scholarly journals Intranasal ChAdOx1 nCoV-19/AZD1222 vaccination reduces viral shedding after SARS-CoV-2 D614G challenge in preclinical models

2021 ◽  
pp. eabh0755
Author(s):  
Neeltje van Doremalen ◽  
Jyothi N. Purushotham ◽  
Jonathan E. Schulz ◽  
Myndi G. Holbrook ◽  
Trenton Bushmaker ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Direct Contact ◽  
Infectious Virus ◽  
Rhesus Macaques ◽  
Upper Respiratory Tract ◽  
Preclinical Models ◽  
Viral Loads ◽  
Viral Shedding ◽  
Nasal Swabs ◽  
Upper Respiratory

ChAdOx1 nCoV-19/AZD1222 is an approved adenovirus-based vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently being deployed globally. Previous studies in rhesus macaques revealed that intramuscular vaccination with ChAdOx1 nCoV-19/AZD1222 provided protection against pneumonia but did not reduce shedding of SARS-CoV-2 from the upper respiratory tract. Here, we investigated whether intranasally administered ChAdOx1 nCoV-19 reduces detection of virus in nasal swabs after challenging vaccinated macaques and hamsters with SARS-CoV-2 carrying a D614G mutation in the spike protein. Viral loads in swabs obtained from intranasally vaccinated hamsters were decreased compared to control hamsters, and no viral RNA or infectious virus was found in lung tissue after a direct challenge or after direct contact with infected hamsters. Intranasal vaccination of rhesus macaques resulted in reduced virus concentrations in nasal swabs and a reduction in viral loads in bronchoalveolar lavage and lower respiratory tract tissue. Intranasal vaccination with ChAdOx1 nCoV-19/AZD1222 reduced virus concentrations in nasal swabs in two different SARS-CoV-2 animal models, warranting further investigation as a potential vaccination route for COVID-19 vaccines.

scholarly journals Daily viral kinetics and innate and adaptive immune responses assessment in COVID-19: a case series

2020 ◽  
Author(s):  
Pauline Vetter ◽  
Christiane Eberhardt ◽  
Benjamin Meyer ◽  
Paola Andrea Martinez Murillo ◽  
Giulia Torriani ◽  
...  
Keyword(s):  
Immune Responses ◽  
Respiratory Tract ◽  
Infectious Virus ◽  
Upper Respiratory Tract ◽  
Innate Response ◽  
Viral Control ◽  
Adaptive Immune Responses ◽  
Viral Loads ◽  
Viral Shedding ◽  
Adaptive Immune

AbstractBackgroundViral shedding patterns and its correlation with the immune responses of mildly symptomatic COVID-19 patients are still poorly characterized.MethodsWe enrolled the first five COVID-19 patients quarantined in our institution; none received immunomodulatory treatment. We monitored shedding of viral RNA and infectious virus by RT-PCR and cell culture from the upper respiratory tract, and characterized the kinetics of systemic innate and adaptive immune responses.ResultsDespite mild clinical disease, high viral loads and shedding of infectious virus were observed from the respiratory tract, with isolation of infectious virus and prolonged positivity by PCR up to day 7 and 19 post onset of symptoms, respectively. Robust innate responses characterized by an increase in activated CD14+CD16+ monocytes and cytokine responses were observed as early as 2 days after symptoms onset. Cellular and humoral SARS-CoV-2 specific adaptive responses were detectable in all patients.ConclusionInfectious virus shedding was limited to the first week of symptom onset in mild cases. A strong innate response, characterized by the mobilization of activated monocytes during the first days of infection, as well as SARS-CoV-2 specific antibodies were detectable, even in patients with mild disease.SummaryWe describe viral and immune profiles of the first five SARS-CoV-2 patients in our institution, showing high viral loads and infectious viral shedding in early acute disease. Mild patients mount an innate response sufficient for viral control and specific immunity.

scholarly journals SARS-CoV-2 Infections in mRNA Vaccinated Individuals are Biased for Viruses Encoding Spike E484K and Associated with Reduced Infectious Virus Loads that Correlate with Respiratory Antiviral IgG levels.

