Impact of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial

Background: Meningococcal conjugate vaccines protect individuals directly, but also confer herd protection by interrupting carriage transmission. This Phase III observer-blind, randomised, controlled study evaluated the effects of meningococcal quadrivalent (ACWY) glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in young adults. Methods: University students (aged 18–24 years) from ten sites in England were randomised to receive two vaccinations one month apart: two doses of Japanese Encephalitis vaccine (controls), two doses of 4CMenB (4CMenB), or one dose of MenACWY-CRM then placebo (MenACWY-CRM). Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over one year. Primary analysis was cross-sectional carriage one month after the vaccine course; secondary analyses included comparison of carriage at any time point after primary analysis until study termination. Findings: 2954 subjects were randomised (control, n=987; 4CMenB, n=988; MenACWY-CRM, n=979); approximately one-third of each group was positive for meningococcal carriage at study entry. By one month, there was no significant difference in carriage between controls and 4CMenB (Odds Ratios (OR) [95% CI]; 1·2 [0·8−1·7]) or MenACWY-CRM (OR [95% CI], 0·9 [0·6–1·3]) groups. From three months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (calculated efficacy 18·2% [95% CI: 3·4–30·8]) and capsular groups BCWY (calculated efficacy 26·6% [95% CI: 10·5–39·9]) compared to control vaccination. Significantly lower carriage rates were also observed in the MenACWY-CRM group compared with controls: calculated efficacies 39·0% [95%CI: 17·3-55·0] and 36.2% [95%CI: 15·6-51·7] for serogroups Y and CWY, respectively. Interpretation: MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates over 12 months post-vaccination and, therefore, may affect transmission where widely implemented

Lipid testing trends in the us before and after the release of the 2013 cholesterol treatment guidelines

Background: The 2013 ACC/AHA cholesterol treatment guidelines removed the recom-mendation to treat adults at risk of cardiovascular disease to goal levels of low-density lipoprotein cholesterol (LDL-C). We anticipated that the frequency of LDL-C testing in clinical practice would decline as a result. To test this hypothesis, we evaluated the frequency of LDL-C testing before and after the guideline release. Methods: We used the MarketScan® Commercial and Medicare Supplemental claims data (1/1/2007–12/31/2016) to identify four cohorts: 1) statin initiators (any intensity), 2) high-intensity statin initiators, 3) ezetimibe initiators, and 4) patients at very high cardiovascular risk (≥2 hospitalizations for myocardial infarction or ischemic stroke, with prevalent statin use). Rates of LDL-C testing by calendar year quarter were estimated for each cohort. To estimate rates in the absence of a guideline change, we fit a time-series model to the pre-guideline rates and extrapolated to the post-guideline period, adjusting for covariates, seasonality, and time trend. Results: Pre-and post-guideline rates (LDL-C tests per 1,000 persons per quarter) were 248 and 235, respectively, for 3.9 million statin initiators; 263 and 246 for 1.3 million high-intensity statin initiators; 277 and 261 for 323,544 ezetimibe initiators; and 180 and 158 for 42,108 very high-risk patients. For all cohorts, observed post-guideline rates were similar to model-predicted rates. On average, the difference between observed and predicted rates was 8.5 for patients initiating any statin; 2.6 for patients initiating a high-intensity statin; 11.4 for patients initiating ezetimibe, and −0.5 for high-risk patients. Conclusion: We observed no discernible impact of the release of the 2013 ACC/AHA guidelines on LDL-C testing rates. Rather, there was a gradual decline in testing rates starting prior to the guideline change and continuing throughout the study period. Our findings suggest that the guidelines had little to no impact on use of LDL-C testing

Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial

Background: Meningococcal conjugate vaccines protect individuals directly, but also confer herd protection by interrupting carriage transmission. This Phase III observer-blind, randomised, controlled study evaluated the effects of meningococcal quadrivalent (ACWY) glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in young adults.Methods: University students (aged 18–24 years) from ten sites in England were randomised to receive two vaccinations one month apart: two doses of Japanese Encephalitis vaccine (controls), two doses of 4CMenB (4CMenB), or one dose of MenACWY-CRM then placebo (MenACWY-CRM). Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over one year. Primary analysis was cross-sectional carriage one month after the vaccine course; secondary analyses included comparison of carriage at any time point after primary analysis until study termination.Findings: 2954 subjects were randomised (control, n=987; 4CMenB, n=988; MenACWY-CRM, n=979); approximately one-third of each group was positive for meningococcal carriage at study entry. By one month, there was no significant difference in carriage between controls and 4CMenB (Odds Ratios (OR) [95% CI]; 1·2 [0·8−1·7]) or MenACWY-CRM (OR [95% CI], 0·9 [0·6–1·3]) groups. From three months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (calculated efficacy 18·2% [95% CI: 3·4–30·8]) and capsular groups BCWY (calculated efficacy 26·6% [95% CI: 10·5–39·9]) compared to control vaccination. Significantly lower carriage rates were also observed in the MenACWY-CRM group compared with controls: calculated efficacies 39·0% [95%CI: 17·3-55·0] and 36.2% [95%CI: 15·6-51·7] for serogroups Y and CWY, respectively.Interpretation: MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates over 12 months post-vaccination and, therefore, may affect transmission where widely implemented

