Interim results from a phase I randomized, placebo-controlled trial of novel SARS-CoV-2 beta variant receptor-binding domain recombinant protein and mRNA vaccines as a 4th dose booster.

BACKGROUND: SARS-CoV-2 booster vaccination should ideally enhance protection against variants and minimise immune imprinting. This Phase I trial evaluated two vaccines targeting SARS-CoV-2 beta-variant receptor-binding domain (RBD): a recombinant dimeric RBD-human IgG1 Fc-fusion protein, and an mRNA encoding a membrane-anchored RBD. METHODS: 76 healthy adults aged 18-64 y, previously triple vaccinated with licensed SARS-CoV-2 vaccines, were randomised to receive a 4th dose of either an adjuvanted (MF59®, CSL Seqirus) protein vaccine (5, 15 or 45 µg, N = 32), mRNA vaccine (10, 20, or 50 µg, N = 32), or placebo (saline, N = 12) at least 90 days after a 3rd boost vaccination or SARS-CoV-2 infection. Bleeds occurred on days 1 (prior to vaccination), 8, and 29. CLINICALTRIALS: govNCT05272605. FINDINGS: No vaccine-related serious or medically-attended adverse events occurred. The protein vaccine reactogenicity was mild, whereas the mRNA vaccine was moderately reactogenic at higher dose levels. Best anti-RBD antibody responses resulted from the higher doses of each vaccine. A similar pattern was seen with live virus neutralisation and surrogate, and pseudovirus neutralisation assays. Breadth of immune response was demonstrated against BA.5 and more recent omicron subvariants (XBB, XBB.1.5 and BQ.1.1). Binding antibody titres for both vaccines were comparable to those of a licensed bivalent mRNA vaccine. Both vaccines enhanced CD4+ and CD8+ T cell activation. INTERPRETATION: There were no safety concerns and the reactogenicity profile was mild and similar to licensed SARS-CoV-2 vaccines. Both vaccines showed strong immune boosting against beta, ancestral and omicron strains. FUNDING: Australian Government Medical Research Future Fund, and philanthropies Jack Ma Foundation and IFM investors.

l-Isoleucine-Schiff Base Copper(II) Coordination Polymers: Crystal Structure, Spectroscopic, Hirshfeld Surface, and DFT Analyses.

A new copper(II) coordination polymer was synthesized from the l-isoleucine-Schiff base and characterized by elemental analysis, Fourier transform infrared (FT-IR) spectroscopy, ultraviolet-visible (UV-vis) spectroscopy, single-crystal X-ray diffraction (XRD) analysis, electronic paramagnetic resonance, and thermogravimetric analysis. XRD analysis confirmed the square planar coordination geometry of metallic centers and a zipper-like polymer structure. Vibrational, electronic, and paramagnetic spectroscopies and thermal analysis were consistent with the crystal structure. A Hirshfeld surface (HS) and density functional theory (DFT) analyses were employed to gain additional insight into interactions responsible for complex packing. The quantitative examination of two-dimensional (2D) fingerprint plots revealed, among other van der Waals forces, the dominating participation of H···H and H···Cl interactions in the molecular packing. The use of computational methods provided great help in detailing the supramolecular interactions occurring in the crystal, which were mainly van der Waals attractions. The electronic transition analysis helped corroborate the electronic transitions observed experimentally in the absorption spectrum. The frequency and vibrational mode analysis gave a deeper insight into the characterization of the CuLCL complex.

SARS-CoV-2 mouse adaptation selects virulence mutations that cause TNF-driven age-dependent severe disease with human correlates.

The diversity of COVID-19 disease in otherwise healthy people, from seemingly asymptomatic infection to severe life-threatening disease, is not clearly understood. We passaged a naturally occurring near-ancestral SARS-CoV-2 variant, capable of infecting wild-type mice, and identified viral genomic mutations coinciding with the acquisition of severe disease in young adult mice and lethality in aged animals. Transcriptomic analysis of lung tissues from mice with severe disease elucidated a host antiviral response dominated mainly by interferon and IL-6 pathway activation in young mice, while in aged animals, a fatal outcome was dominated by TNF and TGF-ß signaling. Congruent with our pathway analysis, we showed that young TNF-deficient mice had mild disease compared to controls and aged TNF-deficient animals were more likely to survive infection. Emerging clinical correlates of disease are consistent with our preclinical studies, and our model may provide value in defining aberrant host responses that are causative of severe COVID-19.

