Bacterial-derived sialidases inhibit porcine rotavirus OSU replication by interfering with the early steps of infection.

Rotavirus infections in suckling and weaning piglets cause severe dehydration and death, resulting in significant economic losses in the pig breeding industry. With the continuous emergence of porcine rotavirus (PoRV) variants and poor vaccine cross-protection among various genotypes, there is an urgent need to develop alternative strategies such as seeking effective antiviral products from nature, microbial metabolites and virus-host protein interaction. Sialidases play a crucial role in various physiopathological processes and offer a promising target for developing antivirus drugs. However, the effect of bacterial-derived sialidases on the infection of PoRVs remains largely unknown. Herein, we investigated the impact of bacterial-derived sialidases (sialidase Cp and Vc) on PoRV strain OSU(Group A) infection, using differentiated epithelial monkey kidney cells (MA104) as a model. Our results indicated that the pretreatment of MA104 with exogenous sialidases effectively suppressed PoRV OSU in a concentration-dependent manner. Notably, even at a concentration of 0.01 µU/mL, sialidases significantly inhibited the virus (MOI = 0.01). Meanwhile, we found that sialidase Vc pretreatment sharply reduced the binding rate of PoRV OSU. Last, we demonstrated that PoRV OSU might recognize α-2,3-linked sialic acid as the primary attachment factor in MA104. Our findings provide new insights into the underlying mechanism of PoRV OSU infections, shedding lights on the development of alternative antivirus approaches based on bacteria-virus interaction.

More than the Infinite Monkey Theorem: NHP Models in the Development of a Pediatric HIV Cure.

PURPOSE OF REVIEW: An HIV cure that eliminates the viral reservoir or provides viral control without antiretroviral therapy (ART) is an urgent need in children as they face unique challenges, including lifelong ART adherence and the deleterious effects of chronic immune activation. This review highlights the importance of nonhuman primate (NHP) models in developing an HIV cure for children as these models recapitulate the viral pathogenesis and persistence. RECENT FINDINGS: Several cure approaches have been explored in infant NHPs, although knowledge gaps remain. Broadly neutralizing antibodies (bNAbs) show promise for controlling viremia and delaying viral rebound after ART interruption but face administration challenges. Adeno-associated virus (AAV) vectors hold the potential for sustained bNAb expression. Therapeutic vaccination induces immune responses against simian retroviruses but has yet to impact the viral reservoir. Combining immunotherapies with latency reversal agents (LRAs) that enhance viral antigen expression should be explored. Current and future cure approaches will require adaptation for the pediatric immune system and unique features of virus persistence, for which NHP models are fundamental to assess their efficacy.

Building a Predictive PBPK Model for Human OATP Substrates: a Strategic Framework for Early Evaluation of Clinical Pharmacokinetic Variations Using Pitavastatin as an Example.

To select a drug candidate for clinical development, accurately and promptly predicting human pharmacokinetic (PK) profiles, assessing drug-drug interactions (DDIs), and anticipating potential PK variations in disease populations are crucial steps in drug discovery. The complexity of predicting human PK significantly increases when hepatic transporters are involved in drug clearance (CL) and volume of distribution (Vss). A strategic framework is developed here, utilizing pitavastatin as an example. The framework includes the construction of a monkey physiologically-based PK (PBPK) model, model calibration to obtain scaling factors (SF) of in vitro-in vivo extrapolation (IVIVE) for various clearance parameters, human model development and validation, and assessment of DDIs and PK variations in disease populations. Through incorporating in vitro human parameters and calibrated SFs from the monkey model of 3.45, 0.14, and 1.17 for CLint,active, CLint,passive, and CLint,bile, respectively, and together with the relative fraction transported by individual transporters obtained from in vitro studies and the optimized Ki values for OATP inhibition, the model reasonably captured observed pitavastatin PK profiles, DDIs and PK variations in human subjects carrying genetic polymorphisms, i.e., AUC within 20%. Lastly, when applying the functional reduction based on measured OATP1B biomarkers, the model adequately predicted PK changes in the hepatic impairment population. The present study presents a strategic framework for early-stage drug development, enabling the prediction of PK profiles and assessment of PK variations in scenarios like DDIs, genetic polymorphism, and hepatic impairment-related disease states, specifically focusing on OATP substrates.

