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1.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-459055

RESUMO

Current COVID-19 vaccines need to take at least one month to complete inoculation and then become effective. Around 51% global population are still not fully vaccinated. Instantaneous protection is an unmet need among those who are not fully vaccinated. In addition, breakthrough infections caused by SARS-CoV-2 are widely reported. All these highlight the unmet needing for short-term instantaneous prophylaxis (STIP) in the communities where SARS-CoV-2 is circulating. Previously, we reported nanobodies isolated from an alpaca immunized with the spike protein, exhibiting ultrahigh potency against SARS-CoV-2 and its variants. Herein, we found that Nb22, among our previously reported nanobodies, exhibited ultrapotent neutralization against Delta variant with an IC50 value of 0.41 ng/ml (5.13 pM). Furthermore, the crystal structural analysis revealed that the binding of Nb22 to WH01 and Delta RBDs both effectively blocked the binding of RBD to hACE2. Additionally, intranasal Nb22 exhibited protection against SARS-CoV-2 Delta variant in the post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP). Of note, intranasal Nb22 also demonstrated high efficacy against SARS-CoV-2 Delta variant in STIP for seven days administered by single dose and exhibited long-lasting retention in the respiratory system for at least one month administered by four doses, providing a means of instantaneous short-term prophylaxis against SARS-CoV-2. Thus, ultrahigh potency, long-lasting retention in the respiratory system as well as stability at room-temperature make the intranasal or inhaled Nb22 to be a potential therapeutic or STIP agent against SARS-CoV-2. Brief summaryNb22 exhibits ultrahigh potency against Delta variant in vitro and is exploited by crystal structural analysis; furthermore, animal study demonstrates high effectiveness in the treatment and short-term instantaneous prophylaxis in hACE2 mice via intranasal administration. HighlightsO_LINb22 exhibits ultrapotent neutralization against Delta variant with an IC50 value of 0.41 ng/ml (5.13 pM). C_LIO_LIStructural analysis elucidates the ultrapotent neutralization of Nb22 against Delta variant. C_LIO_LINb22 demonstrates complete protection in the treatment of Delta variant infection in hACE2 transgenic mice. C_LIO_LIWe complete the proof of concept of STIP against SARS-CoV-2 using intranasal Nb22 with ultrahigh potency and long-lasting retention in respiratory system. C_LI Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/459055v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@144516corg.highwire.dtl.DTLVardef@3dc17forg.highwire.dtl.DTLVardef@6a8962org.highwire.dtl.DTLVardef@619cd7_HPS_FORMAT_FIGEXP M_FIG C_FIG

2.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21254702

RESUMO

Governments worldwide have rapidly deployed non-pharmaceutical interventions (NPIs) to mitigate the COVID-19 pandemic. However, the effect of these individual NPI measures across space and time has yet to be sufficiently assessed, especially with the increase of policy fatigue and the urge for NPI relaxation in the vaccination era. Using the decay ratio in the suppression of COVID-19 infections, we investigated the changing performance of different NPIs across waves from global and regional levels (in 133 countries) to national and subnational (in the United States of America [USA]) scales before the implementation of mass vaccination. The synergistic effectiveness of all NPIs for reducing COVID-19 infections declined along waves, from 95.4% in the first wave to 56.0% in the third wave recently at the global level and similarly from 83.3% to 58.7% at the USA national level, while it had fluctuating performance across waves on regional and subnational scales. Regardless of geographical scale, gathering restrictions and facial coverings played significant roles in epidemic mitigation before the vaccine rollout. Our findings have important implications for continued tailoring and implementation of NPI strategies, together with vaccination, to mitigate future COVID-19 waves, caused by new variants, and other emerging respiratory infectious diseases.

