BACKGROUND:ChAdOx1 nCoV-19 (AZD1222) vaccine was widely deployed to protect against severe COVID-19 in adults, but the relationship between pre-existing immunity to human seasonal coronaviruses (HCoVs) and vaccine-induced SARS-CoV-2 (SCoV2) response across age groups remains unclear. METHODS:We analysed SCoV2 and HCoVs antibody profiles in UK volunteers (aged 6-≥70), assessing antibody levels, avidity, and FcγR binding after receiving one or two doses of ChAdOx1 nCoV-19. Adult cohorts from trials in Brazil and Kenya were also included to evaluate geographical impacts on baseline HCoVs and SCoV2 induced response. FINDINGS:In the UK cohort, younger individuals had higher SCoV2 IgG, avidity, FcγR binding and cross-reactivity, particularly towards OC43 and HKU1. The greatest differences were seen after the first dose of ChAdOx1 nCoV-19, but these effects diminished after the second dose. Although baseline HCoVs IgG varied geographically, similar trends were observed across adult cohorts with younger adults showing higher SCoV2 IgG compared to older adults (UK and Brazil). INTERPRETATION:These findings contribute to a better understanding of the immunogenicity of ChAdOx1-based vaccines in various age groups. Determining whether this applies across other vaccines using same platform is essential for evaluating the viability of one-dose regimens in outbreak responses. FUNDING:The clinical trials COV002, COV003, COV004, and COV006 were made possible by funding from Astra Zeneca, the NIHR and the University of Oxford, UK Department of Health and Social Care, through the UK National Institute for Health and Care Research, the Wellcome Trust (220991), and Innovate UK (project 971614).

Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes-mucosal-associated invariant T (MAIT) cells and Vδ2+ γδ T cells-which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)-mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell-derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ-licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.

