Scaling up a brief alcohol intervention to prevent HIV infection in Vietnam: a cluster randomized, implementation trial.

BACKGROUND: Evidence-based interventions (EBIs) often address normative behaviors. If a behavior is also common among clinicians, they may be skeptical about the necessity or effectiveness of an EBI. Alternatively, clinicians' attitudes and behaviors may be misaligned, or they may lack the knowledge and self-efficacy to deliver the EBI. Several EBIs address unhealthy alcohol use, a common and often culturally acceptable behavior. But unhealthy alcohol use may be particularly harmful to people with HIV (PWH). Here, we present an implementation trial using an experiential implementation strategy to address clinicians' knowledge, attitudes, and behaviors. Clinicians receive the experiential intervention before they begin delivering an evidence-based brief alcohol intervention (BAI) to PWH with unhealthy alcohol use. METHODS: Design: In this hybrid type 3 implementation-effectiveness cluster randomized controlled trial, ART clinics (n = 30) will be randomized 1:1 to facilitation, a flexible strategy to address implementation barriers, or facilitation plus the experiential brief alcohol intervention (EBAI). In the EBAI arm, clinicians, irrespective of their alcohol use, will be offered the BAI as experiential learning. EBAI will address clinicians' alcohol-related attitudes and behaviors and increase their knowledge and confidence to deliver the BAI. PARTICIPANTS: ART clinic staff will be enrolled and assessed at pre-BAI training, post-BAI training, 3, 12, and 24 months. All PWH at the ART clinics who screen positive for unhealthy alcohol use will be offered the BAI. A subset of PWH (n = 810) will be enrolled and assessed at baseline, 3, and 12 months. OUTCOMES: We will compare implementation outcomes (acceptability, fidelity, penetration, costs, and sustainability) and effectiveness outcomes (viral suppression and alcohol use) between the two arms. We will assess the impact of site-level characteristics on scaling-up the BAI. We will also evaluate how experiencing the BAI affected clinical staff's alcohol use and clinic-level alcohol expectations in the EBAI arm. DISCUSSION: This trial contributes to implementation science by testing a novel strategy to implement a behavior change intervention in a setting in which clinicians themselves may engage in the behavior. Experiential learning may be useful to address normative and difficult to change lifestyle behaviors that contribute to chronic diseases. TRIAL REGISTRATION: NCT06358885 (04/10/2024), https://clinicaltrials.gov/study/NCT06358885 .

A sulfonate ligand-defected Zr-based metal-organic framework for the enhanced selective removal of anionic dyes.

In this work, we introduce a novel defective analogue of the representative 6-connected zirconium-based metal-organic framework (MOF-808), by employing 5-sulfoisophthalic acid monosodium salt (H2BTC-SO3Na) as a defect inducer via a mixed-linker approach. The structural integrity and different physicochemical properties were investigated by various characterization techniques, including powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and nitrogen physisorption at 77 K. Additionally, proton nuclear magnetic resonance (1H-NMR), energy-dispersive X-ray (EDX), and inductively coupled plasma optical emission spectroscopy (ICP-OES) were employed to confirm the presence of 6.9 mol% of the 5-sulfoisophthalate ligand within the highly crystalline MOF-808 structure. The defective material exhibited significant enhancements in the removal efficiency of various organic dyes, including approximately 64% and 77% for quinoline yellow and sunset yellow, and 56% and 13% for rhodamine B and malachite green, compared to its pristine counterpart. Importantly, the defective MOF-808 showed a remarkable selectivity toward anionic species in binary-component dyes comprising both anionic and cationic dyes.

Structure and design of Langya virus glycoprotein antigens.

