Summary Background Efficacy of live oral rotavirus vaccines is reduced in low-income compared with high-income settings. Parenteral non-replicating rotavirus vaccines might offer benefits over oral ...vaccines. We assessed the safety and immunogenicity of the P2-VP8-P8 subunit rotavirus vaccine at different doses in South African toddlers and infants. Methods This double-blind, randomised, placebo-controlled, dose-escalation trial was done at a single research unit based at a hospital in South Africa in healthy HIV-uninfected toddlers (aged 2 to <3 years) and term infants (aged 6 to <8 weeks, without previous rotavirus vaccination). Block randomisation (computer-generated, electronic allocation) was used to assign eligible toddlers (in a 6:1 ratio) and infants (in a 3:1 ratio) in each dose cohort (10 μg, followed by 30 μg, then 60 μg if doses tolerated) to parenteral P2-VP8-P8 subunit rotavirus or placebo injection. The two highest tolerated doses were then assessed in an expanded cohort (in a 1:1:1 ratio). Parents of participants and clinical, data, and laboratory staff were masked to treatment assignment. P2-VP8-P8 vaccine versus placebo was assessed first in toddlers (single injection) and then in infants (three injections 4 weeks apart). The primary safety endpoints were local and systemic reactions within 7 days after each injection, adverse events within 28 days after each injection, and all serious adverse events, assessed in toddlers and infants who received at least one dose. In infants receiving all study injections, primary immunogenicity endpoints were anti-P2-VP8-P8 IgA and IgG and neutralising antibody seroresponses and geometric mean titres 4 weeks after the third injection. This trial is registered at ClinicalTrials.gov , number NCT02109484. Findings Between March 17, 2014, and Sept 29, 2014, 42 toddlers (36 to vaccine and six to placebo) and 48 infants (36 to vaccine and 12 to placebo) were enrolled in the dose-escalation phase, in which the 30 μg and 60 μg doses where found to be the highest tolerated doses. A further 114 infants were enrolled in the expanded cohort between Nov 3, 2014, and March 20, 2015, and all 162 infants (12 assigned to 10 μg, 50 to 30 μg, 50 to 60 μg, and 50 to placebo) were included in the safety analysis. Serum IgA seroresponses were observed in 38 (81%, 95% CI 67–91) of 47 infants in the 30 μg group and 32 (68%, 53–81) of 47 in the 60 μg group, compared with nine (20%, 10–35) of 45 in the placebo group; adjusted IgG seroresponses were seen in 46 (98%, 89–100) of 47 infants in the 30 μg group and 47 (100%; 92–100) of 47 in the 60 μg group, compared with four (9%, 2·5–21) of 45 in the placebo group; and adjusted neutralising antibody seroresponses against the homologous Wa-strain were seen in 40 (85%, 72–94) of 47 infants in both the 30 μg and 60 μg groups, compared with three (7%, 1·4–18) of 45 participants in the placebo group. Solicited reactions following any injection occurred with similar frequency and severity in participants receiving vaccine and those receiving placebo. Unsolicited adverse events were mostly mild and occurred at a similar frequency between groups. Eight serious adverse events (one with placebo, two with 30 μg, and five with 60 μg) occurred in seven infants within 28 days of any study injection, none of which were deemed related to study treatment. Interpretation The parenteral P2-VP8-P8 vaccine was well tolerated and immunogenic in infants, providing a novel approach to vaccination against rotavirus disease. On the basis of these results, a phase 1/2 trial of a trivalent P2-VP8 (P4, P6, and P8) subunit vaccine is underway at three sites in South Africa. Funding Bill & Melinda Gates Foundation.