In The Lancet Respiratory Medicine, Fengcai Zhu and colleagues1Zhu F Huang S Liu X et al.Safety and efficacy of the intranasal spray SARS-CoV-2 vaccine dNS1-RBD: a multicentre, randomised, double-blind, placebo-controlled, phase 3 clinical trial.Lancet Respir Med. 2023; (published online Nov 15.)https://doi.org/10.1016/S2213-2600(23)00349-1Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar report the safety and efficacy of a new mucosal vaccine (dNS1-RBD, Pneucolin; Beijing Wantai Biological Pharmacy Enterprise, Beijing, China) against symptomatic SARS-CoV-2 infection confirmed by RT-PCR. The efficacy was 28·2% (95% CI 3·4–46·6) regardless of immunisation history, 23·5% (–8·0 to 45·8) in individuals with a history of SARS-CoV-2 vaccination, and 40·0% (–7·6 to 66·6) in those without. The vaccine is a replication-deficient H1N1 influenza virus vector carrying the RNA sequence for an ancestral SARS-CoV-2 receptor-binding domain (RBD) that was delivered by intranasal inhalation via an atomiser spray. Undertaking an efficacy trial 2 years after the start of the COVID-19 pandemic presents several challenges. The number of participants who were previously exposed to the virus (either previously undiagnosed or with an asymptomatic SARS-CoV-2 infection) has increased; lateral flow antibody tests might be of limited use because of the reported reduced sensitivity for responses against newer SARS-CoV-2 variants; and the sensitivity of the test is further compromised by the natural waning of the antibody response after SARS-CoV-2 infection. The efficacy of protection of this vaccine is difficult to compare directly against the efficacy of established intramuscular vaccines tested originally in naïve individuals, not only because of a change in serostatus of the target population, but also a change in the circulating variant—in this case, the predominant circulating variants were the more transmissible omicron sublineages. Increased pre-existing immunity to SARS-CoV-2, either via viral exposure or vaccination, and a small trial size might have contributed to the fact that the number of participants with severe SARS-CoV-2 infection was too low to assess the vaccine efficacy against severe disease. The results of the trial did not meet the pre-specified criterion for success (>30% efficacy against symptomatic infection). However, the level of protection offered by this vaccine appears broadly similar to the levels of protection afforded by intramuscular booster vaccination programmes, as reported by population efficacy studies done when omicron (B.1.1.529) was the dominant variant.2Andrews N Stowe J Kirsebom F et al.COVID-19 vaccine effectiveness against the omicron (B.1.1.529) variant.N Engl J Med. 2022; 386: 1532-1546Crossref PubMed Scopus (1206) Google Scholar, 3Mohammed H Pham-Tran DD Yeoh ZYM et al.A systematic review and meta-analysis on the real-world effectiveness of COVID-19 vaccines against infection, symptomatic and severe COVID-19 disease caused by the omicron variant (B.1.1.529).Vaccines (Basel). 2023; 11: 224Crossref PubMed Scopus (9) Google Scholar Within the context of a population that has had greater exposure to SARS-CoV-2 and with the majority of infections being due to omicron variants, this mucosal vaccine might be similar in effect to intramuscular booster vaccines. dNS1-RBD shares some similarities with another mucosal SARS-CoV-2 vaccine in development, the Ad5-nCoV vaccine (Beijing Institute of Biotechnology, Beijing, China, and CanSino Biologics, Tianjin, China), which is an aerosolised, orally inhaled, replication-deficient, adenovirus type-5 vectored vaccine encoding the SARS-CoV-2 spike protein.4Li J-X Hou L-H Gou J-B et al.Safety, immunogenicity and protection of heterologous boost with an aerosolised Ad5-nCoV after two-dose inactivated COVID-19 vaccines in adults: a multicentre, open-label phase 3 trial.Lancet Infect Dis. 2023; 23: 1143-1152Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 5Li J-X Wu S-P Guo X-L et al.Safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised Ad5-nCoV after two-dose priming with an inactivated SARS-CoV-2 vaccine in Chinese adults: a randomised, open-label, single-centre trial.Lancet Respir Med. 2022; 10: 739-748Summary Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 6Wu S Huang J Zhang Z et al.Safety, tolerability, and immunogenicity of an aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in adults: preliminary report of an open-label and randomised phase 1 clinical trial.Lancet Infect Dis. 2021; 21: 1654-1664Summary Full Text Full Text PDF PubMed Scopus (161) Google Scholar Both these vaccine candidates are vectored by replication deficient viral backbones, but they are different with regard to design, delivery, and immunogenicity. dNS1-RBD uses the sequence for the RBD as the immunogen, whereas Ad5-nCoV, together with the most commonly used and successful intramuscular vaccines, uses the sequence for the whole spike protein. dNS1-RBD is administered to the nasal mucosa via an atomiser spray, whereas Ad5-nCoV is delivered by aerosolised inhalation, which presumably has more chance of reaching the mucosa of the lower respiratory tract. The immunological differences are perhaps even more striking.7Zhu F Zhuang C Chu K et al.Safety and immunogenicity of a live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine in adults: randomised, double-blind, placebo-controlled, phase 1 and 2 trials.Lancet Respir Med. 2022; 10: 749-760Summary Full Text Full Text PDF PubMed Scopus (43) Google Scholar The aerosolised adenovirus vaccine induces a robust systemic neutralising humoral and cellular response as well as a measurable mucosal secretory IgA response, although this mucosal response appears to be short-lived. In comparison, dNS1-RBD has a much more modest rate of seroconversion and mucoconversion—a concept that might need refinement as mucosal vaccines are developed further. Although the measured immune response might be argued as of secondary importance in the context of a probable efficacy (albeit a low level with the aforementioned caveats), a deeper understanding of the immune response, especially in the context of future pathogens, will be essential. It remains unclear which immune mechanisms offer protection from severe SARS-CoV-2 infection. Future mucosal vaccine candidates might offer protection against symptomatic infection, but a potential concern is whether vaccines that produce low but detectable systemic immune responses also provide protection against severe disease and death. If mucosal protection against symptomatic disease wanes over time, a yet unanswered question would be whether individuals receiving the vaccine are more likely to develop severe illness once this immunity wanes. There is a lot of anticipation surrounding the development of mucosally delivered vaccines and their potential impact. Intramuscular SARS-CoV-2 vaccines can reduce transmission in the short term.8Eyre DW Taylor D Purver M et al.Effect of COVID-19 vaccination on transmission of alpha and delta variants.N Engl J Med. 2022; 386: 744-756Crossref PubMed Scopus (232) Google Scholar Through delivery at the portal of infectious entry, mucosal vaccines might have an increased potential for transmission blocking compared with other types of vaccine. Currently, however, evidence related to this aspect is lacking, and the study by Zhu and colleagues1Zhu F Huang S Liu X et al.Safety and efficacy of the intranasal spray SARS-CoV-2 vaccine dNS1-RBD: a multicentre, randomised, double-blind, placebo-controlled, phase 3 clinical trial.Lancet Respir Med. 2023; (published online Nov 15.)https://doi.org/10.1016/S2213-2600(23)00349-1Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar does not add to the hope that mucosal vaccination might, in the future, be better than intramuscular vaccination. In the absence of clear protection against severe disease in individuals who are seronegative, the results of this trial need to be taken cautiously. Previous precedent suggests that a mucosally delivered vaccine, such as the live-attenuated influenza vaccine, can be just as efficacious as intramuscular vaccines at preventing illness in children,9Belshe RB Edwards KM Vesikari T et al.Live attenuated versus inactivated influenza vaccine in infants and young children.N Engl J Med. 2007; 356: 685-696Crossref PubMed Scopus (724) Google Scholar but it is not clear whether individuals from different age groups might benefit to the same extent.10Monto AS Ohmit SE Petrie JG et al.Comparative efficacy of inactivated and live attenuated influenza vaccines.N Engl J Med. 2009; 361: 1260-1267Crossref PubMed Scopus (246) Google Scholar Overall, mucosal vaccines might be a more acceptable, needle-free alternative, especially to those who are afraid of needles, and have the potential to facilitate a rapid deployment in a future pandemic setting. However, ultimately, the current understanding of mucosal immunity and how to augment it through immunisation remains with many deficits and further research is required to better understand the mucosal immune response to infection and vaccination. I declare no competing interests. Safety and efficacy of the intranasal spray SARS-CoV-2 vaccine dNS1-RBD: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trialAlthough this trial did not meet the predefined efficacy criteria for success, dNS1-RBD was well tolerated and protective against omicron variants, both as a primary immunisation and as a heterologous booster. Full-Text PDF Open Access