Development and evaluation of C10 and SNAC erodible tablets for gastric delivery of a GIP/GLP1 peptide in monkeys.

The permeation enhancers (PEs) sodium caprate (C10) and sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) have been utilized for the intestinal and gastric delivery of macromolecules, respectively. However, the potential of C10 for the gastric delivery of a peptide and the ability of SNAC to deliver other peptides to the stomach beyond semaglutide have not been investigated. In this study, we have developed and evaluated C10 and SNAC-containing erodible tablets for the gastricdelivery of a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP/GLP1) dual agonist peptide (LY) in cynomolgus monkeys. We also evaluated the impact of release rates on the in vivo performance of C10 and SNAC. Furthermore, we compared the oral exposure of the LY peptide and semaglutide with different proteolytic stabilities using a SNAC erodible tablet. Additionally, we investigated the mechanism of action of SNAC for improving gastric absorption of the LY peptide via tissue distribution in monkey. C10 and SNAC tablets released the peptide and PE by erosion from the tablet surface with 100 % release within 60 min at pH 6.8. Following a single oral administration to monkeys, C10 and SNAC erodible tablets at 300 mg exhibited similar LY mean absolute oral bioavailability of 5.7 % and 4.2 %, respectively. The C10 immediate release capsule (500 mg) with faster dissolution profile (10 min) showed a decrease in the LY oral bioavailability; however, a faster dissolution profile (15 min) with erodible SNAC tablet resulted in a relatively higher LY oral bioavailability compared to the slow-release erodible tablets (60 min). Using SNAC as the PE, the combination of slow-release tablet design and LY peptide with higher pepsin stability resulted in about 4-fold higher mean oral bioavailability in the monkeys than semaglutide (4.2 % vs 1.2 %, respectively). In the monkey gastric tissue, SNAC was found to reduce tight junction protein levels and increase the peptide uptake into the gastric epithelium suggesting its permeation enhancing mechanism via both paracellular and transcellular pathways. Taking these data altogether, the enhanced proteolytic stability of the LY peptide combined with the optimal erodible tablets enabled the gastric delivery of the LY peptide with a higher oral bioavailability than semaglutide.

A Novel Retrograde AAV Variant for Functional Manipulation of Cortical Projection Neurons in Mice and Monkeys.

Retrograde adeno-associated viruses (AAVs) are capable of infecting the axons of projection neurons and serve as a powerful tool for the anatomical and functional characterization of neural networks. However, few retrograde AAV capsids have been shown to offer access to cortical projection neurons across different species and enable the manipulation of neural function in non-human primates (NHPs). Here, we report the development of a novel retrograde AAV capsid, AAV-DJ8R, which efficiently labeled cortical projection neurons after local administration into the striatum of mice and macaques. In addition, intrastriatally injected AAV-DJ8R mediated opsin expression in the mouse motor cortex and induced robust behavioral alterations. Moreover, AAV-DJ8R markedly increased motor cortical neuron firing upon optogenetic light stimulation after viral delivery into the macaque putamen. These data demonstrate the usefulness of AAV-DJ8R as an efficient retrograde tracer for cortical projection neurons in rodents and NHPs and indicate its suitability for use in conducting functional interrogations.

Metabolite characterisation of the peptide-drug conjugate LN005 in liver S9s by UHPLC-Orbitrap-HRMS.

LN005 is a peptide-drug conjugate (PDC) targeting glucose-regulated protein 78 (GRP78) to treat several types of cancer, such as breast, colon, and prostate cancer.As a new drug modality, understanding its metabolism and elimination pathways will help us to have a whole picture of it. Currently, there are no metabolic studies on LN005; therefore, this study aimed to investigate the metabolism of LN005, clarify its metabolic profile in the liver S9s of different species, and identify the major metabolic pathways and differences between species.The incubation samples were measured by ultra-high performance liquid chromatography combined with orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS).The results showed that LN005 was metabolised by liver S9s, and four metabolites were identified. The main metabolic pathway of LN005 in liver S9s was oxidative deamination to ketone or hydrolysis. Similar metabolic profiles were observed in mouse, rat, dog, monkey, and human liver S9s, indicating no differences between these four animal species and humans.This study provides information for the structural modification and optimisation of LN005 and affords a reference for subsequent animal experiments and human metabolism of other PDCs.

