One or two doses of live varicella virus-containing vaccines: Efficacy, persistence of immune responses, and safety six years after administration in healthy children during their second year of life

Abstract Background This phase III B follow-up of an initial multicenter study (NCT00226499) will evaluate the ten-year efficacy of two doses of the combined measles-mumps-rubella-varicella vaccine (MMRV) and one dose of the live attenuated varicella vaccine (V) versus a measles-mumps-rubella control group (MMR) for the prevention of clinical varicella disease. Here we present efficacy results for six years post-vaccination. Methods In phase A of the study, healthy children aged 12–22 months from ten European countries were randomized (3:3:1) and received either two doses of MMRV, or one dose of combined MMR and one dose of monovalent varicella vaccine (MMR+V), or two doses of the MMR vaccine (control), 42 days apart. Vaccine efficacy against all and against moderate or severe varicella (confirmed by detection of viral DNA or epidemiological link) was assessed from six weeks up to six years post-dose 2 for the MMRV and MMR+V groups, and was calculated with 95% confidence intervals (CI). The severity of varicella was calculated using the modified Vazquez scale (mild ≤ 7; moderately severe = 8–15; severe ≥ 16). Herpes zoster cases were also recorded. Results 5289 children (MMRV = 2279, mean age = 14.2, standard deviation [SD] = 2.5; MMR+V = 2266, mean age = 14.2, SD = 2.4; MMR = 744, mean age = 14.2, SD = 2.5 months) were included in the efficacy cohort. 815 varicella cases were confirmed. Efficacy of two doses of MMRV against all and against moderate or severe varicella was 95.0% (95% CI: 93.6–96.2) and 99.0% (95% CI: 97.7–99.6), respectively. Efficacy of one dose of varicella vaccine against all and against moderate or severe varicella was 67.0% (95% CI: 61.8–71.4) and 90.3% (95% CI: 86.9–92.8), respectively. There were four confirmed herpes zoster cases (MMR+V = 2, MMR = 2), all were mild and three tested positive for the wild-type virus. Conclusions Two doses of the MMRV vaccine and one dose of the varicella vaccine remain efficacious through six years post-vaccination

Three dose levels of a maternal respiratory syncytial virus vaccine candidate are well tolerated and immunogenic in a randomized trial in non-pregnant women

BACKGROUND: Respiratory syncytial virus (RSV) causes respiratory tract infections, which may require hospitalization especially in early infancy. Transplacental transfer of RSV antibodies could confer protection to infants in their first months of life. METHODS: In this first-in-human, placebo-controlled study, 502 healthy non-pregnant women were randomized 1:1:1:1 to receive a single dose of unadjuvanted vaccine containing 30/60/120 µg of RSV fusion (F) protein stabilized in the prefusion conformation (RSVPreF3), or placebo. RESULTS: Solicited local adverse events (AEs) were more frequently reported in the RSVPreF3 groups (4-53.2%) vs placebo (0-15.9%); most were mild/moderate. Unsolicited AEs were comparably reported among groups. Three serious AEs were reported; none was vaccination-related. Compared with pre-vaccination values, anti-RSV A neutralizing antibody geometric mean titers and anti-RSVPreF3 immunoglobulin G geometric mean concentrations increased 8-14-fold and 12-21-fold at day (D)8 and persisted 5-6-fold and 6-8-fold higher until D91 in the RSVPreF3 groups vs 1-fold in placebo. Comparisons at D8 and D31 showed that the higher dose levels were significantly more immunogenic than the lowest one. CONCLUSIONS: The RSVPreF3 vaccine was well tolerated and immunogenic. The 60 and 120 µg dose levels were selected for further investigation in pregnant women.publishedVersionPeer reviewe

Safety and immunogenicity of a varicella vaccine without human serum albumin (HSA) versus a HSA-containing formulation administered in the second year of life:A phase III, double-blind, randomized study

