Development and characterization of two equine formulations towards SARS-CoV-2 proteins for the potential treatment of COVID-19

AbstractIn the current global emergency due to SARS-CoV-2 outbreak, passive immunotherapy emerges as a promising treatment for COVID-19. Among animal-derived products, equine formulations are still the cornerstone therapy for treating envenomations due to animal bites and stings. Therefore, drawing upon decades of experience in manufacturing snake antivenom, we developed and preclinically evaluated two anti-SARS-CoV-2 polyclonal equine formulations as potential alternative therapy for COVID-19. We immunized two groups of horses with either S1 (anti-S1) or a mixture of S1, N, and SEM mosaic (anti-Mix) viral recombinant proteins. Horses reached a maximum anti-viral antibody level at 7 weeks following priming, and showed no major adverse acute or chronic clinical alterations. Two whole-IgG formulations were prepared via hyperimmune plasma precipitation with caprylic acid and then formulated for parenteral use. Both preparations had similar physicochemical and microbiological quality and showed ELISA immunoreactivity towards S1 protein and the receptor binding domain (RBD). The anti-Mix formulation also presented immunoreactivity against N protein. Due to high anti-S1 and anti-RBD antibody content, final products exhibited high in vitro neutralizing capacity of SARS-CoV-2 infection, 80 times higher than a pool of human convalescent plasma. Pre-clinical quality profiles were similar among both products, but clinical efficacy and safety must be tested in clinical trials. The technological strategy we describe here can be adapted by other producers, particularly in low- and middle-income countries.

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Development and pre-clinical characterization of two therapeutic equine formulations towards SARS-CoV-2 proteins for the potential treatment of COVID-19

10.1101/2020.10.17.343863 ◽

2020 ◽

Author(s):

Guillermo León ◽

María Herrera ◽

Mariángela Vargas ◽

Mauricio Arguedas ◽

Andrés Sánchez ◽

...

Keyword(s):

Alternative Therapy ◽

Microbiological Quality ◽

Middle Income ◽

N Protein ◽

Middle Income Countries ◽

Neutralizing Capacity ◽

Bites And Stings ◽

Potential Alternative ◽

Promising Treatment

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Smartphone microendoscopy for high resolution fluorescence imaging

Journal of Innovative Optical Health Sciences ◽

10.1142/s1793545816500462 ◽

2016 ◽

Vol 09 (05) ◽

pp. 1650046 ◽

Cited By ~ 9

Author(s):

Xiangqian Hong ◽

Vivek K. Nagarajan ◽

Dale H. Mugler ◽

Bing Yu

Keyword(s):

High Resolution ◽

Rural Areas ◽

Ex Vivo ◽

Cost Effective ◽

Internal Organs ◽

Middle Income ◽

Middle Income Countries ◽

The Past

High resolution optical endoscopes are increasingly used in diagnosis of various medical conditions of internal organs, such as the cervix and gastrointestinal (GI) tracts, but they are too expensive for use in resource-poor settings. On the other hand, smartphones with high resolution cameras and Internet access have become more affordable, enabling them to diffuse into most rural areas and developing countries in the past decade. In this paper, we describe a smartphone microendoscope that can take fluorescence images with a spatial resolution of 3.1 [Formula: see text]m. Images collected from ex vivo, in vitro and in vivo samples using the device are also presented. The compact and cost-effective smartphone microendoscope may be envisaged as a powerful tool for detecting pre-cancerous lesions of internal organs in low and middle-income countries (LMICs).

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Piperazine-Derivative MMV665917: An Effective Drug in the Diarrheic Piglet Model of Cryptosporidium hominis

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz105 ◽

2019 ◽

Vol 220 (2) ◽

pp. 285-293 ◽

Cited By ~ 7

Author(s):

Sangun Lee ◽

Melanie Ginese ◽

Don Girouard ◽

Gillian Beamer ◽

Christopher D Huston ◽

...