Unethical behaviour in the military: The role of supervisor ethicality, ethical climate, and right-wing authoritarianism.

Using an anonymous self-report survey of 350 Canadian Armed Forces (CAF) personnel, this study investigated the effect of perceptions of the ethicality of one's immediate supervisor (supervisor ethics), right-wing authoritarianism (RWA), and ethical climate on self-reported unethical behavior in the form of discrimination and obeying an unlawful command (past behavior, behavioral intentions). As well, we investigated how supervisor ethics and RWA interact when predicting unethical behavior, and whether ethical climate mediated the relation between supervisor ethics and self-reported unethical behavior. Unethical behavior depended on perceptions of the ethicality of one's supervisor and RWA. RWA predicted discrimination toward a gay man (behavioral intentions), and supervisor ethics predicted discrimination against outgroups of people, and obedience of an unlawful command (past behavior). As well, the effects of ethical supervision on discrimination (past behavior, behavioral intentions) depended on participants' level of RWA . Finally, ethical climate mediated the relation between supervisor ethics and obeying an unlawful command, such that higher perceptions of supervisor ethics led to a higher ethical climate, which led to less obedience of an unlawful command in the past. This suggests that leaders can affect the ethical climate of on organization, which in turn affects ethical behavior of followers.

Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine.

BACKGROUND: The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage and transport, waning vaccine-induced immunity, and concerns about infrequent adverse events associated with existing vaccines. METHODS: We report on a protein subunit vaccine comprising the receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein, dimerised with an immunoglobulin IgG1 Fc domain. These were tested in conjunction with three different adjuvants: a TLR2 agonist R4-Pam2Cys, an NKT cell agonist glycolipid α-Galactosylceramide, or MF59® squalene oil-in-water adjuvant, using mice, rats and hamsters. We also developed an RBD-human IgG1 Fc vaccine with an RBD sequence of the immuno-evasive beta variant (N501Y, E484K, K417N). These vaccines were also tested as a heterologous third dose booster in mice, following priming with whole spike vaccine. FINDINGS: Each formulation of the RBD-Fc vaccines drove strong neutralising antibody (nAb) responses and provided durable and highly protective immunity against lower and upper airway infection in mouse models of COVID-19. The 'beta variant' RBD vaccine, combined with MF59® adjuvant, induced strong protection in mice against the beta strain as well as the ancestral strain. Furthermore, when used as a heterologous third dose booster, the RBD-Fc vaccines combined with MF59® increased titres of nAb against other variants including alpha, delta, delta+, gamma, lambda, mu, and omicron BA.1, BA.2 and BA.5. INTERPRETATION: These results demonstrated that an RBD-Fc protein subunit/MF59® adjuvanted vaccine can induce high levels of broadly reactive nAbs, including when used as a booster following prior immunisation of mice with whole ancestral-strain spike vaccines. This vaccine platform offers a potential approach to augment some of the currently approved vaccines in the face of emerging variants of concern, and it has now entered a phase I clinical trial. FUNDING: This work was supported by grants from the Medical Research Future Fund (MRFF) (2005846), The Jack Ma Foundation, National Health and Medical Research Council of Australia (NHMRC; 1113293) and Singapore National Medical Research Council (MOH-COVID19RF-003). Individual researchers were supported by an NHMRC Senior Principal Research Fellowship (1117766), NHMRC Investigator Awards (2008913 and 1173871), Australian Research Council Discovery Early Career Research Award (ARC DECRA; DE210100705) and philanthropic awards from IFM investors and the A2 Milk Company.

Grading disorder severity and averted burden by access to treatment within the GBD framework: a case study with anxiety disorders.