BACKGROUND: A new formulation of the live-attenuated varicella vaccine Varilrix (GSK) produced without human serum albumin (HSA) was developed to minimize a theoretical risk of transmission of infectious diseases. A previous study showed that the vaccine was immunologically non-inferior to the HSA-containing vaccine and well-tolerated in toddlers; low-grade fever was numerically higher in children receiving the vaccine without HSA, but the study lacked power to conclude on this difference. METHODS: In this phase III, double-blind, multi-center study, healthy 12-23-month-olds were randomized (1:1) to receive two doses of the varicella vaccine without (Var-HSA group) or with HSA (Varand#8201;+and#8201;HSA group) at days 0 and 42. The primary objective compared safety of the vaccines in terms of incidence of fever andgt;and#8201;39.0and#8201;and#176;C in the 15-day period post-first vaccination. The objective was considered met if the upper limit of the 95% confidence interval for the between-group difference in the incidence of fever andgt;and#8201;39.0and#8201;and#176;C was and#8804;5% (Var-HSA group minus Varand#8201;+and#8201;HSA group). Safety, reactogenicity and immune responses were evaluated. RESULTS: Six hundred fifteen children in the Var-HSA group and 616 in the Varand#8201;+and#8201;HSA group received and#8805;1 vaccination. Fever andgt;and#8201;39.0and#8201;and#176;C was reported in 3.9 and 5.2% of participants in the Var-HSA and Varand#8201;+and#8201;HSA groups, with a between-group difference of -and#8201;1.29 (95% confidence interval: -and#8201;3.72-1.08); therefore, the primary objective was achieved. Fever rates post-each dose and the incidence of solicited local and general adverse events (AEs) were comparable between groups. Unsolicited AEs were reported for 43.9 and 36.5% of children in the Var-HSA group and 45.8 and 36.0% of children in the Varand#8201;+and#8201;HSA group, during 43and#8201;days post-dose 1 and 2, respectively. Serious AEs occurred in 2.1% (group Var-HSA) and 2.4% (group Varand#8201;+and#8201;HSA) of children, throughout the study. In a sub-cohort of 364 children, all had anti-varicella-zoster virus antibody concentrations and#8805;50 mIU/mL post-dose 2; comparable geometric mean concentrations were observed between the groups. CONCLUSIONS: The varicella vaccine formulated without HSA did not induce higher rates of fever during the 15and#8201;day-post-vaccination period, as compared with the original HSA-containing vaccine. The two vaccines displayed similar safety and immunogenicity profiles in toddlers. TRIAL REGISTRATION:NCT02570126 , registered on 5 October 2015 (www.clinicaltrials.gov).</p

Incidence of respiratory syncytial virus-associated lower respiratory tract illness in infants in low- and middle-income regions during the Coronavirus disease 2019 pandemic

DATA AVAILABILITY : Study data and documents can be requested for further research from www.clinicalstudydatarequest.com.BACKGROUND : Incidence data of respiratory syncytial virus–associated lower respiratory tract illness (RSV-LRTI) are sparse in low- and middle-income countries (LMICs). We estimated RSV-LRTI incidence rates (IRs) in infants in LMICs using World Health Organization case definitions. METHODS : This prospective cohort study, conducted in 10 LMICs from May 2019 to October 2021 (largely overlapping with the coronavirus disease 2019 [COVID-19] pandemic), followed infants born to women with low-risk pregnancies for 1 year from birth using active and passive surveillance to detect potential LRTIs, and quantitative reverse-transcription polymerase chain reaction on nasal swabs to detect RSV. RESULTS : Among 2094 infants, 32 (1.5%) experienced an RSV-LRTI (8 during their first 6 months of life, 24 thereafter). Seventeen (0.8%) infants had severe RSV-LRTI and 168 (8.0%) had all-cause LRTI. IRs (95% confidence intervals [CIs]) of first RSV-LRTI episode were 1.0 (.3–2.3), 0.8 (.3–1.5), and 1.6 (1.1–2.2) per 100 person-years for infants aged 0–2, 0–5, and 0–11 months, respectively. IRs (95% CIs) of the first all-cause LRTI episode were 10.7 (8.1–14.0), 11.7 (9.6–14.0), and 8.7 (7.5–10.2) per 100 person-years, respectively. IRs varied by country (RSV-LRTI: 0.0–8.3, all-cause LRTI: 0.0–49.6 per 100 person-years for 0- to 11-month-olds). CONCLUSIONS : RSV-LRTI IRs in infants in this study were relatively low, likely due to reduced viral circulation caused by COVID-19–related nonpharmaceutical interventions. CLINICAL TRIALS REGISTRATION : NCT03614676.https://academic.oup.com/ofidhj2024Medical MicrobiologySDG-03:Good heatlh and well-bein

Immunogenicity and safety of combined measles-mumps-rubella-varicella vaccine using new measles and rubella working seeds in healthy children in Taiwan and Singapore A phase II, randomized, double-blind trial

