First-in-Human Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Rapidly Developed SARS-CoV-2 Therapeutic Antibody, AOD01, in Healthy Adults.

Introduction: AOD01 is a novel, fully human immunoglobulin (Ig) G1 neutralizing monoclonal antibody that was developed as a therapeutic against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). This first-in-human study assessed safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of AOD01 in healthy volunteers.

Methods: Intravenous doses of AOD01 were evaluated in escalating cohorts [four single-dose cohorts (2, 5, 10, and 20 mg/kg) and one two-dose cohort (two doses of 20 mg/kg, 24 h apart)].

The IDentif.AI-x pandemic readiness platform: Rapid prioritization of optimized COVID-19 combination therapy regimens.

IDentif.AI-x, a clinically actionable artificial intelligence platform, was used to rapidly pinpoint and prioritize optimal combination therapies against COVID-19 by pairing a prospective, experimental validation of multi-drug efficacy on a SARS-CoV-2 live virus and Vero E6 assay with a quadratic optimization workflow. A starting pool of 12 candidate drugs developed in collaboration with a community of infectious disease clinicians was first narrowed down to a six-drug pool and then interrogated in 50 combination regimens at three dosing levels per drug, representing 729 possible combinations.

The Cellular Characterization of SARS-CoV-2 Spike Protein in Virus-Infected Cells Using the Receptor Binding Domain Binding Specific Human Monoclonal Antibodies.

A human monoclonal antibody panel (PD4, PD5, PD7, SC23, and SC29) was isolated from the B cells of convalescent patients and used to examine the S protein in SARS-CoV-2-infected cells. While all five antibodies bound conformational-specific epitopes within SARS-CoV-2 spike (S) protein, only PD5, PD7, and SC23 were able to bind to the receptor binding domain (RBD). Immunofluorescence microscopy was used to examine the S protein RBD in cells infected with the Singapore isolates SARS-CoV-2/0334 and SARS-CoV-2/1302.

Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by binding of the viral Spike protein to host receptor angiotensin-converting enzyme 2 (ACE2), followed by fusion of viral and host membranes. Although antibodies that block this interaction are in emergency use as early coronavirus disease 2019 (COVID-19) therapies, the precise determinants of neutralization potency remain unknown. We discovered a series of antibodies that potently block ACE2 binding but exhibit divergent neutralization efficacy against the live virus.

IDentif.AI: Rapidly optimizing combination therapy design against severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) with digital drug development.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to multiple drug repurposing clinical trials that have yielded largely uncertain outcomes. To overcome this challenge, we used IDentif.AI, a platform that pairs experimental validation with artificial intelligence (AI) and digital drug development to rapidly pinpoint unpredictable drug interactions and optimize infectious disease combination therapy design with clinically relevant dosages.

Bivalent binding of a fully human IgG to the SARS-CoV-2 spike proteins reveals mechanisms of potent neutralization.

antibody selection against pathogens from naïve combinatorial libraries can yield various classes of antigen-specific binders that are distinct from those evolved from natural infection. Also, rapid neutralizing antibody discovery can be made possible by a strategy that selects for those interfering with pathogen and host interaction. Here we report the discovery of antibodies that neutralize SARS-CoV-2, the virus responsible for the COVID-19 pandemic, from a highly diverse naïve human Fab library.

A System Based-Approach to Examine Host Response during Infection with Influenza A Virus Subtype H7N9 in Human and Avian Cells.

Although the influenza A virus H7N9 subtype circulates within several avian species, it can also infect humans with a severe disease outcome. To better understand the biology of the H7N9 virus we examined the host response to infection in avian and human cells. In this study we used the A/Anhui/1/2013 strain, which was isolated during the first wave of the H7N9 epidemic.

Nutritional therapies in the neonatal intensive care unit and post-natal growth outcomes of preterm very low birthweight Asian infants.

Aim: A collaborative study was conducted between two Southeast Asian university hospitals to compare the nutritional intervention and growth outcomes and evaluate the extent of post-natal growth faltering (PNGF) among very low birthweight (VLBW) infants.

Methods: Data of all infants admitted during the 2011-2012 period to the two hospitals at Singapore (SG) and Malaysia (MY) were pooled and analysed.

Results: Of the 236 infants, SG infants received lower total protein and energy intake than MY infants (2.

Genetic characterisation of influenza C viruses detected in Singapore in 2006.

In an earlier study on respiratory infections in Singapore military recruits, four influenza C virus (FLUCV) infections were detected out of the 1354 samples collected. All four isolates were detected in 2006, and their whole genome was completely sequenced and analysed. Phylogenetic analysis of the hemagglutinin esterase fusion (HEF) gene revealed that all four Singapore isolates belonged to the C/Japan-Kanagawa/1/76-related lineage.

Helping themselves: optimal virus-specific CD4 T cell responses require help via CD4 T cell licensing of dendritic cells.