Introduction: COVID-19 infection triggers cytokine-driven vascular inflammation, which is measurable from gated or non-gated CT angiograms using a new radiotranscriptomic signature of the perivascular space around the internal mammary artery(IMA)/aorta (C19RS). In this study, we evaluate the dynamic changes of C19RS in COVID-19, and explore its potential role as an early stratification tool for new COVID-19 variants that could be used to guide our response to future infective diseases.

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 (confidence interval): 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 adjusted GMR (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. ISRCTN:27841311 EudraCT:2021-001275-16.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine immunogenicity varies between individuals, and immune responses correlate with vaccine efficacy. Using data from 1,076 participants enrolled in ChAdOx1 nCov-19 vaccine efficacy trials in the United Kingdom, we found that inter-individual variation in normalized antibody responses against SARS-CoV-2 spike and its receptor-binding domain (RBD) at 28 days after first vaccination shows genome-wide significant association with major histocompatibility complex (MHC) class II alleles. The most statistically significant association with higher levels of anti-RBD antibody was HLA-DQB1*06 ( P = 3.2 × 10 −9 ), which we replicated in 1,677 additional vaccinees. Individuals carrying HLA-DQB1*06 alleles were less likely to experience PCR-confirmed breakthrough infection during the ancestral SARS-CoV-2 virus and subsequent Alpha variant waves compared to non-carriers (hazard ratio = 0.63, 0.42–0.93, P = 0.02). We identified a distinct spike-derived peptide that is predicted to bind differentially to HLA-DQB1*06 compared to other similar alleles, and we found evidence of increased spike-specific memory B cell responses in HLA-DQB1*06 carriers at 84 days after first vaccination. Our results demonstrate association of HLA type with Coronavirus Disease 2019 (COVID-19) vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation.