HUMAN VACCINES & IMMUNOTHERAPEUTICS961308-1315United State

Immunogenicity and safety of a second dose of a measles-mumps-rubella vaccine administered to healthy participants 7 years of age or older: A phase III, randomized study

The introduction of vaccination programs against measles, mumps, and rubella (MMR) led to significant global reduction in morbidity and mortality from these diseases. The currently recommended MMR vaccination schedule in the United States of America comprises 2 vaccine doses typically administered at 12–15 months and 4–6 years, respectively. Considering recent outbreaks in the USA, catch-up vaccination with an additional dose of MMR vaccine could contribute to outbreak control and community protection. This phase III, observer-blind, randomized controlled trial (NCT02058563) assessed the immunogenicity and safety of a dose of the MMR-RIT vaccine (Priorix, GSK) compared to MMR II vaccine (control; M-M-R II, Merck&Co Inc.) in ≥7-year-olds who had received ≥1 previous dose of MMR vaccine. We assessed anti-measles, anti-mumps, and anti-rubella antibody geometric mean concentrations (GMCs; primary endpoint) and seroresponse rates (SRRs) at day 42 post-vaccination. Solicited, unsolicited, and serious adverse events (AEs) were recorded. The according-to-protocol cohort for immunogenicity included 869 participants (MMR-RIT: N = 433; MMR II: N = 436). We observed anti-measles, anti-mumps, and anti-rubella antibody GMCs of 1790.2 mIU/mL, 113.5 EU/mL, and 76.1 IU/mL, respectively, and SRRs of 98.8%, 98.4%, and 99.5%, respectively, after a dose of MMR-RIT; non-inferiority compared to MMR II was demonstrated. Both vaccines showed comparable reactogenicity profiles; the most common solicited AEs were injection site redness and pain, and fever (MMR-RIT: 12.2%, 11.8%, and 3.0%; MMR II: 11.7%, 11.5%, and 5.2%, respectively). The dose of MMR-RIT induced robust immune responses that were not inferior to those of MMR II, and was well tolerated

Correlation of protection against varicella in a randomized phase III varicella-containing vaccine efficacy trial in healthy infants /

Background: Varicella vaccination confers high and long-lasting protection against chickenpox and induces robust immune responses, but an absolute correlate of protection (CoP) against varicella has not been established. This study models the relationship between varicella humoral response and protection against varicella. Methods: This was a post-hoc analysis of data from a Phase IIIb, multicenter, randomized trial (NCT00226499) conducted in ten varicella-endemic European countries. Healthy children aged 12–22 months were randomized 3:3:1 to receive one dose of measles-mumps-rubella and one dose of varicella vaccine (one-dose group) or two doses of measles-mumps-rubella-varicella vaccine (two-dose group) or two doses of measles-mumps-rubella vaccine (control group) six weeks apart. The study remained observer-blind until completion, except in countries with obligatory additional immunizations. The objective was to correlate varicella-specific antibody concentrations with protection against varicella and probability of varicella breakthrough, using Cox proportional hazards and Dunning and accelerated failure time statistical models. The analysis was guided by the Prentice framework to explore a CoP against varicella. Results: The trial included 5803 participants, 5289 in the efficacy (2266: one-dose group, 2279: two-dose group and 744: control group) and 5235 (2248, 2245 and 742 in the same groups) in the immunogenicity cohort. The trial ended in 2016 with a median follow-up time of 9.8 years. Six weeks after vaccination with one- or two-dose varicella-containing vaccine, more than 93.0% of vaccinees were seropositive for varicella-specific antibodies. Estimated vaccine efficacy correlated positively with antibody concentrations. The fourth Prentice CoP criterion was not met, due to predicted positive vaccine efficacy in seronegative participants. Further modelling showed decreased probability of moderate to severe varicella breakthrough with increasing varicella-specific antibody concentrations (ten-year probability <0.1 for antibody concentrations ≥2-fold above the seropositivity cut-off). Conclusions: Varicella-specific antibody concentrations are a good predictor of protection, given their inverse correlation with varicella occurrence. Clinical trial: NCT00226499

The immunogenicity and safety of a tetravalent measles-mumps-rubella-varicella vaccine when co-administered with conjugated meningococcal C vaccine to healthy children: A phase IIIb, randomized, multi-center study in Italy

