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1.
Med (N Y) ; 3(3): 157-158, 2022 03 11.
Article in English | MEDLINE | ID: covidwho-1734815

ABSTRACT

The therapeutic and prophylactic uses of monoclonal antibodies (mABs) against SARS-CoV-2 are limited by their short half-life and need for intravenous delivery. In this issue, Cobb et al.1 engineer a neutralizing mAB cocktail with extended half-life that can be delivered intramuscularly to provide prophylactic protection against infection in rhesus macaques.


Subject(s)
Antineoplastic Agents, Immunological , COVID-19 , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , COVID-19/prevention & control , Humans , Macaca fascicularis/immunology , Macaca mulatta/immunology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology
2.
Nature ; 601(7893): 410-414, 2022 01.
Article in English | MEDLINE | ID: covidwho-1521758

ABSTRACT

The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans1. CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression. Here we report the results of a head-to-head comparison of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in non-human primates. We immunized 18 cynomolgus macaques with two doses of 12 µg lipid nanoparticle-formulated CVnCoV or CV2CoV or with sham (n = 6 per group). Compared with CVnCoV, CV2CoV induced substantially higher titres of binding and neutralizing antibodies, memory B cell responses and T cell responses as well as more potent neutralizing antibody responses against SARS-CoV-2 variants, including the Delta variant. Moreover, CV2CoV was found to be comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. Although CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tracts. Binding and neutralizing antibody titres were correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in non-human primates.


Subject(s)
COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine , Nucleosides/chemistry , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology , /immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/standards , Female , Macaca fascicularis/immunology , Male , Nucleosides/genetics , Respiratory System/immunology , Respiratory System/virology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Vaccines, Synthetic/standards , Viral Load , /standards
3.
Proc Natl Acad Sci U S A ; 118(43)2021 10 26.
Article in English | MEDLINE | ID: covidwho-1462067

ABSTRACT

The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global threat to human health and life. A useful pathological animal model accurately reflecting human pathology is needed to overcome the COVID-19 crisis. In the present study, COVID-19 cynomolgus monkey models including monkeys with underlying diseases causing severe pathogenicity such as metabolic disease and elderly monkeys were examined. Cynomolgus macaques with various clinical conditions were intranasally and/or intratracheally inoculated with SARS-CoV-2. Infection with SARS-CoV-2 was found in mucosal swab samples, and a higher level and longer period of viral RNA was detected in elderly monkeys than in young monkeys. Pneumonia was confirmed in all of the monkeys by computed tomography images. When monkeys were readministrated SARS-CoV-2 at 56 d or later after initial infection all of the animals showed inflammatory responses without virus detection in swab samples. Surprisingly, in elderly monkeys reinfection showed transient severe pneumonia with increased levels of various serum cytokines and chemokines compared with those in primary infection. The results of this study indicated that the COVID-19 cynomolgus monkey model reflects the pathophysiology of humans and would be useful for elucidating the pathophysiology and developing therapeutic agents and vaccines.


Subject(s)
COVID-19/immunology , Disease Models, Animal , Macaca fascicularis/immunology , Primate Diseases/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/virology , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Lung/diagnostic imaging , Lung/immunology , Lung/virology , Macaca fascicularis/virology , Male , Primate Diseases/virology , SARS-CoV-2/physiology , Tomography, X-Ray Computed/methods , Virus Shedding/immunology , Virus Shedding/physiology
4.
PLoS Pathog ; 17(7): e1009668, 2021 07.
Article in English | MEDLINE | ID: covidwho-1388961

