Emerging variants develop total escape from potent monoclonal antibodies induced by BA.4/5 infection (preprint)

The rapid evolution of SARS-CoV-2 is driven in part by a need to evade the antibody response in the face of herd immunity. Here, we isolate spike binding monoclonal antibodies (mAbs) from vaccinees who suffered vaccine break-through infections with Omicron sub lineages BA.4 or BA.5. 28 potent antibodies were isolated and characterised functionally, and in some cases structurally. Since the emergence of BA.4/5 SARS-CoV-2 has continued to accrue mutations in the S protein, to understand this we characterize neutralization of a large panel of variants and demonstrate a steady attrition of neutralization by the panel of BA.4/5 mAbs culminating in total loss of function with recent XBB.1.5.70 variants containing the so-called ‘FLip’mutations at positions 455 and 456. Interestingly, activity of some mAbs is regained on the recently reported variant BA.2.86.

Isolation of a pair of potent broadly neutralizing mAb binding to RBD and SD1 domains of SARS-CoV-2 (preprint)

Commercially developed monoclonal antibodies (mAb) have been effective in the prevention or treatment of SARS-CoV-2 infection1-3 but the rapid antigenic evolution of the Omicron sub-lineages has reduced their activity4-8 and they are no longer licensed for use in many countries. Here, we isolate spike binding monoclonal antibodies from vaccinees who suffered vaccine break-through infections with Omicron sublineages BA.4/5. We find that it is possible for antibodies targeting highly mutated regions to recover broad activity through allosteric effects (mAb BA.4/5-35) and characterise a pair of potent mAbs with extremely broad neutralization against current and historical SARS-CoV-2 variants. One, mAb BA.4/5-2, binds at the back of the left shoulder of the receptor binding domain (RBD) in an area which has resisted mutational change to date. The second, mAb BA.4/5-5, binds a conserved epitope in sub-domain 1 (SD1). The isolation of this pair of antibodies with non-overlapping epitopes shows that potent and extremely broadly neutralizing antibodies are still generated following infection and SD1 directed mAbs may increase the resilience of mAb therapeutics/prophylactics against SARS-CoV-2.

Variations in classroom ventilation during the COVID-19 pandemic: Insights from monitoring 36 naturally ventilated classrooms in the UK during 2021

Seasonal changes in the measured CO2 levels at four schools are herein presented through a set of indoor air quality metrics that were gathered during the height of the COVID-19 pandemic in the UK. Data from non-intrusive environmental monitoring units were remotely collected throughout 2021 from 36 naturally ventilated classrooms at two primary schools and two secondary schools in England. Measurements were analysed to assess the indoor CO2 concentration and temperature . Relative to UK school air quality guidance, the CO2 levels within classrooms remained relatively low during periods of warmer weather, with elevated CO2 levels being evident during the colder seasons, indicating lower levels of per person ventilation during these colder periods. However, CO2 data from the cold period during the latter part of 2021, imply that the per person classroom ventilation levels were significantly lower than those achieved during a similarly cold weather period during the early part of the year. Given that the classroom architecture and usage remained unchanged, this finding suggests that changes in the ventilation behaviours within the classrooms may have altered, and raises questions as to what may have given rise to such change, in a year when, messaging and public concerns regarding COVID-19 varied within the UK. Significant variations were observed when contrasting data, both between schools, and between classrooms within the same school building;suggesting that work is required to understand and catalogue the existing ventilation provisions and architecture within UK classrooms, and that more work is required to ascertain the effects of classroom ventilation behaviours.