Introduction Multiple vaccination visits and administrations can be stressful for infants, parents and healthcare providers. Multivalent combination vaccines can deliver the required number of antigens in fewer injections and clinic visits, while vaccine co-administration can also reduce the number of visits. This non-inferiority study was undertaken to evaluate the feasibility of co-administering a combined measles-mumps-rubella-varicella (MMRV) vaccine with conjugated meningococcal C (MenC) vaccine in a large cohort of healthy Italian toddlers. Methods Healthy subjects aged 13–15 months were randomized (2:1:1) to receive single doses of either: co-administered MMRV + MenC at the same visit (MMRV + MenC group); or MMRV followed 42 days later by MenC (MMRV group); or MenC followed 42 days later by MMRV (MenC group). Blood samples were collected before and 43 days after vaccination. Antibody titers against MMRV were measured using ELISA. Functional-anti-meningococcal-serogroup activity (rSBAMenC) was assessed using a serum bactericidal test. Solicited local and general reactions were recorded for up to 4 and 42 days post-vaccination, respectively. Non-inferiority of MMRV + MenC to MMRV (post-dose-1 seroconversion rates) and MMRV + MenC to MenC (post-dose-1 seroprotection rates) was achieved if the lower limit (LL) of the 95% confidence interval (CI) for the group difference was ⩾−10% for each antigen. Results 716 subjects were enrolled in the study. At 42 days post-vaccination, the MMRV seroconversion rates were 99.3% (measles), 94.5% (mumps), 100% (rubella) and 99.7% (varicella) in the MMRV + MenC group, and 99.4%, 93.2%, 100% and 100%, respectively, in the MMRV group. The seroprotection rates against rSBA-MenC were 98.3% in the MMRV + MenC group and 99.3% in the MenC group. Non-inferiority was reached for all the vaccine antigens. The safety profiles were as expected for these vaccines. Conclusion The immune responses elicited by co-administered MMRV + MenC were non-inferior to those elicited by MMRV or MenC alone and support vaccination of children with both vaccines at a single visit. Clinical Trials registration: NCT01506193

Safety and immunogenicity of a varicella vaccine without human serum albumin (HSA) versus a HSA-containing formulation administered in the second year of life: a phase III, double-blind, randomized study

Background: a new formulation of the live-attenuated varicella vaccine Varilrix (GSK) produced without human serum albumin (HSA) was developed to minimize a theoretical risk of transmission of infectious diseases. A previous study showed that the vaccine was immunologically non-inferior to the HSA-containing vaccine and well-tolerated in toddlers; low-grade fever was numerically higher in children receiving the vaccine without HSA, but the study lacked power to conclude on this difference. Methods: in this phase III, double-blind, multi-center study, healthy 12–23-month-olds were randomized (1:1) to receive two doses of the varicella vaccine without (Var-HSA group) or with HSA (Var + HSA group) at days 0 and 42. The primary objective compared safety of the vaccines in terms of incidence of fever &gt; 39.0 °C in the 15-day period post-first vaccination. The objective was considered met if the upper limit of the 95% confidence interval for the between-group difference in the incidence of fever &gt; 39.0 °C was ≤5% (Var-HSA group minus Var + HSA group). Safety, reactogenicity and immune responses were evaluated. Results: six hundred fifteen children in the Var-HSA group and 616 in the Var + HSA group received ≥1 vaccination. Fever &gt; 39.0 °C was reported in 3.9 and 5.2% of participants in the Var-HSA and Var + HSA groups, with a between-group difference of − 1.29 (95% confidence interval: − 3.72–1.08); therefore, the primary objective was achieved. Fever rates post-each dose and the incidence of solicited local and general adverse events (AEs) were comparable between groups. Unsolicited AEs were reported for 43.9 and 36.5% of children in the Var-HSA group and 45.8 and 36.0% of children in the Var + HSA group, during 43 days post-dose 1 and 2, respectively. Serious AEs occurred in 2.1% (group Var-HSA) and 2.4% (group Var + HSA) of children, throughout the study. In a sub-cohort of 364 children, all had anti-varicella-zoster virus antibody concentrations ≥50 mIU/mL post-dose 2; comparable geometric mean concentrations were observed between the groups. Conclusions: the varicella vaccine formulated without HSA did not induce higher rates of fever during the 15 day-post-vaccination period, as compared with the original HSA-containing vaccine. The two vaccines displayed similar safety and immunogenicity profiles in toddlers