Although CD4(+) T cell help (Th) is critical for inducing optimal B cell and CD8(+) T cell responses, it remains unclear whether induction of CD4(+) Th responses postinfection are also dependent on CD4(+) T cell help. In this study, we show that activation of adoptively transferred Th cells during primary influenza A virus (IAV) infection enhances both the magnitude and functional breadth of endogenous primary IAV-specific CD4(+) T cell responses. This enhancement was dependent on CD154-CD40-dependent dendritic cell licensing and resulted in a greater recall capacity of IAV-specific CD4(+) and CD8(+) T memory responses after heterologous IAV infection.

CD154+ CD4+ T-cell dependence for effective memory influenza virus-specific CD8+ T-cell responses.

CD40-CD154 (CD40 ligand) interactions are essential for the efficient priming of CD8(+) cytotoxic T lymphocyte (CTL) responses. This is typically via CD4(+)CD154(+) T-cell-dependent 'licensing' of CD40(+) dendritic cells (DCs); however, DCs infected with influenza A virus (IAV) upregulate CD154 expression, thus enabling efficient CTL priming in the absence of CD4(+) T activation. Therefore, it is unclear whether CD4 T cells and DCs have redundant or unique roles in the priming of primary and secondary CTL responses after infection.

Influenza-induced, helper-independent CD8+ T cell responses use CD40 costimulation at the late phase of the primary response.

The helper-dependent pathway of priming CD8(+) T cells involves "licensing" of DCs by CD40L on CD4(+) T cells. The helper-independent ("helpless") pathways elicited by many viruses, including influenza, are less widely understood. We have postulated that CD40L can be up-regulated on DCs by such viruses, and this promotes priming of CD8(+) T cells via CD40.

Unlike CD4+ T-cell help, CD28 costimulation is necessary for effective primary CD8+ T-cell influenza-specific immunity.

The importance of costimulation on CD4(+) T cells has been well documented. However, primary CTLs against many infections including influenza can be generated in the absence of CD4(+) T-cell help. The role of costimulation under such "helpless" circumstances is not fully elucidated.

GM-CSF increases cross-presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells.

Resident CD8(+) DCs perform several functions, including cross-presenting antigen and rapidly engulfing the Gram-positive intracellular pathogen Listeria monocytogenes. Little is known about how these functions of CD8(+) DCs are modulated. Here, we show that granulocyte-macrophage CSF (GM-CSF), a cytokine that exists at low levels at steady state but is elevated during infection and inflammation, enhances cross-presentation and rapid uptake of L.

Resident and monocyte-derived dendritic cells become dominant IL-12 producers under different conditions and signaling pathways.

IL-12 is such a pivotal cytokine that it has been called the third signal for T cell activation, TCR engagement being the first and costimulation being the second. It has been generally viewed that the resident CD8(+) dendritic cell (DC) subset is the predominant IL-12-producing cell type. In this study, we found, although this is so under steady state conditions, under inflammatory conditions monocyte-derived DC (mDC) became a major cell type producing IL-12.

Viral agents responsible for febrile respiratory illnesses among military recruits training in tropical Singapore.

Background: Military personnel are highly susceptible to febrile respiratory illnesses (FRI), likely due to crowding, stress and other risk factors present in the military environment.

Objective: Our objective was to investigate the viral etiological agents responsible for FRI among military recruits training in a tropical climate in Singapore.

Study Design: From March 2006 through April 2007, a total of 1354 oropharyngeal (throat) swabs were collected from military recruits who reported sick with an oral temperature of > or =38 degrees C and a cough and/or sore throat.

The incidence of human bocavirus infection among children admitted to hospital in Singapore.

Human bocavirus (HBoV) is a parvovirus, belonging to the genus Bocavirus. The virus was identified recently in Sweden, and has now been detected in several different countries. Although it is associated with lower respiratory tract infections in pediatric patients, the incidence of HBoV infection in a developed country in South East Asia, has not been examined.

Responses against complex antigens in various models of CD4 T-cell deficiency: surprises from an anti-CD4 antibody transgenic mouse.

The most common models of CD4 T-cell deficiency are mice exogenously injected with anti-CD4 antibody (Ab), CD4 knockout (CD4-/-) and major histocompatibility complex (MHC) class II knockout (class II-/-) mice. We recently described the anti-CD4 Ab transgenic mouse (GK) as an improved CD4 cell-deficient model. This review compares this new GK mouse model with the widely available class II-/- and CD4-/- mice, when exposed to complex antigens (foreign grafts and during bacterial or viral infection).

Diagnostic value of real-time capillary thermal cycler in virus detection.

Molecular-based detection methods such as PCR techniques have had a significant impact on the diagnosis of viral infections because of their superior sensitivity and rapid turnaround time. This review describes the use of real-time PCR on the capillary thermal cycler, the Roche LightCycler trade mark, for early disease detection in diagnostic virology. The advantages of using the LightCycler, the detection processes using SYBR Green I and different hybridization strategies will be discussed in detail, with specific examples drawn from our in-house viral assays.