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1.
Front Immunol ; 12: 645210, 2021.
Article in English | MEDLINE | ID: covidwho-1383856

ABSTRACT

Vaccination is one of the most efficient public healthcare measures to fight infectious diseases. Nevertheless, the immune mechanisms induced in vivo by vaccination are still unclear. The route of administration, an important vaccination parameter, can substantially modify the quality of the response. How the route of administration affects the generation and profile of immune responses is of major interest. Here, we aimed to extensively characterize the profiles of the innate and adaptive response to vaccination induced after intradermal, subcutaneous, or intramuscular administration with a modified vaccinia virus Ankara model vaccine in non-human primates. The adaptive response following subcutaneous immunization was clearly different from that following intradermal or intramuscular immunization. The subcutaneous route induced a higher level of neutralizing antibodies than the intradermal and intramuscular vaccination routes. In contrast, polyfunctional CD8+ T-cell responses were preferentially induced after intradermal or intramuscular injection. We observed the same dichotomy when analyzing the early molecular and cellular immune events, highlighting the recruitment of cell populations, such as CD8+ T lymphocytes and myeloid-derived suppressive cells, and the activation of key immunomodulatory gene pathways. These results demonstrate that the quality of the vaccine response induced by an attenuated vaccine is shaped by early and subtle modifications of the innate immune response. In this immunization context, the route of administration must be tailored to the desired type of protective immune response. This will be achieved through systems vaccinology and mathematical modeling, which will be critical for predicting the efficacy of the vaccination route for personalized medicine.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , CD8-Positive T-Lymphocytes/immunology , Myeloid-Derived Suppressor Cells/immunology , Vaccination , Vaccinia virus/immunology , Vaccinia/immunology , Viral Vaccines/pharmacology , Animals , Injections, Intradermal , Injections, Intramuscular , Macaca fascicularis , Male , Vaccines, Attenuated/pharmacology
2.
NPJ Vaccines ; 6(1): 50, 2021 Apr 09.
Article in English | MEDLINE | ID: covidwho-1387358

ABSTRACT

The development of an effective AIDS vaccine remains a challenge. Nucleoside-modified mRNAs formulated in lipid nanoparticles (mRNA-LNP) have proved to be a potent mode of immunization against infectious diseases in preclinical studies, and are being tested for SARS-CoV-2 in humans. A critical question is how mRNA-LNP vaccine immunogenicity compares to that of traditional adjuvanted protein vaccines in primates. Here, we show that mRNA-LNP immunization compared to protein immunization elicits either the same or superior magnitude and breadth of HIV-1 Env-specific polyfunctional antibodies. Immunization with mRNA-LNP encoding Zika premembrane and envelope or HIV-1 Env gp160 induces durable neutralizing antibodies for at least 41 weeks. Doses of mRNA-LNP as low as 5 µg are immunogenic in macaques. Thus, mRNA-LNP can be used to rapidly generate single or multi-component vaccines, such as sequential vaccines needed to protect against HIV-1 infection. Such vaccines would be as or more immunogenic than adjuvanted recombinant protein vaccines in primates.

3.
J Control Release ; 335: 237-246, 2021 07 10.
Article in English | MEDLINE | ID: covidwho-1233005

ABSTRACT

Lipid nanoparticles (LNP) are effective delivery vehicles for messenger RNA (mRNA) and have shown promise for vaccine applications. Yet there are no published reports detailing how LNP biophysical properties can impact vaccine performance. In our hands, a retrospective analysis of mRNA LNP vaccine in vivo studies revealed a relationship between LNP particle size and immunogenicity in mice using LNPs of various compositions. To further investigate this, we designed a series of studies to systematically change LNP particle size without altering lipid composition and evaluated biophysical properties and immunogenicity of the resulting LNPs. While small diameter LNPs were substantially less immunogenic in mice, all particle sizes tested yielded a robust immune response in non-human primates (NHP).