Summary Background Administration of vaccines by needle-free technology such as jet injection might offer an alternative to needles and syringes that avoids the issue of needle phobia and the risk of ...needle-stick injury. We aimed to assess the immunogenicity and safety of trivalent influenza vaccine given by needle-free jet injector compared with needle and syringe. Methods For this randomised, comparator-controlled trial, we randomly assigned (1:1) healthy adults (aged 18–64 years) who attended one of four employee health clinics in the University of Colorado health system, with stratification by site, to receive one dose of the trivalent inactivated influenza vaccine Afluria given either intramuscularly with a needle-free jet injector (Stratis; PharmaJet, Golden, CO, USA) or with needle and syringe. Randomisation was done with a computer-generated randomisation schedule with a block size of 100. Because of the nature of the study, masking of participants was not possible. Immunogenicity was assessed by measurement of the hemagglutination inhibition antibody titres in serum for the three viral strains included in the vaccine. We included six coprimary endpoints: three strain-specific geometric mean titre ratios and the absolute differences in three strain-specific seroconversion rates. The immune response of the jet injector group was regarded as non-inferior to that of the needle and syringe group if both the upper bound of each of the three 95% CIs for the strain-specific geometric mean titre ratios was 1.5 or less, and the upper bound of the three 95% CIs for the strain-specific seroconversion rate differences was less than 10 percentage points. We used t test for group comparison. This study is registered with ClinicalTrials.gov , number NCT01688921. Findings During the 2012–13 influenza season of the northern hemisphere, we allocated 1250 participants to receive vaccination by needle-free jet injector (n=627) or needle and syringe (n=623). In the intention-to-treat immunogenicity population, all participants with two serum samples were included (575 in the jet injector group and 574 in the needle and syringe group). The immune response to Afluria when given by needle-free jet injector met the criteria for non-inferiority for all six coprimary endpoints. The jet injector group met the geometric mean titre criterion for non-inferiority for the A/H1N1, A/H3N2, and B strains (upper bound of the 95% CI for the geometric mean titre ratios were 1·10 for A/H1N1, 1·17 for A/H3N2, and 1·04 for B strains). The jet injector group met the seroconversion rate criterion for non-inferiority for the A/H1N1, A/H3N2, and B strains (upper bound of the 95% CI of the seroconversion rate differences were 6·0% for A/H1N1, 7·0% for A/H3N2, and 5·7% for B strains). We recorded serious adverse events in three participants, none of which were study related. Interpretation The immune response to influenza vaccine given with the jet injector device was non-inferior to the immune response to influenza vaccine given with needle and syringe. The device had a clinically acceptable safety profile, but was associated with a higher frequency of local injection site reactions than was the use of needle and syringe. The Stratis needle-free jet injector device could be used as an alternative method of administration of Afluria trivalent influenza vaccine. Funding Biomedical Advanced Research and Development Authority (BARDA), PATH, bioCSL, and PharmaJet.
Abstract Objectives The purpose of this study was to develop and validate a simple-to-use nomogram for prediction of 5-, 10-, and 15-year survival among asymptomatic adults. Background Simple-to-use ...prognostication tools that incorporate robust methods such as coronary artery calcium scoring (CACS) for predicting near-, intermediate- and long-term mortality are warranted. Methods In a consecutive series of 9,715 persons (mean age: 53.4 ± 10.5 years; 59.3% male) undergoing CACS, we developed a nomogram using Cox proportional hazards regression modeling that included: age, sex, smoking, hypertension, dyslipidemia, diabetes, family history of coronary artery disease, and CACS. We developed a prognostic index (PI) summing the number of risk points corresponding to weighted covariates, which was used to configure the nomogram. Validation of the nomogram was assessed by discrimination and calibration applied to a separate cohort of 7,824 adults who also underwent CACS. Results A total of 936 and 294 deaths occurred in the derivation and validation sets at a median follow-up of 14.6 years (interquartile range: 13.7 to 15.5 years) and 9.4 years (interquartile range: 6.8 to 11.5 years), respectively. The developed model effectively predicted 5-, 10-, and 15-year probability of survival. The PI displayed high discrimination in the derivation and validation sets (C-index 0.74 and 0.76, respectively), indicating suitable external performance of our nomogram model. The predicted and actual estimates of survival in each dataset according to PI quartiles were similar (though not identical), demonstrating improved model calibration. Conclusions A simple-to-use nomogram effectively predicts 5-, 10- and 15-year survival for asymptomatic adults undergoing screening for cardiac risk factors. This nomogram may be considered for use in clinical care.
Abstract Objectives The purpose of this study was to examine sex-specific associations, if any, between per-vessel coronary artery disease (CAD) extent and the risk of major adverse cardiovascular ...events (MACE) over a 5-year study duration. Background The presence and extent of CAD diagnosed by coronary computed tomography angiography (CTA) is associated with increased short-term mortality and MACE. Nevertheless, some uncertainty remains regarding the influence of sex on these findings. Methods 5,632 patients (mean age 60.2 ± 11.8 years, 36.5% women) from the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry were followed for 5 years. Obstructive CAD was defined as ≥50% luminal stenosis in a coronary vessel. Using Cox proportional hazards models, we calculated the hazard ratio (HR) for incident MACE among women and men, defined as death or myocardial infarction. Results Obstructive CAD was more prevalent in men (42% vs. 26%; p < 0.001), whereas women were more likely to have normal coronary arteries (43% vs. 27%; p < 0.001). There were a total of 798 incident MACE events. After adjustment, there was a strong association between increased MACE risk and nonobstructive CAD (HR: 2.16 for women, 2.56 for men; p < 0.001 for both), obstructive 1-vessel CAD (HR: 3.69 and 2.66; p < 0.001), 2-vessel CAD (HR: 3.92 and 3.55; p < 0.001), and 3-vessel/left main CAD (HR: 5.94 and 4.44; p < 0.001). Further exploratory analyses of atherosclerotic burden did not identify sex-specific patterns predictive of MACE. Conclusions In a large prospective coronary CTA cohort followed long-term, we did not observe an interaction of sex for the association between MACE risk and increased per-vessel extent of obstructive CAD. These findings highlight the persistent prognostic significance of anatomic CAD subsets as detected by coronary CTA for the risk of MACE in both women and men.