Racial differences in vaccine acceptance in a rural southern US state (preprint)

Introduction: To assess vaccine acceptance among adults living in a largely rural Southern state. Methods: Data were collected between October 3 and October 17, 2020 using random digit dialing. Participants included residents aged 18+, able to understand English or Spanish, and provide informed consent. The primary outcome was a multi-dimensional COVID-19 vaccine acceptance measure. Scores varied between -3 to +3. Results: The sample (n=1,164) was weighted to be representative of the state's population. Black participants had the lowest overall vaccine acceptance (0.5) compared to White participants (1.2). Hispanic participants had the highest scores (1.4). In adjusted models, Black participants had 0.81 points lower acceptance than White participants, and Hispanic participants had 0.35 points higher acceptance. Hispanic participants had the highest scores for all five vaccine acceptance dimensions, relatively equivalent to White participants. Black participants had consistently lower scores, especially perceived vaccine safety (mean -0.2, SD 0.1). Conclusions: The lowest vaccine acceptance rates were among Black participants particularly on perceived vaccine safety. While Black participants had the lowest acceptance scores, Hispanic participants had the highest. This variability shows the value of a multi-dimensional vaccine acceptance measure to inform COVID-19 vaccination campaign strategies.

Bebtelovimab, alone or together with bamlanivimab and etesevimab, as a broadly neutralizing monoclonal antibody treatment for mild to moderate, ambulatory COVID-19 (preprint)

BACKGROUND: Bebtelovimab is a potent, fully human IgG1 monoclonal antibody (mAb) targeting the S-protein of SARS-CoV-2, with broad neutralizing activity to all currently known SARS-CoV-2 variants of concern, including omicron variant lineages. Specialized developmental approaches accelerated the initiation of a clinical trial designed to evaluate the efficacy and safety of bebtelovimab alone (BEB) or together with bamlanivimab (BAM) and etesevimab (ETE) delivered via slow intravenous push for the treatment of mild-to-moderate COVID-19. METHODS: This portion of the phase 2, BLAZE-4 trial (J2X-MC-PYAH; NCT04634409) enrolled 714 patients (between May and July 2021) with mild-to-moderate COVID-19 within 3 days ([≤]3 days) of laboratory diagnosis of SARS-CoV-2 infection. Patients at low risk for severe COVID-19 were randomized 1:1:1 (double-blinded) to placebo, BEB 175 mg, or BEB 175 mg+BAM 700 mg+ETE 1400 mg (BEB+BAM+ETE). Patients at high risk for progression to severe COVID-19 were randomized 2:1 (open-label) to BEB or BEB+BAM+ETE, and a subsequent treatment arm enrolled patients to BEB+BAM+ETE using Centers for Disease Control and Prevention (CDC) updated criteria for High-risk. All treatments were administered intravenously over [≥]30 seconds (open-label BEB) or [≥]6.5 minutes (all other treatment arms). For the placebo-controlled patients (termed Low-risk), the primary endpoint was the proportion of patients with persistently high viral load (PHVL) (log viral load >5.27) on Day 7. For the open-label patients (termed High-risk), the primary endpoint was safety. In nonclinical studies, SARS-CoV-2 isolates were tested using an endpoint neutralization assay to measure BEB's inhibitory concentration greater than 99% (IC99). RESULTS: Baseline viral sequencing data were available from 611 patients; 90.2% (n=551) aligned with a variant of interest or concern (WHO designation), with the majority infected with delta (49.8%) or alpha (28.6%) variants. Among the Low-risk patients, PHVL occurred in 19.8% of patients treated with placebo, as compared to 12.7% (p=0.132) of patients treated with BEB+BAM+ETE and 12.0% (p=0.097) of patients treated with BEB, a 36% and 40% relative risk reduction, respectively. Viral load-area under the curve analysis from baseline to Day 11 showed statistically signficant reductions for patients treated with BEB (p=0.006) and BEB+BAM+ETE (p=0.043) compared to patients who received placebo. Time to sustained symptom resolution was reduced by a median of 2 days for patients treated with BEB (6 days; p=0.003) and 1 day for patients treated with BEB+BAM+ETE (7 days; p=0.289) compared to placebo (8 days). The incidence of COVID-19-related hospitalization or all-cause deaths by day 29 were similar across treatment arms, as expected given the patients' risk status (the Low risk cohorts had a Low risk of hospitalization, and High risk cohorts received only active therapy without placebo). Overall, safety results were consistent with previous studies investigating mAbs targeting SARS-CoV-2. The proportion of patients with treatment emergent adverse events (AEs) were 9.7% in Low-risk (n=37/380) and 14.7% in High-risk (n=48/326) patients treated with BEB or BEB+BAM+ETE; majority of AEs were considered mild or moderate in severity. Serious AEs were reported in 2.1% of High-risk patients (n=7/326), including one death (a cerebrovascular accident); 1 serious AE was reported among Low-risk patients. In an in vitro neutralization assay, BEB neutralized the omicron isolate (BA.1) with <2.44ng/ml estimated IC99. CONCLUSIONS: In patients with mild-to-moderate COVID-19, treatment with BEB or BEB+BAM+ETE was associated with greater viral clearance, a reduction in time to sustained symptom resolution, and safety results consistent with mAbs that target SARS-CoV-2. Integration of clinical findings with in vitro neutralization of emerging viral variants offered a pragmatic framework for investigating the efficacy of a new antiviral mAb agent, as demonstrated by bebtelovimab.