Human Embryonic Stem Cell-Derived Immature Midbrain Dopaminergic Neurons Transplanted in Parkinsonian Monkeys.

Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopaminergic neurons (DANs), and Non-human primates (NHPs) injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine develop some alterations observed in Parkinson's disease (PD) patients. Here, we obtained well-characterized DANs from hESCs and transplanted them into two parkinsonian monkeys to assess their behavioral and imaging changes. DANs from hESCs expressed dopaminergic markers, generated action potentials, and released dopamine (DA) in vitro. These neurons were transplanted bilaterally into the putamen of parkinsonian NHPs, and using magnetic resonance imaging techniques, we calculated the fractional anisotropy (FA) and mean diffusivity (MD), both employed for the first time for these purposes, to detect in vivo axonal and cellular density changes in the brain. Likewise, positron-emission tomography scans were performed to evaluate grafted DANs. Histological analyses identified grafted DANs, which were quantified stereologically. After grafting, animals showed signs of partially improved motor behavior in some of the HALLWAY motor tasks. Improvement in motor evaluations was inversely correlated with increases in bilateral FA. MD did not correlate with behavior but presented a negative correlation with FA. We also found higher 11C-DTBZ binding in positron-emission tomography scans associated with grafts. Higher DA levels measured by microdialysis after stimulation with a high-potassium solution or amphetamine were present in grafted animals after ten months, which has not been previously reported. Postmortem analysis of NHP brains showed that transplanted DANs survived in the putamen long-term, without developing tumors, in immunosuppressed animals. Although these results need to be confirmed with larger groups of NHPs, our molecular, behavioral, biochemical, and imaging findings support the integration and survival of human DANs in this pre-clinical PD model.

Prediction of pharmacokinetics of an anaplastic lymphoma kinase inhibitor in rat and monkey: application of physiologically based pharmacokinetic model as an alternative tool to minimise animal studies.

The pharmacokinetic (PK) and toxicokinetic profile of a drug from its preclinical evaluation helps the researcher determine whether the drug should be tested in humans based on its safety and toxicity.Preclinical studies require time and resources and are prone to error. Moreover, according to the United States Food and Drug Administration Modernisation Act 2, animal testing is no longer mandatory for new drug development, and an animal-free alternative, such as cell-based assay and computer models, can be used.Different physiologically based PK models were developed for an anaplastic lymphoma kinase inhibitor in rats and monkeys after intravenous and oral administration using its physicochemical properties and in vitro characterisation data.The developed model was validated against the in vivo data available in the literature, and the validation results were found within the acceptable limit. A parameter sensitivity analysis was performed to identify the properties of the compound influencing the PK profile.This work demonstrates the application of the physiologically based PK model to predict the PKs of a drug, which will eventually assist in reducing the number of animal studies and save time and cost of drug discovery and development.

Evaluation of the effect of pelvis type in percutaneous acetabular column fixation: a computed tomography study.

This study aimed to evaluate the effect of pelvis type in percutaneous acetabular column fixation. What is the effect of pelvis type in percutaneous acetabular colon fixation? The available pelvic computed tomography (CT) scans which were obtained in the diagnostic imaging center with a 1 mm slice width were evaluated. The pelvic type was classified with the help of MPR (Multiplanar Reformat) and 3D (Three Dimensional) imaging modes. All evaluated bony pelvic structures were anatomically intact. 40 types of android, gynecoid, anthropoid, and platypelloid pelvis were determined. CT sections were created in MPR imaging mode. Anterior obturator oblique (AOO) and inlet images were created for anterior column evaluation, while iliac oblique (IO) and outlet images were created for posterior column evaluation. The possibility of obtaining a linear corridor for acetabular columns was investigated by measuring corridor width and lengthon images of pelvic CTs. A linear corridor could not be obtained between the pubic tubercle and the supraacetabular region of 12 (30%) CTs in the anterior column of gynecoid pelvis group. The diameter of the anterior column corridor was below 5.5 mm in 10 (25%) of Gynecoid pelvis group, 5 (12.5%) of Anthropoid pelvis group, and 10 of Platypelloid pelvis group, , and all those scans belonged to the female gender. There was a statistically significant difference between pelvis types in terms of anterior and posterior column diameters (p <0.001). While the android pelvis type had the highest diameter and corridor length in both anterior column and posterior column measurements, the gynecoid pelvic type had the lowest diameter and corridor length. In the evaluations made according to gender, both anterior and posterior column diameters were larger and longer in males than in females (p <0.001). Pelvis type is an important factor which can affect anterior and posterior column diameter and length of acetabulum. Pelvic typing before acetabular surgery can help the surgeon determining the most appropriate patient position, surgical approach, and implant selection. Level of Evidence: Level 2.

