Perceptual rivalry across animal species

This review in memoriam of Jack Pettigrew provides an overview of past and current research into the phenomenon of multistable perception across multiple animal species. Multistable perception is characterized by two or more perceptual interpretations spontaneously alternating, or rivaling, when animals are exposed to stimuli with inherent sensory ambiguity. There is a wide array of ambiguous stimuli across sensory modalities, ranging from the configural changes observed in simple line drawings, such as the famous Necker cube, to the alternating perception of entire visual scenes that can be instigated by interocular conflict. The latter phenomenon, called binocular rivalry, in particular caught the attention of the late Jack Pettigrew, who combined his interest in the neuronal basis of perception with a unique comparative biological approach that considered ambiguous sensation as a fundamental problem of sensory systems that has shaped the brain throughout evolution. Here, we examine the research findings on visual perceptual alternation and suppression in a wide variety of species including insects, fish, reptiles, and primates. We highlight several interesting commonalities across species and behavioral indicators of perceptual alternation. In addition, we show how the comparative approach provides new avenues for understanding how the brain suppresses opposing sensory signals and generates alternations in perceptual dominance.     

Enhanced normograms and pregnancy outcome analysis in nonhuman primate developmental toxicity studies

The incidence of spontaneous pregnancy/infant losses is highly variable in long-tailed macaques (cynomolgus monkey), making it potentially difficult to ascertain test item-related effects in developmental toxicity studies. Therefore, pregnancy normograms had been developed by Jarvis et al. [1] to aid in the distinction of normal (e.g. test facility background) versus non-normal pregnancy outcomes. These normograms were mostly derived from embryo-fetal development studies and from PPND studies with a postnatal phase limited to seven days. However, the enhanced pre- and postnatal developmental (ePPND) study paradigm has essentially replaced these former study types. This work aims at providing enhanced normograms (e-normograms) in the context of regulatory ePPND studies. Survival functions for the prenatal phase (286 control pregnancies) and the postnatal phase (222 live infants) were estimated using the Kaplan-Meier estimator. Normograms were generated from survival curves and pseudo-study simulations. Data were available from two test facilities with comparable EU-compliant animal husbandry. Pregnancy duration/outcome as well as survival functions did not differ significantly between test facilities indicating that this husbandry system yields comparable developmental observations across different test facilities, at least in this NHP species. These novel e-normograms were developed for pregnant long-tailed macaques and provide an extended postnatal period up to three months, a new concept of separate normograms for the prenatal and the postnatal period, specific information on the perinatal phase events, a prediction of expected number of live infants for group size management, and the option to evaluate effects on pregnancy duration through distinction of live births and infant losses.     

New immunosuppressive agents in transplantation

Immunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival.Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection.The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials.Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38…) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology.     

Assessment of Multiplate platelet aggregometry using citrate,heparin or hirudin in Rhesus macaques

Electrical impedance aggregometry (EIA) has gained popularity in clinical and research applications. Nonhuman primates are used to study disease and drug-related mechanisms that affect hemostasis, therefore establishing normal EIA parameters are necessary. The anticoagulants sodium heparin, hirudin and sodium citrate and three agonists, ADP, ASPI, and collagen were evaluated. Whole blood from 12 adult male rhesus macaques was collected to evaluate anticoagulants, sodium heparin, hirudin and sodium citrate using three agonists (ADP, ASPI and collagen), on the Multiplate® 5.0 Analyzer. Platelet function was reported for three parameters: Area under the curve (AUC), aggregation, and aggregation velocity. There was a significant difference in mean AUC between citrate and heparin samples, and citrate and hirudin samples regardless of the agonist used. There was no difference in AUC between heparin and hirudin. ADP-activated samples showed an increase in impedance with hirudin samples compared to citrate. Furthermore, heparin and hirudin out-perform citrate as the anticoagulant for EIA in the macaque. Finally, this study demonstrates the utility of the Multiplate® system in this model and provides important insight into anticoagulant choice when using EIA.     

Consensus summary report for CEPI/BC March 12–13, 2020 meeting: Assessment of risk of disease enhancement with COVID-19 vaccines

A novel coronavirus (CoV), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 in Wuhan, China and has since spread as a global pandemic. Safe and effective vaccines are thus urgently needed to reduce the significant morbidity and mortality of Coronavirus Disease 2019 (COVID-19) disease and ease the major economic impact. There has been an unprecedented rapid response by vaccine developers with now over one hundred vaccine candidates in development and at least six having reached clinical trials. However, a major challenge during rapid development is to avoid safety issues both by thoughtful vaccine design and by thorough evaluation in a timely manner. A syndrome of “disease enhancement” has been reported in the past for a few viral vaccines where those immunized suffered increased severity or death when they later encountered the virus or were found to have an increased frequency of infection. Animal models allowed scientists to determine the underlying mechanism for the former in the case of Respiratory syncytial virus (RSV) vaccine and have been utilized to design and screen new RSV vaccine candidates. Because some Middle East respiratory syndrome (MERS) and SARS-CoV-1 vaccines have shown evidence of disease enhancement in some animal models, this is a particular concern for SARS-CoV-2 vaccines. To address this challenge, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a scientific working meeting on March 12 and 13, 2020 of experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns and how animal models and immunological assessments in early clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for safety assessment of COVID-19 vaccine candidates in accelerated vaccine development.     

Development of an IgG-Fc fusion COVID-19 subunit vaccine,AKS-452

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.     

Autoradiographic mapping of synaptic vesicle glycoprotein 2A in non-human primate and human brain

Synaptic vesicle glycoprotein 2A (SV2A) has been previously characterized as an imaging biomarker for assessment of synaptic density in positron emission tomography (PET) studies of patients with neurological conditions. To provide detailed maps of the brain localization of SV2A autoradiography studies were carried out using the SV2A radioligand [¹¹C]UCB-J and whole hemisphere sections of non-human primate (NHP) and human brain. Binding of [¹¹C]UCB-J was observed in all evaluated grey matter structures of the primate brain, with highest density in the caudate nucleus and cortex and lowest density in pons and globus pallidus. The density of [¹¹C]UCB-J binding sites in human brain showed a good correlation with that in NHP brain. Binding of [¹¹C]UCB-J in the white matter was very low relative to that in grey matter containing structures and was only inhibited to a minor extent by co-incubation with a saturating concentration of unlabelled UCB-J. The high-resolution images obtained in the present study may aid the interpretation of data acquired in human subjects examined using [¹¹C]UCB-J in PET studies. In addition, observation of low binding for [¹¹C]UCB-J in white matter (centrum semiovale) supports that this structure can be used as a reference region for quantitative analysis of [¹¹C]UCB-J PET data.     

Evidence in primates supporting the use of chemogenetics for the treatment of human refractory neuropsychiatric disorders

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