Langya virus (LayV) is a recently discovered henipavirus (HNV), isolated from febrile patients in China. HNV entry into host cells is mediated by the attachment (G) and fusion (F) glycoproteins which are the main targets of neutralizing antibodies. We show here that the LayV F and G glycoproteins promote membrane fusion with human, mouse, and hamster target cells using a different, yet unknown, receptor than Nipah virus (NiV) and Hendra virus (HeV) and that NiV- and HeV-elicited monoclonal and polyclonal antibodies do not cross-react with LayV F and G. We determined cryoelectron microscopy structures of LayV F, in the prefusion and postfusion states, and of LayV G, revealing their conformational landscape and distinct antigenicity relative to NiV and HeV. We computationally designed stabilized LayV G constructs and demonstrate the generalizability of an HNV F prefusion-stabilization strategy. Our data will support the development of vaccines and therapeutics against LayV and closely related HNVs.

"Very" Very Late Stent Thrombosis: The Occurrence of Thrombosis 12.3 Years After Paclitaxel-Eluting Stent Implantation.

Very late stent thrombosis (VLST) refers to stent thrombosis occurring beyond one year after coronary intervention. "Very" very or extremely late stent thrombosis (VVLST), occurring after five years of drug-eluting stent (DES) implantation, is extremely rare. We report a case of a 60-year-old male patient with ST-elevation myocardial infarction (STEMI) due to in-stent thrombosis 12.3 years after first-generation DES implantation; we also engage in a brief discussion of its pathogenesis and prevention.

Synthesis of 2-benzyl benzoxazoles and benzothiazoles via elemental sulfur promoted cyclization of styrenes with 2-nitrophenols and N,N-dialkyl-3-nitroanilines.

Herein we report a method for affording 2-benzyl benzoxazoles from substituted styrenes and 2-nitrophenols. The success of this method relies on the use of simple reagents, namely elemental sulfur and DABCO. A combination of identical reagents was utilized for the annulation of styrenes with N,N-dialkyl-3-nitroanilines to afford 2-benzyl benzothiazoles. Overall, benzoxazoles and benzothiazoles bearing useful functionalities such as halogens, amines, and heterocyclic groups were isolated in moderate to good yields. Our methods are a rare example of divergent transformations of substituted nitroarenes towards 2-benzyl benzoxazoles and benzothiazoles.

Efficacy and safety of long-acting cabotegravir compared with daily oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV infection in cisgender men and transgender women who have sex with men 1 year after study unblinding: a secondary analysis of the phase 2b and 3 HPTN 083 randomised controlled trial.

BACKGROUND: Injectable cabotegravir was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine for HIV prevention in two clinical trials. Both trials had the primary aim of establishing the HIV prevention efficacy of long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) compared with tenofovir disoproxil fumarate plus emtricitabine daily oral PrEP. Long-acting PrEP was associated with diagnostic delays and integrase strand-transfer inhibitor (INSTI) resistance. This report presents findings from the first unblinded year of the HIV Prevention Trials Network (HPTN) 083 study. METHODS: The HPTN 083 randomised controlled trial enrolled HIV-uninfected cisgender men and transgender women at elevated HIV risk who have sex with men, from 43 clinical research sites in Africa, Asia, Latin America, and the USA. Inclusion criteria included: a negative HIV serological test at the screening and study entry, undetectable HIV RNA levels within 14 days of study entry, age 18 years or older, overall good health as determined by clinical and laboratory evaluations, and a creatinine clearance of 60 mL/min or higher. Participants were randomly allocated to receive long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP. After study unblinding, participants remained on their original regimen awaiting an extension study. HIV infections were characterised retrospectively at a central laboratory. Here we report the secondary analysis of efficacy and safety for the first unblinded year. The primary outcome was incident HIV infection. Efficacy analyses were done on the modified intention-to-treat population using a Cox regression model. Adverse events were compared across treatment groups and time periods (blinded vs unblinded). This trial is registered with ClinicalTrials.gov, NCT02720094. FINDINGS: Of the 4488 participants who contributed person-time to the blinded analysis, 3290 contributed person-time to the first unblinded year analysis between May 15, 2020, and May 14, 2021. Updated HIV incidence in the blinded phase was 0·41 per 100 person-years for long-acting injectable cabotegravir PrEP and 1·29 per 100 person-years for daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP (hazard ratio [HR] 0·31 [95% CI 0·17-0·58], p=0·0003). HIV incidence in the first unblinded year was 0·82 per 100 person-years for long-acting PrEP and 2·27 per 100 person-years for daily oral PrEP (HR 0·35 [0·18-0·69], p=0·002). Adherence to both study products decreased after study unblinding. Additional infections in the long-acting PrEP group included two with on-time injections; three with one or more delayed injections; two detected with long-acting PrEP reinitiation; and 11 more than 6 months after their last injection. Infection within 6 months of cabotegravir exposure was associated with diagnostic delays and INSTI resistance. Adverse events were generally consistent with previous reports; incident hypertension in the long-acting PrEP group requires further investigation. INTERPRETATION: Long-acting injectable cabotegravir PrEP retained high efficacy for HIV prevention in men and transgender women who have sex with men during the first year of open-label follow-up, with a near-identical HR for HIV risk reduction between long-acting injectable cabotegravir and daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP during the first year after unblinding compared with the blinded period. Extended follow-up further defined the risk period for diagnostic delays and emergence of INSTI resistance. FUNDING: Division of AIDS at the National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and Gilead Sciences.

Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells.

High-grade serous ovarian cancer (HGSOC) is responsible for the majority of gynecology cancer-related deaths. Patients in remission often relapse with more aggressive forms of disease within 2 years post-treatment. Alternative immuno-oncology (IO) strategies, such as immune checkpoint blockade (ICB) targeting the PD-(L)1 signaling axis, have proven inefficient so far. Our aim is to utilize epigenetic modulators to maximize the benefit of personalized IO combinations in ex vivo 3D patient-derived platforms and in vivo syngeneic models. Using patient-derived tumor ascites, we optimized an ex vivo 3D screening platform (PDOTS), which employs autologous immune cells and circulating ascites-derived tumor cells, to rapidly test personalized IO combinations. Most importantly, patient responses to platinum chemotherapy and poly-ADP ribose polymerase inhibitors in 3D platforms recapitulate clinical responses. Furthermore, similar to clinical trial results, responses to ICB in PDOTS tend to be low and positively correlated with the frequency of CD3+ immune cells and EPCAM+/PD-L1+ tumor cells. Thus, the greatest response observed with anti-PD-1/anti-PD-L1 immunotherapy alone is seen in patient-derived HGSOC ascites, which present with high levels of systemic CD3+ and PD-L1+ expression in immune and tumor cells, respectively. In addition, priming with epigenetic adjuvants greatly potentiates ICB in ex vivo 3D testing platforms and in vivo tumor models. We further find that epigenetic priming induces increased tumor secretion of several key cytokines known to augment T and NK cell activation and cytotoxicity, including IL-6, IP-10 (CXCL10), KC (CXCL1), and RANTES (CCL5). Moreover, epigenetic priming alone and in combination with ICB immunotherapy in patient-derived PDOTS induces rapid upregulation of CD69, a reliable early activation of immune markers in both CD4+ and CD8+ T cells. Consequently, this functional precision medicine approach could rapidly identify personalized therapeutic combinations able to potentiate ICB, which is a great advantage, especially given the current clinical difficulty of testing a high number of potential combinations in patients.

Structure and design of Langya virus glycoprotein antigens.

Langya virus (LayV) is a recently discovered henipavirus (HNV), isolated from febrile patients in China. HNV entry into host cells is mediated by the attachment (G) and fusion (F) glycoproteins which are the main targets of neutralizing antibodies. We show here that the LayV F and G glycoproteins promote membrane fusion with human, mouse and hamster target cells using a different, yet unknown, receptor than NiV and HeV and that NiV- and HeV-elicited monoclonal and polyclonal antibodies do not cross-react with LayV F and G. We determined cryo-electron microscopy structures of LayV F, in the prefusion and postfusion states, and of LayV G, revealing previously unknown conformational landscapes and their distinct antigenicity relative to NiV and HeV. We computationally designed stabilized LayV G constructs and demonstrate the generalizability of an HNV F prefusion-stabilization strategy. Our data will support the development of vaccines and therapeutics against LayV and closely related HNVs.

