Immunogenicity and safety of the adjuvanted recombinant zoster vaccine co-administered with the 23-valent pneumococcal polysaccharide vaccine in adults ≥50 years of age: A randomized trial

BackgroundThis study evaluated immunogenicity and safety of the adjuvanted recombinant zoster vaccine (RZV) when the first dose was co-administered with the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in adults aged ≥50 years.MethodsIn this open label, multi-center study (NCT02045836), participants were randomized 1:1 to receive either the first dose of RZV and PPSV23, co-administered at Day 0 and the second dose of RZV at Month 2 (Co-Ad group), or PPSV23 at Day 0, the first dose of RZV at Month 2 and second dose of RZV at Month 4 (Control group). Co-primary objectives were the RZV vaccine response rate (VRR) in the Co-Ad group and the non-inferiority of the antibody responses to RZV and PPSV23 in the Co-Ad group compared to the Control group. Reactogenicity and safety were also assessed.Results865 participants were vaccinated (Co-Ad: 432, Control: 433). VRRs to RZV were >98% in both groups. Humoral immune responses to co-administration of RZV and PPSV23 were non-inferior to sequential administration. All three co-primary immunogenicity objectives were met. Solicited local symptoms after the first RZV dose were reported by similar percentages of participants in both groups. Solicited general symptoms were more frequently reported when the first dose of RZV and PPSV23 were co-administered. No differences were apparent between groups after the second RZV dose.ConclusionsNo immunologic interference was observed between RZV and PPSV23 when co-administered in adults ≥50 years. No safety concerns were raised.     

Trends in the uptake of pediatric measles-containing vaccine in the United States: A Disneyland effect?

BackgroundThe measles outbreak that began in December 2014 at the California Disneyland theme park in the United States (U.S.) received a high amount of media attention. Media attention can influence health-related behaviors. We investigated the effect of the Disneyland outbreak on measles-containing vaccine (MCV) uptake among U.S. children.MethodsWe used 2012–2017 National Immunization Survey-Child (NIS-Child) data to examine MCV uptake among U.S. children by 19 months of age. We classified MCV coverage among birth cohorts as exposed based on age at the time of the outbreak. A difference-in-differences design with adjustment for categorical birth cohort was implemented in base models to estimate the exposure effect on the outcomes, ≥1-dose MCV coverage or age at first MCV dose, with pneumococcal conjugate vaccination as a control. Primary analyses included this model adjusted for geographic region, maternal education, race/ethnicity, household income, and insurance status, and an exposure-interaction term with maternal education. All analyses included sampling weights.ResultsThe study population represented 34,471,357 children. In base models, the Disneyland outbreak was associated with a 1.0% (95% CI: 0.2%, 1.8%) increase in ≥1-dose MCV coverage and a 6.6 (95% CI: 4.8, 8.5)-day decrease in MCV administration age. In primary analyses, the outbreak was associated with a 3.9% (95% CI: 3.1%, 4.8%) increase in ≥1-dose MCV coverage among children of college-educated mothers, and a 3.2% (95% CI: 0.6%, 5.9%) decrease among children of mothers earning less than a high school degree. Decreases in MCV administration age ranging from 5.9 (95% CI: 3.3, 8.5) to 9.1 (95% CI: 6.8, 11.4) days were observed across maternal education categories.ConclusionsThe Disneyland outbreak was associated with differential effects on MCV coverage by maternal education and decreases in MCV administration age among U.S. children. These findings may provide useful insights to inform methods to address pediatric MCV undervaccination.     

A randomized controlled Alzheimer’s disease prevention trial’s evolution into an exposure trial: The preadvise trial

Objectives

To summarize the ongoing Prevention of Alzheimer’s Disease (AD) by Vitamin E and Selenium (PREADViSE) trial as an ancillary study to SELECT (a large prostate cancer prevention trial) and to present the blinded results of the first year as an exposure study.

Design

PREADViSE was designed as a double blind randomized controlled trial (RCT).

Setting

SELECT terminated after median of 5.5 years of exposure to supplements due to a futility analysis. Both trials then converted into an exposure study.

Participants

In the randomized component PREADViSE enrolled 7,547 men age 62 or older (60 if African American). Once the trial terminated 4,246 of these men volunteered for the exposure study. Demographics were similar for both groups with exposure volunteers having baseline mean age 67.3 ± 5.2 years, 15.3 ± 2.4 years of education, 9.8% African Americans, and 22.0% reporting a family history of dementia.

Intervention

In the RCT men were randomly assigned to either daily doses of 400 IU of vitamin E or placebo and 200 µg of selenium or placebo using a 2×2 factorial structure.