Subject(s)
Immunogenicity, Vaccine , Nanoparticles , Animals , Humans , Lipids , Mice , RNA, Messenger , Retrospective Studies
4.
Am J Primatol ; 83(6): e23255, 2021 06.
Article in English | MEDLINE | ID: covidwho-1269093

ABSTRACT

The novel coronavirus SARS-CoV-2, which in humans leads to the disease COVID-19, has caused global disruption and more than 2 million fatalities since it first emerged in late 2019. As we write, infection rates are at their highest point globally and are rising extremely rapidly in some areas due to more infectious variants. The primary target of SARS-CoV-2 is the cellular receptor angiotensin-converting enzyme-2 (ACE2). Recent sequence analyses of the ACE2 gene predict that many nonhuman primates are also likely to be highly susceptible to infection. However, the anticipated risk is not equal across the Order. Furthermore, some taxonomic groups show high ACE2 amino acid conservation, while others exhibit high variability at this locus. As an example of the latter, analyses of strepsirrhine primate ACE2 sequences to date indicate large variation among lemurs and lorises compared to other primate clades despite low sampling effort. Here, we report ACE2 gene and protein sequences for 71 individual strepsirrhines, spanning 51 species and 19 genera. Our study reinforces previous results while finding additional variability in other strepsirrhine species, and suggests several clades of lemurs have high potential susceptibility to SARS-CoV-2 infection. Troublingly, some species, including the rare and endangered aye-aye (Daubentonia madagascariensis), as well as those in the genera Avahi and Propithecus, may be at high risk. Given that lemurs are endemic to Madagascar and among the primates at highest risk of extinction globally, further understanding of the potential threat of COVID-19 to their health should be a conservation priority. All feasible actions should be taken to limit their exposure to SARS-CoV-2.


Subject(s)
COVID-19/veterinary , Lemur , Lorisidae , Primate Diseases/epidemiology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/epidemiology , Lemur/genetics , Lorisidae/genetics , Primate Diseases/virology , Risk Factors
5.
Sci Transl Med ; 13(593)2021 05 12.
Article in English | MEDLINE | ID: covidwho-1255516

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a public health threat for which preventive and therapeutic agents are urgently needed. Neutralizing antibodies are a key class of therapeutics that may bridge widespread vaccination campaigns and offer a treatment solution in populations less responsive to vaccination. Here, we report that high-throughput microfluidic screening of antigen-specific B cells led to the identification of LY-CoV555 (also known as bamlanivimab), a potent anti-spike neutralizing antibody from a hospitalized, convalescent patient with coronavirus disease 2019 (COVID-19). Biochemical, structural, and functional characterization of LY-CoV555 revealed high-affinity binding to the receptor-binding domain, angiotensin-converting enzyme 2 binding inhibition, and potent neutralizing activity. A pharmacokinetic study of LY-CoV555 conducted in cynomolgus monkeys demonstrated a mean half-life of 13 days and a clearance of 0.22 ml hour-1 kg-1, consistent with a typical human therapeutic antibody. In a rhesus macaque challenge model, prophylactic doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract in samples collected through study day 6 after viral inoculation. This antibody has entered clinical testing and is being evaluated across a spectrum of COVID-19 indications, including prevention and treatment.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral/immunology , COVID-19 , Animals , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19/prevention & control , Macaca mulatta , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology
6.
Front Plant Sci ; 12: 682953, 2021.
Article in English | MEDLINE | ID: covidwho-1247902

ABSTRACT

The emergence of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected global public health and economy. Despite the substantial efforts, only few vaccines are currently approved and some are in the different stages of clinical trials. As the disease rapidly spreads, an affordable and effective vaccine is urgently needed. In this study, we investigated the immunogenicity of plant-produced receptor-binding domain (RBD) of SARS-CoV-2 in order to use as a subunit vaccine. In this regard, RBD of SARS-CoV-2 was fused with Fc fragment of human IgG1 and transiently expressed in Nicotiana benthamiana by agroinfiltration. The plant-produced RBD-Fc fusion protein was purified from the crude extract by using protein A affinity column chromatography. Two intramuscular administration of plant-produced RBD-Fc protein formulated with alum as an adjuvant have elicited high neutralization titers in immunized mice and cynomolgus monkeys. Further it has induced a mixed Th1/Th2 immune responses and vaccine-specific T-lymphocyte responses which was confirmed by interferon-gamma (IFN-γ) enzyme-linked immunospot assay. Altogether, our results demonstrated that the plant-produced SARS-CoV-2 RBD has the potential to be used as an effective vaccine candidate against SARS-CoV-2. To our knowledge, this is the first report demonstrating the immunogenicity of plant-produced SARS-CoV-2 RBD protein in mice and non-human primates.