Generation of inactivated IL2RG and RAG1 monkeys with severe combined immunodeficiency using base editing.

Severe combined immunodeficiency (SCID) encompasses a range of inherited disorders that lead to a profound deterioration of the immune system. Among the pivotal genes associated with SCID, RAG1 and IL2RG play crucial roles. IL2RG is essential for the development, differentiation, and functioning of T, B, and NK cells, while RAG1 critically contributes to adaptive immunity by facilitating V(D)J recombination during the maturation of lymphocytes. Animal models carrying mutations in these genes exhibit notable deficiencies in their immune systems. Non-human primates (NHPs) are exceptionally well-suited models for biomedical research due to their genetic and physiological similarities to humans. Cytosine base editors (CBEs) serve as powerful tools for precisely and effectively modifying single-base mutations in the genome. Their successful implementation has been demonstrated in human cells, mice, and crop species. This study outlines the creation of an immunodeficient monkey model by deactivating both the IL2RG and RAG1 genes using the CBE4max system. The base-edited monkeys exhibited a severely compromised immune system characterized by lymphopenia, atrophy of lymphoid organs, and a deficiency of mature T cells. Furthermore, these base-edited monkeys were capable of hosting and supporting the growth of human breast cancer cells, leading to tumor formation. In summary, we have successfully developed an immunodeficient monkey model with the ability to foster tumor growth using the CBE4max system. These immunodeficiency monkeys show tremendous potential as valuable tools for advancing biomedical and translational research.

Evaluation of the risk of diarrhea induced by epidermal growth factor receptor tyrosine kinase inhibitors with cultured intestinal stem cells originated from crypts in humans and monkeys.

Severe diarrhea is a common side effect of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We aimed to evaluate the risk of EGFR-TKI-induced diarrhea using spheroids of human and monkey crypt-derived intestinal stem cells. Intestinal spheroids exhibited higher toxic susceptibility to EGFR-TKIs than Caco-2 cells. As concentration of EGFR-TKIs increased, cellular ATP first decreased relative to the control condition, followed by an increase in LDH release, in contrast with their simultaneous changes with traditional cytotoxic anticancer drugs. The toxic sensitivity of spheroids to various EGFR-TKIs corresponded to clinical diarrhea incidence. Afatinib, a second-generation EGFR-TKI, exhibited higher toxic sensitivity compared with the first-generation ones, corresponding to the clinical evidence that afatinib-induced diarrhea is almost inevitable and severe. By contrast, the third-generation osimertinib, which reduces the risk of diarrhea, showed mitigated cytotoxicity compared with afatinib. For irreversible EGFR-TKIs, the decreased ATP level persisted or its recovery was delayed even after drug removal compared with reversible ones. Furthermore, the highest drug accumulation in spheroids (TKIspheroids) and inhibition potency against EGFR (TKIspheroids/Ki) were observed for afatinib. This system would be useful for predicting the risk of EGFR-TKI-induced diarrhea; moreover, on-target cytotoxicity against intestinal stem cells might contribute to clinically observed diarrhea.

Alternatives to Monkey Reproductive Toxicology Testing for Biotherapeutics.

