scholarly journals ChAdOx1 nCoV-19 protection against SARS-CoV-2 in rhesus macaque and ferret challenge models

2021 ◽  
Author(s):  
Teresa Lambe ◽  
Alexandra Spencer ◽  
Kelly Thomas ◽  
Stephen Thomas ◽  
Andrew White ◽  
...  
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Rhesus Macaque ◽  
Clinical Evaluation ◽  
Rhesus Macaques ◽  
Antibody Responses ◽  
Lung Pathology ◽  
Virus Shedding ◽  
Antibody Titers ◽  
Immune Profiling

Abstract Vaccines against SARS-CoV-2 are urgently required. Here we report detailed immune profiling after ChAdOx1 nCoV-19 (AZD1222) and subsequent challenge in two animal models of SARS-CoV-2 mediated disease. We demonstrate in rhesus macaques the lung pathology caused by SARS-CoV-2 mediated pneumonia is reduced by prior vaccination with ChAdOx1 nCoV-19 which induced neutralising antibody responses after a single intramuscular administration. In a second animal model, ferrets, ChAdOx1 nCoV-19 reduced both virus shedding and lung pathology. Antibody titers were boosted by a second dose. Data from these challenge models and the detailed immune profiling, support the continued clinical evaluation of ChAdOx1 nCoV-19.

scholarly journals ChAdOx1 nCoV-19 protection against SARS-CoV-2 in rhesus macaque and ferret challenge models

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Teresa Lambe ◽  
Alexandra J. Spencer ◽  
Kelly M. Thomas ◽  
Karen E. Gooch ◽  
Stephen Thomas ◽  
...  
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Antibody Responses ◽  
High Dose ◽  
Lung Pathology ◽  
Virus Shedding ◽  
Immune Profiling ◽  
Careful Assessment

AbstractVaccines against SARS-CoV-2 are urgently required, but early development of vaccines against SARS-CoV-1 resulted in enhanced disease after vaccination. Careful assessment of this phenomena is warranted for vaccine development against SARS CoV-2. Here we report detailed immune profiling after ChAdOx1 nCoV-19 (AZD1222) and subsequent high dose challenge in two animal models of SARS-CoV-2 mediated disease. We demonstrate in rhesus macaques the lung pathology caused by SARS-CoV-2 mediated pneumonia is reduced by prior vaccination with ChAdOx1 nCoV-19 which induced neutralising antibody responses after a single intramuscular administration. In a second animal model, ferrets, ChAdOx1 nCoV-19 reduced both virus shedding and lung pathology. Antibody titre were boosted by a second dose. Data from these challenge models on the absence of enhanced disease and the detailed immune profiling, support the continued clinical evaluation of ChAdOx1 nCoV-19.

scholarly journals Bridging Vaccine-Induced HIV-1 Neutralizing and Effector Antibody Responses in Rabbit and Rhesus Macaque Animal Models

2019 ◽  
Vol 93 (10) ◽  
Author(s):  
Justin Pollara ◽  
Dorothy I. Jones ◽  
Tori Huffman ◽  
R. Whitney Edwards ◽  
Maria Dennis ◽  
...  
Keyword(s):  
Animal Models ◽  
Rhesus Macaque ◽  
Rhesus Macaques ◽  
Rabbit Model ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Target Cells ◽  
Human Natural Killer Cells ◽  
Hiv 1