BACKGROUND: The Global Burden of Disease Study (GBD) estimates burden by cause with major relevance for resource allocators globally. Non-fatal burden estimates are influenced by disorder severity. However, for many disorders, global severity is sourced from a single high-income country survey. We aimed to estimate severity distributions that vary by Healthcare Access Quality Index (HAQI) using anxiety disorders as a case study and present the usefulness of this method in simulating averted and avoidable burden globally. METHODS: In this case study, we estimated treatment use among respondents with anxiety disorder in the 1997 Australian National Survey of Mental Health and Wellbeing (NSMHWB), the source used to estimate severity of anxiety disorders in GBD. Treatment effects were sourced from the Cochrane Database of Systematic Reviews and pooled via network meta-analysis. Severity distribution was established via a meta-regression of their disability weights, derived from 12-item short form survey scores. We simulated the shift in severity across scenarios without access to treatment and with full access to optimal treatment (cognitive behavioural therapy and antidepressants). We interpolated this shift linearly along the HAQI, extrapolated country-specific severity from HAQI scores, and calculated averted and avoidable burden. FINDINGS: The database review sourced 56 reviews, of which eight were eligible for inclusion. These eight reviews reported on 156 randomised controlled trials, with 194 treatment effects. Respondents to the 1997 NSMHWB consisted of 5936 women (55·8%) and 4705 (44·2%) men aged 18 years or older (mean age and ethnicity data not available). The survey-weighted treatment effect size was -0·28 (95% uncertainty interval -0·45 to -0·12). The pooled treatment effect for full coverage optimal treatment was -1·07 (-1·47 to -0·64). The sequela-weighted disability weight among people with anxiety disorder in the NSMHWB was 0·141 (0·042 to 0·275). The estimated disability weight was 0·188 (0·070 to 0·341) after removing the benefits of treatment and 0·056 (0·013 to 0·140) after providing all people with anxiety disorder access to optimal treatment. Globally, 12·5% (4·6 to 21·5) of anxiety disorder burden was averted because of available treatment. However, 71·1% (46·2 to 87·6) of global anxiety disorder burden could be averted if all people with anxiety disorders had access to optimal treatment. INTERPRETATION: Because it is based on guidance from a single survey done in one high-income country, the burden of anxiety disorders in low-income and middle-income countries is probably underestimated by GBD. Despite the availability of effective treatments, low use of these treatments means that most burden is still avoidable. Most of the burden could be averted if all people with anxiety disorders had access to optimal treatment, highlighting the importance of public promotion and referral pathways of treatment for anxiety disorders. Location-specific severity distributions in GBD would greatly increase precision in burden estimates and highlight avertable burden to clinicians, public health practitioners, and policy makers. FUNDING: Queensland Health and Bill & Melinda Gates Foundation.

Evolutionary rate of SARS-CoV-2 increases during zoonotic infection of farmed mink.

To investigate genetic signatures of adaptation to the mink host, we characterised the evolutionary rate heterogeneity in mink-associated severe acute respiratory syndrome coronaviruses (SARS-CoV-2). In 2020, the first detected anthropozoonotic spillover event of SARS-CoV-2 occurred in mink farms throughout Europe and North America. Both spill-back of mink-associated lineages into the human population and the spread into the surrounding wildlife were reported, highlighting the potential formation of a zoonotic reservoir. Our findings suggest that the evolutionary rate of SARS-CoV-2 underwent an episodic increase upon introduction into the mink host before returning to the normal range observed in humans. Furthermore, SARS-CoV-2 lineages could have circulated in the mink population for a month before detection, and during this period, evolutionary rate estimates were between 3 × 10-3 and 1.05 × 10-2 (95 per cent HPD, with a mean rate of 6.59 × 10-3) a four- to thirteen-fold increase compared to that in humans. As there is evidence for unique mutational patterns within mink-associated lineages, we explored the emergence of four mink-specific Spike protein amino acid substitutions Y453F, S1147L, F486L, and Q314K. We found that mutation Y453F emerged early in multiple mink outbreaks and that mutations F486L and Q314K may co-occur. We suggest that SARS-CoV-2 undergoes a brief, but considerable, increase in evolutionary rate in response to greater selective pressures during species jumps, which may lead to the occurrence of mink-specific mutations. These findings emphasise the necessity of ongoing surveillance of zoonotic SARS-CoV-2 infections in the future.

Diagnostic accuracy of the Composite International Diagnostic Interview (CIDI 3.0) in an urban Indigenous Australian sample.