3.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-429275

RESUMO

The dramatically expanding COVID-19 needs multiple effective countermeasures. Neutralizing antibodies are a potential therapeutic strategy for treating COVID-19. A number of neutralizing nanobodies (Nbs) were reported for their in vitro activities. However, in vivo protection of these nanobodies was not reported in animal models. In the current report, we characterized several RBD-specific Nbs isolated from a screen of an Nb library derived from an alpaca immunized with SARS-CoV-2 spike glycoprotein (S); among them, three Nbs exhibited picomolar potency against SARS-CoV-2 live virus, pseudotyped viruses, and 15 circulating SARS-CoV-2 variants. To improve the efficacy, various configurations of Nbs were engineered. Nb15-NbH-Nb15, a novel trimer constituted of three Nbs, was constructed to be bispecific for human serum albumin (HSA) and RBD of SARS-CoV-2. Nb15-NbH-Nb15 exhibited sub-ng/ml neutralization potency against the wild-type and currently circulating variants of SARS-CoV-2 with a long half-life in vivo. In addition, we showed that intranasal administration of Nb15-NbH-Nb15 provided 100% protection for both prophylactic and therapeutic purposes against SARS-CoV-2 infection in transgenic hACE2 mice. Nb15-NbH-Nb15 is a potential candidate for both prevention and treatment of SARS-CoV-2 through respiratory administration. One sentence summaryNb15-NbH-Nb15, with a novel heterotrimeric bispecific configuration, exhibited potent and broad neutralization potency against SARS-CoV-2 in vitro and provided in vivo protection against SARS-CoV-2 infection in hACE2 transgenic mice via intranasal delivery. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/429275v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@a30bc8org.highwire.dtl.DTLVardef@5a872eorg.highwire.dtl.DTLVardef@1610f74org.highwire.dtl.DTLVardef@13d9bd8_HPS_FORMAT_FIGEXP M_FIG Graphical abstract: C_FIG HighlightsO_LIWe described a novel heterotrimeric configuration of Nb-NbH-Nb (Nb15-NbH-Nb15) that exhibited improved viral inhibition and stability. C_LIO_LINb15-NbH-Nb15 provides ultrahigh neutralization potency against SARS-CoV-2 wild type and 18 mutant variants, including the current circulating variants of D614G and N501Y predominantly in the UK and South Africa. C_LIO_LIIt is the first to demonstrate the Nbs efficacy in preventing and treating SARS-CoV-2 infection in hACE2 transgenic mice via intranasal delivery. C_LI

4.
Chinese Journal of Neurology ; (12): 161-165, 2019.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-745909

RESUMO

Alzheimer's disease is a chronic progressive neurodegeneration disease,currently the pathogenesis of which is not fully elucidated and no disease-modifying therapies are available.The amyloid-beta cascade hypothesis is still predominant in the field.Although has been proposed for decades,the herpes virus hypothesis remains controversial due to lack of solid evidence.New evidence supporting the hypothesis is emerging while debates remain,which would be the focus of this paper.

5.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-734002

RESUMO

Objective To revise rumination on sadness scale (RSS) and evaluate the reliability and validity of the Chinese version rumination on sadness scale (RSS-C) in Chinese undergraduates.Methods A total of 1 166 undergraduates from 4 universities in Hunan province completed RSS,ruminative response scale (RRS) and Beck depression inventory-Ⅱ (BDI-Ⅱ).The test-retest was conducted in 111 participants 2 weeks later.Results Item analysis and exploratory factor analysis showed the RSS-C included 11 items,consisting of causal analysis,understanding oneself and one's sadness and uncontrollability of ruminative thinking factors.The scores of each item in the high score group were significantly higher than those in the low group(P<0.001),and the correlation between each item and the total score was significant(r=0.594-0.719,P<0.001).The confirmatory factor analysis indicated good fit(x2/df=3.938,GFI =0.957,NFI =0.940,CFI =0.954,TLI =0.930,IFI =0.954,RMSEA =0.070).The internal consistency for RSS-C and three factors ranged from 0.694 to 0.868,and the test-retest reliability ranged from 0.620 to 0.833.The scores on RSS-C and three factors were significantly associated with RRS(r=0.555-0.637,P<0.01),BDI-Ⅱ (r=0.211-0.403,P<0.01) respectively.Conclusion RSS-C has good reliability and validity and can be used as an effective instrument to assess rumination on sadness in Chinese undergraduates.

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