Embryofetal toxicity studies are conducted to support inclusion of women of childbearing potential in clinical trials and to support labeling for the marketed pharmaceutical product. For biopharmaceuticals, which frequently lack activity in the rodent or rabbit, the nonhuman primate is the standard model to evaluate embryofetal toxicity. These studies have become increasingly challenging to conduct due to the small number of facilities capable of performing them and a shortage of sexually mature monkeys. The low number of animals per group and the high rate of spontaneous abortion in cynomolgus monkeys further complicate interpretation of the data. Recent FDA guidance has proposed a weight of evidence (WoE) approach to support product labeling for reproductive toxicity of products intended to be used for the treatment of cancer (Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling Recommendations), an approach that has also supported the approval of biotherapeutics for non-cancer indications. Considerations to determine the appropriateness and content of a WoE approach to support product labeling for embryofetal risk include known class effects in humans; findings from genetically modified animals with or without drug administration; information from surrogate compounds; literature-based assessments about the developmental role of the pharmaceutical target; and the anticipated exposure during embryofetal development. This paper summarizes the content of a session presented at the 42nd annual meeting at the American College of Toxicology, which explored the conditions under which alternative approaches may be appropriate to support product labeling for reproductive risk, and how sponsors can best justify the use of this approach.

A sensitive LC-MS/MS assay to quantitate free payload Aur0101 from ADC PYX-201 in rat and monkey plasma.

Aim: Aur0101 is a cytotoxic and small-molecule microtubule depolymerizing agent, and is the payload conjugated to antibody-drug conjugate PYX-201. Developing and validating a sensitive bioanalytical method to quantitate Aur0101 was novel and crucial in preclinical PYX-201 studies. Materials & methods: Reference standard Aur0101 and its stable isotope labelled internal standard Aur0101-d8 were used in this LC-MS/MS method. Results: This sensitive assay was validated at a lower limit of quantitation of 15 pg/ml and successfully applied to support preclinical rat and monkey toxicology studies. Preclinical plasma toxicokinetic parameters were presented. Conclusion: A sensitive and robust LC-MS/MS assay was validated for Aur0101 in rat and monkey plasma.

Detection and identification of imperatorin metabolites in rat, dog, monkey, and human liver microsomes by ultra-high-performance liquid chromatography combined with high-resolution mass spectrometry and Compound Discoverer software.

Imperatorin, a furanocoumarin that widely exists in many umbelliferous herbs, has been demonstrated to have a variety of pharmacological effects, including anti-inflammatory, antiosteoporosis, and antitumor activities. The purpose of this study was to investigate the metabolism of imperatorin using liver microsomes. The metabolites were generated by individually incubating imperatorin with rat, dog, monkey, and human liver microsomes. To trap the reactive metabolites during microsomal metabolism, glutathione (GSH) was included in the incubation. A LC technique coupled with benchtop orbitrap MS with full mass/data-dependent tandem mass spectrometry acquisition mode was used to detect and identify the generated metabolites. The possible structures of the metabolites were characterized according to their accurate masses and fragment ions. Under the current conditions, a total of 10 metabolites, including four GSH adducts, were identified. The results indicated that imperatorin underwent extensive metabolic reactions including hydroxylation, oxidation, glucuronidation, and GSH conjugation. This study provides essential data on the metabolism of imperatorin, which will be helpful for us to understand the safety and efficacy of this bioactive compound.

Perspectives: Methods for Evaluating Primate Spermatogonial Stem Cells.

Mammalian spermatogenesis is a complex, highly productive process generating millions of sperm per day. Spermatogonial stem cells (SSCs) are at the foundation of spermatogenesis and can either self-renew, producing more SSCs, or differentiate to initiate spermatogenesis and produce sperm. The biological potential of SSCs to produce and maintain spermatogenesis makes them a promising tool for the treatment of male infertility. However, translating knowledge from rodents to higher primates (monkeys and humans) is challenged by different vocabularies that are used to describe stem cells and spermatogenic lineage development in those species. Furthermore, while rodent SSCs are defined by their biological potential to produce and maintain spermatogenesis in a transplant assay, there is no equivalent routine and accessible bioassay to test monkey and human SSCs or replicate their functions in vitro. This chapter describes progress characterizing, isolating, culturing, and transplanting SSCs in higher primates.

Vegetable Oil-Peroxidation Product 'Hydroxynonenal' Causes Hepatocyte Injury and Steatosis via Hsp70.1 and BHMT Disorders in the Monkey Liver.