Measurements

In the RCT, participants completed the Memory Impairment Screen (MIS), and if they failed, underwent a longer screening (based on an expanded Consortium to Establish a Registry in AD [CERAD] battery). CERAD failure resulted in visits to their clinician for medical examination with records of these examinations forwarded to the PREADViSE center for further review. In the exposure study, men are contacted by telephone and complete the telephone version of the memory impairment screen (MIS-T) screen. If they fail the MIS-T, a Modified Telephone Interview of Cognitive Status (TICS-M) exam is given. A failed TICS-M exam also leads to a visit to their clinician for an in-depth examination and forwarding of records for a centralized consensus diagnosis by expert clinicians. A subgroup of the men who pass the MIS-T also take the TICS-M exam for validation purposes.

Results

While this ancillary trial was open to all 427 SELECT clinical sites, only 130 (30.0%) of the sites chose to participate in PREADViSE. Staff turnover at the sites presented challenges when training persons unfamiliar with cognitive testing procedures to conduct the memory screens. In the RCT few participants (1.6%) failed the MIS screen and among those who passed this screen a significant practice effect was encountered. In the exposure study 3,581 men were reached by phone in year 1, 15.7% could not be reached after 5 calls, and of those contacted 6.0% refused the screen even after consenting to the procedures at their clinical site. Most notable is that the failure rate for the MIS-T increased fourfold to 7.2%. Of the 257 men who took the TICS-M, 84.0% failed and were asked to contact their physicians for a more detailed memory assessment, and approximately half of these had some form of dementia or cognitive impairment. Several of these dementia cases are not AD.

Conclusion

Partnering with SELECT led to an AD prevention trial conducted at a very reasonable cost by taking advantage of the experience and efficient clinical trial management found in a cancer cooperative group (Southwest Oncology Group or SWOG). Once unblinded, the RCT and exposure study data have the potential to yield new information on long term exposure to antioxidant supplements under controlled conditions.     

Effects of person-centred care on health outcomes—A randomized controlled trial in patients with acute coronary syndrome

Objectives

To study the effects of person-centred care provided to patients with acute coronary syndrome, using four different health-related outcome measures. Also, to examine the performance of these outcomes when measuring person-centred care.

A randomized, double-blind trial to evaluate immunogenicity and safety of 13-valent pneumococcal conjugate vaccine given concomitantly with trivalent influenza vaccine in adults aged ≥65 years

This randomized, double-blind study evaluated concomitant administration of 13-valent pneumococcal conjugate vaccine (PCV13) and trivalent inactivated influenza vaccine (TIV) in adults aged ≥65 years who were naïve to 23-valent pneumococcal polysaccharide vaccine. Patients (N = 1160) were randomized 1:1 to receive PCV13 + TIV followed by placebo, or Placebo + TIV followed by PCV13 at 0 and 1 months, with blood draws at 0, 1, and 2 months. Slightly lower pneumococcal serotype-specific anticapsular polysaccharide immunoglobulin G geometric mean concentrations were observed with PCV13 + TIV relative to PCV13. Concomitant PCV13 + TIV demonstrates acceptable immunogenicity and safety compared with either agent given alone.     

Counselling of non-communicable diseases’ patients for COVID-19 vaccine uptake in Jordan: Evaluating the intervention

BackgroundPeople with noncommunicable diseases (NCDs) are at a significantly higher risk of worst outcomes if infected with COVID-19 and thus amongst the main target population for vaccination. Despite prioritizing them for vaccination, the number of vaccinated patients with comorbidities stalled post vaccine introduction. Despite that the government along with partners ran a national awareness campaign to ramp up vaccination coverage, the coverage remained suboptimal. Thus, a one-to-one health counselling initiative was implemented to explore the acceptance of COVID-19 vaccines by the NCDs patients and address the main issues surrounding vaccine hesitancy. This study evaluates the impact of this intervention by analyzing the change in COVID-19 vaccine acceptance.MethodsIn this analytical observational study, a random sample of 57,794 people living with NCDs were approached. Out of them, 12,144 received one-to-one counselling by a group of trained health professionals. The counselled group’s vaccine acceptance was assessed on a Likert scale from 1 to 5 pre- and post- counselling. Moreover, a random sample was followed up 2 months after initial counselling to measure their vaccine acceptance and update their vaccination status.Results44.5% of total respondents were already registered in the vaccination platform. On a scale from 1 to 5, the overall mean confidence significantly increased by 1.63 from 2.48 pre-counselling to 4.11 post-counselling. Two-months post counselling, a random sample was contacted again and had a mean vaccine confidence of 3.71, which is significantly higher than pre-counselling confidence level despite a significant decrease to post-counselling results.DiscussionImplementing an intervention that targets all key factors impacting health decisions, such as health literacy, risk appraisal and response efficacy, helps reach an adaptive response and increase vaccine confidence. Scholars should be cautious when implementing an intervention since it could lead to maladaptive defensive responses. One-to-one interventions are more effective in population when addressing new interventions and vaccines.     