ABSTRACTStudies in animal models are essential prerequisites for clinical trials of candidate HIV vaccines. Small animals, such as rabbits, are used to evaluate promising strategies prior to further immunogenicity and efficacy testing in nonhuman primates. Our goal was to determine how HIV-specific vaccine-elicited antibody responses, epitope specificity, and Fc-mediated functions in the rabbit model can predict those in the rhesus macaque (RM) model. Detailed comparisons of the HIV-1-specific IgG response were performed on serum from rabbits and RM given identical modified vaccinia virus Ankara-prime/gp120-boost immunization regimens. We found that vaccine-induced neutralizing antibody, gp120-binding antibody levels and immunodominant specificities, antibody-dependent cellular phagocytosis of HIV-1 virions, and antibody-dependent cellular cytotoxicity (ADCC) responses against gp120-coated target cells were similar in rabbits and RM. However, we also identified characteristics of humoral immunity that differed across species. ADCC against HIV-infected target cells was elicited in rabbits but not in RM, and we observed differences among subdominantly targeted epitopes. Human Fc receptor binding assays and analysis of antibody-cell interactions indicated that rabbit vaccine-induced antibodies effectively recruited and activated human natural killer cells, while vaccine-elicited RM antibodies were unable to activate either human or RM NK cells. Thus, our data demonstrate that both Fc-independent and Fc-dependent functions of rabbit antibodies can be measured with commonly usedin vitroassays; however, the ability of immunogenicity studies performed in rabbits to predict responses in RM will vary depending on the particular immune parameter of interest.IMPORTANCENonneutralizing antibody functions have been associated with reduced infection risk, or control of virus replication, for HIV-1 and related viruses. It is therefore critical to evaluate development of these responses throughout all stages of preclinical testing. Rabbits are conventionally used to evaluate the ability of vaccine candidates to safely elicit antibodies that bind and neutralize HIV-1. However, it remained unexplored how effectively rabbits model the development of nonneutralizing antibody responses in primates. We administered identical HIV-1 vaccine regimens to rabbits and rhesus macaques and performed detailed comparisons of vaccine-induced antibody responses. We demonstrated that nonneutralizing HIV-specific antibody responses can be studied in the rabbit model and have identified aspects of these responses that are common, and those that are unique, to rabbits and rhesus macaques. Our findings will help determine how to best utilize preclinical rabbit and rhesus macaque models to accelerate HIV vaccine candidate testing in human trials.

scholarly journals Rhesus macaque rhadinovirus-associated non-Hodgkin lymphoma: animal model for KSHV-associated malignancies

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4227-4234 ◽  
Author(s):  
Beata U. Orzechowska ◽  
Michael F. Powers ◽  
Jerald Sprague ◽  
He Li ◽  
Bonnie Yen ◽  
...  
Keyword(s):  
Animal Model ◽  
Rhesus Macaque ◽  
Primary Effusion Lymphoma ◽  
Rhesus Macaques ◽  
Kaposi Sarcoma ◽  
Polymerase Chain Reaction Analysis ◽  
Open Reading Frames ◽  
Inhibitory Protein ◽  
Cell Hyperplasia ◽  
Reading Frames

AbstractRhesus macaque rhadinovirus (RRV) is closely related to Kaposi sarcoma-associated herpesvirus (KSHV) and is associated with the development of B-cell hyperplasia and persistent lymphadenopathy resembling multicentric Castleman disease in rhesus macaques (RMs) coinfected with simian immunodeficiency virus (SIV). Here we investigated whether RMs experimentally infected with SIV and RRV can develop other disease manifestations observed in HIV- and KSHV-infected patients. As reported earlier, inoculation of SIV-infected RMs with RRV results in persistent RRV infection, whereas immunocompetent animals infected with RRV exhibit viremia 2 weeks after infection, followed by a period of no virus detection until they are subsequently made immunodeficient by SIV infection. A subset of animals developed abnormal cellular proliferations characterized as extranodal lymphoma and a proliferative mesenchymal lesion. In situ hybridization and immunohistochemistry analysis indicate RRV is present in both malignancies, and DNA microarray analysis detected viral interleukin-6 (vIL-6) and viral FLICE-like inhibitory protein (vFLIP) transcripts. Reverse-transcriptase polymerase chain reaction analysis confirmed vIL-6 and vFLIP expression, and that of RRV open reading frames 72 and 73, homologs of KSHV open reading frames shown to be expressed in primary effusion lymphoma. These data support the utility of the RRV-/SIV-infected RM as an excellent animal model to investigate KSHV-like pathogenesis.

A Meta-Analysis of Rhesus Macaques (Macaca mulatta), Cynomolgus Macaques (Macaca fascicularis), African green monkeys (Chlorocebus aethiops), and Ferrets (Mustela putorius furo) as Large Animal Models for COVID-19

2021 ◽  
Author(s):  
Alexandra N Witt ◽  
Rachel D Green ◽  
Andrew N Winterborn
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Macaca Mulatta ◽  
Macaca Fascicularis ◽  
Rhesus Macaques ◽  
Meta Analysis ◽  
Large Animal ◽  
Mustela Putorius ◽  
Cynomolgus Macaques ◽  
Green Monkeys

Animal models are at the forefront of biomedical research for studies of viral transmission, vaccines, and pathogenesis, yetthe need for an ideal large animal model for COVID-19 remains. We used a meta-analysis to evaluate published data relevantto this need. Our literature survey contained 22 studies with data relevant to the incidence of common COVID-19 symptomsin rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), African green monkeys (Chlorocebusaethiops), and ferrets (Mustela putorius furo). Rhesus macaques had leukocytosis on Day 1 after inoculation and pneumonia on Days 7 and 14 after inoculation, in frequencies that were similar enough to humans to reject the null hypothesis of a Fisher exact test. However, the differences in overall presentation of disease were too different from that of humans to successfully identify any of these 4 species as an ideal large animal of COVID-19. The greatest limitation to the current study is a lack of standardization in experimentation and reporting. To expand our understanding of the pathology of COVID-19 and evaluate vaccine immunogenicity, we must extend the unprecedented collaboration that has arisen in the study of COVID-19 to include standardization of animal-based research in an effort to find the optimal animal model.

Chronic Collection of Cerebrospinal Fluid from Rhesus Macaques (Macaca mulatta) with Cisterna Magna Ports: Update on Refinements

2021 ◽  
Author(s):  
David B Gilberto ◽  
Maria S Michener ◽  
Brad E Smith ◽  
Peter J Szczerba ◽  
Marie A Holahan ◽  
...  
Keyword(s):  
Animal Model ◽  
Cerebrospinal Fluid ◽  
Animal Models ◽  
Macaca Mulatta ◽  
Rhesus Macaques ◽  
Implant Design ◽  
Cisterna Magna ◽  
Chronic Models ◽  
New Procedures ◽  
Green Monkeys

More than 20 y ago, we developed an animal model for chronic and continuous collection of cerebrospinal fluid (CSF) from conscious rhesus macaques. Since our previous publication in 2003, we have successfully implanted 168 rhesus macaquesusing this approach. Our experience enables us to provide up-to-date information regarding the model, including refinementsto our implant design, reductions in maintenance, and new procedures for dealing with contamination. The results of our experiences have reduced the number of surgeries required and helped to increase the longevity of the implant, with some functioning for more than 18 y. Building on our success in rhesus macaques, we attempted to develop similar animal models in the African green monkeys and dogs but have been unable to develop reliable chronic models for CSF collection in these species.

scholarly journals A Novel Staphylococcus aureus Vaccine: Iron Surface Determinant B Induces Rapid Antibody Responses in Rhesus Macaques and Specific Increased Survival in a Murine S. aureus Sepsis Model

2006 ◽  
Vol 74 (4) ◽  
pp. 2215-2223 ◽  
Author(s):  
Nelly A. Kuklin ◽  
Desmond J. Clark ◽  
Susan Secore ◽  
James Cook ◽  
Leslie D. Cope ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Responses ◽  
Rhesus Macaques ◽  
Surface Protein ◽  
Antibody Responses ◽  
Iron Surface ◽  
Methicillin Resistant ◽  
Treatment And Prevention ◽  
Antibody Titers ◽  
High Level

ABSTRACT Staphylococcus aureus is a major cause of nosocomial infections worldwide, and the rate of resistance to clinically relevant antibiotics, such as methicillin, is increasing; furthermore, there has been an increase in the number of methicillin-resistant S. aureus community-acquired infections. Effective treatment and prevention strategies are urgently needed. We investigated the potential of the S. aureus surface protein iron surface determinant B (IsdB) as a prophylactic vaccine against S. aureus infection. IsdB is an iron-sequestering protein that is conserved in diverse S. aureus clinical isolates, both methicillin resistant and methicillin sensitive, and it is expressed on the surface of all isolates tested. The vaccine was highly immunogenic in mice when it was formulated with amorphous aluminum hydroxyphosphate sulfate adjuvant, and the resulting antibody responses were associated with reproducible and significant protection in animal models of infection. The specificity of the protective immune responses in mice was demonstrated by using an S. aureus strain deficient for IsdB and HarA, a protein with a high level of identity to IsdB. We also demonstrated that IsdB is highly immunogenic in rhesus macaques, inducing a more-than-fivefold increase in antibody titers after a single immunization. Based on the data presented here, IsdB has excellent prospects for use as a vaccine against S. aureus disease in humans.

scholarly journals Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2

2020 ◽  
Author(s):  
Vincent J. Munster ◽  
Friederike Feldmann ◽  
Brandi N. Williamson ◽  
Neeltje van Doremalen ◽  
Lizzette Pérez-Pérez ◽  
...  
Keyword(s):  
Rhesus Macaque ◽  
Respiratory Disease ◽  
Rhesus Macaques ◽  
Case Fatality ◽  
World Health ◽  
Virus Shedding ◽  
Viral Loads ◽  
Repeated Sampling ◽  
Novel Coronavirus ◽  
Health Organization

An outbreak of a novel coronavirus, now named SARS-CoV-2, causing respiratory disease and a ∼2% case fatality rate started in Wuhan, China in December 2019. Following unprecedented rapid global spread, the World Health Organization declared COVID-19 a pandemic on March 11, 2020. Although data on disease in humans are emerging at a steady pace, certain aspects of the pathogenesis of SARS-CoV-2 can only be studied in detail in animal models, where repeated sampling and tissue collection is possible. Here, we show that SARS-CoV-2 causes respiratory disease in infected rhesus macaques, with disease lasting 8-16 days. Pulmonary infiltrates, a hallmark of human disease, were visible in lung radiographs of all animals. High viral loads were detected in swabs from the nose and throat of all animals as well as in bronchoalveolar lavages; in one animal we observed prolonged rectal shedding. Taken together, the rhesus macaque recapitulates moderate disease observed in the majority of human cases. The establishment of the rhesus macaque as a model of COVID-19 will increase our understanding of the pathogenesis of this disease and will aid development and testing of medical countermeasures.

scholarly journals Robust IgM responses following intravenous vaccination with Bacille Calmette–Guérin associate with prevention of Mycobacterium tuberculosis infection in macaques

2021 ◽  
Author(s):  
Edward B. Irvine ◽  
Anthony O’Neil ◽  
Patricia A. Darrah ◽  
Sally Shin ◽  
Alok Choudhary ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Rhesus Macaques ◽  
Antibody Responses ◽  
Bacterial Burden ◽  
Complete Protection ◽  
Mycobacterium Tuberculosis Infection ◽  
Bacille Calmette Guerin ◽  
Correlates Of Protection ◽  
Antibody Titers

AbstractDevelopment of an effective tuberculosis (TB) vaccine has suffered from an incomplete understanding of the correlates of protection against Mycobacterium tuberculosis (Mtb). Intravenous (i.v.) vaccination with Bacille Calmette–Guérin (BCG) provides nearly complete protection against TB in rhesus macaques, but the antibody response it elicits remains incompletely defined. Here we show that i.v. BCG drives superior antibody responses in the plasma and the lungs of rhesus macaques compared to traditional intradermal BCG administration. While i.v. BCG broadly expands antibody titers and functions, IgM titers in the plasma and lungs of immunized macaques are among the strongest markers of reduced bacterial burden. IgM was also enriched in macaques that received protective vaccination with an attenuated strain of Mtb. Finally, an Mtb-specific IgM monoclonal antibody reduced Mtb survival in vitro. Collectively, these data highlight the potential importance of IgM responses as a marker and mediator of protection against TB.