7.
Nature ; 594(7862): 253-258, 2021 06.
Article in English | MEDLINE | ID: covidwho-1192479

ABSTRACT

The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative1. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).


Subject(s)
Adjuvants, Immunologic , Antibodies, Neutralizing/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Vaccines, Subunit/immunology , Alum Compounds , Animals , Antibodies, Viral/immunology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , COVID-19/virology , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Disease Models, Animal , Immunity, Cellular , Immunity, Humoral , Macaca mulatta/immunology , Male , Oligodeoxyribonucleotides , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Squalene
8.
Virol Sin ; 36(5): 879-889, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1174014

ABSTRACT

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused more than 96 million infections and over 2 million deaths worldwide so far. However, there is no approved vaccine available for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the disease causative agent. Vaccine is the most effective approach to eradicate a pathogen. The tests of safety and efficacy in animals are pivotal for developing a vaccine and before the vaccine is applied to human populations. Here we evaluated the safety, immunogenicity, and efficacy of an inactivated vaccine based on the whole viral particles in human ACE2 transgenic mouse and in non-human primates. Our data showed that the inactivated vaccine successfully induced SARS-CoV-2-specific neutralizing antibodies in mice and non-human primates, and subsequently provided partial (in low dose) or full (in high dose) protection of challenge in the tested animals. In addition, passive serum transferred from vaccine-immunized mice could also provide full protection from SARS-CoV-2 infection in mice. These results warranted positive outcomes in future clinical trials in humans.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19 , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/prevention & control , Mice , Mice, Transgenic , Primates , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccines, Inactivated/immunology
9.
Vaccines (Basel) ; 9(3)2021 Mar 19.
Article in English | MEDLINE | ID: covidwho-1167773

ABSTRACT

Non-human primates (NHPs) are used extensively in the development of vaccines and therapeutics for human disease. High standards in the design, conduct, and reporting of NHP vaccine studies are crucial for maximizing their scientific value and translation, and for making efficient use of precious resources. A key aspect is consideration of the 3Rs principles of replacement, reduction, and refinement. Funders of NHP research are placing increasing emphasis on the 3Rs, helping to ensure such studies are legitimate, ethical, and high-quality. The UK's National Centre for the 3Rs (NC3Rs) and the Coalition for Epidemic Preparedness Innovations (CEPI) have collaborated on a range of initiatives to support vaccine developers to implement the 3Rs, including hosting an international workshop in 2019. The workshop identified opportunities to refine NHP vaccine studies to minimize harm and improve welfare, which can yield better quality, more reproducible data. Careful animal selection, social housing, extensive environmental enrichment, training for cooperation with husbandry and procedures, provision of supportive care, and implementation of early humane endpoints are features of contemporary good practice that should and can be adopted more widely. The requirement for high-level biocontainment for some pathogens imposes challenges to implementing refinement but these are not insurmountable.

10.
Cell Rep Med ; 2(4): 100230, 2021 04 20.
Article in English | MEDLINE | ID: covidwho-1147272

ABSTRACT

The deployment of a vaccine that limits transmission and disease likely will be required to end the coronavirus disease 2019 (COVID-19) pandemic. We recently described the protective activity of an intranasally administered chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike (S) protein (ChAd-SARS-CoV-2-S [chimpanzee adenovirus-severe acute respiratory syndrome-coronavirus-2-S]) in the upper and lower respiratory tracts of mice expressing the human angiotensin-converting enzyme 2 (ACE2) receptor. Here, we show the immunogenicity and protective efficacy of this vaccine in non-human primates. Rhesus macaques were immunized with ChAd-Control or ChAd-SARS-CoV-2-S and challenged 1 month later by combined intranasal and intrabronchial routes with SARS-CoV-2. A single intranasal dose of ChAd-SARS-CoV-2-S induces neutralizing antibodies and T cell responses and limits or prevents infection in the upper and lower respiratory tracts after SARS-CoV-2 challenge. As ChAd-SARS-CoV-2-S confers protection in non-human primates, it is a promising candidate for limiting SARS-CoV-2 infection and transmission in humans.

11.
PeerJ ; 9: e10955, 2021.
Article in English | MEDLINE | ID: covidwho-1140797

ABSTRACT

BACKGROUND: Non-human primates (NHPs) play an important role in biomedical research, where they are often being re-used in multiple research studies over the course of their life-time. Researchers employ various study-specific screening criteria to reduce potential variables associated with subsequent re-use of NHPs. However, criteria set for NHP re-assignments largely neglect the impact of previous exposures on overall biology. Since the immune system is a key determinant of overall biological outcome, an altered biological state could be predicted by monitoring global changes in the immune profile. We postulate that every different exposure or a condition can generate a unique global immune profile in NHPs. METHODS: Changes in the global immune profile were evaluated in three different groups of rhesus macaques previously enrolled in dengue or malaria vaccine studies over six months after their last exposure. Naïve animals served as the baseline. Fresh blood samples were stained with various immune cell surface markers and analyzed by multi-color flow-cytometry to study immune cell dynamics in the peripheral blood. Serum cytokine profile in the pre-exposed animals were analyzed by mesoscale assay using a customized U-PLEX NHP biomarker panel of 12 cytokines/chemokines. RESULTS: Pre-exposed macaques showed altered dynamics in circulating cytokines and certain innate and adaptive immune cell subsets such as monocytes, HLA-DR+NKT cells, B cells and T cells. Some of these changes were transient, while some lasted for more than six months. Each group seemed to develop a global immune profile unique to their particular exposure. CONCLUSION: Our data strongly suggest that re-used NHPs should be evaluated for long-term, overall immunological changes and randomly assigned to new studies to avoid study bias.

12.
Mol Biol Evol ; 38(7): 2715-2731, 2021 06 25.
Article in English | MEDLINE | ID: covidwho-1121171

ABSTRACT

SARS-CoV-2 infects humans through the binding of viral S-protein (spike protein) to human angiotensin I converting enzyme 2 (ACE2). The structure of the ACE2-S-protein complex has been deciphered and we focused on the 27 ACE2 residues that bind to S-protein. From human sequence databases, we identified nine ACE2 variants at ACE2-S-protein binding sites. We used both experimental assays and protein structure analysis to evaluate the effect of each variant on the binding affinity of ACE2 to S-protein. We found one variant causing complete binding disruption, two and three variants, respectively, strongly and mildly reducing the binding affinity, and two variants strongly enhancing the binding affinity. We then collected the ACE2 gene sequences from 57 nonhuman primates. Among the 6 apes and 20 Old World monkeys (OWMs) studied, we found no new variants. In contrast, all 11 New World monkeys (NWMs) studied share four variants each causing a strong reduction in binding affinity, the Philippine tarsier also possesses three such variants, and 18 of the 19 prosimian species studied share one variant causing a strong reduction in binding affinity. Moreover, one OWM and three prosimian variants increased binding affinity by >50%. Based on these findings, we proposed that the common ancestor of primates was strongly resistant to and that of NWMs was completely resistant to SARS-CoV-2 and so is the Philippine tarsier, whereas apes and OWMs, like most humans, are susceptible. This study increases our understanding of the differences in susceptibility to SARS-CoV-2 infection among primates.


Subject(s)
COVID-19 , Disease Resistance/genetics , Peptidyl-Dipeptidase A , SARS-CoV-2 , Animals , COVID-19/genetics , COVID-19/immunology , Chlorocebus aethiops , Humans , Macaca mulatta , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology
13.
Viruses ; 13(2)2021 02 19.
Article in English | MEDLINE | ID: covidwho-1090286

ABSTRACT

Vaccine development against SARS-CoV-2 has been fierce due to the devastating COVID-19 pandemic and has included all potential approaches for providing the global community with safe and efficient vaccine candidates in the shortest possible timeframe. Viral vectors have played a central role especially using adenovirus-based vectors. Additionally, other viral vectors based on vaccinia viruses, measles viruses, rhabdoviruses, influenza viruses and lentiviruses have been subjected to vaccine development. Self-amplifying RNA virus vectors have been utilized for lipid nanoparticle-based delivery of RNA as COVID-19 vaccines. Several adenovirus-based vaccine candidates have elicited strong immune responses in immunized animals and protection against challenges in mice and primates has been achieved. Moreover, adenovirus-based vaccine candidates have been subjected to phase I to III clinical trials. Recently, the simian adenovirus-based ChAdOx1 vector expressing the SARS-CoV-2 S spike protein was approved for use in humans in the UK.


Subject(s)
Adenoviridae/immunology , COVID-19 Vaccines , COVID-19/prevention & control , Genetic Vectors/immunology , RNA, Viral/immunology , Viral Vaccines/immunology , Animals , Antibodies, Viral/immunology , Clinical Trials as Topic , Humans , Mice , Pandemics
14.
Lancet Microbe ; 1(1): e14-e23, 2020 05.
Article in English | MEDLINE | ID: covidwho-1087358

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported from China in January, 2020. SARS-CoV-2 is efficiently transmitted from person to person and, in 2 months, has caused more than 82 000 laboratory-confirmed cases of coronavirus disease 2019 (COVID-19) and 2800 deaths in 46 countries. The total number of cases and deaths has surpassed that of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Although both COVID-19 and severe acute respiratory syndrome (SARS) manifest as pneumonia, COVID-19 is associated with apparently more efficient transmission, fewer cases of diarrhoea, increased mental confusion, and a lower crude fatality rate. However, the underlying virus-host interactive characteristics conferring these observations on transmissibility and clinical manifestations of COVID-19 remain unknown. METHODS: We systematically investigated the cellular susceptibility, species tropism, replication kinetics, and cell damage of SARS-CoV-2 and compared findings with those for SARS-CoV. We compared SARS-CoV-2 and SARS-CoV replication in different cell lines with one-way ANOVA. For the area under the curve comparison between SARS-CoV-2 and SARS-CoV replication in Calu3 (pulmonary) and Caco2 (intestinal) cells, we used Student's t test. We analysed cell damage induced by SARS-CoV-2 and SARS-CoV with one-way ANOVA. FINDINGS: SARS-CoV-2 infected and replicated to comparable levels in human Caco2 cells and Calu3 cells over a period of 120 h (p=0·52). By contrast, SARS-CoV infected and replicated more efficiently in Caco2 cells than in Calu3 cells under the same multiplicity of infection (p=0·0098). SARS-CoV-2, but not SARS-CoV, replicated modestly in U251 (neuronal) cells (p=0·036). For animal species cell tropism, both SARS-CoV and SARS-CoV-2 replicated in non-human primate, cat, rabbit, and pig cells. SARS-CoV, but not SARS-CoV-2, infected and replicated in Rhinolophus sinicus bat kidney cells. SARS-CoV-2 consistently induced significantly delayed and milder levels of cell damage than did SARS-CoV in non-human primate cells (VeroE6, p=0·016; FRhK4, p=0·0004). INTERPRETATION: As far as we know, our study presents the first quantitative data for tropism, replication kinetics, and cell damage of SARS-CoV-2. These data provide novel insights into the lower incidence of diarrhoea, decreased disease severity, and reduced mortality in patients with COVID-19, with respect to the pathogenesis and high transmissibility of SARS-CoV-2 compared with SARS-CoV. FUNDING: May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, The Hong Kong Hainan Commercial Association South China Microbiology Research Fund, The Jessie & George Ho Charitable Foundation, Perfect Shape Medical, The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government, The Theme-Based Research Scheme of the Research Grants Council, Sanming Project of Medicine in Shenzhen, and The High Level-Hospital Program, Health Commission of Guangdong Province, China.


Subject(s)
COVID-19 , Animals , Caco-2 Cells , Diarrhea , Humans , Kinetics , Rabbits , SARS-CoV-2 , Swine , Tropism
16.
Indian J Med Res ; 153(1 & 2): 93-114, 2021.
Article in English | MEDLINE | ID: covidwho-1000418

ABSTRACT

BACKGROUND & OBJECTIVES: The COVID-19 pandemic has emerged as a global public health crisis and research groups worldwide are engaged in developing vaccine candidates to curb its transmission, with a few vaccines having progressed to advanced stages of clinical trials. The aim of this systematic review was to compare immunogenicity and protective efficacy of various SARS-CoV-2 vaccine candidates tested in non-human primate (NHP) models. METHODS: Literature on effect of SARS-CoV-2 vaccines in NHP models reported on PubMed and preprint platforms (medRxiv and bioRxiv) till October 22, 2020, was searched with the following terms: coronavirus vaccine, COVID-19 vaccine, SARS-CoV-2 vaccine, nonhuman primate, and rhesus macaque. RESULTS: Our search yielded 19 studies, which reported immune response elicited by 18 vaccine candidates in NHP. All the vaccines induced detectable neutralizing antibody (NAb) titres in the serum of vaccinated animals, with some showing effective viral clearance from various organs. The vaccinated animals also showed nil to mild histopathological changes in their lungs compared to placebo groups in the trials that performed necropsy. INTERPRETATION & CONCLUSIONS: Our findings highlighted onset of quick immunogenicity and protective efficacy of mRNA-1273, followed by Ad26.CoV2.S, NVX-CoV2373, BNT162b2, RBD and BBV152 vaccine candidates in preclinical trials as compared to the others. NHP data also showed correlation with clinical trial data available for a few vaccines. Preclinical trials of COVID-19 vaccine candidates in NHPs yielded promising results, with some candidates faring better than others.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine , Primates , 2019-nCoV Vaccine mRNA-1273 , Ad26COVS1 , Animals , Antibodies, Neutralizing , Antibodies, Viral , BNT162 Vaccine , Disease Models, Animal , Macaca mulatta
17.
Nat Commun ; 11(1): 6078, 2020 11 27.
Article in English | MEDLINE | ID: covidwho-947538

ABSTRACT

Understanding SARS-CoV-2 associated immune pathology is crucial to develop pan-effective vaccines and treatments. Here we investigate the immune events from the acute state up to four weeks post SARS-CoV-2 infection, in non-human primates (NHP) with heterogeneous pulmonary pathology. We show a robust migration of CD16 expressing monocytes to the lungs occurring during the acute phase, and we describe two subsets of interstitial macrophages (HLA-DR+CD206-): a transitional CD11c+CD16+ cell population directly associated with IL-6 levels in plasma, and a long-lasting CD11b+CD16+ cell population. Trafficking of monocytes is mediated by TARC (CCL17) and associates with viral load measured in bronchial brushes. We also describe associations between disease outcomes and high levels of cell infiltration in lungs including CD11b+CD16hi macrophages and CD11b+ neutrophils. Accumulation of macrophages is long-lasting and detectable even in animals with mild or no signs of disease. Interestingly, animals with anti-inflammatory responses including high IL-10:IL-6 and kynurenine to tryptophan ratios show less severe illness. Our results unravel cellular mechanisms of COVID-19 and suggest that NHP may be appropriate models to test immune therapies.


Subject(s)
COVID-19/immunology , Disease Models, Animal , Lung/immunology , SARS-CoV-2/immunology , Acute Disease , Animals , COVID-19/diagnosis , COVID-19/pathology , COVID-19/virology , Cytokines/metabolism , Disease Progression , Female , Humans , Lung/cytology , Lung/virology , Macaca mulatta/immunology , Macaca mulatta/virology , Macrophages/immunology , Male , Monocytes/immunology , Monocytes/metabolism , Neutrophils/immunology , Neutrophils/metabolism , SARS-CoV-2/isolation & purification , Severity of Illness Index , Viral Load/immunology , Virus Replication/immunology
18.
Acta Naturae ; 12(3): 114-123, 2020.
Article in English | MEDLINE | ID: covidwho-918830

ABSTRACT

The Middle East Respiratory Syndrome (MERS) is an acute inflammatory disease of the respiratory system caused by the MERS-CoV coronavirus. The mortality rate for MERS is about 34.5%. Due to its high mortality rate, the lack of therapeutic and prophylactic agents, and the continuing threat of the spread of MERS beyond its current confines, developing a vaccine is a pressing task, because vaccination would help limit the spread of MERS and reduce its death toll. We have developed a combined vector vaccine for the prevention of MERS based on recombinant human adenovirus serotypes 26 and 5. Studies of its immunogenicity have shown that vaccination of animals (mice and primates) induces a robust humoral immune response that lasts for at least six months. Studies of the cellular immune response in mice after vaccination showed the emergence of a specific CD4+ and CD8+ T cell response. A study of the vaccine protectivity conducted in a model of transgenic mice carrying the human DPP4 receptor gene showed that our vaccination protected 100% of the animals from the lethal infection caused by the MERS-CoV virus (MERS-CoV EMC/2012, 100LD50 per mouse). Studies of the safety and tolerability of the developed vaccine in rodents, rabbits, and primates showed a good safety profile and tolerance in animals; they revealed no contraindications for clinical testing.