Validation of the combined Patient Health Questionnaire Anxiety and Depression Scale among people with HIV in Vietnam.

BACKGROUND: Our study aims to examine the factor structure, validity, and reliability of the combined scale Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS) among people with HIV (PWH) in Vietnam. METHODS: Baseline data from an alcohol-reduction intervention trial among ART clients in Thai Nguyen, Vietnam were used for this analysis (n = 1547). A score ≥10 on the PHQ-9, GAD-7 and PHQ-ADS scale was considered having clinically meaningful depression, anxiety and distress symptoms. Factor structure of the combined PHQ-ADS scale was validated using confirmatory factor analysis, and three models were tested: a one-factor, a two-factor, and a bi-factor model. Reliability and construct validity were examined. RESULTS: The prevalence of clinically meaningful depression and anxiety symptoms was 7% and 2%, respectively, while 19% had distress symptoms. A bi-factor model had the best fit to the data (RMSEA = 0.048; CFI = 0.99; TLI = 0.98). The Omega index of the bi-factor model was 0.97. The scale showed good construct validity through negative associations between depression, anxiety, distress symptoms and quality of life. CONCLUSIONS: Our study supports the use of a combined scale to measure general distress for PWH, which has good validity, reliability and is unidimensional enough to justify the use of a composite depression and anxiety score.

A pan-influenza antibody inhibiting neuraminidase via receptor mimicry.

Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift1 and suboptimal immune responses2. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses.

A daily and complete PM2.5 dataset derived from space observations for Vietnam from 2012 to 2020.

PM2.5 pollution is a serious problem in Vietnam and around the world, having bad impacts on human health, animals and environment. Regular monitoring at a large scale is important to assess the status of air pollution, develop solutions and evaluate the effectiveness of policy implementation. However, air quality monitoring stations in Vietnam are limited. In this article, we propose an approach to estimate daily PM2.5 concentration from 2012 to 2020 over the Vietnamese territory, which is strongly affected by cloudy conditions, using a modern statistical model named Mixed Effect Model (MEM) on a dataset consisting of ground PM2.5 measurements, integrated satellite Aerosol Optical Depth (AOD), meteorological and land use maps. The result of this approach is the first long-term, full coverage and high quality PM2.5 dataset of Vietnam. The daily mean PM2.5 maps have high validation results in comparison with ground PM2.5 measurement (Pearson r of 0.87, R2 of 0.75, RMSE of 11.76 µg/m3, and MRE of 36.57 % on a total of 13,886 data samples). The aggregated monthly and annual average maps from 2012 to 2020 in Vietnam have outstanding quality when compared with another global PM2.5 product. The PM2.5 concentration maps has shown spatial distribution and seasonal variations of PM2.5 concentration in Vietnam in a long period from 2012 to 2020 and has been used in other studies and applications in the environment and public health at the national scale, which has not been possible before because of the lack of monitoring stations and an appropriate PM2.5 modeling approach.

Stigma experienced by people living with HIV who are on methadone maintenance treatment and have symptoms of common mental disorders in Hanoi, Vietnam: a qualitative study.

