scholarly journals Protection of K18-hACE2 mice and ferrets against SARS-CoV-2 challenge by a single-dose mucosal immunization with a parainfluenza virus 5–based COVID-19 vaccine

2021 ◽  
Vol 7 (27) ◽  
pp. eabi5246
Author(s):  
Dong An ◽  
Kun Li ◽  
Dawne K. Rowe ◽  
Maria Cristina Huertas Diaz ◽  
Emily F. Griffin ◽  
...  
Keyword(s):  
Single Dose ◽  
Respiratory Tract ◽  
Virus Replication ◽  
Severe Disease ◽  
Mucosal Vaccine ◽  
Parainfluenza Virus ◽  
Upper Respiratory Tract ◽  
Vaccine Strategy ◽  
Upper Respiratory ◽  
Parainfluenza Virus 5

Transmission-blocking vaccines are urgently needed to reduce transmission of SARS-CoV 2, the cause of the COVID-19 pandemic. The upper respiratory tract is an initial site of SARS-CoV-2 infection and, for many individuals, remains the primary site of virus replication. An ideal COVID-19 vaccine should reduce upper respiratory tract virus replication and block transmission as well as protect against severe disease. Here, we optimized a vaccine candidate, parainfluenza virus 5 (PIV5) expressing the SARS-CoV-2 S protein (CVXGA1), and then demonstrated that a single-dose intranasal immunization with CVXGA1 protects against lethal infection of K18-hACE2 mice, a severe disease model. CVXGA1 immunization also prevented virus infection of ferrets and blocked contact transmission. This mucosal vaccine strategy inhibited SARS-CoV-2 replication in the upper respiratory tract, thus preventing disease progression to the lower respiratory tract. A PIV5-based mucosal vaccine provides a strategy to induce protective innate and cellular immune responses and reduce SARS-CoV-2 infection and transmission in populations.

scholarly journals CoViD-19: An early intervention therapeutic strategy to prevent developing a severe disease as an alternative approach to control the pandemic

2020 ◽  
Author(s):  
HAMID MERCHANT
Keyword(s):  
Early Intervention ◽  
Respiratory Tract ◽  
Therapeutic Strategy ◽  
Wide Spectrum ◽  
Severe Disease ◽  
Antimicrobial Properties ◽  
The Body ◽  
Upper Respiratory Tract ◽  
Holistic Treatment ◽  
Upper Respiratory

While we wait for a confirmed drug or a vaccine for CoViD-19, it may be possible to intervene early to prevent the virus causing a severe disease to offer an alternative therapeutic strategy to control the pandemic. The global burden of CoViD-19 on the healthcare system can be significantly reduced by targeting CoViD-19 patients with or without symptoms who are self-isolating at home or in quarantine. If any therapeutic support can be offered to this group of patients that could attenuate the virus within the upper respiratory tract during the early stages of CoViD-19, it can give the body the time to produce enough antibodies to recover naturally from the disease before progressing into severe disease. An early intervention can, therefore, prevent the virus to get down the lower respiratory tract, reduce the number of cases with severe disease involving pneumonia and the need for hospitalisation. This article presents a simple yet holistic treatment strategy that involves inhaling steam supplemented with essential oils possessing wide spectrum antimicrobial properties in conjunction with oropharyngeal sanitisation to all those who are CoViD-19 positive or are under self-isolation due to symptoms. The approach is very simple, cheap, and effective in relieving the symptoms of the disease and is likely to reduce the viral load in the upper respiratory tract that may help recover from the infection. Since there is no vaccine or treatment yet approved to prevent or treat the CoViD-19, the importance of early intervention is invaluable in reducing the global disease burden. In the authors opinion, this strategy may be very effective to nip the infection in the bud before it gets difficult to treat and therefore, have a potential to significantly reduce the CoViD-19 associated hospitalisation.

scholarly journals Predicting Disease Severity and Viral Spread of H5N1 Influenza Virus in Ferrets in the Context of Natural Exposure Routes

2015 ◽  
Vol 90 (4) ◽  
pp. 1888-1897 ◽  
Author(s):  
Kathryn M. Edenborough ◽  
Suzanne Lowther ◽  
Karen Laurie ◽  
Manabu Yamada ◽  
Fenella Long ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Respiratory Tract ◽  
Disease Severity ◽  
Severe Disease ◽  
Upper Respiratory Tract ◽  
H5n1 Influenza Virus ◽  
Viral Spread ◽  
H5n1 Influenza ◽  
Upper Respiratory ◽  
The Brain

ABSTRACTAlthough avian H5N1 influenza virus has yet to develop the capacity for human-to-human spread, the severity of the rare cases of human infection has warranted intensive follow-up of potentially exposed individuals that may require antiviral prophylaxis. For countries where antiviral drugs are limited, the World Health Organization (WHO) has developed a risk categorization for different levels of exposure to environmental, poultry, or human sources of infection. While these take into account the infection source, they do not account for the likely mode of virus entry that the individual may have experienced from that source and how this could affect the disease outcome. Knowledge of the kinetics and spread of virus after natural routes of exposure may further inform the risk of infection, as well as the likely disease severity. Using the ferret model of H5N1 infection, we compared the commonly used but artificial inoculation method that saturates the total respiratory tract (TRT) with virus to upper respiratory tract (URT) and oral routes of delivery, those likely to be encountered by humans in nature. We show that there was no statistically significant difference in survival rate with the different routes of infection, but the disease characteristics were somewhat different. Following URT infection, viral spread to systemic organs was comparatively delayed and more focal than after TRT infection. By both routes, severe disease was associated with early viremia and central nervous system infection. After oral exposure to the virus, mild infections were common suggesting consumption of virus-contaminated liquids may be associated with seroconversion in the absence of severe disease.IMPORTANCERisks for human H5N1 infection include direct contact with infected birds and frequenting contaminated environments. We used H5N1 ferret infection models to show that breathing in the virus was more likely to produce clinical infection than swallowing contaminated liquid. We also showed that virus could spread from the respiratory tract to the brain, which was associated with end-stage disease, and very early viremia provided a marker for this. With upper respiratory tract exposure, infection of the brain was common but hard to detect, suggesting that human neurological infections might be typically undetected at autopsy. However, viral spread to systemic sites was slower after exposure to virus by this route than when virus was additionally delivered to the lungs, providing a better therapeutic window. In addition to exposure history, early parameters of infection, such as viremia, could help prioritize antiviral treatments for patients most at risk of succumbing to infection.

scholarly journals Virological assessment of hospitalized cases of coronavirus disease 2019

2020 ◽  
Author(s):  
Roman Wölfel ◽  
Victor M. Corman ◽  
Wolfgang Guggemos ◽  
Michael Seilmaier ◽  
Sabine Zange ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Virus Replication ◽  
Acute Respiratory Tract Infection ◽  
Rapid Decline ◽  
Upper Respiratory Tract ◽  
Virus Shedding ◽  
Active Virus ◽  
Virus Rna ◽  
Upper Respiratory ◽  
High Virus

Coronavirus disease 2019 (COVID-19) is an acute respiratory tract infection that emerged in late 20191,2. Initial outbreaks in China involved 13.8% cases with severe-, and 6.1% with critical courses3. This severe presentation corresponds to the usage of a virus receptor that is expressed predominantly in the lung2,4. By causing an early onset of severe symptoms, this same receptor tropism is thought to have determined pathogenicity but also aided the control of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of COVID-19 cases with mild upper respiratory tract symptoms, suggesting a potential for pre- or oligosymptomatic transmission6-8. There is an urgent need for information on body site - specific virus replication, immunity, and infectivity. Here we provide a detailed virological analysis of nine cases, providing proof of active virus replication in upper respiratory tract tissues. Pharyngeal virus shedding was very high during the first week of symptoms (peak at 7.11 × 108 RNA copies per throat swab, day 4). Infectious virus was readily isolated from throat- and lung-derived samples, but not from stool samples in spite of high virus RNA concentration. Blood and urine never yielded virus. Active replication in the throat was confirmed by viral replicative RNA intermediates in throat samples. Sequence-distinct virus populations were consistently detected in throat- and lung samples of one same patient. Shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 6-12 days, but was not followed by a rapid decline of viral loads. COVID-19 can present as a mild upper respiratory tract illness. Active virus replication in the upper respiratory tract puts prospects of COVID-19 containment in perspective.