Safety and immunogenicity of a novel 10-valent pneumococcal conjugate vaccine candidate in adults,toddlers, and infants in The Gambia—Results of a phase 1/2 randomized,double-blinded,controlled trial

BackgroundA more affordable pneumococcal conjugate vaccine (PCV) that provides comparable protection to current PCVs is needed to ensure sustainable access in resource-limited settings. Serum Institute of India Pvt. Ltd.’s PCV candidate (SIIPL-PCV) has the potential to meet this need as manufacturing efficiency has been optimized and the vaccine targets the most prevalent disease-causing serotypes in Africa and Asia. We report SIIPL-PCV’s safety, tolerability, and immunogenicity in adults, toddlers, and infants in The Gambia.MethodsThis phase 1/2, randomized, double-blind trial sequentially enrolled 34 PCV-naive adults (18–40 years old), 112 PCV (Prevenar 13® [PCV13])-primed toddlers (12–15 months old), and 200 PCV-naive infants (6–8 weeks old), who were randomized (1:1) to receive SIIPL-PCV or a licensed comparator vaccine. Infants received three-doses of SIIPL-PCV or PCV13 at 6, 10, and 14 weeks of age co-administered with routine Expanded Program on Immunization (EPI) vaccines. Reactogenicity was solicited through seven-days post-vaccination; unsolicited adverse events (AEs) were assessed throughout the study. The safety and immunogenicity of a matching booster at 10–14 months of age were evaluated in a subset of 96 infants. Immune responses were evaluated post-primary and pre- and post-booster vaccinations.ResultsReactogenicity was primarily mild-to-moderate in severity. In infants, the most common solicited reactions were injection-site tenderness and fever, with no meaningful treatment-group differences. There were no serious or severe vaccine-related AEs and no meaningful trends in SAEs, vaccine-related AEs, or overall AEs. Infant post-primary seroresponse rates (IgG level ≥ 0.35 µg/mL) were ≥89% for all serotypes except 6A (79%) in the SIIPL-PCV group. IgG GMCs were >1 µg/mL for all serotypes in both SIIPL-PCV and PCV13 groups. Post-booster GMCs were comparable between groups.ConclusionSIIPL-PCV was well-tolerated, had an acceptable safety profile, and was immunogenic for all vaccine serotypes. Results support the evaluation of SIIPL-PCV in a phase 3 non-inferiority trial.Clinicaltrials.gov: NCT02308540.     

Safety and immunogenicity of high-dose quadrivalent influenza vaccine in adults ≥65 years of age: A phase 3 randomized clinical trial

BackgroundA high-dose, split-virion inactivated trivalent influenza vaccine (IIV3-HD; Fluzone® High-Dose, Sanofi Pasteur) is available for adults ≥65 years of age. This study examined the safety and immunogenicity of a quadrivalent high-dose split-virion inactivated influenza vaccine (IIV4-HD).MethodsThis was a randomized, modified double-blind, active-controlled, multi-center trial in healthy adults ≥65 years of age. Subjects were randomized in a 4:1:1 ratio to receive a single intramuscular injection of IIV4-HD, the licensed IIV3-HD, or an IIV3-HD containing the alternate B-lineage strain. Hemagglutination inhibition (HAI), seroneutralisation, and anti-neuraminidase antibody titers were measured at baseline and day 28. Solicited reactions were collected for up to 7 days, unsolicited adverse events up to 28 days, and serious adverse events up to 180 days. The primary immunogenicity objective was to demonstrate that IIV4-HD induces HAI geometric mean titers (GMTs) and seroconversion rates that are non-inferior to those induced by IIV3-HD. Secondary objectives were to describe the safety of IIV4-HD and IIV3-HD and to demonstrate that IIV4-HD induces HAI GMTs and seroconversion rates that are superior to those induced by IIV3-HD not containing the same B-lineage strain.ResultsThe study included 2670 adults ≥65 years of age. For all four strains, HAI GMTs and seroconversion rates induced by IIV4-HD were non-inferior to those induced by IIV3-HDs containing the same strains. For both B strains, HAI GMTs and seroconversion rates induced by IIV4-HD were superior to those induced by IIV3-HD not containing the same B–lineage strain. Seroneutralisation and anti-neuraminidase antibody responses, measured in a subset of subjects, were similar. No new safety concerns were identified, and the safety profiles of IIV4-HD and IIV3-HD were similar.ConclusionsAdding a second B strain in IIV4-HD resulted in improved immunogenicity against the added strain without compromising the immunogenicity of the other strains or the vaccine’s tolerability.Clinical trial registration: NCT03282240.     

