Robust SARS-CoV-2 Infection in Nasal Turbinate Despite Systemic Neutralizing Antibody

Zhou, Dongyan; Chan, Jasper Fuk‐Woo; Zhou, Runhong; Li, Liu; Li, Shuang; Zhang, Anna Jinxia; Chen, Serena J.; Chan, Chris; Shan, Sicong; Poon, Vincent Kwok-Man; Yuan, Shuofeng; Chik, Kenn Ka-Heng; Cao, Jianli; Zhou, Biao; Li, Cun; Zhang, Qi; Zhou, Jie; Zhang, Linqi; To, Kelvin Kai‐Wang; Yuen, Kwok‐Yung; Chen, Zhiwei

doi:10.2139/ssrn.3699794

Cited by 6 publications

(14 citation statements)

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“…Similarly, viral RNA levels in the lung, heart, spleen, and brain of LCB1-Fc treated animals were at or near the limit of detection of the assay at 4 or 7 dpi ( Fig 1F-I ). LCB1-Fc treatment had no effect on viral RNA levels in nasal wash samples obtained at 4 dpi ( Fig 1J ), results that are similar to a recent study of a neutralizing human antibody in hamsters (Zhou et al, 2021). However, viral RNA levels were reduced at 7 dpi, suggesting that LCB1-Fc treatment accelerated viral clearance or prevented spread in the upper respiratory tract.…”

Section: Resultssupporting

confidence: 89%

“…Plates were harvested 24-30 h later by removing overlays and fixed with 4% PFA in PBS for 20 min at room temperature. Plates were washed and sequentially incubated with an oligoclonal pool of SARS2-2, SARS2-11, SARS2-16, SARS2-31, SARS2-38, SARS2-57, and SARS2-71 anti-spike protein antibodies (Zhou et al, 2021) and HRP-conjugated goat anti-mouse IgG in PBS supplemented with 0.1% saponin and 0.1% bovine serum albumin. SARS-CoV-2-infected cell foci were visualized using TrueBlue peroxidase substrate (KPL) and quantitated on an ImmunoSpot microanalyzer (Cellular Technologies).…”

Section: Star Methodsmentioning

confidence: 99%

“…Plates were harvested 24-30 h later by removing overlays and fixed with 4% PFA in PBS for 20 min at room temperature. Plates were washed and sequentially incubated with an oligoclonal pool of SARS2-2, SARS2-11, SARS2-16, SARS2-31, SARS2-38, SARS2-57, and SARS2-71 anti-spike protein antibodies (Zhou et al, 2021) (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted March 1, 2021. ; https://doi.org/10.1101/2021.03.01.433110 doi: bioRxiv preprint 26 incubated in each well at room temperature for min.…”

Section: Respiratory Mechanicsmentioning

confidence: 99%

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Ultrapotent miniproteins targeting the receptor-binding domain protect against SARS-CoV-2 infection and disease in mice

Case

Chen

Cao

et al. 2021

Preprint

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SUMMARYDespite the introduction of public health measures and spike protein-based vaccines to mitigate the COVID-19 pandemic, SARS-CoV-2 infections and deaths continue to rise. Previously, we used a structural design approach to develop picomolar range miniproteins targeting the SARS-CoV-2 receptor binding domain. Here, we investigated the capacity of modified versions of one lead binder, LCB1, to protect against SARS-CoV-2-mediated lung disease in human ACE2-expressing transgenic mice. Systemic administration of LCB1-Fc reduced viral burden, diminished immune cell infiltration and inflammation, and completely prevented lung disease and pathology. A single intranasal dose of LCB1v1.3 reduced SARS-CoV-2 infection in the lung even when given as many as five days before or two days after virus inoculation. Importantly, LCB1v1.3 protected in vivo against a historical strain (WA1/2020), an emerging B.1.1.7 strain, and a strain encoding key E484K and N501Y spike protein substitutions. These data support development of LCB1v1.3 for prevention or treatment of SARS-CoV-2 infection.

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Section: Resultssupporting

confidence: 89%

Section: Star Methodsmentioning

confidence: 99%

“…Plates were harvested 24-30 h later by removing overlays and fixed with 4% PFA in PBS for 20 min at room temperature. Plates were washed and sequentially incubated with an oligoclonal pool of SARS2-2, SARS2-11, SARS2-16, SARS2-31, SARS2-38, SARS2-57, and SARS2-71 anti-spike protein antibodies (Zhou et al, 2021) (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted March 1, 2021. ; https://doi.org/10.1101/2021.03.01.433110 doi: bioRxiv preprint 26 incubated in each well at room temperature for min.…”

Section: Respiratory Mechanicsmentioning

confidence: 99%

See 1 more Smart Citation

Ultrapotent miniproteins targeting the receptor-binding domain protect against SARS-CoV-2 infection and disease in mice

Case

Chen

Cao

et al. 2021

Preprint

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“…In this study, the sample size calculation in mice experiments to find difference between groups was used as mentioned previously [21]. Normal distribution data were conducted using SPSS software.…”

Section: Discussionmentioning

confidence: 99%

Q493K and Q498H substitutions in Spike promote adaptation of SARS-CoV-2 in mice

et al. 2021

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Background: An ideal animal model to study SARS-coronavirus 2 (SARS-CoV-2) pathogenesis and evaluate therapies and vaccines should reproduce SARS-CoV-2 infection and recapitulate lung disease like those seen in humans. The angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS-CoV-2, but mice are resistant to the infection because their ACE2 is incompatible with the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein .Methods: SARS-CoV-2 was passaged in BALB/c mice to obtain mouse-adapted virus strain. Complete genome deep sequencing of different generations of viruses was performed to characterize the dynamics of the adaptive mutations in SARS-CoV-2. Indirect immunofluorescence analysis and Biolayer interferometry experiments determined the binding affinity of mouse-adapted SARS-CoV-2 WBP-1 RBD to mouse ACE2 and human ACE2. Finally, we tested whether TLR7/8 agonist Resiquimod (R848) could also inhibit the replication of WBP-1 in the mouse model. Findings: The mouse-adapted strain WBP-1 showed increased infectivity in BALB/c mice and led to severe interstitial pneumonia. We characterized the dynamics of the adaptive mutations in SARS-CoV-2 and demonstrated that Q493K and Q498H in RBD significantly increased its binding affinity towards mouse ACE2. Additionally, the study tentatively found that the TLR7/8 agonist Resiquimod was able to protect mice against WBP-1 challenge. Therefore, this mouse-adapted strain is a useful tool to investigate COVID-19 and develop new therapies. Interpretation: We found for the first time that the Q493K and Q498H mutations in the RBD of WBP-1 enhanced its interactive affinities with mACE2. The mouse-adapted SARS-CoV-2 provides a valuable tool for the evaluation of novel antiviral and vaccine strategies. This study also tentatively verified the antiviral activity of TLR7/8 agonist Resiquimod against SARS-CoV-2 in vitro and in vivo.

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“…Our data do not allow this answer to be determined but they do raise the possibility and suggest that additional studies in this area would be fruitful. A recent report of SARS-CoV-2 infection in rhesus macaques shows that virus can replicate in nasal turbinates when it is suppressed in the lungs by passively transferred NAbs (12). Assays of vaccineinduced antibodies extracted from NP swabs might provide additional information.…”

mentioning

confidence: 99%

Antibody responses to SARS-CoV-2 mRNA vaccines are detectable in saliva

Ketas

Chaturbhuj

Cruz-Portillo

et al. 2021

Preprint

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Vaccines are critical for curtailing the COVID-19 pandemic. In the USA, two highly protective mRNA vaccines are available: BNT162b2 from Pfizer/BioNTech and mRNA-1273 from Moderna. These vaccines induce antibodies to the SARS-CoV-2 S-protein, including neutralizing antibodies (NAbs) predominantly directed against the Receptor Binding Domain (RBD). Serum NAbs are induced at modest levels within ~1 week of the first dose, but their titers are strongly boosted by a second dose at 3 (BNT162b2) or 4 weeks (mRNA-1273). SARS-CoV-2 is most commonly transmitted nasally or orally and infects cells in the mucosae of the respiratory and to some extent also the gastrointestinal tract. Although serum NAbs may be a correlate of protection against COVID-19, mucosal antibodies might directly prevent or limit virus acquisition by the nasal, oral and conjunctival routes. Whether the mRNA vaccines induce mucosal immunity has not been studied. Here, we report that antibodies to the S-protein and its RBD are present in saliva samples from mRNA-vaccinated healthcare workers (HCW). Within 1-2 weeks after their second dose, 37/37 and 8/8 recipients of the Pfizer and Moderna vaccines, respectively, had S-protein IgG antibodies in their saliva, while IgA was detected in a substantial proportion. These observations may be relevant to vaccine-mediated protection from SARS-CoV-2 infection and disease.

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Robust SARS-CoV-2 Infection in Nasal Turbinate Despite Systemic Neutralizing Antibody

Cited by 6 publications

References 0 publications

Ultrapotent miniproteins targeting the receptor-binding domain protect against SARS-CoV-2 infection and disease in mice

Ultrapotent miniproteins targeting the receptor-binding domain protect against SARS-CoV-2 infection and disease in mice

Q493K and Q498H substitutions in Spike promote adaptation of SARS-CoV-2 in mice

Antibody responses to SARS-CoV-2 mRNA vaccines are detectable in saliva

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