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

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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Case Report: Infection With SARS-CoV-2 in the Presence of High Levels of Vaccine-Induced Neutralizing Antibody Responses

Frontiers in Medicine ◽

10.3389/fmed.2021.704719 ◽

2021 ◽

Vol 8 ◽

Author(s):

Bianca Schulte ◽

Benjamin Marx ◽

Marek Korencak ◽

Dorian Emmert ◽

Souhaib Aldabbagh ◽

...

Keyword(s):

Case Report ◽

Respiratory Tract ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Upper Respiratory Tract ◽

Protective Measures ◽

Specific Antibodies ◽

Household Members ◽

Upper Respiratory

We present a case of SARS-CoV-2 B.1. 525 infection in a healthcare worker despite the presence of highly neutralizing, multivariant-specific antibodies 7 weeks after full vaccination with the mRNA vaccine BNT162b2. We show that the virus replicated to high levels in the upper respiratory tract over the course of several days in the presence of strong antibody responses. The virus was readily propagatable in vitro, demonstrating the potential to transmit to others, bolstered by the fact that several household members were equally infected. This highlights the importance of protective measures even in vaccinated individuals.

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Effect of prophylactic use of intra-nasal oil formulations in the hamster model of Covid-19

10.1101/2021.06.25.449990 ◽

2021 ◽

Author(s):

Zaigham Abbas Rizvi ◽

Manas Ranjan Tripathy ◽

Nishant Sharma ◽

Sandeep Goswami ◽

N Srikanth ◽

...

Keyword(s):

Viral Load ◽

Respiratory Tract ◽

Viral Entry ◽

Body Weight Loss ◽

Lung Pathology ◽

Upper Respiratory Tract ◽

Hamster Model ◽

Reduced Body ◽

Upper Respiratory ◽

Prophylactic Use

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection initiates with viral entry in upper respiratory tract leading to coronavirus disease 2019 (Covid-19). Severe Covid-19 is characterized by pulmonary pathologies associated with respiratory failure. Thus, therapeutics aimed at inhibiting entry of the virus or its internalization in the upper respiratory tract, are of interest. Herein, we report the prophylactic application of two intra-nasal formulations provided by the National Medicinal Plant Board (NMPB), Anu oil and Til tailya in SARS-CoV2 infection hamster model. Prophylactic nasal instillation of these oil formulations exhibited reduced viral load in lungs, and resulted in reduced body weight loss and pneumonitis. In line with reduced viral load, histopathlogical analysis revealed a reduction in lung pathology in Anu oil group as compared to the control infected group. However, Til tailya group did not show a significant reduction in lung pathology. Furthermore, molecular analysis using mRNA expression profiling indicated reduced expression of pro-inflammatory cytokines genes, including Th1 and Th17 cytokines for both the intra-nasal formulations as a result of decreased viral load. Together, the prophylactic intra-nasal application of Annu oil seems to be useful in limiting both the viral load and disease severity disease in SARS-CoV2 infection in hamster model.

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

10.14293/s2199-1006.1.sor-.ppurwmt.v1 ◽

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.

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Ad26.COV2.S-elicited immunity protects against G614 spike variant SARS-CoV-2 infection in Syrian hamsters and does not enhance respiratory disease in challenged animals with breakthrough infection after sub-optimal vaccine dosing

10.1101/2021.01.08.425915 ◽

2021 ◽

Author(s):

Joan E.M. van der Lubbe ◽

Sietske K. Rosendahl Huber ◽

Aneesh Vijayan ◽

Liesbeth Dekking ◽

Ella van Huizen ◽

...

Keyword(s):

Respiratory Tract ◽

Respiratory Disease ◽

Syrian Hamster ◽

Vaccine Dose ◽

Neutralizing Antibody ◽

Upper Respiratory Tract ◽

Breakthrough Infection ◽

Syrian Hamsters ◽

Antibody Titers ◽

Upper Respiratory

Previously we have shown that a single dose of recombinant adenovirus serotype 26 (Ad26) vaccine expressing a prefusion stabilized SARS-CoV-2 spike antigen (Ad26.COV2.S) is immunogenic and provides protection in Syrian hamster and non-human primate SARS-CoV-2 infection models. Here, we investigated the immunogenicity, protective efficacy and potential for vaccine-associated enhanced respiratory disease (VAERD) mediated by Ad26.COV2.S in a moderate disease Syrian hamster challenge model, using the currently most prevalent G614 spike SARS-CoV-2 variant. Vaccine doses of 1x109 vp and 1x1010 vp elicited substantial neutralizing antibodies titers and completely protected over 80% of SARS-CoV-2 inoculated Syrian hamsters from lung infection and pneumonia but not upper respiratory tract infection. A second vaccine dose further increased neutralizing antibody titers which was associated with decreased infectious viral load in the upper respiratory tract after SARS-CoV-2 challenge. Suboptimal non-protective immune responses elicited by low-dose A26.COV2.S vaccination did not exacerbate respiratory disease in SARS-CoV-2-inoculated Syrian hamsters with breakthrough infection. In addition, dosing down the vaccine allowed to establish that binding and neutralizing antibody titers correlate with lower respiratory tract protection probability. Overall, these pre-clinical data confirm efficacy of a 1-dose vaccine regimen with Ad26.COV2.S in this G614 spike SARS-CoV-2 virus variant Syrian hamster model, show the added benefit of a second vaccine dose, and demonstrate that there are no signs of VAERD under conditions of suboptimal immunity.

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

Journal of Virology ◽

10.1128/jvi.01878-15 ◽

2015 ◽

Vol 90 (4) ◽

pp. 1888-1897 ◽

Cited By ~ 5

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.

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Ad26.COV2.S protects Syrian hamsters against G614 spike variant SARS-CoV-2 and does not enhance respiratory disease

npj Vaccines ◽

10.1038/s41541-021-00301-y ◽

2021 ◽

Vol 6 (1) ◽

Cited By ~ 1

Author(s):

Joan E. M. van der Lubbe ◽

Sietske K. Rosendahl Huber ◽

Aneesh Vijayan ◽

Liesbeth Dekking ◽

Ella van Huizen ◽

...

Keyword(s):

Respiratory Tract ◽

Respiratory Disease ◽

Syrian Hamster ◽

Neutralizing Antibodies ◽

Vaccine Dose ◽

Neutralizing Antibody ◽

Upper Respiratory Tract ◽

Syrian Hamsters ◽

Antibody Titers ◽

Upper Respiratory

AbstractPreviously we have shown that a single dose of recombinant adenovirus serotype 26 (Ad26) vaccine expressing a prefusion stabilized SARS-CoV-2 spike antigen (Ad26.COV2.S) is immunogenic and provides protection in Syrian hamster and non-human primate SARS-CoV-2 infection models. Here, we investigated the immunogenicity, protective efficacy, and potential for vaccine-associated enhanced respiratory disease (VAERD) mediated by Ad26.COV2.S in a moderate disease Syrian hamster challenge model, using the currently most prevalent G614 spike SARS-CoV-2 variant. Vaccine doses of 1 × 109 and 1 × 1010 VP elicited substantial neutralizing antibodies titers and completely protected over 80% of SARS-CoV-2 inoculated Syrian hamsters from lung infection and pneumonia but not upper respiratory tract infection. A second vaccine dose further increased neutralizing antibody titers that was associated with decreased infectious viral load in the upper respiratory tract after SARS-CoV-2 challenge. Suboptimal non-protective immune responses elicited by low-dose A26.COV2.S vaccination did not exacerbate respiratory disease in SARS-CoV-2-inoculated Syrian hamsters with breakthrough infection. In addition, dosing down the vaccine allowed to establish that binding and neutralizing antibody titers correlate with lower respiratory tract protection probability. Overall, these preclinical data confirm efficacy of a one-dose vaccine regimen with Ad26.COV2.S in this G614 spike SARS-CoV-2 virus variant Syrian hamster model, show the added benefit of a second vaccine dose, and demonstrate that there are no signs of VAERD under conditions of suboptimal immunity.