2021 ◽  
Author(s):  
Heba H Mostafa ◽  
chun Huai Luo ◽  
C. Paul Morris ◽  
Maggie Li ◽  
Nicholas J Swanson ◽  
...  
Keyword(s):  
Cell Culture ◽  
Respiratory Tract ◽  
Large Scale ◽  
Infectious Virus ◽  
Time Frame ◽  
Molecular Testing ◽  
Upper Respiratory Tract ◽  
Symptomatic Infection ◽  
Viral Loads ◽  
Upper Respiratory

Abstract Introduction COVID-19 large scale immunization in the US has been associated with infrequent breakthrough positive molecular testing. Whether a positive test is associated with a high viral RNA load, specific viral variant, recovery of infectious virus, or symptomatic infection is largely not known. Methods In this study, we identified 133 SARS-CoV-2 positive patients who had received two doses of either Pfizer-BioNTech (BNT162b2) or Moderna (mRNA-1273) vaccines, the 2nd of which was received between January and April of 2021. The positive samples were collected between January and May of 2021 with a time that extended from 2 to 100 days after the second dose. Samples were sequenced to characterize the whole genome and Spike protein changes and cycle thresholds that reflect viral loads were determined using a single molecular assay. Local SARS-CoV-2 IgG antibodies were examined using ELISA and specimens were grown on cell culture to assess the recovery of infectious virus as compared to a control unvaccinated cohort from a matched time frame. Results Of 133 specimens, 24 failed sequencing and yielded a negative or very low viral load on the repeat PCR. Of 109 specimens that were used for further genome analysis, 68 (62.4%) were from symptomatic infections, 11 (10.1%) were admitted for COVID-19, and 2 (1.8%) required ICU admission with no associated mortality. The predominant virus variant was the alpha (B.1.1.7), however a significant association between lineage B.1.526 and amino acid change S: E484K with positives after vaccination was noted when genomes were compared to a large control cohort from a matched time frame. A significant reduction of the recovery of infectious virus on cell culture as well as delayed time to the first appearance of cytopathic effect was accompanied by an increase in local IgG levels in respiratory samples of vaccinated individuals but upper respiratory tract IgG levels were not different between symptomatic or asymptomatic infections. Conclusions Vaccination reduces the recovery of infectious virus in breakthrough infections accompanied by an increase in upper respiratory tract local immune responses.

scholarly journals Transmission and protection against re-infection in the ferret model with the SARS-CoV-2 USA-WA1/2020 reference isolate

2021 ◽  
Author(s):  
Devanshi R. Patel ◽  
Cassandra J. Field ◽  
Kayla M. Septer ◽  
Derek G. Sim ◽  
Matthew J. Jones ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Direct Contact ◽  
Reference Strain ◽  
Infectious Virus ◽  
Natural Infection ◽  
Upper Respiratory Tract ◽  
Nasal Wash ◽  
The Usa ◽  
Upper Respiratory ◽  
Mode Of Transmission

SARS-CoV-2 has initiated a global pandemic and several vaccines have now received emergency use authorization. Using the reference strain SARS-CoV-2 USA-WA1/2020, we evaluated modes of transmission and the ability of prior infection or vaccine-induced immunity to protect against infection in ferrets. Ferrets were semi-permissive to infection with the USA-WA1/2020 isolate. When transmission was assessed via the detection of vRNA at multiple timepoints, direct contact transmission was efficient to 3/3 and 3/4 contact animals in two respective studies, while respiratory droplet transmission was poor to only 1/4 contact animals. To determine if previously infected ferrets were protected against re-infection, ferrets were re-challenged 28 or 56 days post-infection. Following viral challenge, no infectious virus was recovered in nasal wash samples. In addition, levels of vRNA in the nasal wash were several orders of magnitude lower than during primary infection, and vRNA was rapidly cleared. To determine if intramuscular vaccination protected ferrets, ferrets were vaccinated using a prime-boost strategy with the S-protein receptor-binding domain formulated with an oil-in-water adjuvant. Upon viral challenge, none of the mock or vaccinated animals were protected against infection, and there were no significant differences in vRNA or infectious virus titers in the nasal wash. Combined these studies demonstrate that in ferrets direct contact is the predominant mode of transmission of the USA-WA1/2020 isolate and immunity to SARS-CoV-2 is maintained for at least 56 days. Our studies also indicate protection of the upper respiratory tract against SARS-CoV-2 will require vaccine strategies that mimic natural infection or induce site-specific immunity. Importance: The SARS-CoV-2 USA-WA1/2020 strain is a CDC reference strain used by multiple research laboratories. Here, we show the predominant mode of transmission of this isolate in ferrets is by direct contact. We further demonstrate ferrets are protected against re-infection for at least 56 days even when levels of neutralizing antibodies are low or undetectable. Last, we show that when ferrets were vaccinated by the intramuscular route to induce antibodies against SARS-CoV-2, ferrets remain susceptible to infection of the upper respiratory tract. Collectively, these studies suggest protection of the upper respiratory tract will require vaccine approaches that mimic natural infection.

scholarly journals Transmission and protection against re-infection in the ferret model with the SARS-CoV-2 USA-WA1/2020 reference isolate

2020 ◽  
Author(s):  
Devanshi R. Patel ◽  
Cassandra J. Field ◽  
Kayla M. Septer ◽  
Derek G. Sim ◽  
Matthew J. Jones ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Direct Contact ◽  
Primary Infection ◽  
Reference Strain ◽  
Infectious Virus ◽  
Natural Infection ◽  
Upper Respiratory Tract ◽  
Nasal Wash ◽  
Upper Respiratory ◽  
Mode Of Transmission

AbstractSARS-CoV-2 has initiated a global pandemic and vaccines are being rapidly developed. Using the reference strain SARS-CoV-2 USA-WA1/2020, we evaluated modes of transmission and the ability of prior infection or vaccine-induced immunity to protect against infection in ferrets. Ferrets were semi-permissive to infection with the USA-WA1/2020 isolate. When transmission was assessed via the detection of vRNA at multiple timepoints, direct contact transmission was efficient to 3/3 and 3/4 contact animals in two respective studies, while respiratory transmission was poor to only 1/4 contact animals. To assess the durability of immunity, ferrets were re-challenged 28 or 56 days post-primary infection. Following viral challenge, no infectious virus was recovered in nasal wash samples. In addition, levels of vRNA in the nasal wash were several orders of magnitude lower than during primary infection, and vRNA was rapidly cleared. To determine if intramuscular vaccination protected ferrets against infection, ferrets were vaccinated using a prime-boost strategy with the S-protein receptor-binding domain formulated with an oil-in-water adjuvant. Upon viral challenge, none of the mock or vaccinated animals were protected against infection, and there were no significant differences in vRNA or infectious virus titers in the nasal wash. Combined these studies demonstrate that in ferrets direct contact is the predominant mode of transmission of the SARS-CoV-2 USA-WA1/2020 isolate and immunity to SARS-CoV-2 is maintained for at least 56 days. Our studies also indicate protection of the upper respiratory tract against SARS-CoV-2 will require vaccine strategies that mimic natural infection or induce site-specific immunity.ImportanceThe SARS-CoV-2 USA-WA1/2020 strain is a CDC reference strain used by multiple research laboratories. Here, we show the predominant mode of transmission of this isolate in ferrets is by direct contact. We further demonstrate ferrets are protected against re-infection for at least 56 days even when levels of neutralizing antibodies are low or undetectable. Last, we show that when ferrets were vaccinated by the intramuscular route to induce antibodies against SARS-CoV-2, ferrets remain susceptible to infection of the upper respiratory tract. Collectively, these studies suggest protection of the upper respiratory tract will require vaccine approaches that mimic natural infection.

scholarly journals Asymptomatic COVID-19 Adult Outpatients identified as Significant Viable SARS-CoV-2 Shedders 

2021 ◽  
Author(s):  
Marie Glenet ◽  
Anne-Laure Lebreil ◽  
Laetitia Heng ◽  
Yohan N’Guyen ◽  
Ittah Meyer ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Control Measures ◽  
Upper Respiratory Tract ◽  
Rna Detection ◽  
Viral Loads ◽  
Infection Control Measures ◽  
Infected Adult ◽  
Asymptomatic Adult ◽  
Upper Respiratory ◽  
Kinetics Of

Abstract Differential kinetics of RNA loads and infectious viral levels in the upper respiratory tract between asymptomatic and symptomatic SARS-CoV-2 infected adult outpatients remain unclear limiting recommendations that may guide clinical management, infection control measures and occupational health decisions. In the present investigation, 496 (2.5%) of 17,911 French adult outpatients were positive for an upper respiratory tract SARS-CoV-2 RNA detection by a quantitative RT-PCR assay, of which 180 (36.3%) were COVID-19 asymptomatic. Of these adult asymptomatic viral shedders, 84.4% had mean to high RNA viral loads (Ct values<30) which median value was significantly higher than that observed in symptomatic subjects (P=0.029), and 50.6% were positive by cell culture assays of their upper respiratory tract specimens. Our findings indicate that COVID-19 asymptomatic adult outpatients are significant viable SARS-CoV-2 shedders in their upper respiratory tract playing a major potential role as SARS-CoV-2 transmitters in various epidemiological transmission chains, promoting COVID-19 resurgence in populations.

scholarly journals Reduced Pathogenicity of the SARS-CoV-2 Omicron Variant in Hamsters

2022 ◽  
Author(s):  
Katherine McMahan ◽  
Victoria Giffin ◽  
Lisa Tostanoski ◽  
Benjamin Chung ◽  
Mazuba Siamatu ◽  
...  
Keyword(s):  
Weight Loss ◽  
Respiratory Tract ◽  
Lung Parenchyma ◽  
Clinical Disease ◽  
Upper Respiratory Tract ◽  
Viral Loads ◽  
Syrian Golden Hamsters ◽  
The World ◽  
Pulmonary Pathology ◽  
Upper Respiratory