Hsp70.1 has a dual function as a chaperone protein and lysosomal stabilizer. In 2009, we reported that calpain-mediated cleavage of carbonylated Hsp70.1 causes neuronal death by inducing lysosomal rupture in the hippocampal CA1 neurons of monkeys after transient brain ischemia. Recently, we also reported that consecutive injections of the vegetable oil-peroxidation product 'hydroxynonenal' induce hepatocyte death via a similar cascade in monkeys. As Hsp70.1 is also related to fatty acid ß-oxidation in the liver, its deficiency causes fat accumulation. The genetic deletion of betaine-homocysteine S-methyltransferase (BHMT) was reported to perturb choline metabolism, inducing a decrease in phosphatidylcholine and resulting in hepatic steatosis. Here, focusing on Hsp70.1 and BHMT disorders, we studied the mechanisms of hepatocyte degeneration and steatosis. Monkey liver tissues with and without hydroxynonenal injections were compared using proteomics, immunoblotting, immunohistochemical, and electron microscopy-based analyses. Western blotting showed that neither Hsp70.1 nor BHMT were upregulated, but an increased cleavage was observed in both. Proteomics showed a marked downregulation of Hsp70.1, albeit a two-fold increase in the carbonylated BHMT. Hsp70.1 carbonylation was negligible, in contrast to the ischemic hippocampus, which was associated with ~10-fold increments. Although histologically, the control liver showed very little lipid deposition, numerous tiny lipid droplets were seen within and around the degenerating/dying hepatocytes in monkeys after the hydroxynonenal injections. Electron microscopy showed permeabilization/rupture of lysosomal membranes, dissolution of the mitochondria and rough ER membranes, and proliferation of abnormal peroxisomes. It is probable that the disruption of the rough ER caused impaired synthesis of the Hsp70.1 and BHMT proteins, while impairment of the mitochondria and peroxisomes contributed to the sustained generation of reactive oxygen species. In addition, hydroxynonenal-induced disorders facilitated degeneration and steatosis in the hepatocytes.

Identification and characterization of the metabolites of moscatilin in mouse, rat, dog, monkey and human hepatocytes by LC-Orbitrap-MS/MS combined with diagnostic fragment ions and accurate mass measurements.

Moscatilin, a bibenzyl derivative from the stem of Dendrobium loddigesii, has been shown to have anticancer activity. The aim of this study was to identify and characterize the possible in vitro metabolites of moscatilin generated from hepatocytes. The metabolites generated in the hepatocytes of mouse, rat, dog, monkey and human were identified and characterized employing ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap tandem mass spectrometry (LC-Orbitrap-MS/MS) based on diagnostic fragment ions and accurate mass measurements. A total of 18 metabolites were identified, among which seven were phase I and 11 were phase II metabolites. The plausible structures of the metabolites and the probable biotransformation pathways were proposed based on the diagnostic fragment ions, chemical formula and mass fragmentation pattern, as well as the accurate masses. The majority of phase I metabolites were generated by demethylation and hydroxylation, while phase II metabolites were mainly generated by glucuronidation, glutathione conjugation and sulfation. Our study first expounded the metabolites of moscatilin in mouse, rat, dog, monkey and human hepatocytes and provided a foundation for a further pharmacokinetic and toxicity study. More importantly, LC-Orbitrap-MS/MS combined with diagnostic fragment ions and accurate mass measurements has been proved to be an effective method for the rapid identification of bibenzyl derivatives and their metabolites.

Toxicidad a dosis repetida e inmunogenicidad en Cercopithecus aethiops, del candidato vacunal SOBERANA 01 (FINLAY-FR-01) contra el coronavirus de tipo 2 causante del síndrome respiratorio agudo severo / Repeated dose toxicity and immunogenicity in Cercopithecus aethiops of SARS-CoV-2 SOBERANA 01 (FINLAY-FR-01) vaccine candidate