BACKGROUND: Stigma around human immunodeficiency virus (HIV), injection drug use (IDU), and mental health disorders can be co-occurring and have different impacts on the well-being of people living with HIV (PWH) who use drugs and have mental health disorders. This stigma can come from society, health professionals, and internalized stigma. A person who has more than one health condition can experience overlapping health-related stigma and levels of stigma which can prevent them from receiving necessary support and healthcare, serving to intensify their experience with stigma. This study investigates HIV, drug use, and mental health stigmas in three dimensions (social, internalized, and professional) around PWH on methadone maintenance treatment (MMT) who have common mental disorders (CMDs) including depression, anxiety, and stress-related disorders in Hanoi, Vietnam.Please check and confirm whether corresponding author's email id is correctly identified.The cooresponding author's email is correct METHODS: We conducted semi-structured, in-depth interviews (IDIs) (n = 21) and two focus group discussions (FGDs) (n = 10) with PWH receiving MMT who have CMD symptoms, their family members, clinic health care providers, and clinic directors. We applied thematic analysis using NVIVO software version 12.0, with themes based on IDI and FGD guides and emergent themes from interview transcripts. RESULTS: The study found evidence of different stigmas towards HIV, IDU, and CMDs from the community, family, health care providers, and participants themselves. Community and family members were physically and emotionally distant from patients due to societal stigma around illicit drug use and fears of acquiring HIV. Participants often conflated stigmas around drug use and HIV, referring to these stigmas interchangeably. The internalized stigma around having HIV and injecting drugs made PWH on MMT hesitant to seek support for CMDs. These stigmas compounded to negatively impact participants' health. CONCLUSIONS: Strategies to reduce stigma affecting PWH on MMT should concurrently address stigmas around HIV, drug addiction, and mental health. Future studies could explore approaches to address internalized stigma to improve self-esteem, mental health, and capacities to cope with stigma for PWH on MMT. TRIAL REGISTRATION: NCT04790201, available at clinicaltrials.gov.

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant-neutralizing antibody that is a strong candidate for clinical development.

Clinical Utility of Combined Whole-cell Antigen and Recombinant Hemolysis Co-regulated Protein 1-Enzyme-linked Immunosorbent Assays Reveals Underdiagnosed Cases of Melioidosis in Vietnam.

Melioidosis is a fatal infectious disease in the tropics and subtropics. Currently, bacterial culture is the gold standard for diagnosis of the disease, but its sensitivity is relatively low. In this study, we evaluated four ELISAs using sera collected from culture-confirmed cases of melioidosis (n = 63), cases with other bacterial infections (n = 62), and healthy donors (n = 60). Antigens used for ELISAs were the whole-cell (WC) antigens and recombinant proteins of hemolysis co-regulated protein 1 (Hcp1), GroEL1, and alkyl hydroperoxide reductase subunit C (AhpC). Using the cutoff values for optical density at 490 nm defined at a specificity of > 95%, the sensitivity of the WC, Hcp1, GroEL1, and AhpC ELISAs was 93.7%, 87.3%, 61.9%, and 57.1%, respectively. The combined WC/Hcp1 ELISA showed the greatest sensitivity and specificity of 98.4% and 95.1%, respectively. Of 511 and 500 sera collected from clinically suspected febrile patients admitted to the General Hospital of Ha Tinh Province and the Hue Central Hospital, respectively, combined WC/Hcp1 ELISAs showed 52 (10.2%) and 41 (8.2%) patients positive for melioidosis, respectively. The assay detected 14 of 14 (100%) and 21 of 23 (91.3%) culture-confirmed cases of melioidosis at Ha Tinh and Hue, respectively. A follow-up study of 38 patients positive for melioidosis by combined WC/Hcp1 ELISAs but negative for Burkholderia pseudomallei by culture method or not assigned to examine for bacterial culture resulted in 2 (5.3%) culture-reconfirmed patients with melioidosis, 9 (23.7%) deaths, 17 (44.7%) unhealthy patients, and 10 (26.3%) healthy persons. Combined WC/Hcp1 ELISA was a reliable serological method to detect underdiagnosed cases of melioidosis. Further investigations are needed to estimate the true sensitivity and specificity of the assay and the true number of cases of melioidosis.

Adaptation of a Problem-solving Program (Friendship Bench) to Treat Common Mental Disorders Among People Living With HIV and AIDS and on Methadone Maintenance Treatment in Vietnam: Formative Study.