The SARS-CoV-2 Omicron (B.1.1.529) variant has proven 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. 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, as expected. 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 still led to substantial viral replication in both the upper and lower respiratory tracts and pulmonary pathology, but with a trend towards higher viral loads in nasal turbinates and lower viral loads in lung parenchyma compared with WA1/2020 infection. These data suggest that the SARS-CoV-2 Omicron variant may result in more robust upper respiratory tract infection but less severe lower respiratory tract clinical disease compared with prior SARS-CoV-2 variants.

scholarly journals Induction of interferon response by high viral loads at early stage infection may protect against severe outcomes in COVID-19 patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eric C. Rouchka ◽  
Julia H. Chariker ◽  
Brian Alejandro ◽  
Robert S. Adcock ◽  
Richa Singhal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Load ◽  
Respiratory Tract ◽  
Disease Severity ◽  
Critical Factor ◽  
Interferon Response ◽  
Upper Respiratory Tract ◽  
Viral Loads ◽  
Antiviral Responses ◽  
Upper Respiratory

AbstractKey elements for viral pathogenesis include viral strains, viral load, co-infection, and host responses. Several studies analyzing these factors in the function of disease severity of have been published; however, no studies have shown how all of these factors interplay within a defined cohort. To address this important question, we sought to understand how these four key components interplay in a cohort of COVID-19 patients. We determined the viral loads and gene expression using high throughput sequencing and various virological methods. We found that viral loads in the upper respiratory tract in COVID-19 patients at an early phase of infection vary widely. While the majority of nasopharyngeal (NP) samples have a viral load lower than the limit of detection of infectious viruses, there are samples with an extraordinary amount of SARS-CoV-2 RNA and a high viral titer. No specific viral factors were identified that are associated with high viral loads. Host gene expression analysis showed that viral loads were strongly correlated with cellular antiviral responses. Interestingly, however, COVID-19 patients who experience mild symptoms have a higher viral load than those with severe complications, indicating that naso-pharyngeal viral load may not be a key factor of the clinical outcomes of COVID-19. The metagenomics analysis revealed that the microflora in the upper respiratory tract of COVID-19 patients with high viral loads were dominated by SARS-CoV-2, with a high degree of dysbiosis. Finally, we found a strong inverse correlation between upregulation of interferon responses and disease severity. Overall our study suggests that a high viral load in the upper respiratory tract may not be a critical factor for severe symptoms; rather, dampened antiviral responses may be a critical factor for a severe outcome from the infection.

IDENTIFICATION OF UPPER RESPIRATORY TRACT VIRAL PATHOGENS ISOLATED FROM NASAL SWABS USING OLIGONUCLEOTIDE MICROARRAY

CHEST Journal ◽  
2009 ◽  
Vol 136 (4) ◽  
pp. 65S
Author(s):  
Maria Avgoulea ◽  
Niki Apostolopoulou ◽  
Evangelos Balis ◽  
Nikolaos Spanakis ◽  
Eugenios Metaxas ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Oligonucleotide Microarray ◽  
Upper Respiratory Tract ◽  
Viral Pathogens ◽  
Nasal Swabs ◽  
Upper Respiratory

scholarly journals Age-related susceptibility of ferrets to SARS-CoV-2 infection

2021 ◽  
Author(s):  
Mathias Martins ◽  
Maureen H.V. Fernandes ◽  
Lok R Joshi ◽  
Diego Diel
Keyword(s):  
Respiratory Tract ◽  
Viral Entry ◽  
Infectious Virus ◽  
Health Conditions ◽  
Upper Respiratory Tract ◽  
Infectious Dose ◽  
Virus Shedding ◽  
Age Related ◽  
Upper Respiratory ◽  
Effect Of Age

Susceptibility to SARS-CoV-2 and the outcome of COVID-19 have been linked to underlying health conditions and the age of affected individuals. Here we assessed the effect of age on SARS-CoV-2 infection using a ferret model. For this, young (6-month-old) and aged (18-to-39-month-old) ferrets were inoculated intranasally with various doses of SARS-CoV-2. By using infectious virus shedding in respiratory secretions and seroconversion, we estimated that the infectious dose of SARS-CoV-2 in aged animals is ~32 plaque forming units (PFU) per animal while in young animals it was estimated to be ~100 PFU. We showed that viral replication in the upper respiratory tract and shedding in respiratory secretions is enhanced in aged ferrets when compared to young animals. Similar to observations in humans, this was associated with higher expressions levels of two key viral entry factors - ACE2 and TMPRSS2 - in the upper respiratory tract of aged ferrets.

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