Persistence of immune response in heterologous COVID vaccination schedules in the Com-COV2 study - a single-blind, randomised trial incorporating mRNA, viral-vector and protein-adjuvant vaccines

Background Heterologous COVID vaccine priming schedules are immunogenic and effective. This report aims to understand the persistence of immune response to the viral vectored, mRNA and protein-based COVID-19 vaccine platforms used in homologous and heterologous priming combinations, which will inform the choice of vaccine platform in future vaccine development. Methods Com-COV2 was a single-blinded trial in which adults ≥50 years, previously immunised with single dose 'ChAd' (ChAdOx1 nCoV-19, AZD1222, Vaxzevria, Astrazeneca) or 'BNT' (BNT162b2, tozinameran, Comirnaty, Pfizer/BioNTech), were randomised 1:1:1 to receive a second dose 8-12 weeks later with either the homologous vaccine, or 'Mod' (mRNA-1273, Spikevax, Moderna) or 'NVX' (NVX-CoV2373, Nuvaxovid, Novavax). Immunological follow-up and the secondary objective of safety monitoring were performed over nine months. Analyses of antibody and cellular assays were performed on an intention-to-treat population without evidence of COVID-19 infection at baseline or for the trial duration. Findings In April/May 2021, 1072 participants were enrolled at a median of 9.4 weeks after receipt of a single dose of ChAd (N= 540, 45% female) or BNT (N=532, 39% female) as part of the national vaccination programme. In ChAd-primed participants, ChAd/Mod had the highest anti-spike IgG from day 28 through to 6 months, although the heterologous vs homologous geometric mean ratio (GMR) dropped from 9.7 (95%CI: 8.2,11.5) at D28 to 6.2 (95%CI: 5.0, 7.7) at D196. The heterologous/homologous GMR for ChAd/NVX similarly dropped from 3.0 (95%CI:2.5-3.5) to 2.4 (95%CI:1.9-3.0). In BNT-primed participants, decay was similar between heterologous and homologous schedules with BNT/Mod inducing the highest anti-spike IgG for the duration of follow-up. The aGMR for BNT/Mod compared with BNT/BNT increased from 1.36 (95%CI: 1.17, 1.58) at D28 to 1.52 (95%CI: 1.21, 1.90) at D196, whilst for BNT/NVX this aGMR was 0.55 (95%CI: 0.47, 0.64) at day 28 and 0.62 (95%CI: 0.49, 0.78) at day 196. Heterologous ChAd-primed schedules produced and maintained the largest T-cell responses until D196. Immunisation with BNT/NVX generated a qualitatively different antibody response to BNT/BNT, with the total IgG significantly lower than BNT/BNT during all follow-up time points, but similar levels of neutralising antibodies. Interpretation Heterologous ChAd-primed schedules remain more immunogenic over time in comparison to ChAd/ChAd. BNT-primed schedules with a second dose of either mRNA vaccine also remain more immunogenic over time in comparison to BNT/NVX. The emerging data on mixed schedules using the novel vaccine platforms deployed in the COVID-19 pandemic, suggest that heterologous priming schedules might be considered as a viable option sooner in future pandemics

Impact of meningococcal ACWY conjugate vaccines on pharyngeal carriage in adolescents: evidence for herd protection from the UK MenACWY programme

Objective: Serogroup W and Y invasive meningococcal disease increased globally from 2000 onwards. Responding to a rapid increase in serogroup W clonal complex 11 (W:cc11) invasive meningococcal disease, the UK replaced an adolescent booster dose of meningococcal C conjugate vaccine with quadrivalent MenACWY conjugate vaccine in 2015. By 2018, the vaccine coverage in the eligible school cohorts aged 14 to 19 years was 84%. We assessed the impact of the MenACWY vaccination programme on meningococcal carriage. Methods: An observational study of culture-defined oropharyngeal meningococcal carriage prevalence before and after the start of the MenACWY vaccination programme in UK school students, aged 15 to 19 years, using two cross-sectional studies: 2014 to 2015 “UKMenCar4” and 2018 “Be on the TEAM” (ISRCTN75858406). Results: A total of 10 625 participants preimplementation and 13 434 postimplementation were included. Carriage of genogroups C, W, and Y (combined) decreased from 2.03 to 0.71% (OR 0.34 [95% CI 0.27–0.44], p < 0.001). Carriage of genogroup B meningococci did not change (1.26% vs 1.23% [95% CI 0.77–1.22], p = 0.80) and genogroup C remained rare (n = 7/10 625 vs 17/13 488, p = 0.135). The proportion of serogroup positive isolates (i.e. those expressing capsule) decreased for genogroup W by 53.8% (95% CI –5.0 to 79.8, p = 0.016) and for genogroup Y by 30.1% (95% CI 8.9–46·3, p = 0.0025). Discussion: The UK MenACWY vaccination programme reduced carriage acquisition of genogroup and serogroup Y and W meningococci and sustained low levels of genogroup C carriage. These data support the use of quadrivalent MenACWY conjugate vaccine for indirect (herd) protection

Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial

Background: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. Methods: Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. Findings: Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. Interpretation: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. Funding: UK Vaccine Task Force and National Institute for Health Research

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

BackgroundA safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials.MethodsThis analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674.FindingsBetween April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation.InterpretationChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials.FundingUK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D’Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca