
Group B Streptococcus (GBS) is a leading cause of neonatal sepsis in developed countries. Its burden in the developing world is less clear. Studies reporting neonatal GBS disease incidence from developing countries were identified from 5 literature databases. Studies were assessed with respect to case finding and culture methods. Only 20 studies were identified. The GBS incidence ranged 0-3.06 per 1000 live births with variation within and between geographic regions. All but 1 study identified GBS cases within a hospital setting, despite the potential for births in the community. Possible case under-ascertainment was only discussed in 2 studies. A higher GBS incidence was reported when using automated culture methods. Prospective, population-based surveillance is urgently needed in developing countries to provide an accurate assessment of the neonatal GBS disease burden. This will be crucial for the design of interventions, including novel vaccines, and the understanding of their potential to impact mortality from neonatal sepsis.
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Países en Desarrollo/estadística & datos numéricos , Enfermedades del Recién Nacido/epidemiología , Enfermedades del Recién Nacido/microbiología , Infecciones Estreptocócicas/epidemiología , Streptococcus agalactiae/aislamiento & purificación , Técnicas Bacteriológicas , Notificación de Enfermedades , Humanos , Incidencia , Recién NacidoRESUMEN
T-cell immunotherapy that takes advantage of Epstein-Barr virus (EBV)-stimulated immunity has the potential to fill an important niche in targeted therapy for EBV-related cancers. To address questions of long-term efficacy, safety, and practicality, we studied 114 patients who had received infusions of EBV-specific cytotoxic T lymphocytes (CTLs) at 3 different centers to prevent or treat EBV(+) lymphoproliferative disease (LPD) arising after hematopoietic stem cell transplantation. Toxicity was minimal, consisting mainly of localized swelling at sites of responsive disease. None of the 101 patients who received CTL prophylaxis developed EBV(+) LPD, whereas 11 of 13 patients treated with CTLs for biopsy-proven or probable LPD achieved sustained complete remissions. The gene-marking component of this study enabled us to demonstrate the persistence of functional CTLs for up to 9 years. A preliminary analysis indicated that a patient-specific CTL line can be manufactured, tested, and infused for $6095, a cost that compares favorably with other modalities used in the treatment of LPD. We conclude that the CTL lines described here provide safe and effective prophylaxis or treatment for lymphoproliferative disease in transplantation recipients, and the manufacturing methodology is robust and can be transferred readily from one institution to another without loss of reproducibility.
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Infecciones por Virus de Epstein-Barr/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Herpesvirus Humano 4/inmunología , Trastornos Linfoproliferativos/terapia , Linfocitos T Citotóxicos/inmunología , Adolescente , Traslado Adoptivo/economía , Traslado Adoptivo/métodos , Adulto , Niño , Preescolar , Infecciones por Virus de Epstein-Barr/etiología , Infecciones por Virus de Epstein-Barr/virología , Femenino , Estudios de Seguimiento , Humanos , Inmunofenotipificación , Lactante , Linfoma/etiología , Linfoma/mortalidad , Linfoma/terapia , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/mortalidad , Masculino , Tasa de Supervivencia , Linfocitos T Citotóxicos/trasplante , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
SeVRSV is a replication-competent Sendai virus (SeV)-based vaccine carrying the respiratory syncytial virus (RSV) fusion protein (F) gene. Unmanipulated, non-recombinant SeV is a murine parainfluenza virus type 1 (PIV-1) and serves as a Jennerian vaccine for human PIV-1 (hPIV-1). SeV protects African green monkeys (AGM) from infection after hPIV-1 challenge. The recombinant SeVRSV additionally targets RSV and protects AGM from lower respiratory infections after RSV challenge. The present study is the first to report on the safety, viral genome detection, and immunogenicity following SeVRSV vaccination of healthy adults. Seventeen and four healthy adults received intranasal SeVRSV and PBS, respectively, followed by six months of safety monitoring. Virus genome (in nasal wash) and vaccine-specific antibodies (in sera) were monitored for two and four weeks, respectively, post-vaccination. The vaccine was well-tolerated with only mild to moderate reactions that were also present in the placebo group. No severe reactions occurred. As expected, due to preexisting immunity toward hPIV-1 and RSV in adults, vaccine genome detection was transient. There were minimal antibody responses to SeV and negligible responses to RSV F. Results encourage further studies of SeVRSV with progression toward a clinical trial in seronegative children. Abbreviations: AE-adverse event; SAE-serious adverse event; SeV-Sendai virus; RSV-respiratory syncytial virus; PIV-1-parainfluenza virus-type 1; hPIV-1-human parainfluenza virus-type 1; F-RSV fusion protein; SeVRSV-recombinant SeV carrying the RSV F gene; Ab-antibody; MSW-medically significant wheezing; NOCMC-new onset chronic medical condition, mITT-modified Intent to Treat; ALRI-acute lower respiratory tract infection.