OBJECTIVE: The Composite International Diagnostic Interview 3.0 is a standardised diagnostic interview commonly used in population-based mental health surveys, but has not been used in community-residing Indigenous Australians. This paper seeks to determine whether the Composite International Diagnostic Interview 3.0 can produce valid diagnostic information when compared with a diagnostic interview in an urban Indigenous Australian sample. METHOD: This research was conducted over 10 weeks with adult Indigenous clients of two participating Aboriginal Medical Services in South-East Queensland. Using a cross-sectional, repeated-measures design, participants were administered the Composite International Diagnostic Interview 3.0 by an Indigenous interviewer and within 2 weeks attended a second appointment with an Indigenous clinical psychologist, who produced a diagnostic summary. The Composite International Diagnostic Interview 3.0 diagnoses were compared with the diagnostic summaries and clinical concordance between the two measures was calculated. RESULTS: The diagnostic accuracy of the Composite International Diagnostic Interview 3.0 differed by module. The Post-traumatic Stress Disorder and Major Depression modules had good utility in diagnosing post-traumatic stress disorder and major depressive episodes, respectively; however, the Mania module that provides diagnoses of bipolar disorder was found to be unsuitable for this population. Although there were no identified contraindications for the use of the Generalised Anxiety and Alcohol Use Disorder modules, further research on the diagnostic accuracy of these modules is warranted. CONCLUSIONS: The Composite International Diagnostic Interview 3.0 can accurately diagnose some common mental disorders in an Indigenous Australian population, but was found to be unsuitable for others. Given these findings, care should be taken when using the Composite International Diagnostic Interview 3.0 in epidemiological prevalence studies with Indigenous Australian populations.

Unsupervised machine-learning algorithms for the identification of clinical phenotypes in the osteoarthritis initiative database.

OBJECTIVES: Osteoarthritis (OA) is a complex disease comprising diverse underlying patho-mechanisms. To enable the development of effective therapies, segmentation of the heterogenous patient population is critical. This study aimed at identifying such patient clusters using two different machine learning algorithms. METHODS: Using the progression and incident cohorts of the Osteoarthritis Initiative (OAI) dataset, deep embedded clustering (DEC) and multiple factor analysis with clustering (MFAC) approaches, including 157 input-variables at baseline, were employed to differentiate specific patient profiles. RESULTS: DEC resulted in 5 and MFAC in 3 distinct patient phenotypes. Both identified a "comorbid" cluster with higher body mass index (BMI), relevant burden of comorbidity and low levels of physical activity. Both methods also identified a younger and physically more active cluster and an elderly cluster with functional limitations, but low disease impact. The additional two clusters identified with DEC were subgroups of the young/physically active and the elderly/physically inactive clusters. Overall pain trajectories over 9 years were stable, only the numeric rating scale (NRS) for pain showed distinct increase, while physical activity decreased in all clusters. Clusters showed different (though non-significant) trajectories of joint space changes over the follow-up period of 8 years. CONCLUSION: Two different clustering approaches yielded similar patient allocations primarily separating complex "comorbid" patients from healthier subjects, the latter divided in young/physically active vs elderly/physically inactive subjects. The observed association to clinical (pain/physical activity) and structural progression could be helpful for early trial design as strategy to enrich for patients who may specifically benefit from disease-modifying treatments.

Heparin Inhibits SARS-CoV-2 Replication in Human Nasal Epithelial Cells.

SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Vaccination, supported by social and public health measures, has proven efficacious for reducing disease severity and virus spread. However, the emergence of highly transmissible viral variants that escape prior immunity highlights the need for additional mitigation approaches. Heparin binds the SARS-CoV-2 spike protein and can inhibit virus entry and replication in susceptible human cell lines and bronchial epithelial cells. Primary infection predominantly occurs via the nasal epithelium, but the nasal cell biology of SARS-CoV-2 is not well studied. We hypothesized that prophylactic intranasal administration of heparin may provide strain-agnostic protection for household contacts or those in high-risk settings against SARS-CoV-2 infection. Therefore, we investigated the ability of heparin to inhibit SARS-CoV-2 infection and replication in differentiated human nasal epithelial cells and showed that prolonged exposure to heparin inhibits virus infection. Furthermore, we establish a method for PCR detection of SARS-CoV-2 viral genomes in heparin-treated samples that can be adapted for the detection of viruses in clinical studies.

Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2.