Multiple candidate vaccines to prevent COVID-19 have entered large-scale phase 3 placebo-controlled randomized clinical trials, and several have demonstrated substantial short-term efficacy. At some ...point after demonstration of substantial efficacy, placebo recipients should be offered the efficacious vaccine from their trial, which will occur before longer-term efficacy and safety are known. The absence of a placebo group could compromise assessment of longer-term vaccine effects. However, by continuing follow-up after vaccination of the placebo group, this study shows that placebo-controlled vaccine efficacy can be mathematically derived by assuming that the benefit of vaccination over time has the same profile for the original vaccine recipients and the original placebo recipients after their vaccination. Although this derivation provides less precise estimates than would be obtained by a standard trial where the placebo group remains unvaccinated, this proposed approach allows estimation of longer-term effect, including durability of vaccine efficacy and whether the vaccine eventually becomes harmful for some. Deferred vaccination, if done open-label, may lead to riskier behavior in the unblinded original vaccine group, confounding estimates of long-term vaccine efficacy. Hence, deferred vaccination via blinded crossover, where the vaccine group receives placebo and vice versa, would be the preferred way to assess vaccine durability and potential delayed harm. Deferred vaccination allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain them on placebo, yet still allows important insights about immunologic and clinical effectiveness over time.
Abstract Objectives The aim of this study was to examine the long-term prognosis in asymptomatic individuals with a coronary artery calcium (CAC) score of 0 and its associated warranty period. ...Background Emerging evidence supports a CAC score of 0 as a favorable cardiovascular short-to intermediate-term prognostic factor. Methods A total of 9,715 individuals undergoing CAC imaging were stratified by age, Framingham risk score (FRS), and National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) categories and followed for a mean of 14.6 years (range 12.9 to 16.8 years). Cox regression, area under the receiver-operating characteristic curve, and net reclassification information were used to assess all-cause mortality, discrimination, and reclassification of a CAC score of 0 compared with the FRS and NCEP ATP III, respectively. A warranty period was pre-defined as <1% annual mortality rate. Vascular age was estimated by linear regression. Results In 4,864 individuals with a baseline CAC score of 0 (mean age, 52.1 ± 10.8 years; 57.9% male), 229 deaths occurred. The warranty period of a CAC score of 0 was almost 15 years for individuals at low and intermediate risk with no significant differences regarding age and sex. A CAC score of 0 was associated with a vascular age of 1, 10, 20, and 30 years less than the chronological age of individuals between 50 and 59, 60 and 69, 70 and 79, and 80 years of age and older, respectively. The CAC score was the strongest predictor of death (hazard ratio: 2.67, 95% confidence interval: 2.29 to 3.11) that enabled discrimination and consistent reclassification beyond the FRS (area under the receiver-operating characteristic curve: 0.71 vs. 0.64, p < 0.001) and NCEP ATP III (area under the receiver-operating characteristic curve: 0.72 vs. 0.64, p < 0.001). Conclusions A CAC score of 0 confers a 15-year warranty period against mortality in individuals at low to intermediate risk that is unaffected by age or sex. Furthermore, in individuals considered at high risk by clinical risk scores, a CAC score of 0 confers better survival than in individuals at low to intermediate risk but with any CAC score.
Hemagglutination inhibition (HAI) assay is the standard method for evaluating inactivated influenza vaccines, but no standard assay has been established for evaluating live attenuated influenza ...vaccines (LAIV). LAIV containing A/Beijing/262/95(H1N1) induced low serum HAI antibody responses to the antigenic variant, A/New Caledonia/20/99(H1N1) in a serologic study but provided protection against the A/New Caledonia-like viruses in a community study. Neutralization and HAI assays were compared by measuring H1N1 cross-reactive antibody responses to the LAIV in children.
Sera were collected from 50 children 1-8 years of age before vaccination and 4-6 weeks after each dose of the LAIV. Antibody titers to the 3 vaccine viruses were measured by the HAI assay, whereas antibody titers against the H1N1 vaccine virus (A/Beijing/262/95) and 2 H1N1 antigenic variants (A/Shenzhen/227/95 and A/New Caledonia/20/99) were measured by the HAI and neutralization assays.