scholarly journals An HIV Envelope gp120-Fc Fusion Protein Elicits Effector Antibody Responses in Rhesus Macaques

2017 ◽  
Vol 24 (6) ◽  
Author(s):  
Zhanna Shubin ◽  
Weizhong Li ◽  
Bhawna Poonia ◽  
Guido Ferrari ◽  
Celia LaBranche ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Rhesus Macaque ◽  
Germ Line ◽  
Rhesus Macaques ◽  
Serum Antibody ◽  
Antibody Responses ◽  
Immunization Study ◽  
Monomeric Gp120 ◽  
Protective Antibodies ◽  
Hiv Envelope

ABSTRACT A goal for HIV prevention programs is to develop safe, effective vaccines that elicit durable and broadly protective antibodies. Many vaccine programs focus on the immune responses to critical epitopes in the gp120 portion of HIV envelope glycoprotein (Env) and seek to improve the quality and quantity of antibodies by altering the sequence, conformation, oligomerization, or glycosylation of gp120 to activate appropriate germ line B cells and mimic the subsequent maturation pathways seen in infected individuals. As a complement to these strategies, we developed dimeric fusion protein immunogens consisting of HIVBaL gp120 monomer attached to a Gly/Ser linker that is, in turn, fused to one half of the dimeric Fc domain from rhesus macaque IgG1 (Env-rFc). We envisioned that Env-rFc may mimic some aspects of immune complexes by binding Fc gamma receptors (FcγRs) on immune cells to increase the strength, breadth, and durability of Env-specific antibody responses. The Env-rFc retained a capacity to bind both cell surface CD4 and FcγRs. In a rhesus macaque immunization study, Env-rFc elicited higher gp120 binding antibody titers than Env and elicited antibodies that recognize CD4-induced epitopes. Env-rFc also induced antibodies capable of neutralizing tier 1A HIV pseudotyped viruses and mediating antibody-dependent cellular cytotoxicity, outcomes not observed with monomeric gp120 in our study. Serum antibodies produced in Env-rFc-immunized macaques had increased durability compared to that of Env monomer immunization. Our work suggests that adding IgG1 Fc to Env-based immunogens may stimulate increased effector capacity in the immune sera and improve the protective serum antibody response.

scholarly journals SARS-CoV-2 protein subunit vaccination elicits potent neutralizing antibody responses

2020 ◽  
Author(s):  
Marco Mandolesi ◽  
Daniel J Sheward ◽  
Leo Hanke ◽  
Junjie Ma ◽  
Pradeepa Pushparaj ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Host Cells ◽  
High Dose ◽  
Protein Subunit ◽  
High Dose Regimen ◽  
Antibody Titers ◽  
Protein Immunization

The outbreak and spread of SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2), the cause of coronavirus disease 2019 (COVID-19), is a current global health emergency and a prophylactic vaccine is needed urgently. The spike glycoprotein of SARS-CoV-2 mediates entry into host cells, and thus is a target for neutralizing antibodies and vaccine design. Here we show that adjuvanted protein immunization with SARS-CoV-2 spike trimers, stabilized in prefusion conformation, results in potent antibody responses in mice and rhesus macaques with neutralizing antibody titers orders of magnitude greater than those typically measured in serum from SARS-CoV-2 seropositive humans. Neutralizing antibody responses were observed after a single dose, with exceptionally high titers achieved after boosting. Furthermore, neutralizing antibody titers elicited by a dose-sparing regimen in mice were similar to those obtained from a high dose regimen. Taken together, these data strongly support the development of adjuvanted SARS-CoV-2 prefusion-stabilized spike protein subunit vaccines.

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