The development of therapeutics to prevent or treat COVID-19 remains an area of intense focus. Protein biologics, including monoclonal antibodies and nanobodies that neutralize virus, have potential for the treatment of active disease. Here, we have used yeast display of a synthetic nanobody library to isolate nanobodies that bind the receptor-binding domain (RBD) of SARS-CoV-2 and neutralize the virus. We show that combining two clones with distinct binding epitopes within the RBD into a single protein construct to generate biparatopic reagents dramatically enhances their neutralizing capacity. Furthermore, the biparatopic nanobodies exhibit enhanced control over clinically relevant RBD variants that escaped recognition by the individual nanobodies. Structural analysis of biparatopic binding to spike (S) protein revealed a unique binding mode whereby the two nanobody paratopes bridge RBDs encoded by distinct S trimers. Accordingly, biparatopic nanobodies offer a way to rapidly generate powerful viral neutralizers with enhanced ability to control viral escape mutants.

The Burden of Proof studies: assessing the evidence of risk.

Exposure to risks throughout life results in a wide variety of outcomes. Objectively judging the relative impact of these risks on personal and population health is fundamental to individual survival and societal prosperity. Existing mechanisms to quantify and rank the magnitude of these myriad effects and the uncertainty in their estimation are largely subjective, leaving room for interpretation that can fuel academic controversy and add to confusion when communicating risk. We present a new suite of meta-analyses-termed the Burden of Proof studies-designed specifically to help evaluate these methodological issues objectively and quantitatively. Through this data-driven approach that complements existing systems, including GRADE and Cochrane Reviews, we aim to aggregate evidence across multiple studies and enable a quantitative comparison of risk-outcome pairs. We introduce the burden of proof risk function (BPRF), which estimates the level of risk closest to the null hypothesis that is consistent with available data. Here we illustrate the BPRF methodology for the evaluation of four exemplar risk-outcome pairs: smoking and lung cancer, systolic blood pressure and ischemic heart disease, vegetable consumption and ischemic heart disease, and unprocessed red meat consumption and ischemic heart disease. The strength of evidence for each relationship is assessed by computing and summarizing the BPRF, and then translating the summary to a simple star rating. The Burden of Proof methodology provides a consistent way to understand, evaluate and summarize evidence of risk across different risk-outcome pairs, and informs risk analysis conducted as part of the Global Burden of Diseases, Injuries, and Risk Factors Study.

The contribution of general medical conditions to the non-fatal burden of mental disorders: register-based cohort study in Denmark.

BACKGROUND: General medical conditions (GMCs) often co-occur with mental and substance use disorders (MSDs). AIMS: To explore the contribution of GMCs to the burden of disease in people with MSDs, and investigate how this varied by age. METHOD: A population-based cohort of 6 988 507 persons living in Denmark during 2000-2015 followed for up to 16 years. Danish health registers were used to identify people with MSDs and GMCs. For each MSD, years lived with disability and health loss proportion (HeLP) were estimated for comorbid MSDs and GMCs, using a multiplicative model for disability weights. RESULTS: Those with any MSD lost the equivalent of 43% of healthy life (HeLP = 0.43, 95% CI 0.40-0.44) after including information on GMCs, which was an increase from 25% before including GMCs (HeLP = 0.25, 95% CI 0.23-0.27). Schizophrenia was associated with the highest burden of disease (HeLP = 0.77, 95% CI 0.68-0.85). However, within each disorder, the relative contribution of MSDs and GMCs varied. For example, in those diagnosed with schizophrenia, MSDs and GMCs accounted for 86% and 14% of the total health loss; in contrast, in those with anxiety disorders, the same proportions were 59% and 41%. In general, HeLP increased with age, and was mainly associated with increasing rates of pulmonary, musculoskeletal and circulatory diseases. CONCLUSIONS: In those with mental disorders, the relative contribution of comorbid GMCs to the non-fatal burden of disease increases with age. GMCs contribute substantially to the non-fatal burden of disease in those with MSDs.

Electrospun Cellulose Acetate Membranes Coated with Polypyrrole and Their Potential Application in the Recovery of Metals.