scholarly journals Efficacy of Aminomethyl Spectinomycins against Complex Upper Respiratory Tract Bacterial Infections

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Amy Iverson ◽  
Christopher J. Meyer ◽  
Peter Vogel ◽  
Samanthi Waidyarachchi ◽  
Nisha Das ◽  
...  
Keyword(s):  
Single Dose ◽  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Otitis Media ◽  
Respiratory Infections ◽  
Acute Otitis Media ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Upper Respiratory

ABSTRACT The most frequent ailment for which antibiotics are prescribed is otitis media (ear infections), which is most commonly caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Treatment of otitis media is complicated by the fact that the bacteria in the middle ear typically form biofilms, which can be recalcitrant to antibiotic treatment. Furthermore, bacterial respiratory infections can be greatly exacerbated by viral coinfection, which is particularly evidenced by the synergy between influenza and S. pneumoniae. In this study, we sought to ascertain the in vivo efficacy of aminomethyl spectinomycin lead 1950, an effective antibacterial agent both in vitro and in vivo against Streptococcus pneumoniae in the context of complex respiratory infections and acute otitis media. A single dose of 1950 significantly reduced bacterial burden in the respiratory tract for all three pathogens, even when species were present in a coinfection model. Additionally, a single dose of 1950 effectively reduced pneumococcal acute otitis media from the middle ear. The agent 1950 also proved efficacious in the context of influenza-pneumococcal super infection. These data further support the development of this family of compounds as potential therapeutic agents against the common causes of complex upper respiratory tract infections and acute otitis media.

scholarly journals Randomised, Double-Blind, Placebo-Controlled Study of a Single Dose of an Amylmetacresol/2,4-dichlorobenzyl Alcohol Plus Lidocaine Lozenge or a Hexylresorcinol Lozenge for the Treatment of Acute Sore Throat Due to Upper Respiratory Tract Infection

2012 ◽  
Vol 15 (2) ◽  
pp. 281 ◽  
Author(s):  
Damien McNally ◽  
Adrian Shephard ◽  
Emma Field
Keyword(s):  
Single Dose ◽  
Tract Infection ◽  
Respiratory Tract ◽  
Respiratory Tract Infection ◽  
Sore Throat ◽  
Controlled Study ◽  
Upper Respiratory Tract ◽  
Post Dose ◽  
Double Blind ◽  
Upper Respiratory

Purpose: Sore throat is a frequent reason for seeking medical care but few prescription options are available. Lozenges are effective in delivering active ingredients to the throat. This study was conducted to determine the analgesic efficacy of two lozenges  one containing amylmetacresol (AMC)/2,4-dichlorobenzyl alcohol (DCBA) and lidocaine and one containing hexylresorcinol  versus placebo in patients with acute sore throat due to upper respiratory tract infection (URTI). Methods: This was a multicentre, randomised, double-blind, parallel group, placebo-controlled study. In total, 190 patients were randomised 1:1:1 to a single dose of AMC/DCBA + lidocaine, hexylresorcinol or placebo lozenge. Subjective ratings of throat soreness, difficulty swallowing, swollen throat, numbing, and sore throat relief were obtained up to 2 hours post dose. Patient and investigator global ratings and a consumer questionnaire were also collected. The primary endpoint was the change from baseline in severity of throat soreness for both lozenges versus placebo at 2 hours post dose. Results: The hexylresorcinol lozenge demonstrated superiority over placebo for primary and secondary efficacy variables including those related to throat soreness, sore throat relief and difficulty swallowing; the AMC/DCBA + lidocaine lozenge was also superior to placebo for secondary endpoints at various time points but did not reach significance for the primary efficacy variable. Both lozenges had a rapid onset of action from 1–10 minutes post dose for the AMC/DCBA + lidocaine lozenge and 1–5 minutes post dose for the hexylresorcinol lozenge. Numbness was reported from 1 minute post dose with the AMC/DCBA + lidocaine lozenge and was greatest at 15 minutes. Numbness was reported from 5 minutes post dose with the hexylresorcinol lozenge and was greatest at 10 minutes. Both lozenges were well tolerated. Conclusions: Both AMC/DCBA + lidocaine and hexylresorcinol lozenges provided rapid and effective sore throat relief in patients with URTI. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Refocusing Functional Anatomy and Immunology of the Respiratory Mucosa in the Advent of Covid-19

2021 ◽  
Author(s):  
Humphrey Simukoko
Keyword(s):  
Respiratory Tract ◽  
Respiratory System ◽  
Mammalian Cells ◽  
Atmospheric Oxygen ◽  
Severe Disease ◽  
Pulmonary Ventilation ◽  
Functional Anatomy ◽  
Upper Respiratory Tract ◽  
Mucosal Cells ◽  
Upper Respiratory

Atmospheric oxygen is an indispensable element required in order for mammalian cells to function normally. The mammalian respiratory system, through pulmonary ventilation and gas diffusion, provides the physical mechanisms by which oxygen gains access to all body cells and through which carbon dioxide is eliminated from the body. The network of tissues and organs of the respiratory system helps the mammalian body cells to absorb oxygen from the air to enable the tissues and organs to function optimally. The advent of the coronavirus disease 2019 (Covid-19) Pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has stimulated heightened and refocused interest in the study of various aspects of the respiratory system. The SARS-CoV-2 targets the respiratory system mucosal cells and in a cascade of biological processes curtails the ability of the respiratory system to absorb and deliver oxygen to the pulmonary blood and body cells often resulting in severe disease and/or death. The mucosa and submucosa of the respiratory tract are adapted to provide both innate and adaptive immune defense mechanisms against pathogens including the SARS-CoV-2. The entire respiratory tract is covered by a mucosa that transitions in its structural and functional characteristics from the upper respiratory tract to the lower respiratory tract. This chapter provides an overview of the functional anatomy and immunology of the respiratory tract covering the mucosa from the upper respiratory tract all the way up to the alveolar epithelium. In the advent of the covid-19 pandemic, a broader perspective and understanding of the anatomy and immunology of the respiratory tract will enable general readers and researchers to fully appreciate the discourse in covid-19 research as it affects the respiratory tract.

scholarly journals Combinatorial mRNA vaccination enhances protection against SARS-CoV-2 delta variant

2021 ◽  
Author(s):  
Renee L Hajnik ◽  
Jessica A Plante ◽  
Yuejin Liang ◽  
Mohamad-Gabriel Alameh ◽  
Jinyi Tang ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
T Cell Response ◽  
Antibody Activity ◽  
Upper Respiratory Tract ◽  
Hamster Model ◽  
Significant Control ◽  
Fold Reduction ◽  
Upper Respiratory

Emergence of SARS-CoV-2 variants of concern (VOC), including the highly transmissible delta strain, has posed challenges to current COVID-19 vaccines that principally target the viral spike protein (S). Here, we report a nucleoside-modified mRNA vaccine that expresses the more conserved viral nucleoprotein (mRNA-N). We show that mRNA-N alone was able to induce a modest but significant control of SARS-CoV-2 in mice and hamsters. Critically, by combining mRNA-N with the clinically approved S-expressing mRNA vaccine (mRNA-S-2P), we found that combinatorial mRNA vaccination (mRNA-S+N) led to markedly enhanced protection against the SARS-CoV-2 delta variant compared to mRNA-S. In a hamster model, we demonstrated that while mRNA-S alone elicited significant control of the delta strain in the lungs (~45-fold reduction in viral loads compared to un-vaccinated control), its effectiveness in the upper respiratory tract was weak, whereas combinatorial mRNA-S+N vaccination induced markedly more robust control of the delta variant infection in the lungs (~450-fold reduction) as well as in the upper respiratory tract (~20-fold reduction). Immune analyses indicated that induction of N-specific immunity as well as augmented S-specific T-cell response and neutralizing antibody activity were collectively associated the enhanced protection against SARS-CoV-2 delta strain by combinatorial mRNA vaccination. These findings suggest that the combined effects of protection in the lungs and upper respiratory tract could both reduce the risk of severe disease as well as of infection and transmission.

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