Keyword(s):

Oral Treatment ◽

Blood Cholesterol ◽

Oocyst Excretion ◽

Cryptosporidium Hominis ◽

Middle Income ◽

Middle Income Countries ◽

Piperazine Derivative ◽

Gnotobiotic Piglets

Abstract Background Cryptosporidiosis, an enteric protozoon, causes substantial morbidity and mortality associated with diarrhea in children <2 years old in low- to middle-income countries. There is no vaccine and treatments are inadequate. A piperazine-based compound, MMV665917, has in vitro and in vivo efficacy against Cryptosporidium parvum. In this study, we evaluated the efficacy of MMV665917 in gnotobiotic piglets experimentally infected with Cryptosporidium hominis, the species responsible for >75% of diarrhea reported in these children. Methods Gnotobiotic piglets were orally challenged with C hominis oocysts, and oral treatment with MMV665917 was commenced 3 days after challenge. Oocyst excretion and diarrhea severity were observed daily, and mucosal colonization and lesions were recorded after necropsy. Results MMV665917 significantly reduced fecal oocyst excretion, parasite colonization and damage to the intestinal mucosa, and peak diarrheal symptoms, compared with infected untreated controls. A dose of 20 mg/kg twice daily for 7 days was more effective than 10 mg/kg. There were no signs of organ toxicity at either dose, but 20 mg/kg was associated with slightly elevated blood cholesterol and monocytes at euthanasia. Conclusions These results demonstrate the effectiveness of this drug against C hominis. Piperazine-derivative MMV665917 may potentially be used to treat human cryptosporidiosis; however, further investigations are required.

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How to implement new diagnostic products in low-resource settings: an end-to-end framework

BMJ Global Health ◽

10.1136/bmjgh-2018-000914 ◽

2018 ◽

Vol 3 (6) ◽

pp. e000914 ◽

Cited By ~ 3

Author(s):

Melissa Latigo Mugambi ◽

Trevor Peter ◽

Samuel F Martins ◽

Cristina Giachetti

Keyword(s):

Best Practices ◽

Product Development ◽

Healthcare Systems ◽

Regulatory Requirements ◽

Middle Income ◽

Low Resource Settings ◽

Middle Income Countries ◽

In Vitro Diagnostic ◽

Phase Gate

Diagnostics developers often face challenges introducing in-vitro diagnostic (IVD) products to low- and middle-income countries (LMICs) because of difficulty in accessing robust market data, navigating policy and regulatory requirements and implementing and supporting products in healthcare systems with limited infrastructure. Best practices recommend the use of a phase-gate model with defined activities and milestones by phase to successfully move a product from concept to commercialisation. While activities for commercialisation of products in high-income countries (HICs) are well understood, the activities required for introduction of IVDs in LMICs are not. In this paper, we identify the key activities needed for IVD product development and implementation and map them to the various phases of the model, paying particular attention to those activities that might be conducted differently in LMICs.

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In vitro growth competition experiments that suggest consequences of the substandard artemisinin epidemic that may be accelerating drug resistance in P. falciparum malaria

PLoS ONE ◽

10.1371/journal.pone.0248057 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0248057

Author(s):

Matthew R. Hassett ◽

Paul D. Roepe

Keyword(s):

World Health ◽

Middle Income ◽

Middle Income Countries ◽

Recommended Treatment ◽

Drug Treatments ◽

Resistant Strains ◽

Health Organization ◽

Treat All ◽

Drug Resistant Strains

Over the past decade, artemisinin (ART)-combination therapies (ACTs) have shown declining efficacy within Southeast Asia (SEA). These resistance-like phenomena manifest as a delayed clearance phenotype (DCP) in some patients treated with ACTs. ACTs are currently the recommended treatment for P. falciparum infections by the World Health Organization (WHO), and they are our last line of defense to effectively treat all strains of malaria. Acceleration of antimicrobial resistance (AMR) is often theorized to be exacerbated by the use of subtherapeutic dosages of drugs (“substandard” drug), which for ACTs has been well documented over the last decade. Troublingly, in 2017, the WHO estimated that nearly 1 in 10 medical products tested in low- and middle-income countries failed to meet quality standards. We have developed a tissue culture-based approach for testing possible connections between substandard treatment and the spread of ACT resistant blood stage forms of P. falciparum. Via sequencing of pfk13, a molecular marker that is predictive for ART resistance (ARTR), we monitor competition of sensitive vs resistant strains over time and under various conditions and define conditions that favor emergence of ARTR parasites. Our findings help to define the conditions under which substandard drug treatments might favor the proliferation of mutant PfK13-mediated drug resistant strains over drug sensitive.