The purpose of this paper is to study the effect of polypyrrole (PPy) on cellulose acetate (CA) membranes prepared by the electrospinning technique (controlled variables) in the recovery of gold complexes of aqueous solutions that are environmentally ecofriendly. CA-PPy membranes were characterized by SEM, EDS, FTIR spectroscopy, contact angle measurements, electrical conductivity, and mechanical tests. They were submerged in two aqueous solutions using two gold complexes, AuI2 - and AuBr4 -, at room temperature. The recovery percentage was evaluated for several hours using the atomic adsorption technique for both complexes. The main findings indicate that the percentage of recovery in the first hours of the test was very high (>80%). The adsorption efficiency maxima were similar for both complexes (91%). The Langmuir model suggests the formation of a monolayer on the surface. The electrical conductivity did not change over time, and the mechanical properties indicate reuse in several experiments. Furthermore, the theoretical analysis showed that the system is helpful at acidic pH, funding its minimum energy. It is shown in this study that the used CA-PPy membranes show adsorption, absorption, and reusable properties with the effective recovery of the complexes in the first hours. These membranes could substitute for materials that are not environmentally ecofriendly.

Surface Inactivation of Highly Mutated SARS-CoV-2 Variants of Concern: Alpha, Delta, and Omicron.

Continued SARS-CoV-2 transmission among the human population has meant the evolution of the virus to produce variants of increased infectiousness and virulence, coined variants of concern (VOCs). The last wave of pandemic infections was driven predominantly by the delta VOC, but because of continued transmission and adaptive mutations, the more highly transmissible omicron variant emerged and is now dominant. However, due to waning immunity and emergence of new variants, vaccines alone cannot control the pandemic. The application of an antiviral coating to high-touch surfaces and physical barriers such as masks are an effective means to inactivate the virus and their spread. Here, we demonstrate an environmentally friendly water-borne polymer coating that can completely inactivate SARS-CoV-2 independent of the infectious variant. The polymer was designed to target the highly glycosylated spike protein on the virion surface and inactivate the virion by disruption of the viral membrane through a nano-mechanical process. Our findings show that, even with low amounts of coating on the surface (1 g/m2), inactivation of alpha, delta, and omicron VOCs and degradation of their viral genome were complete. Furthermore, our data shows that the polymer induces little to no skin sensitization in mice and is non-toxic upon oral ingestion in rats. We anticipate that our transparent polymer coating can be applied to face masks and many other surfaces to capture and inactivate the virus, aiding in the reduction of SARS-CoV-2 transmission and evolution of new variants of concern.

Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine

The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage and transport, waning vaccine-induced immunity, and concerns about infrequent adverse events associated with existing vaccines. Here, we report on a protein subunit vaccine comprising the receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein, dimerised with an immunoglobulin IgG1 Fc domain. These were tested in conjunction with three different adjuvants: a TLR2 agonist R4-Pam2Cys, an NKT cell agonist glycolipid -Galactosylceramide, or MF59(R) squalene oil-in-water adjuvant. Each formulation drove strong neutralising antibody (nAb) responses and provided durable and highly protective immunity against lower and upper airway infection in mouse models of COVID-19. We have also developed an RBD-human IgG1 Fc vaccine with an RBD sequence of the highly immuno-evasive beta variant (N501Y, E484K, K417N). This beta variant RBD vaccine, combined with MF59(R) adjuvant, induced strong protection in mice against the beta strain as well as the ancestral strain. Furthermore, when used as a third dose booster vaccine following priming with whole spike vaccine, anti-sera from beta-RBD-Fc immunised mice increased titres of nAb against other variants including alpha, delta, delta+, gamma, lambda, mu, and omicron BA.1 and BA.2. These results demonstrated that an RBD-Fc protein subunit/MF59(R) adjuvanted vaccine can induce high levels of broad nAbs, including when used as a booster following prior immunisation of mice with whole ancestral-strain Spike vaccines. This vaccine platform offers a potential approach to augment some of the currently approved vaccines in the face of emerging variants of concern, and it has now entered a phase I clinical trial.

Nonhuman primate models for evaluation of SARS-CoV-2 vaccines.

INTRODUCTION: Evaluation of immunogenicity and efficacy in animal models provide critical data in vaccine development. Nonhuman primates (NHPs) have been used extensively in the evaluation of SARS-CoV-2 vaccines. AREAS COVERED: A critical synthesis of SARS-CoV-2 vaccine development with a focus on challenge studies in NHPs is provided. The benefits and drawbacks of the NHP models are discussed. The citations were selected by the authors based on PubMed searches of the literature, summaries from national public health bodies, and press-release information provided by vaccine developers. EXPERT OPINION: We identify several aspects of NHP models that limit their usefulness for vaccine-challenge studies and numerous variables that constrain comparisons across vaccine platforms. We propose that studies conducted in NHPs for vaccine development should use a standardized protocol and, where possible, be substituted with smaller animal models. This will ensure continued rapid progression of vaccines to clinical trials without compromising assessments of safety or efficacy.