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Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Adulto , Animales , Anticuerpos Antivirales , Chlorocebus aethiops , Humanos , Inmunogenicidad Vacunal , Virus de la Parainfluenza 1 Humana/genética , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/efectos adversos , Vacunas contra Virus Sincitial Respiratorio/genética , Virus Sincitial Respiratorio Humano/genética , Virus Sendai/genética , Proteínas Virales de Fusión/genéticaRESUMEN
This article is dedicated to Dr. Peter Doherty. While Peter continues to make groundbreaking discoveries in the field of immunology, he also provides outstanding scientific mentorship to his trainees. Here we contemplate our past training with Peter, Peter's teachings of basic immunological principles, and how basic principles may instruct the design of a successful human immunodeficiency virus-type 1 vaccine.
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Vacunas contra el SIDA/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Desarrollo de Medicamentos , HumanosRESUMEN
A major obstacle to the design of a global HIV-1 vaccine is viral diversity. At present, data suggest that a vaccine comprising a single antigen will fail to generate broadly reactive B-cell and T-cell responses able to confer protection against the diverse isolates of HIV-1. While some B-cell and T-cell epitopes lie within the more conserved regions of HIV-1 proteins, many are localized to variable regions and differ from one virus to the next. Neutralizing B-cell responses may vary toward viruses with different i) antibody contact residues and/or ii) protein conformations while T-cell responses may vary toward viruses with different (i) T-cell receptor contact residues and/or (ii) amino acid sequences pertinent to antigen processing. Here we review previous and current strategies for HIV-1 vaccine development. We focus on studies at St. Jude Children's Research Hospital (SJCRH) dedicated to the development of an HIV-1 vaccine cocktail strategy. The SJCRH multi-vectored, multi-envelope vaccine has now been shown to elicit HIV-1-specific B- and T-cell functions with a diversity and durability that may be required to prevent HIV-1 infections in humans.
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Vacunas contra el SIDA/química , Diseño de Fármacos , Infecciones por VIH/prevención & control , VIH-1/metabolismo , Animales , Química Farmacéutica/métodos , Anticuerpos Anti-VIH/química , Proteínas del Virus de la Inmunodeficiencia Humana/química , Humanos , Sistema Inmunológico/virología , Pruebas de Neutralización , PrimatesRESUMEN
OBJECTIVES: The main aim of this exploratory study was to evaluate functional activity of antibodies elicited by a maternal Group B Streptococcus (GBS) investigational vaccine composed of capsular polysaccharides Ia, Ib, and III conjugated to genetically detoxified Diphtheria toxin CRM197. The second objective was to investigate the relationship between serotype-specific IgG concentrations and functional activity in maternal and cord sera. METHODS: Maternal and cord sera collected at baseline and at delivery from vaccine and placebo recipients during a double-blind placebo-controlled Phase II study (www.clinicaltrials.gov, NCT01446289) were tested in an opsono-phagocytic bacterial killing assay. Cord sera from vaccine recipients were also passively transferred to newborn mice to investigate conferred protection against bacterial challenge. RESULTS: Antibody-mediated GBS phagocytic killing was significantly increased in maternal serum at delivery and in cord sera from the investigational vaccine group as compared to the placebo group. Anti-capsular IgG concentrations above 1 µg/mL mediated in vitro killing against GBS strains belonging to all three serotypes and IgG levels correlated with functional titers. Passively administered cord sera elicited a dose-dependent protective response against all GBS serotypes in the in vivo model. CONCLUSIONS: The maternal vaccine elicited functional antibodies that were placentally transferred. Anti-capsular IgG concentrations in maternal and cord sera were predictive of functional activity and in vivo protection in the mouse model.
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Anticuerpos Antibacterianos/sangre , Sangre Fetal/inmunología , Glicoconjugados/inmunología , Inmunización Pasiva , Vacunas Estreptocócicas/inmunología , Adolescente , Adulto , Animales , Animales Recién Nacidos , Método Doble Ciego , Femenino , Humanos , Inmunidad Materno-Adquirida , Inmunoglobulina G/análisis , Inmunoglobulina G/sangre , Ratones , Embarazo , Serogrupo , Infecciones Estreptocócicas/prevención & control , Vacunas Estreptocócicas/administración & dosificación , Streptococcus agalactiae , Vacunas Conjugadas/administración & dosificación , Adulto JovenRESUMEN
HIV-1-specific T cell responses correlate with control of infection and disease, thus encouraging a full understanding of the peptides and antigen-processing mechanisms that govern T cell activation. We have previously demonstrated that CD4(+) T cell epitopes cluster nonrandomly within envelope protein "hotspot" regions. The current study was initiated to determine whether envelope-specific CD8(+) T cells might share epitope "hotspots" with the CD4(+) T cell population. Identification of CD8(+) T cell determinants by ELISPOT assays with peripheral blood mononuclear cells from four HIV-1-infected individuals, in conjunction with a survey of determinants in the Los Alamos database, revealed similarities among "hotspot" positions for CD4(+) and CD8T(+) cells within mice and humans. These results emphasized the important influence that envelope peptide position may have on antigen processing, and the consequent impact such processing may have on HIV-1-specific CD4(+) and CD8(+) T-cell activities.