Initially seronegative participants were more likely to develop HAI seroconversion responses to the 3 vaccine viruses than the baseline seropositive participants (77% versus 14% for H1N1, 100% versus 20% for H3N2, 100% versus 19% for B, P < 0.01, Fisher's exact test). For the H1N1 cross-reactive antibody responses, seroconversion rates measured by the neutralization assay were significantly higher than those measured by the HAI assay (95% versus 78%, P = 0.0485 for A/Beijing/262/95; 75% versus 24%, P < 0.0001 for A/Shenzhen/227/95; 51% versus 5%, P < 0.0001 for A/New Caledonia/20/99).
The neutralization assay was more sensitive than the HAI assay for measuring H1N1 antibody responses after vaccination of children with the LAIV and may provide a better correlate of clinical protection provided by the LAIV.
This study was designed to compare the safety and immunogenicity of a trivalent live-attenuated, cold-adapted influenza vaccine (CAIV-T) blended and filled at two different manufacturing facilities ...(Medeva and Aviron-PA). The vaccines contained approximately 10
7 TCID
50 (median tissue culture infectious dose) of each of the three recommended 1997–1998 influenza vaccine components, A/Shenzhen/227/95 (H1N1) (A/Bayern/7/95 (H1N1)-like strain), A/Wuhan/359/95 (H3N2), and B/Ann Arbor/1/94 (B/Beijing/184/93-like strain). Two hundred and twenty-five healthy Australian children aged 12–42 months were enrolled and randomized in a 3:2 ratio to receive CAIV-T blended and filled either at Medeva or at Aviron-PA. Two doses of CAIV-T were given 4–6 weeks apart as an intranasal spray. Three blood specimens were collected (immediately before doses one and two, and 28±5 days following dose two) for measuring hemagglutination inhibition (HAI) antibody responses. Adverse events occurring within 10 days and serious adverse events occurring within 42 days were collected. Serum HAI antibody levels were measured against the three vaccine strains. Equivalent immunogenicity between the two vaccine groups was pre-specified as: (1) within 20% difference in seroconversion rates (HAI titers ≥4-fold rise); and (2) within 4-fold difference in the 90% confidence interval of geometric mean titer ratio. Among 10 pre-specified adverse events, only vomiting had significantly different incidence rates in the two vaccine groups following dose one (3% versus 13%,
P=0.01) but the difference disappeared following dose two (4% versus 4%). Differences in seroconversion rates following dose two between the two vaccine groups in pre-vaccination seronegative children were all <20% for the three vaccine strains (16% for H1N1, 0% for H3N2, and 0% for B). The results indicate that CAIV-T blended and filled in the two facilities had equivalent profiles of safety and immunogenicity.
During a phase 2 trial of parainfluenza virus type 3 (PIV3) vaccine, sequential serum samples were obtained from infants at 2, 6, 7, 12–15, and 13–16 months of age. Paired serum samples obtained at 2 ...and 6 months of age were used to estimate the biologic half-life of human PIV3 (hPIV3) maternal antibody in young infants. On the basis of the assumption that hPIV3 maternal antibody decays exponentially and constantly, the biologic half-life was estimated without adjusting for body weight increases. Cumulative proportions of hPIV3 infection in young infants were further estimated after adjusting for maternal antibody decline. A hemagglutination inhibition assay was used to quantify hPIV3 antibody. The mean (95% confidence interval) biologic half-life was estimated to be 51 (42–60) days, on the basis of which cumulative proportions of hPIV3 infection were estimated to be 11% at 6 months of age, 47% at 12–15 months of age, and 50% at 13–16 months of age
A phase 2 clinical trial was conducted to evaluate the antibody responses to bovine parainfluenza virus type 3 (bPIV3) vaccination in young infants. Three groups were tested as follows: placebo ...(n=66) and 105 (n=64) or 106 (n=62) TCID50 of bPIV3. The vaccine or placebo was administered intranasally at ages 2, 4, 6, and 12–15 months, and serum specimens were collected at ages 2, 6, 7, 12–15, and 13–16 months. Serum hemagglutination inhibition (HI) and IgA antibody titers against bPIV3 and human PIV3 (hPIV3) were measured. The results indicate that antibody responses to bPIV3 vaccination are more likely to be detected by the bPIV3 IgA and HI assays than by the hPIV3 IgA and HI assays, that bPIV3-induced antibody response can be differentiated from hPIV3-induced antibody response most reliably by comparing bPIV3 and hPIV3 HI titers, and that bPIV3 vaccine prevents vaccine recipients from developing antibody profiles of hPIV3 primary infection
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