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Breastmilk; a source of SARS-CoV-2 specific IgA antibodies

10.1101/2020.08.18.20176743 ◽

2020 ◽

Author(s):

Britt J van Keulen ◽

Michelle Romijn ◽

Albert Bondt ◽

Kelly A Dingess ◽

Eva Kontopodi ◽

...

Keyword(s):

Rapid Development ◽

Neutralization Capacity ◽

N Protein ◽

Lactating Mothers ◽

Neutralizing Capacity ◽

Before And After ◽

Additional Protection ◽

Good Hygiene ◽

Control Study

Background: Since the outbreak of COVID-19, many put their hopes in the rapid development of effective immunizations. For now patient isolation, physical distancing and good hygiene are the sole measures for prevention. Processed breast milk with antibodies against SaRS-CoV-2 may serve as additional protection. We aimed to determine the presence and neutralization capacity of antibodies against SaRS-CoV-2 in breastmilk of mothers who have recovered from COVID-19. Methods: This prospective case control study included lactating mothers, recovered from (suspected) COVID-19 and healthy controls. Serum and breastmilk was collected. To assess the presence of antibodies in breastmilk and serum, we used multiple complementary assays, namely ELISA with the SARS-CoV-2 spike protein, SARS-CoV-2 receptor binding domain (RBD) and with the SARS-CoV-2 nucleocapsid (N) protein for IgG and bridging ELISA with the SARS-CoV-2 RBD and N protein for total Ig. To assess the effect of pasteurization breastmilk was exposed to Holder Pasteurization and High Pressure Pasteurization. Results: Breastmilk contained antibodies against SARS-CoV-2 using any of the assays in 24 out of 29 (83%) proven cases, in six out of nine (67%) suspected cases and in none of the 13 controls. In vitro neutralization of SARS-CoV-2 clinical isolate virus strain was successful in a subset of serum (13%) and milk samples (26%). Although after pasteurization of the milk SARS-CoV-2 antibodies were detected with both methods of pasteurization, virus neutralizing capacity of those antibodies was only retained with the HPP approach. Conclusion: Breastmilk of mothers who recovered from COVID-19 contains significant amounts of IgA against SARS-CoV-2, both before and after pasteurization.

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Drug repurposing in malignant pleural mesothelioma: a breath of fresh air?

European Respiratory Review ◽

10.1183/16000617.0098-2017 ◽

2018 ◽

Vol 27 (147) ◽

pp. 170098 ◽

Cited By ~ 11

Author(s):

Arnaud Boyer ◽

Eddy Pasquier ◽

Pascale Tomasini ◽

Joseph Ciccolini ◽

Laurent Greillier ◽

...

Keyword(s):

Clinical Trials ◽

Malignant Pleural Mesothelioma ◽

Drug Repurposing ◽

Pleural Mesothelioma ◽

Middle Income ◽

Middle Income Countries ◽

Lower Treatment ◽

Lower Treatment Cost

Drug repurposing is the use of known drugs for new indications. Malignant pleural mesothelioma (MPM) is a rare cancer with a poor prognosis. So far, few treatments have been approved in this disease. However, its incidence is expected to increase significantly, particularly in developing countries. Consequently, drug repurposing appears as an attractive strategy for drug development in MPM, since the known pharmacology and safety profile based on previous approvals of repurposed drugs allows for faster time-to-market for patients and lower treatment cost. This is critical in low- and middle-income countries where access to expensive drugs is limited. This review assesses the published preclinical and clinical data about drug repurposing in MPM.In this review, we identified 11 therapeutic classes that could be repositioned in mesothelioma. Most of these treatments have been evaluatedin vitro, half have been evaluatedin vivoin animal models of MPM and only three (i.e.valproate, thalidomide and zoledronic acid) have been investigated in clinical trials, with limited benefits so far. Efforts could be coordinated to pursue further investigations and test promising drugs identified in preclinical experiments in appropriately designed clinical trials.

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