BACKGROUND: The prevalence of common mental disorders (CMDs) among people living with HIV and people who inject drugs is high worldwide and in Vietnam. However, few evidence-informed CMD programs for people living with HIV who inject drugs have been adapted for use in Vietnam. We adapted the Friendship Bench (FB), a problem-solving therapy (PST)-based program that was successfully implemented among patients with CMDs in primary health settings in Zimbabwe and Malawi for use among people living with HIV on methadone maintenance treatment (MMT) with CMDs in Hanoi, Vietnam. OBJECTIVE: This study aimed to describe the adaptation process with a detailed presentation of 4 phases from the third (adaptation) to the sixth (integration) of the Assessment-Decision-Adaptation-Production-Topical Experts-Integration-Training-Testing (ADAPT-ITT) framework. METHODS: The adaptation phase followed a qualitative study design to explore symptoms of CMDs, facilitators, and barriers to conducting FB for people living with HIV on MMT in Vietnam, and patient, provider, and caretaker concerns about FB. In the production phase, we revised the original program manual and developed illustrated PST cases. In the topical expert and integration phases, 2 investigators (BNG and BWP) and 3 subject matter experts (RV, DC, and GML) reviewed the manual, with reviewer comments incorporated in the final, revised manual to be used in the training. The draft program will be used in the training and testing phases. RESULTS: The study was methodologically aligned with the ADAPT-ITT goals as we chose a proven, effective program for adaptation. Insights from the adaptation phase addressed the who, where, when, and how of FB program implementation in the MMT clinics. The ADAPT-ITT framework guided the appropriate adaptation of the program manual while maintaining the core components of the PST of the original program throughout counseling techniques in all program sessions. The deliverable of this study was an adapted FB manual to be used for training and piloting to make a final program manual. CONCLUSIONS: This study successfully illustrated the process of operationalizing the ADAPT-ITT framework to adapt a mental health program in Vietnam. This study selected and culturally adapted an evidence-informed PST program to improve CMDs among people living with HIV on MMT in Vietnam. This adapted program has the potential to effectively address CMDs among people living with HIV on MMT in Vietnam. TRIAL REGISTRATION: ClinicalTrials.gov NCT04790201; https://clinicaltrials.gov/ct2/show/NCT04790201.

Resilience of S309 and AZD7442 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron lineage strains.

Omicron variant strains encode large numbers of changes in the spike protein compared to historical SARS-CoV-2 isolates. Although in vitro studies have suggested that several monoclonal antibody therapies lose neutralizing activity against Omicron variants, the effects in vivo remain largely unknown. Here, we report on the protective efficacy against three SARS-CoV-2 Omicron lineage strains (BA.1, BA.1.1, and BA.2) of two monoclonal antibody therapeutics (S309 [Vir Biotechnology] monotherapy and AZD7442 [AstraZeneca] combination), which correspond to ones used to treat or prevent SARS-CoV-2 infections in humans. Despite losses in neutralization potency in cell culture, S309 or AZD7442 treatments reduced BA.1, BA.1.1, and BA.2 lung infection in susceptible mice that express human ACE2 (K18-hACE2) in prophylactic and therapeutic settings. Correlation analyses between in vitro neutralizing activity and reductions in viral burden in K18-hACE2 or human FcγR transgenic mice suggest that S309 and AZD7442 have different mechanisms of protection against Omicron variants, with S309 utilizing Fc effector function interactions and AZD7442 acting principally by direct neutralization. Our data in mice demonstrate the resilience of S309 and AZD7442 mAbs against emerging SARS-CoV-2 variant strains and provide insight into the relationship between loss of antibody neutralization potency and retained protection in vivo.

Omicron spike function and neutralizing activity elicited by a comprehensive panel of vaccines.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern comprises several sublineages, with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1 and with BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations leads to enhanced angiotensin-converting enzyme 2 (ACE2) binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.

Activation of Tumor-Cell STING Primes NK-Cell Therapy.

Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist-induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies.