REACTOGENICITY AMONG PEOPLE LIVING WITH HIV AFTER mRNA-1273 VACCINE IN UBUNTU STUDY

Background: The tolerability of mRNA COVID-19 vaccines among people living with HIV (PLWH) has been understudied in vaccine trials. CoVPN 3008 (Ubuntu) is the largest multicenter Phase 3 efficacy trial of mRNA vaccines in sub-Saharan Africa. Method(s): We enrolled adults age >=18 years living with HIV or another comorbidity associated with severe COVID-19. Previously vaccinated individuals were excluded. Baseline testing included HIV, CD4 count and HIV viral load (VL) (if HIV+), anti-SARS-CoV-2 antibodies, and nasal swab SARS-CoV-2 nucleic acid amplification test (NAAT). All participants receive vaccinations at months 0 and 6, and SARS-CoV-2 seronegative individuals also receive vaccination at month 1. This analysis includes mRNA-1273 vaccinations at months 0 and 1. Reactogenicity (solicited adverse events [AEs]) was assessed among a representative subset of participants (Safety Subset, SS) for 7 days post-vaccination. Baseline characteristics associated with moderate/severe reactogenicity events were assessed by univariate and multivariate logistic regression. Result(s): 14002 participants were enrolled in the trial (1510 into the SS) at 46 sites from 2 Dec 2021 to 9 Sep 2022. At baseline in the SS, 71% (1065) were female, median age 38 years (IQR 32-46), and median BMI 25.0 (IQR 20.7-30.2). 73% (1108) were SARS-CoV-2 seropositive, and 8.7% (131) had a positive nasal NAAT swab. 16% (197) had a history of tuberculosis. 84% (1267) were PLWH, with median CD4 count of 614 cells/muL (IQR 414-861);7.8% had CD4 count < 200. 21% (238) had detectable HIV VL (>=50 copies/mL), with median VL 1660 (IQR 182-23932). 14% (172/1262) and 12% (64/542) of PLWH reported moderate/severe reactogenicity after the 1st and 2nd vaccination (Figure), with no hospitalizations. Female PLWH and CD4 count >500 had 35% (p=0.03) and 44% (p=0.04) increased odds of moderate/severe reactogenicity, respectively. Other baseline characteristics were not associated with the odds of reporting moderate/severe reactogenicity among PLWH after 1st vaccination. Similar trends were seen after the 2nd vaccination, but none reached statistical significance. In multivariate models, female sex remained associated with increased odds of moderate/severe reactogenicity after the 2nd vaccination. Conclusion(s): Similar to observations in HIV-negative populations, mRNA-1273 was well tolerated by PLWH with more reactogenicity in females. Impaired inflammatory responses among participants with CD4 counts < 500 cell/muL may explain less moderate/severe reactions.

NK CELLS ARE CRITICAL FOR IN VIVO CONTROL OF SARS-CoV-2 REPLICATION AND DISEASE

Background: Natural killer (NK) cells play a critical role in control of viral infections. However, empirical evidence thus far has been unclear on the role of NK cells in pathogenesis and control of SARS-CoV-2 infection with some research suggesting NK cell accumulation as beneficial while others indicate it as deleterious. To address this crucial deficit in understanding, we employed a non-human primate infection model with a validated experimental NK cell depletion technique. Method(s): A total of 12 experimentally naive (75% female) cynomolgus macaques (CM) of Cambodian origin were used in this study. Six CM were NK cell-depleted using an anti-IL-15 neutralizing antibody, while six controls received placebo, prior to intranasal and intratracheal challenge with the SARS-CoV-2 Delta variant at a TCID50 of 1X105. The cohort was monitored for five weeks with scheduled blood, colorectal (CR) biopsies, and lymph node (LN) collections. Total envelope and sub-genomic viral loads (VL) were measured in the nasal cavity, throat, and bronchoalveolar lavage (BAL). 23-color flow cytometry, pathology, and 27-plex inflammatory analyte Luminex analyses were conducted. Statistical tests used were Mann-Whitney U and Spearman's Correlation. Result(s): Control CM exhibited an increase in the frequency of circulating NK cells, reaching a peak at 10 days post-infection (DPI) and returning to baseline by 22DPI. Simultaneously, NK cells expressing activation and tissue retention marker, CD69, also significantly increased. Cytotoxic NK cells were positively associated with VL (r=0.66;p=0.02), suggestive of a virus-induced mobilization. Total experimental NK cell ablation was verified in blood, CR, and LN of NK celldepleted CM, which had higher VL compared to controls in all tissues evaluated, reaching significance at 10DPI (p=0.01) and demonstrated a longer duration of viremia. Although Luminex measures were similar in plasma, BAL samples from NK cell-depleted CM had universally higher concentrations of inflammatory mediators, most notably a 25-fold higher concentration of IFN-alpha compared to controls. Lung pathology scores were also higher in NK cell-depleted CM with increased evidence of fibrosis, syncytia, pneumocyte hyperplasia, and endothelialitis. Conclusion(s): Overall, we find significant and conclusive evidence for NK cell-mediated control of SARS-CoV-2 virus replication and disease pathology. These data suggest adjunct therapies for infection could largely benefit from NK cell-targeted approaches.

COVID-19 and drinking water security in rural, remote and indigenous communities: the role of collaboration among diverse actors in responding to a global pandemic. (Special Issue: COVID-19 and rural Canada: rural impacts and resilience.)

Many rural and remote Indigenous and non-Indigenous communities in Canada lack access to clean, safe drinking water due to inadequate drinking water infrastructure, among other challenges. The case of Newfoundland and Labrador (NL) highlights that water security and water infrastructure challenges can be exacerbated by a pandemic. We examine the impacts of the COVID-19 global pandemic on diverse communities in NL that rely on Potable Water Dispensing Units (PWDUs) as key elements of their drinking water systems, finding that the unique capacities of communities with PWDUs resulted in a spectrum of responses and abilities to adapt. Of the concerns and challenges mentioned, the most common included: evolving guidance and resources;limited capacity to adapt to new guidelines and procedures;COVID-19 related barriers affecting training and construction;and, added stress for local jurisdictions to maintain/provide services. Through a collaborative analysis of communities' experiences, we conclude that there is a need for a more coordinated and tailored response to effectively support rural and remote communities during a pandemic. Such a response would include a place-specific approach that leverages local, regional, and provincial capacities. In particular, a community-specific understanding of preferred communications mechanisms and content is required. Additionally, sharing knowledge and resources in advance of an emergency situation, such as a pandemic, will be critical for more informed and nimble response in the case of future crises. The diverse experiences and responses of communities in NL with PWDU, along with that of other governing agencies and organizations, illustrate that collaboration across multiple actor groups and jurisdictions are key to addressing drinking water challenges in times of crisis. As a result, this research concludes that the capacity of rural and remote communities to provide clean safe drinking water, during a pandemic and beyond, is strengthened when various levels of governments and organizations (Indigenous and non-Indigenous) with drinking water-related responsibilities adopt a collaborative multi-level governance approach that facilitates connections across diverse actors within the water governance system.

The End of the World, for Whom? or, Whose World? Whose Ending? An Afrofuturist and Afropessimist Counter Perspective on Climate Apocalypse

If we don't want to face that reality of the billions of apocalypses both gone and current, and instead choose half measures that will take carbon from the air but leave the world a shattered and unequal place. then do we even deserve this precious planet? For many fearing climate change apocalypse, they fear their lives changing forever, their access to natural wonders canceled, their children's economic futures uncertain, their sacrifices of comfort and convenience in vain due to petty partisan politics. [...]the world has already ended several times. Perhaps that is a large part of the problem at hand: we need to learn how to radically reimagine the world that's possible.

Upper Limb Function in Survivors of COVID-19 Requiring Mechanical Ventilation

Rationale Upper limb dysfunction is well recognised in survivors of intensive care (Gustafson et al Crit Care Med 2018;46:1769-1774). A mainstay of respiratory support through the COVID-19 pandemic has been use of repeated patient prone positioning to improve ventilation. Potential complications reported with prone positioning of sedated patients include brachial plexopathy, shoulder subluxation and peripheral nerve injury. We hypothesised that there would be a high prevalence of upper limb dysfunction, disability and pain in survivors of COVID-19 requiring mechanical ventilation, particularly in those who were prone positioned. Methods Eligible patients were laboratory-confirmed swab positive for SARS-CoV-2, mechanically ventilated for a minimum of 72 hours on the Royal Brompton Hospital Adult Intensive Care Units. We measured handgrip strength (HGS), normalised for age and sex, the Disability of Arm Shoulder Hand (DASH) questionnaire (Beaton et al J Hand Ther 2001;14:128-146) and Upper limb Pain Numerical Rating Scale (from 0-10). Health related quality of life was measured using the EuroQol-5 dimensions 5-level (EQ5D5L Utility Index (UI) and Visual Analogue Score (VAS)). Patients were stratified according to whether they received prone positioning or not. Results Twenty-seven consecutive patients were assessed at mean 45 days after hospital discharge. Baseline demographics, admission characteristics, and follow-up upper limb assessment data are shown in Table 1. There was evidence of upper limb weakness (mean (SD) right HGS: 44.77(19.31) %predicted;left HGS 47.69 (18.41) %predicted), with 63% showing upper limb dysfunction (DASH ≥ 16) and 33% showing severe upper limb dysfunction (DASH ≥40). Median (IQR) pain scores were 4 (0.75-6.25) with 53% reporting severe pain (≥ 5). DASH correlated significantly with EQ5D5L UI and VAS (r=-0.69 and r=-0.73 respectively;both p<0.001). No significant differences in upper limb parameters were seen between patients who did or did not receive prone positioning.