Abstract The safety of novel therapeutics and vaccines are typically assessed in early phase clinical trials involving “healthy volunteers.” Abnormalities in such individuals can be difficult to interpret and may indicate previously unrecognized medical conditions. The frequency of incidental findings (IFs) in healthy volunteers who attend for clinical trial screening is unclear. To assess this, we retrospectively analyzed data for 1838 “healthy volunteers” screened for enrolment in a UK multicenter, phase I/II severe acute respiratory syndrome‐coronavirus 2 (SARS‐COV‐2) vaccine trial. Participants were predominantly White (89.7%, 1640/1828) with a median age of 34 years (interquartile range [IQR] = 27–44). There were 27.7% of participants (510/1838) who had at least one IF detected. The likelihood of identifying evidence of a potential, new blood‐borne virus infection was low (1 in 238 participants) compared with identification of an elevated alanine transaminase (ALT; 1 in 17 participants). A large proportion of participants described social habits that could impact negatively on their health; 21% consumed alcohol in excess, 10% were current smokers, 11% described recreational drug use, and only 48% had body weight in the ideal range. Our data demonstrate that screening prior to enrollment in early phase clinical trials identifies a range of IFs, which should inform discussion during the consent process. Greater clarity is needed to ensure an appropriate balance is struck between early identification of medical problems and avoidance of exclusion of volunteers due to spurious or physiological abnormalities. Debate should inform the role of the trial physician in highlighting and advising about unhealthy social habits.

Background Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored vaccine (ChAdOx1 nCoV-19 [ChAd], AstraZeneca), two mRNA vaccines (BNT162b2 [BNT], Pfizer-BioNTech, and mRNA-1273 [m1273], Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 [NVX], Novavax). Methods Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8-12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0.63 for the one-sided 98.75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311. Findings Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9.4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL [95% CI 18 160 to 22 279]) and ChAd/NVX (5597 ELU/mL [4756 to 6586]) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL [1718 to 2262]) with a GMR of 10.2 (one-sided 98.75% CI 8.4 to infinity) for ChAd/m1273 and 2.8 (2.2 to infinity) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL [95% CI 20 597 to 25 636]) but not for BNT/NVX (8874 ELU/mL [7391 to 10 654]), compared with BNT/BNT (16 929 ELU/mL [15 025 to 19 075]) with a GMR of 1.3 (one-sided 98.75% CI 1.1 to infinity) for BNT/m1273 and 0.5 (0.4 to infinity) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation. Interpretation Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

In this report, we present live neutralisation titres against SARS-CoV-2 Omicron variant, compared with neutralisation against Victoria, Beta and Delta variants. Sera from day-28 post second-dose were obtained from participants in the Com-COV2 study who had received a two-dose COVID-19 vaccination schedule with either AstraZeneca (AZD1222) or Pfizer (BNT162b2) vaccines. There was a substantial fall in neutralisation titres in recipients of both AZD1222 and BNT162b2 primary courses, with evidence of some recipients failing to neutralise at all. This will likely lead to increased breakthrough infections in previously infected or double vaccinated individuals, which could drive a further wave of infection, although there is currently no evidence of increased potential to cause severe disease, hospitalisation or death.

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 center dot 4 (95% CI 1 center dot 1-1 center dot 8) for homologous BNT162b2, 1 center dot 5 (1 center dot 2-1 center dot 9) for ChAdOx1 nCoV-19-BNT162b2, 1 center dot 6 (1 center dot 3-2 center dot 1) for BNT162b2-ChAdOx1 nCoV-19, and 2 center dot 4 (1 center dot 7-3 center dot 2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0 center dot 17- 0 center dot 24 of the 28-day postsecond 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. Copyright (c) 2022 The Author(s). Published by Elsevier Ltd.