En el Instituto Finlay de Vacunas se desarrolló el candidato vacunal SOBERANA 01 (FINLAY-FR-01) contra el coronavirus de tipo 2 causante del síndrome respiratorio agudo severo. Este trabajo tuvo como objetivo evaluar la inmunogenicidad y posibles efectos toxicológicos del candidato vacunal SOBERANA 01 (FINLAY-FR-01 en Cercopithecus aethiops. Se utilizaron cinco primates no humanos (hembras), de 1-3 años de edad y 1-4 kg de peso corporal, distribuidos en dos grupos experimentales: Control (Solución Salina Fisiológica) y Tratado SOBERANA 01 (FINLAY-FR-01). El estudio se extendió por 84 días, en un esquema a dosis repetida de cuatro inmunizaciones los días 0, 28, 56 y 70. Se realizaron observaciones clínicas diarias, peso corporal, signos vitales (temperatura rectal, frecuencia respiratoria, y frecuencia cardíaca), exámenes electrocardiográficos, toma de la temperatura del sitio de inyección, musculometría e irritabilidad dérmica. Fueron realizados exámenes de hematología, bioquímica sanguínea, así como estudios inmunológicos. El ensayo concluyó con una supervivencia del 100por ciento, no se manifestaron signos de toxicidad, no hubo variaciones hematológicas, ni de la bioquímica sanguínea asociadas a la sustancia de ensayo. Además, no se observaron efectos locales en el sitio de administración. Por último, el candidato vacunal resultó inmunogénico, ya que se indujeron títulos altos de IgG anti-RBD, así como de la inhibición de la unión de RBD a ACE2(AU)

At Finlay Vaccine Institute has been developed the vaccine candidate SOBERANA 01 (FINLAY-FR-01) against SARS-CoV-2 virus, causing COVID-19. This work aims to evaluate the immunogenicity and possible toxicological effects of the SOBERANA 01 (FINLAY-FR-01) vaccine candidate in Cercopithecus aethiops. Five non-human primates (females) from 1-3 years old and 1-4 kg of body weight were distributed in two experimental groups: Control (Physiological Saline Solution) and Treated (SOBERANA 01 FINLAY-FR-01). The study extended through 84 days, in a repeated dose schedule of four immunizations on days 0, 28, 56, and 70. Daily clinical observations, body weight, vital signs (rectal temperature, respiratory rate, and heart rate), electrocardiographic examinations, temperature of the injection site, musculometry and dermic irritability, were performed. Hematological and blood biochemistry tests, as well as immunological studies were assessed. At the end of the assay 100percent survival was obtained, there were no signs of toxicity neither hematological or blood biochemistry variations associated with the test substance. In addition, no local effects were observed at the administration site. Finally, the vaccine candidate was immunogenic, since high titers of anti-RBD IgG, as well as inhibition of the RBD to ACE2 binding were induced(AU)

Hematological reference values for Alouatta palliata (Primates: Atelidae) and Cebus imitator (Primates: Cebidae) from the Pacific Coast of Costa Rica / Valores de referencia hematológicos para Alouatta palliata (Primates: Atelidae) y Cebus imitator (Primates: Cebidae) de la costa Pacífica de Costa Rica

Abstract Introduction: Wildlife hematological patterns are fundamental for health monitoring, and allows elucidating variations both within and between populations. Among these, hematological parameters are particularly valuable to evaluate the health status of neotropical primate species in the wild. Objective: To define hematological reference values for two species of monkeys in Costa Rica. Methods: During 2014, we collected blood samples from free-ranging mantled howler monkeys, Alouatta palliata (17 females, 18 males) and white-faced capuchin monkeys, Cebus imitator (5 females, 7 males) in seven localities of the Costa Rican Pacific coast. Results: For both species, the hematological values were higher in males, and howler monkey populations differed significantly except for platelets. Conclusions: These hematological values, which differ by sex and locality, will help evaluate the health status of these neotropical primate populations.

Resumen Introducción: Los patrones hematológicos de la vida silvestre son fundamentales para el monitoreo de la salud y permiten dilucidar las variaciones tanto dentro como entre poblaciones. Entre estos, los parámetros hematológicos son particularmente valiosos para evaluar el estado de salud de las especies de primates neotropicales en la naturaleza. Objetivo: Definir valores de referencia hematológicos para dos especies de monos en Costa Rica. Métodos: Durante el 2014 recolectamos muestras de sangre de monos aulladores de manto, Alouatta palliata (17 hembras, 18 machos) y monos capuchinos cariblancos, Cebus imitador (5 hembras, 7 machos) en siete localidades de la costa Pacífica de Costa Rica. Resultados: Para ambas especies, los valores hematológicos fueron mayores en los machos, y las poblaciones de monos aulladores difirieron significativamente con excepción de las plaquetas. Conclusiones: Estos valores hematológicos, que difieren según el sexo y la localidad, ayudarán a evaluar el estado de salud de estas poblaciones de primates neotropicales.