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1.
Vet Pathol ; 59(4): 648-660, 2022 07.
Article in English | MEDLINE | ID: covidwho-1832989

ABSTRACT

There is a need to standardize pathologic endpoints in animal models of SARS-CoV-2 infection to help benchmark study quality, improve cross-institutional comparison of data, and assess therapeutic efficacy so that potential drugs and vaccines for SARS-CoV-2 can rapidly advance. The Syrian hamster model is a tractable small animal model for COVID-19 that models clinical disease in humans. Using the hamster model, the authors used traditional pathologic assessment with quantitative image analysis to assess disease outcomes in hamsters administered polyclonal immune sera from previously challenged rhesus macaques. The authors then used quantitative image analysis to assess pathologic endpoints across studies performed at different institutions using different tissue processing protocols. The authors detail pathological features of SARS-CoV-2 infection longitudinally and use immunohistochemistry to quantify myeloid cells and T lymphocyte infiltrates during SARS-CoV-2 infection. High-dose immune sera protected hamsters from weight loss and diminished viral replication in tissues and reduced lung lesions. Cumulative pathology scoring correlated with weight loss and was robust in distinguishing IgG efficacy. In formalin-infused lungs, quantitative measurement of percent area affected also correlated with weight loss but was less robust in non-formalin-infused lungs. Longitudinal immunohistochemical assessment of interstitial macrophage infiltrates showed that peak infiltration corresponded to weight loss, yet quantitative assessment of macrophage, neutrophil, and CD3+ T lymphocyte numbers did not distinguish IgG treatment effects. Here, the authors show that quantitative image analysis was a useful adjunct tool for assessing SARS-CoV-2 treatment outcomes in the hamster model.


Subject(s)
COVID-19 , Rodent Diseases , Animals , COVID-19/veterinary , COVID-19 Vaccines , Cricetinae , Disease Models, Animal , Humans , Immune Sera , Immunoglobulin G , Lung/pathology , Macaca mulatta , Mesocricetus , Rodent Diseases/pathology , SARS-CoV-2 , Weight Loss
2.
Med (N Y) ; 3(4): 262-268.e4, 2022 04 08.
Article in English | MEDLINE | ID: covidwho-1829236

ABSTRACT

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant has proven to be highly transmissible and has outcompeted the Delta variant in many regions of the world. Early reports have also suggested that Omicron may result in less severe clinical disease in humans. Here, we show that Omicron is less pathogenic than prior SARS-CoV-2 variants in Syrian golden hamsters. Methods: Hamsters were inoculated with either SARS-CoV-2 Omicron or other SARS-CoV-2 variants. Animals were followed for weight loss, and upper and lower respiratory tract tissues were assessed for viral loads and histopathology. Findings: Infection of hamsters with the SARS-CoV-2 WA1/2020, Alpha, Beta, or Delta strains led to 4%-10% weight loss by day 4 and 10%-17% weight loss by day 6. In contrast, infection of hamsters with two different Omicron challenge stocks did not result in any detectable weight loss, even at high challenge doses. Omicron infection led to substantial viral replication in both the upper and lower respiratory tracts but demonstrated lower viral loads in lung parenchyma and reduced pulmonary pathology compared with WA1/2020 infection. Conclusions: These data suggest that the SARS-CoV-2 Omicron variant may result in robust upper respiratory tract infection, but less severe lower respiratory tract clinical disease, compared with prior SARS-CoV-2 variants. Funding: Funding for this study was provided by NIH grant CA260476, the Massachusetts Consortium for Pathogen Readiness, the Ragon Institute, and the Musk Foundation.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Cricetinae , SARS-CoV-2/genetics , Virulence , Weight Loss
3.
Sci Adv ; 8(11): eabl6015, 2022 Mar 18.
Article in English | MEDLINE | ID: covidwho-1745843

ABSTRACT

Authorized vaccines against SARS-CoV-2 remain less available in low- and middle-income countries due to insufficient supply, high costs, and storage requirements. Global immunity could still benefit from new vaccines using widely available, safe adjuvants, such as alum and protein subunits, suited to low-cost production in existing manufacturing facilities. Here, a clinical-stage vaccine candidate comprising a SARS-CoV-2 receptor binding domain-hepatitis B surface antigen virus-like particle elicited protective immunity in cynomolgus macaques. Titers of neutralizing antibodies (>104) induced by this candidate were above the range of protection for other licensed vaccines in nonhuman primates. Including CpG 1018 did not significantly improve the immunological responses. Vaccinated animals challenged with SARS-CoV-2 showed reduced median viral loads in bronchoalveolar lavage (~3.4 log10) and nasal mucosa (~2.9 log10) versus sham controls. These data support the potential benefit of this design for a low-cost modular vaccine platform for SARS-CoV-2 and other variants of concern or betacoronaviruses.

4.
Sci Transl Med ; 13(618): eabj2641, 2021 Nov 03.
Article in English | MEDLINE | ID: covidwho-1546435

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that result in increased transmissibility and partial evasion of neutralizing antibodies have recently emerged. Whether natural immunity induced by the original SARS-CoV-2 WA1/2020 strain protects against rechallenge with these SARS-CoV-2 variants remains a critical unresolved question. In this study, we show that natural immunity induced by the WA1/2020 strain leads to partial but incomplete protection against the SARS-CoV-2 variants B.1.1.7 (alpha) and B.1.351 (beta) in rhesus macaques. We challenged rhesus macaques with B.1.1.7 and B.1.351 and showed that infection with these variants resulted in high viral replication in the upper and lower respiratory tract. We then infected rhesus macaques with the WA1/2020 strain and rechallenged them on day 35 with the WA1/2020, B.1.1.7, or B.1.351 variants. Natural immunity to WA1/2020 led to robust protection against rechallenge with WA1/2020 but only partial protection against rechallenge with B.1.351. An intermediate degree of protection was observed in rhesus macaques against rechallenge with B.1.1.7. These data demonstrate partial but incomplete protective efficacy of natural immunity induced by WA1/2020 against SARS-CoV-2 variants of concern. Our findings have important implications for both vaccination and public health strategies in the context of emerging SARS-CoV-2 variants of concern.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Neutralizing , Antibodies, Viral , Humans , Macaca mulatta , Reinfection
5.
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
6.
J Virol ; 96(2): e0159921, 2022 01 26.
Article in English | MEDLINE | ID: covidwho-1494959

ABSTRACT

Live oral vaccines have been explored for their protective efficacy against respiratory viruses, particularly for adenovirus serotypes 4 and 7. The potential of a live oral vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, remains unclear. In this study, we assessed the immunogenicity of live SARS-CoV-2 delivered to the gastrointestinal tract in rhesus macaques and its protective efficacy against intranasal and intratracheal SARS-CoV-2 challenge. Postpyloric administration of SARS-CoV-2 by esophagogastroduodenoscopy resulted in limited virus replication in the gastrointestinal tract and minimal to no induction of mucosal antibody titers in rectal swabs, nasal swabs, and bronchoalveolar lavage fluid. Low levels of serum neutralizing antibodies were induced and correlated with modestly diminished viral loads in nasal swabs and bronchoalveolar lavage fluid following intranasal and intratracheal SARS-CoV-2 challenge. Overall, our data show that postpyloric inoculation of live SARS-CoV-2 is weakly immunogenic and confers partial protection against respiratory SARS-CoV-2 challenge in rhesus macaques. IMPORTANCE SARS-CoV-2 remains a global threat, despite the rapid deployment but limited coverage of multiple vaccines. Alternative vaccine strategies that have favorable manufacturing timelines, greater ease of distribution, and improved coverage may offer significant public health benefits, especially in resource-limited settings. Live oral vaccines have the potential to address some of these limitations; however, no studies have yet been conducted to assess the immunogenicity and protective efficacy of a live oral vaccine against SARS-CoV-2. Here, we report that oral administration of live SARS-CoV-2 in nonhuman primates may offer prophylactic benefits, but the formulation and route of administration will require further optimization.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Administration, Oral , Animals , Female , Macaca mulatta , Male
7.
Sci Transl Med ; 13(618): eabj3789, 2021 Nov 03.
Article in English | MEDLINE | ID: covidwho-1494936

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged and may pose a threat to both the efficacy of vaccines based on the original WA1/2020 strain and the natural immunity induced by infection with earlier SARS-CoV-2 variants. We investigated how mutations in the spike protein of circulating SARS-CoV-2 variants, which have been shown to partially evade neutralizing antibodies, affect natural and vaccine-induced immunity. We adapted a Syrian hamster model of moderate to severe clinical disease for two variant strains of SARS-CoV-2: B.1.1.7 (alpha variant) and B.1.351 (beta variant). We then assessed the protective efficacy conferred by either natural immunity from WA1/2020 infection or by vaccination with a single dose of the adenovirus serotype 26 vaccine, Ad26.COV2.S. Primary infection with the WA1/2020 strain provided potent protection against weight loss and viral replication in lungs after rechallenge with WA1/2020, B.1.1.7, or B.1.351. Ad26.COV2.S induced cross-reactive binding and neutralizing antibodies that were reduced against the B.1.351 strain compared with WA1/2020 but nevertheless still provided robust protection against B.1.351 challenge, as measured by weight loss and pathology scoring in the lungs. Together, these data support hamsters as a preclinical model to study protection against emerging variants of SARS-CoV-2 conferred by prior infection or vaccination.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , COVID-19 Vaccines , Cricetinae , Humans , Vaccination
8.
Nature ; 596(7872): 423-427, 2021 08.
Article in English | MEDLINE | ID: covidwho-1279884

ABSTRACT

The emergence of SARS-CoV-2 variants that partially evade neutralizing antibodies poses a threat to the efficacy of current COVID-19 vaccines1,2. The Ad26.COV2.S vaccine expresses a stabilized spike protein from the WA1/2020 strain of SARS-CoV-2, and has recently demonstrated protective efficacy against symptomatic COVID-19 in humans in several geographical regions-including in South Africa, where 95% of sequenced viruses in cases of COVID-19 were the B.1.351 variant3. Here we show that Ad26.COV2.S elicits humoral and cellular immune responses that cross-react with the B.1.351 variant and protects against B.1.351 challenge in rhesus macaques. Ad26.COV2.S induced lower binding and neutralizing antibodies against B.1.351 as compared to WA1/2020, but elicited comparable CD8 and CD4 T cell responses against the WA1/2020, B.1.351, B.1.1.7, P.1 and CAL.20C variants. B.1.351 infection of control rhesus macaques resulted in higher levels of virus replication in bronchoalveolar lavage and nasal swabs than did WA1/2020 infection. Ad26.COV2.S provided robust protection against both WA1/2020 and B.1.351, although we observed higher levels of virus in vaccinated macaques after B.1.351 challenge. These data demonstrate that Ad26.COV2.S provided robust protection against B.1.351 challenge in rhesus macaques. Our findings have important implications for vaccine control of SARS-CoV-2 variants of concern.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , COVID-19/virology , Immunity, Cellular , Immunity, Humoral , Macaca mulatta/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Bronchoalveolar Lavage Fluid/virology , COVID-19/immunology , COVID-19/pathology , Female , Macaca mulatta/virology , Male , Nose/virology , SARS-CoV-2/growth & development , SARS-CoV-2/pathogenicity , T-Lymphocytes/immunology , Virus Replication
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