Broad and ultra-potent cross-clade neutralization of HIV-1 by a vaccine-induced CD4 binding site bovine antibody.

Human immunodeficiency virus type 1 (HIV-1) vaccination of cows has elicited broadly neutralizing antibodies (bNAbs). In this study, monoclonal antibodies (mAbs) are isolated from a clade A (KNH1144 and BG505) vaccinated cow using a heterologous clade B antigen (AD8). CD4 binding site (CD4bs) bNAb (MEL-1872) is more potent than a majority of CD4bs bNAbs isolated so far. MEL-1872 mAb with CDRH3 of 57 amino acids shows more potency (geometric mean half-maximal inhibitory concentration [IC50]: 0.009 µg/mL; breadth: 66%) than VRC01 against clade B viruses (29-fold) and than CHO1-31 against tested clade A viruses (21-fold). It also shows more breadth and potency than NC-Cow1, the only other reported anti-HIV-1 bovine bNAb, which has 60% breadth with geometric mean IC50 of 0.090 µg/mL in this study. Using successive different stable-structured SOSIP trimers in bovines can elicit bNAbs focusing on epitopes ubiquitous across subtypes. Furthermore, the cross-clade selection strategy also results in ultra-potent bNAbs.

Detection of Chimeric Cellular: HIV mRNAs Generated Through Aberrant Splicing in HIV-1 Latently Infected Resting CD4+ T Cells.

Latent HIV-1 provirus in infected individuals on suppressive therapy does not always remain transcriptionally silent. Both HIV-1 LTR and human gene promoter derived transcriptional events can contribute HIV-1 sequences to the mRNA produced in the cell. In addition, chimeric cellular:HIV mRNA can arise through readthrough transcription and aberrant splicing. Using target enrichment coupled to the Illumina Mi-Seq and PacBio RS II platforms, we show that 3' LTR activation is frequent in latently infected cells from both the CCL19-induced primary cell model of HIV-1 latency as well as ex vivo samples. In both systems of latent HIV-1 infection, we detected several chimeric species that were generated via activation of a cryptic splice donor site in the 5' LTR of HIV-1. Aberrant splicing involving the major HIV-1 splice donor sites, SD1 and SD4 disrupts post-transcriptional processing of the gene in which HIV-1 is integrated. In the primary cell model of HIV-1 latency, Tat-encoding sequences are incorporated into the chimeric mRNA transcripts through the use of SD4. Our study unravels clues to the characteristics of HIV-1 integrants that promote formation of chimeric cellular:HIV mRNA and improves the understanding of the HIV-1 RNA footprint in latently infected cells.

The Efficacy of Common Household Cleaning Agents for SARS-CoV-2 Infection Control.

The COVID-19 pandemic caused by SARS-CoV-2 is having devastating effects on a global scale. Since common household disinfectants are often used to minimise the risk of infection in the home and work environment, we investigated the ability of some of these products to inactivate the virus. We tested generic brands of vinegar, bleach, and dishwashing detergent, as well as laboratory-grade acetic acid, sodium hypochlorite, and ethanol. Assays were conducted at room temperature (18-20 °C, 40% relative humidity), and two time points were used to reflect a quick wipe (30 s) and a brief soak (5 min). Vinegar, and its active ingredient, acetic acid, were completely ineffective at virus inactivation even when exposed to the virus at 90% v/v (a final concentration equivalent to 3.6% v/v acetic acid). In contrast, ethanol was capable of inactivating the virus at dilutions as low as 40% v/v. Dishwashing detergent effectively rendered SARS-CoV-2 inactive when diluted 100-fold (1% v/v). Bleach was found to be fully effective against SARS-CoV-2 at 0.21 g/L sodium hypochlorite after a 30 s exposure (1/200 dilution of commercial product). Given reports of infectious virus recovered from the surface of frozen packaging, we tested the persistence of infectiousness after multiple freeze-thaw cycles and found no change in infectious SARS-CoV-2 titre after seven freeze-thaw cycles. These results should help inform readers of how to effectively disinfect surfaces and objects that have potentially been contaminated with SARS-CoV-2 using common household chemicals.