Effect of priming interval on reactogenicity, peak immunological response, and waning after homologous and heterologous COVID-19 vaccine schedules: exploratory analyses of Com-COV, a randomised control trial

Background: Priming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com-COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca). Methods: Com-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020–005085–33). Findings: Between Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77–89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS-CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4-week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2–ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1·4 (95% CI 1·1–1·8) for homologous BNT162b2, 1·5 (1·2–1·9) for ChAdOx1 nCoV-19–BNT162b2, 1·6 (1·3–2·1) for BNT162b2–ChAdOx1 nCoV-19, and 2·4 (1·7–3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17–0·24 of the 28-day post-second dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19–BNT162b2 were up to 80% less reactogenic than 4-week schedules. Interpretation: These data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals. Funding: UK Vaccine Taskforce and National Institute for Health and Care Research

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Changes in Surface Area, Pore Structure and Density during Formation of High-temperature Chars from Representative U.S. Coals

Multiple techniques (CO 2 and N 2 adsorptions, NMR spin relaxation of adsorbed water, He pycnometry and Hg porosimetry) have been combined in a comprehensive study to determine changes in surface area (CO 2 and nitrogen), density (solid, particle and bulk), and pore structure (pore size and volume distributions of micro-, meso- and macro-pores) in high-temperature char formation from rank representative U.S. coals of the ANL and PETC Banks (i.e. Beulah Zap, Dietz, Utah Blind Canyon, Pittsburgh No.8 and Pocahontas No.3). Chars were formed at high heating rates in a flat-frame burner (maximum temperature of 1473 K), a process representative of char formation in pulverized coal combustion. Most of the surface area of the coals was found in micropores with radii less than 1.5 nm, while 95% or more of the pore volume in the coals (85% of that in chars) was contained in mesopores less than 20 nm). During the high-temperature formation of char in a flame: (I) CO 2 surface areas (involving mainly micropores, r pore < 1.5 nm) increase two- to three-fold, while N 2 surface areas (involving mesopores. 1.5 nm < r pore < 20 nm) increase 20–200-fold; (2) solid densities increase about 25% due to graphitization, while particle densities decrease by about a factor of two due to large increases in particle porosity; (3) pore volumes increase 5–10-fold; and (4) total porosities increase three- to four-fold, most of this increase occurring in the macropore range. The larger surface areas and porosities of chars relative to coals may be explained by (i) the removal by pyrolysis of strongly adsorbed molecules or volatile hydrocarbons from micropores and small mesopores that would otherwise hinder access of CO 2 and N 2 molecules; (ii) the creation of new pores during the restructuring process involved in charification; and (iii) opening up by gasification with oxygen of new pores previously blocked to gas adsorption. The preparation conditions (e.g. atmosphere, heating rate and temperature) greatly affect the physical properties including the surface area, porosity and density of the resulting chars. The degree of carbon burnout is an important correlating factor affecting these properties

Delaying natural flowering in pineapple through foliar application of aviglycine, an inhihitor of ethylene biosynthesis

In Taiwan, the major yield constraint in pineapple cultivation is natural flowering, which occurs when daylengths are shorter and nights are cooler. This natural (precocious) flowering increases the cost of cultivation and reduces the percentage of fruits of marketable size. Two field experiments were conducted to evaluate the inhibitory potential of aviglycine [(S)-trans-2-amino-4-(2 aminoethoxy)-3-butenoic acid hydrochloride, AVG on natural flowering of 'Tainon 17' pineapple plants during the 2003 to 2004 and 2004 to 2005 cropping seasons. In the 2003 to 2004 season, bolting in the control exceeded 80% on 2 Mar. 2004, whereas no bolting was observed in the treatments. Inhibition of bolting by aviglycine (AVG) was dependent on the concentration and frequency of application. Bolting was less than 40% when plants were treated in Nov. and Dec. 2003 with 500 mg center dot L-1 of AVG four times at 15-day intervals or with five applications made at 10-day intervals. For the 2004 to 2005 season, bolting of plants treated with 250 or 375 mg center dot L-1 AVG was delayed 4 weeks relative to the control, whereas bolting was delayed 7 weeks by four or five applications of 500 mg center dot L-1 of AVG applied at 10- or 15-dav intervals. Both experiments showed that four to live applications of 500 mg center dot L-1 of, VG at 10- or 15-day intervals delayed inflorescence emergence relative to the control for the duration of the treatments. We assume control was maintained for 1 to 2 weeks after treatments stopped. Based on these results, the date AVG treatments stop can be used to estimate the duration of delay in flowering. AVG inhibits ethylene biosynthesis and has the potential to be effectively used to delay or completely control the problem of precocious flowering and associated crop losses in pineapple