Patient-to-patient transmission has a well-recognised role in nosocomial COVID-19 infections,[1][1] but identifying and isolating infectious individuals is challenging, due to limitations in the speed and accuracy of testing.[2][2] To mediate this, many hospitals attempted to cohort patients based

Background Nosocomial spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been widely reported, but the transmission pathways among patients and healthcare workers (HCWs) are unclear. Identifying the risk factors and drivers for these nosocomial transmissions is critical for infection prevention and control interventions. The main aim of our study was to quantify the relative importance of different transmission pathways of SARS-CoV-2 in the hospital setting. Methods and findings This is an observational cohort study using data from 4 teaching hospitals in Oxfordshire, United Kingdom, from January to October 2020. Associations between infectious SARS-CoV-2 individuals and infection risk were quantified using logistic, generalised additive and linear mixed models. Cases were classified as community- or hospital-acquired using likely incubation periods of 3 to 7 days. Of 66,184 patients who were hospitalised during the study period, 920 had a positive SARS-CoV-2 PCR test within the same period (1.4%). The mean age was 67.9 (±20.7) years, 49.2% were females, and 68.5% were from the white ethnic group. Out of these, 571 patients had their first positive PCR tests while hospitalised (62.1%), and 97 of these occurred at least 7 days after admission (10.5%). Among the 5,596 HCWs, 615 (11.0%) tested positive during the study period using PCR or serological tests. The mean age was 39.5 (±11.1) years, 78.9% were females, and 49.8% were nurses. For susceptible patients, 1 day in the same ward with another patient with hospital-acquired SARS-CoV-2 was associated with an additional 7.5 infections per 1,000 susceptible patients (95% credible interval (CrI) 5.5 to 9.5/1,000 susceptible patients/day) per day. Exposure to an infectious patient with community-acquired Coronavirus Disease 2019 (COVID-19) or to an infectious HCW was associated with substantially lower infection risks (2.0/1,000 susceptible patients/day, 95% CrI 1.6 to 2.2). As for HCW infections, exposure to an infectious patient with hospital-acquired SARS-CoV-2 or to an infectious HCW were both associated with an additional 0.8 infection per 1,000 susceptible HCWs per day (95% CrI 0.3 to 1.6 and 0.6 to 1.0, respectively). Exposure to an infectious patient with community-acquired SARS-CoV-2 was associated with less than half this risk (0.2/1,000 susceptible HCWs/day, 95% CrI 0.2 to 0.2). These assumptions were tested in sensitivity analysis, which showed broadly similar results. The main limitations were that the symptom onset dates and HCW absence days were not available. Conclusions In this study, we observed that exposure to patients with hospital-acquired SARS-CoV-2 is associated with a substantial infection risk to both HCWs and other hospitalised patients. Infection control measures to limit nosocomial transmission must be optimised to protect both staff and patients from SARS-CoV-2 infection.

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 ELI SA) at 28 days after boost, when comparing ChAd/BNTwith 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 (12906 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 infinity). 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 infinity). 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. Copyright Crown Copyright (C) 2021 Published by Elsevier Ltd.