‘It’s second best’: mixed-methods evaluation of the experiences of people with musculoskeletal pain towards physiotherapist delivered telehealth during COVID-19 pandemic

IntroductionTelehealth was rapidly adopted in musculoskeletal physiotherapy practice during the COVID-19 pandemic, providing a unique opportunity to evaluate the experiences and attitudes of people would not usually engage with these services.Materials and MethodsA sequential mixed-methods study recruited people with musculoskeletal pain conditions accessing private practice physiotherapist services in Australia. Participants completed an online survey of telehealth services accessed, treatments, self-reported global change in condition, and attitudes toward telehealth. A subset of survey participants completed semi-structured interviews to explore experiences and attitudes towards telehealth. Data was summarized descriptively (quantitative), analyzed using inductive thematic analysis (qualitative), and integrated facilitating deeper understanding.Results172 participants responded to the survey and 19 were interviewed. 95% accessed video-based telehealth, typically via zoom;and 85% reported improvement in their condition. 84% agreed it was an efficient use of time, 75% agreed it was financially viable, and 73% agreed their condition was accurately diagnosed. 62% percent believed telehealth should be less expensive than face-to-face services. Qualitative analysis revealed four themes (17 subthemes), including (i) value of telehealth;(ii) challenges;(iii) advantages;and (iv) use of technology to support patient experience.ConclusionAustralians with musculoskeletal pain conditions accessing physiotherapy via telehealth during the COVID-19 pandemic felt this care was valuable, although less so than traditional face-to-face care. Key challenges included the perception that lack of physical contact prevented accurate assessment, diagnosis and ‘hands on’ treatment, and requirements for technology to facilitate a quality service. Advantages included access to expert care and convenience.

Temporal Variations in Seroprevalence of SARS-CoV-2 Infections by Race and Ethnicity in Arkansas. (preprint)

Objective: Our objective is to estimate CoV-2 infection rates in a rural state using seroprevalence of antibodies to CoV-2 as an indicator of infection. Study Design and Setting: This is a single-site study within an academic center and regional programs within the state of Arkansas. We obtained residual serum samples from a convenience sample of adults who were outpatients and came to the hospital or regional clinic for non-COVID-related reasons. We collected remnant in three time periods (August 15 to September 5, September 12 to October 24, and November 7 to December 19). Results: In 2020, the overall age, gender, and race standardized prevalence of CoV-2 antibodies was 2.6% (August to September), 4.1% (September to October), and 7.4% (November to December). There was no difference in seroprevalence between urban compared to rural areas. Positive tests were not uniformly distributed across racial and ethnic minorities. Higher seroprevalence rates were found in Hispanics and Blacks or African Americans compared to whites across all time periods. Conclusions: In a state with a large rural population, 2.6-7.4% of people experienced CoV-2 infection by December 2020. Blacks and Hispanics had disproportionately higher rates of CoV-2 infections than whites.