19.
PeerJ ; 8: e9816, 2020.
Article in English | MEDLINE | ID: covidwho-908950

ABSTRACT

Currently, ~65% of extant primate species (ca 512 species) distributed in 91 countries in the Neotropics, mainland Africa, Madagascar, South Asia and Southeast Asia are threatened with extinction and 75% have declining populations as a result of deforestation and habitat loss resulting from increasing global market demands, and land conversion for industrial agriculture, cattle production and natural resource extraction. Other pressures that negatively impact primates are unsustainable bushmeat hunting, the illegal trade of primates as pets and as body parts, expanding road networks in previously isolated areas, zoonotic disease transmission and climate change. Here we examine current and future trends in several socio-economic factors directly or indirectly affecting primates to further our understanding of the interdependent relationship between human well-being, sustainable development, and primate population persistence. We found that between 2001 and 2018 ca 191 Mha of tropical forest (30% canopy cover) were lost as a result of human activities in the five primate range regions. Forty-six percent of this loss was in the Neotropics (Mexico, Central and South America), 30% in Southeast Asia, 21% in mainland Africa, 2% in Madagascar and 1% in South Asia. Countries with the greatest losses (ca 57% of total tree cover loss) were Brazil, Indonesia, DRC, China, and Malaysia. Together these countries harbor almost 50% of all extant primate species. In 2018, the world human population was estimated at ca 8bn people, ca 60% of which were found in primate range countries. Projections to 2050 and to 2100 indicate continued rapid growth of the human populations in these five primate range regions, with Africa surpassing all the other regions and totaling ca 4bn people by the year 2100. Socioeconomic indicators show that, compared to developed nations, most primate range countries are characterized by high levels of poverty and income inequality, low human development, low food security, high levels of corruption and weak governance. Models of Shared Socioeconomic Pathway scenarios (SSPs) projected to 2050 and 2100 showed that whereas practices of increasing inequality (SSP4) or unconstrained growth in economic output and energy use (SSP5) are projected to have dire consequences for human well-being and primate survivorship, practices of sustainability-focused growth and equality (SSP1) are expected to have a positive effect on maintaining biodiversity, protecting environments, and improving the human condition. These results stress that improving the well-being, health, and security of the current and future human populations in primate range countries are of paramount importance if we are to move forward with effective policies to protect the world's primate species and promote biodiversity conservation.

20.
Commun Biol ; 3(1): 641, 2020 10 27.
Article in English | MEDLINE | ID: covidwho-894423

ABSTRACT

The emergence of SARS-CoV-2 has caused over a million human deaths and massive global disruption. The viral infection may also represent a threat to our closest living relatives, nonhuman primates. The contact surface of the host cell receptor, ACE2, displays amino acid residues that are critical for virus recognition, and variations at these critical residues modulate infection susceptibility. Infection studies have shown that some primate species develop COVID-19-like symptoms; however, the susceptibility of most primates is unknown. Here, we show that all apes and African and Asian monkeys (catarrhines), exhibit the same set of twelve key amino acid residues as human ACE2. Monkeys in the Americas, and some tarsiers, lemurs and lorisoids, differ at critical contact residues, and protein modeling predicts that these differences should greatly reduce SARS-CoV-2 binding affinity. Other lemurs are predicted to be closer to catarrhines in their susceptibility. Our study suggests that apes and African and Asian monkeys, and some lemurs, are likely to be highly susceptible to SARS-CoV-2. Urgent actions have been undertaken to limit the exposure of great apes to humans, and similar efforts may be necessary for many other primate species.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/veterinary , Host Specificity/genetics , Pandemics/veterinary , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/veterinary , Primate Diseases/enzymology , Primates/genetics , Receptors, Virus/genetics , Amino Acid Sequence , Amino Acid Substitution , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/physiology , Biological Evolution , COVID-19 , Chiroptera/genetics , Conserved Sequence , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Genetic Predisposition to Disease , Mammals/genetics , Models, Molecular , Mutation, Missense , Peptidyl-Dipeptidase A/chemistry , Phylogeny , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Point Mutation , Primate Diseases/virology , Protein Binding , Protein Conformation , Risk , SARS-CoV-2 , Sequence Alignment , Sequence Homology, Amino Acid , Species Specificity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
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