Background: SARS-CoV-2 can spread efficiently in hospitals, but the transmission pathways amongst patients and healthcare workers are unclear. Methods: We analysed data from four teaching hospitals in Oxfordshire, UK, from January to October 2020. Associations between infectious SARS-CoV-2 individuals and infection risk were quantified using logistic, generalised additive and linear mixed models. Cases were classified as community- or hospital-acquired using likely incubation periods. Results: Nine-hundred and twenty of 66184 patients who were hospitalised during the study period had a positive SARS-CoV-2 PCR test within the same period (1%). Out of these, 571 patients had their first positive PCR tests while hospitalised (62%), and 97 of these occurred at least seven days after admission (11%). Amongst the 5596 healthcare workers, 615 (11%) tested positive during the study period using PCR or serological tests. For susceptible patients, one day in the same ward with another patient with hospital-acquired SARS-CoV-2 was associated with an additional eight infections per 1000 susceptible patients (95%CrI 6-10). Exposure to an infectious patient with community-acquired COVID-19 or to an infectious healthcare worker was associated with substantially lower infection risks (2/1000 susceptible patients/day, 95%CrI 1-2). As for healthcare worker infections, exposure to an infectious patient with hospital-acquired SARS-CoV-2 or to an infectious healthcare worker were both associated with an additional one infection per 1000 susceptible healthcare workers per day (95%CrI 1-2). Exposure to an infectious patient with community-acquired SARS-CoV-2 was associated with half this risk (0.5/1000 susceptible healthcare workers/day, 95%CrI 0.3-0.7). Interpretation: Exposure to patients with hospital-acquired SARS-CoV-2 poses a substantial infection risk. Infection control measures to limit nosocomial transmission must be optimised to protect both staff and patients from SARS-CoV-2 infection. Funding: National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Oxford University in partnership with Public Health England (PHE) (NIHR200915). Medical Research Council, Nosocomial transmission of SARS-CoV-2 (MR/V028456/1).

There is significant international interest in heterologous prime-boost COVID-19 vaccination to mitigate against supply shocks or shortages that might otherwise reduce the speed of vaccine roll-out. Additionally, in light of changing recommendations regarding use of the ChAdOx1 nCoV-19 (ChAd) COVID-19 vaccine (Vaxzevria, AstraZeneca), several countries are now advising that individuals previously primed with this vaccine should now receive an alternative vaccine as their second dose, most commonly mRNA vaccines such as the BNT162b2 (BNT) COVID-19 vaccine (Comirnaty, Pfizer-BioNTech), administered in a heterologous prime-boost schedule.

We conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using naso-/oro-pharyngeal PCR testing and immunoassays for IgG antibodies. 1128/10,034 (11.2%) staff had evidence of Covid-19 at some time. Using questionnaire data provided on potential risk-factors, staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.82 [95%CI 3.45–6.72]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (22.6% vs. 8.6% elsewhere) (aOR 2.47 [1.99–3.08]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.52 [1.07–2.16]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit staff were relatively protected (0.44 [0.28–0.69]), likely by a bundle of PPE-related measures. Positive results were more likely in Black (1.66 [1.25–2.21]) and Asian (1.51 [1.28–1.77]) staff, independent of role or working location, and in porters and cleaners (2.06 [1.34–3.15]).

AbstractBackgroundPersonal protective equipment (PPE) and social distancing are designed to mitigate risk of occupational SARS-CoV-2 infection in hospitals. Why healthcare workers nevertheless remain at increased risk is uncertain.MethodsWe conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using nasopharyngeal PCR testing and immunoassays for IgG antibodies. A positive result by either modality determined a composite outcome. Risk-factors for Covid-19 were investigated using multivariable logistic regression.Results1083/9809(11.0%) staff had evidence of Covid-19 at some time and provided data on potential risk-factors. Staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.63 [95%CI 3.30-6.50]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (21.2% vs. 8.2% elsewhere) (aOR 2.49 [2.00-3.12]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.50 [1.05-2.15]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit (ICU) staff were relatively protected (0.46 [0.29-0.72]). Positive results were more likely in Black (1.61 [1.20-2.16]) and Asian (1.58 [1.34-1.86]) staff, independent of role or working location, and in porters and cleaners (1.93 [1.25-2.97]). Contact tracing around asymptomatic staff did not lead to enhanced case identification. 24% of staff/patients remained PCR-positive at ≥6 weeks post-diagnosis.ConclusionsIncreased Covid-19 risk was seen in acute medicine, among Black and Asian staff, and porters and cleaners. A bundle of PPE-related interventions protected staff in ICU.