Preparation for a pneumococcal vaccine trial in The Gambia: individual or community randomisation?

In preparation for a large phase-3 trial of pneumococcal polysaccharide/conjugate vaccine among infants in The Gambia, the relative merits of community and individual randomisation were considered. The impact of vaccination might be enhanced in a community randomised trial if there was a substantial 'herd' effect. This might occur if those vaccinated comprise a substantial proportion of potential transmitters of infection. However, there are few data on the sources of pneumococcal infections in The Gambia and with the high degree of mobility of people in The Gambia, it seems unlikely that any herd effect would be strong. In the absence of a herd effect, a community-randomised trial would have lower power for the mortality end-points compared to an individually randomised trial of the same size. In addition, a community-randomised trial might not provide sufficient control against potential confounders and blinding might be difficult to sustain if the vaccine has a strong effect. An individually randomised trial seems a better strategy under the conditions prevailing in The Gambia.     

A randomized phase 3 trial to assess the immunogenicity and safety of 3 consecutively produced lots of freeze-dried MVA-BN® vaccine in healthy adults

Since vaccination remains the only effective protection against orthopox virus-induced diseases such as smallpox or monkeypox, the strategic use and stockpiling of these vaccines remains of significant public health importance. The approved liquid-frozen formulation of Bavarian Nordic's Modified Vaccinia Ankara (MVA-BN) smallpox vaccine has specific cold-chain requirements, while the freeze-dried (FD) formulation of this vaccine provides more flexibility in terms of storage conditions and shelf life.In this randomized phase 3 trial, the immunogenicity and safety of 3 consecutively manufactured lots of the FD MVA-BN vaccine was evaluated. A total of 1129 healthy adults were randomized to 3 treatment groups (lots 1 to 3) and received 2 vaccinations 4 weeks apart.For both neutralizing and total antibodies, a robust increase of geometric mean titer (GMT) was observed across all lot groups 2 weeks following the second vaccination, comparable to published data. For the primary results, the ratios of the neutralizing antibody GMTs between the lot group pairs ranged from 0.936 to 1.115, with confidence ratios well within the pre-specified margin of equivalence. Results for total antibodies were similar. In addition, seroconversion rates were high across the 3 lots, ranging between 99.1 % and 99.7 %.No safety concerns were identified; particularly, no inflammatory cardiac disorders were detected. The most common local solicited adverse events (AEs) reported across lot groups were injection site pain (87.2%) and erythema (73.2%), while the most common general solicited adverse events were myalgia, fatigue, and headache in 40.6% to 45.5% of all participants, with no meaningful differences among the lot groups. No related serious AEs were reported.In conclusion, the data demonstrate consistent and robust immunogenicity and safety results with a freeze-dried formulation of MVA-BN.Clinical Trial Registry Number: NCT03699124.     

Learning with computerized guidelines in general practice?: A randomized controlled trial

BACKGROUND: Evidence-based guidelines are seen as an important instrument to transfer scientifically generated knowledge into daily clinical practice and to ensure high standards of clinical care. Despite wide promulgation, clinical guidelines so far have a limited impact on individual professional learning and on changing daily medical practice. OBJECTIVES: Our aims were (i) to study a potential knowledge increase among German GPs after implementation of web- and evidence-based guidelines and (ii) to identify and analyse potential barriers to individual professional learning with computerized guidelines. METHODS: A prospective, randomized controlled trial was conducted including 72 GPs (21% female, 79% male). The intervention group (n = 38) had access to clinical guidelines via the Internet or CD-ROM, the control group had not (n = 34). Both groups received a standardized two-part questionnaire. An increase of knowledge was measured with 25 multiple choice questions related to four different medical topics. In addition, reasons for using or not using computerized guidelines were analysed after access to guidelines was open to all participating physicians. RESULTS: There was no significant knowledge increase in the intervention group (P = 0.69). Twenty-two (58%) GPs of the intervention group had used the guidelines. Unspecified curiosity (76%) and a specific medical question (38%) were predominant motives for usage among physicians who had used the guidelines. Among 'non-users', 78% stated 'lack of time' as the main reason for not using guidelines. CONCLUSION: An efficient knowledge transfer through computerized guidelines was not achieved. Usage, individual learning and potential implementation depend on adequate incentives and pragmatic aspects of clinical practice: easy and quick access.