ABSTRACT

SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8+ T-cell responses in convalescent individuals, the role of virus-specific CD8+ T-cell responses in the control of SARS-CoV-2 replication remains unknown. In the present study, we show that subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques. Eight macaques were intranasally inoculated with 105 or 106 TCID50 of SARS-CoV-2, and three of the eight macaques were treated with a monoclonal anti-CD8 antibody on days 5 and 7 post-infection. In these three macaques, CD8+ T cells were undetectable on day 7 and thereafter, while virus-specific CD8+ T-cell responses were induced in the remaining five untreated animals. Viral RNA was detected in nasopharyngeal swabs for 10-17 days post-infection in all macaques, and the kinetics of viral RNA levels in pharyngeal swabs and plasma neutralizing antibody titers were comparable between the anti-CD8 antibody treated and untreated animals. SARS-CoV-2 RNA was detected in the pharyngeal mucosa and/or retropharyngeal lymph node obtained at necropsy on day 21 in two of the untreated group but undetectable in all macaques treated with anti-CD8 antibody. CD8+ T-cell responses may contribute to viral control in SARS-CoV-2 infection, but our results indicate possible containment of subacute viral replication in the absence of CD8+ T cells, implying that CD8+ T-cell dysfunction may not solely lead to viral control failure.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/veterinary , Macaca fascicularis/immunology , Macaca fascicularis/virology , Monkey Diseases/immunology , Monkey Diseases/virology , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/immunology , COVID-19/virology , Disease Models, Animal , Female , Humans , Kinetics , Lymphocyte Depletion/veterinary , Male , RNA, Viral/genetics , RNA, Viral/metabolism , SARS-CoV-2/genetics , Virus Replication/immunology
5.
Nature ; 590(7845): 320-325, 2021 02.
Article in English | MEDLINE | ID: covidwho-953381

ABSTRACT

The expanding pandemic of coronavirus disease 2019 (COVID-19) requires the development of safe, efficacious and fast-acting vaccines. Several vaccine platforms are being leveraged for a rapid emergency response1. Here we describe the development of a candidate vaccine (YF-S0) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express a noncleavable prefusion form of the SARS-CoV-2 spike antigen. We assess vaccine safety, immunogenicity and efficacy in several animal models. YF-S0 has an excellent safety profile and induces high levels of SARS-CoV-2 neutralizing antibodies in hamsters (Mesocricetus auratus), mice (Mus musculus) and cynomolgus macaques (Macaca fascicularis), and-concomitantly-protective immunity against yellow fever virus. Humoral immunity is complemented by a cellular immune response with favourable T helper 1 polarization, as profiled in mice. In a hamster model2 and in macaques, YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose conferred protection from lung disease in most of the vaccinated hamsters within as little as 10 days. Taken together, the quality of the immune responses triggered and the rapid kinetics by which protective immunity can be attained after a single dose warrant further development of this potent SARS-CoV-2 vaccine candidate.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Genetic Vectors/genetics , SARS-CoV-2/immunology , Vaccines, Attenuated/immunology , Yellow Fever Vaccine/genetics , Animals , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/genetics , Cricetinae , Disease Models, Animal , Female , Glycosylation , Macaca fascicularis/genetics , Macaca fascicularis/immunology , Macaca fascicularis/virology , Male , Mesocricetus/genetics , Mesocricetus/immunology , Mesocricetus/virology , Mice , Safety , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Vaccines, Attenuated/administration & dosage , Vaccines, Attenuated/adverse effects , Vaccines, Attenuated/genetics
6.
Signal Transduct Target Ther ; 5(1): 157, 2020 10 19.
Article in English | MEDLINE | ID: covidwho-724972

ABSTRACT

Identification of a suitable nonhuman primate (NHP) model of COVID-19 remains challenging. Here, we characterized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in three NHP species: Old World monkeys Macaca mulatta (M. mulatta) and Macaca fascicularis (M. fascicularis) and New World monkey Callithrix jacchus (C. jacchus). Infected M. mulatta and M. fascicularis showed abnormal chest radiographs, an increased body temperature and a decreased body weight. Viral genomes were detected in swab and blood samples from all animals. Viral load was detected in the pulmonary tissues of M. mulatta and M. fascicularis but not C. jacchus. Furthermore, among the three animal species, M. mulatta showed the strongest response to SARS-CoV-2, including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues. Collectively, these data revealed the different susceptibilities of Old World and New World monkeys to SARS-CoV-2 and identified M. mulatta as the most suitable for modeling COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , Callithrix/virology , Coronavirus Infections/epidemiology , Disease Models, Animal , Macaca fascicularis/virology , Macaca mulatta/virology , Pandemics , Pneumonia, Viral/epidemiology , Animals , Antibodies, Viral/biosynthesis , Betacoronavirus/immunology , Body Temperature , Body Weight , COVID-19 , Callithrix/immunology , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokines/biosynthesis , Cytokines/classification , Cytokines/immunology , Disease Susceptibility , Female , Humans , Lung/diagnostic imaging , Lung/immunology , Lung/pathology , Lung/virology , Macaca fascicularis/immunology , Macaca mulatta/immunology , Male , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , SARS-CoV-2 , Species Specificity , Tomography, X-Ray Computed , Viral Load , Virus Replication
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