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Loss of recognition of SARS-CoV-2 B.1.351 variant spike epitopes but overall preservation of T cell immunity

10.1101/2021.06.03.21258307 ◽

2021 ◽

Author(s):

Catherine Riou ◽

Roanne Keeton ◽

Thandeka Moyo-Gwete ◽

Tandile Hermanus ◽

Prudence Kgagudi ◽

...

Keyword(s):

T Cell ◽

Severe Disease ◽

T Cell Responses ◽

Neutralizing Antibody ◽

Cd8 T Cell ◽

T Cell Immunity ◽

Antibody Activity ◽

Cell Responses ◽

Cell Immunity ◽

Fold Reduction

SARS-CoV-2 variants have emerged that escape neutralization and potentially impact vaccine efficacy. T cell responses play a role in protection from reinfection and severe disease, but the potential for spike mutations to affect T cell immunity is poorly studied. We assessed both neutralizing antibody and T cell responses in 44 South African COVID-19 patients infected either with B.1.351, now dominant in South Africa, or infected prior to its emergence (first wave), to provide an overall measure of immune evasion. We show for the first time that robust spike-specific CD4 and CD8 T cell responses were detectable in B.1.351-infected patients, similar to first wave patients. Using peptides spanning only the B.1.351 mutated regions, we identified CD4 T cell responses targeting the wild type peptides in 12/22 (54.5%) first wave patients, all of whom failed to recognize corresponding B.1.351-mutated peptides (p=0.0005). However, responses to the mutated regions formed only a small proportion (15.7%) of the overall CD4 response, and few patients (3/44) mounted CD8 responses that targeted the mutated regions. First wave patients showed a 12.7 fold reduction in plasma neutralization of B.1.351. This study shows that despite loss of recognition of immunodominant CD4 epitope(s), overall CD4 and CD8 T cell responses to B.1.351 are preserved. These observations may explain why, despite substantial loss of neutralizing antibody activity against B.1.351, several vaccines have retained the ability to protect against severe COVID-19 disease.

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Effect of Prophylactic Use of Intranasal Oil Formulations in the Hamster Model of COVID-19

Frontiers in Pharmacology ◽

10.3389/fphar.2021.746729 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zaigham Abbas Rizvi ◽

Manas Ranjan Tripathy ◽

Nishant Sharma ◽

Sandeep Goswami ◽

N Srikanth ◽

...

Keyword(s):

Viral Load ◽

Respiratory Tract ◽

Viral Entry ◽

Body Weight Loss ◽

Histopathological Analysis ◽

Lung Pathology ◽

Upper Respiratory Tract ◽

Hamster Model ◽

Reduced Body ◽

Upper Respiratory

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection initiates with viral entry in the upper respiratory tract, leading to coronavirus disease 2019 (COVID-19). Severe COVID-19 is characterized by pulmonary pathologies associated with respiratory failure. Thus, therapeutics aimed at inhibiting the entry of the virus or its internalization in the upper respiratory tract are of interest. Herein, we report the prophylactic application of two intranasal formulations provided by the National Medicinal Plant Board (NMPB), Anu oil and til tailya, in the hamster model of SARS-CoV-2 infection. Prophylactic intra-nasal instillation of these oil formulations exhibited reduced viral load in lungs and resulted in reduced body weight loss and lung-pneumonitis. In line with reduced viral load, histopathological analysis revealed a reduction in lung pathology in the Anu oil group as compared to the control infected group. However, the til tailya group did not show a significant reduction in lung pathology. Furthermore, molecular analysis using mRNA expression profiling indicated reduced expression of pro-inflammatory cytokine genes, including Th1 and Th17 cytokines for both the intranasal formulations as a result of decreased viral load. Together, the prophylactic intranasal application of Anu oil seems to be useful in limiting both viral load and severity in SARS-CoV2 infection in the hamster model.

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

10.5772/intechopen.96251 ◽

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.

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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

Science Advances ◽

10.1126/sciadv.abi5246 ◽

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.

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