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Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Epítopos de Linfocito T , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Subgrupos de Linfocitos T , Secuencia de Aminoácidos , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Humanos , Ratones , Datos de Secuencia Molecular , Fragmentos de Péptidos/inmunología , Alineación de Secuencia , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/virologíaRESUMEN
OBJECTIVE: To evaluate the safety and immunogenicity of an investigational trivalent group B streptococcal vaccine in pregnant women and antibody transfer to their newborns. METHODS: The primary outcome of this observer-blind, randomized study was to estimate placental antibody transfer rates at birth. Secondary outcomes included measurement of serotype-specific antibodies at screening, 30 days postvaccination, at delivery, and 91 days postpartum, infant antibody levels at 3 months of age, the potential effect on routine infant diphtheria vaccination at 1 month after the third infant series dose, and safety in mother and infant participants through at least 5 months postpartum. Sample size was based on 60 participants in the vaccine group giving a probability of observing at least one adverse event of 90% if the actual rate of the event was 3.8%. RESULTS: From September 2011 to October 2013, 86 pregnant women were allocated in a 3:2 ratio to receive an investigational group B streptococcal vaccine containing glycoconjugates of serotypes Ia, Ib, and III or placebo. Demographics were similar across groups. Transfer ratios were 66-79% and maternal geometric mean concentrations increased 16-, 23-, and 20-fold by delivery against serotypes Ia, Ib, and III, respectively, Women with no detectable antibodies at inclusion had lower responses than those with detectable antibodies. Three months after birth, infant antibody concentrations were 22-25% of birth levels. Antidiphtheria geometric mean concentrations were similar across groups. In the vaccine and placebo groups, 32 of 51 women (63%) and 26 of 35 women (74%) reported adverse effects, respectively. CONCLUSION: The investigational vaccine was well-tolerated without safety signals in recipients and their infants or interference with routine infant diphtheria vaccination, although further studies on safety and effectiveness are needed. The investigational vaccine was immunogenic for all serotypes, particularly among women with detectable antibody levels at baseline. Antibody transfer to neonates was at similar levels to other maternally administered polysaccharide vaccines. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01446289.
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Infecciones Estreptocócicas/prevención & control , Vacunas Estreptocócicas , Streptococcus agalactiae/inmunología , Adulto , Femenino , Humanos , Inmunización , Recién Nacido , Embarazo , Adulto JovenRESUMEN
BACKGROUND: Group B streptococcus (GBS) is a leading cause of sepsis and meningitis in early infancy. Substantial data demonstrate that women with higher levels of circulating antibody against the capsular polysaccharide (CPS) deliver infants at reduced risk of GBS infection, which serves as the basis for vaccine design. This study evaluates two different dosages, two injection schedules and three formulations of an investigational trivalent (serotypes Ia, Ib and III) CRM197-glycoconjugate GBS vaccine in healthy, non-pregnant women. METHODS: 678 healthy non-pregnant women received one or two injections of one of two dosages (5/5/5 µg or 20/20/20 µg) of the investigational vaccine, formulated with or without aluminum hydroxide (Enrollment Group 1), or with full or half dosages of MF59(®) (Enrollment Group 2); or a placebo (Enrollment Groups 1 and 2). Geometric mean serotype-specific antibody concentrations (GMCs) at Days 61 (Enrollment Group 1) and 361 (both Groups) were analyzed to select a formulation suitable for pregnant or non-pregnant women, respectively. Solicited adverse reactions were recorded up to Day 7 and adverse events (AEs) were recorded throughout the study. RESULTS: Rates of reported AEs were similar across all groups. Higher rates of local reactogenicity were seen in adjuvanted vaccine groups compared with non-adjuvanted vaccine (or placebo) groups. All vaccine groups elicited higher GMCs than placebo; differences between treatments were not statistically significant, indicating no additional potential benefit of higher antigen content, addition of adjuvant, or a second dose. CONCLUSIONS: All GBS vaccine formulations induced a persistent antibody response and showed similar immunogenicity profiles (NCT01150123).