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Objective To investigated the in vitro antiviral activity of chloroquine and hydroxychloroquine sulfate against different variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Prototype, Beta, Delta, Omicron) by changing the sequence of drug and virus introduction. Methods Prophylactic treatment: Vero E6 cells were treated with Chloroquine or hydroxychloroquine sulfate (200.00, 150.00, 100.00, 50.00, 16.70, 5.55, 1.85, 0.62, 0.21 micromol.L-1) for 1 h, then the virus was added and incubated for another 2 h. The virus-drug mixture was repalced with fresh medium until the end of the experiment. Post-entry treatment: Vero E6 cells were incubated with virus for 2 h, then the virus was removed and the cells were cultured with drug-containing medium until the end of the experiment. Full-time treatment: Vero E6 cells were pretreated with the drug for 1 h ahead, then virus was added and incubated for another 2 h. The virus-drug mixture was discarded and the cells were cultured with drug-containing medium until the end of the experiment. After 72 h of culture, the cells were observed to see whether they became round and shed to determine the cytopathic situation, and the semi-maximum effect concentration (EC50) and drug selection index (SI) were calculated. Results Both drugs were less effective in preventing SARS-CoV-2. Chloroquine/hydroxychloroquine sulfate showed good antiviral activity under both therapeutic and full-time treatment. EC50 of hydroxychloroquine sulfate was less than chloroquine, SI was greater than chloroquine, antiviral effect of hydroxychloroquine sulfate was better than chloroquine. The antiviral effect of chloroquine (EC50 = 0.904 micromol.L-1) and hydroxychloroquine sulfate (EC50 = 0.143 micromol.L-1) was more significant against Omicron variant than other variants under therapeutic and full-time treatment conditions. Conclusion Chloroquine/hydroxychloroquine sulfate showed good antiviral activity under both therapeutic and full-time treatment, and both drugs were significantly more active against the Omicron variant than the other variants.Copyright © 2023 Authors. All rights reserved.
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Introduction. The rapid spread of a new coronavirus infection among populations in many countries worldwide has contributed to the genetic evolution of the virus, resulting in the emergence of multiple genetic variants of the SARSCoV-2 coronavirus. Mutations in the viral genome can affect the ability of the virus to bypass the immune system and complicate development of diagnostic and prophylactic drugs. Data on the neutralizing activity of the sera obtained against previously circulating genetic variants of the virus in relation to current SARS-CoV-2 strains may serve as a scientific basis for the selection of the antigens in vaccine development. The aim of this work was to study cross-reactivity of SARSCoV-2 coronavirus strains belonging to different genetic variants, which were isolated in the territory of the Russian Federation during 2020-2022 in the neutralization reaction using mouse hyperimmune sera. Materials and methods. Ten strains of SARS-CoV-2 coronavirus belonging to different genetic variants were used (three non-VOC strains, alpha, beta, gamma, delta, delta+AY, omicron 1 and omicron 2). The hCoV-19/Australia/VIC01/2020 strain (Wuhan) was included in the study as a prototypical variant. BALBc mice were immunized with inactivated concentrated antigen mixed with a 1:1 adjuvant, which was a virus-like immunostimulatory complex based on Quillaja saponaria (Quillaja saponaria). The antibody titer was determined in the neutralization reaction. Results. Essential decrease of neutralizing ability of antibodies specific to non-vOC genetic variants of SARS-CoV-2 coronavirus was revealed against beta VOC and to a lesser degree against alpha and gamma VOC variants. The differences in the neutralizing activity level of antibodies for alpha and beta VOC variants are not significant among themselves, and with gamma VOC variants - there are no significant differences. Neutralizing ability of antibodies specific to delta VOC against alpha and beta VOC variants decreased 4-fold. Neutralizing activity of sera obtained to omicron 1 and 2 variants in relation to the prototype coronavirus variant was reduced 18-fold, to the gamma variant - 12-fold, to delta variants - more than 30-fold;for other variants it was even lower. Conclusions. The results obtained testify to the presence of cross-reactivity between strains of coronavirus belonging to genetic lines Wuhan, alpha, beta, gamma;it is weaker for delta variants. Mutations in the genome of VOC omicron variants led to a significant decrease in antigenic cross-links with earlier genetic variants of the coronavirus. These findings explain the low efficacy of vaccines based on the Wuhan strain, synthetic immunogens, and recombinant proteins based on it against omicron VOC variants, which have caused a rise in morbidity since early 2022, as well as cases of re-infection of humans with new genetic variants of the coronavirus.Copyright © 2023 Saint Petersburg Pasteur Institute. All rights reserved.
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Background: More than 12 billion doses of COVID-19 vaccine administrations and over 630 million natural infections should have developed adequate levels of herd immunity over the last three years. However, there have been many new waves of coronavirus infections. The development of safe and effective vaccines to control breakthrough SARS-CoV-2 infections remain an urgent priority. We have developed a recombinant VSV vector-based vaccine to fulfill this worldwide need. Method(s): We have used a recombinant vesicular stomatitis virus (rVSV)-based prime-boost immunization strategy to develop an effective COVID-19 recall vaccine candidate. We have constructed an attenuated recombinant VSV genome carrying the full-length Spike protein gene of SARS-CoV-2. Adding the honeybee melittin signal peptide (msp) at the N-terminus enhanced the protein expression and adding the VSV G protein transmembrane domain and the cytoplasmic tail (Gtc) at the C-terminus of the Spike protein allowed efficient incorporation of the Spike protein into pseudotype VSV. Result(s): In immunized mice, rVSV with chimeric rVSV-msp-S-Gtc induced high levels of potent neutralizing antibodies (nAbs) and CD8+ T cell responses, while the full-length Spike with Gtc proved to be the superior immunogen. More importantly, rVSV-msp-S-Gtc-vaccinated animals were completely protected from subsequent SARS-CoV-2 challenges. Furthermore, rVSV-Wuhan and rVSV-Delta vaccines, and an rVSV-Trivalent (mixed rVSV-Wuhan, -Beta and -Delta) vaccine elicited potent nAbs against live SARS-CoV-2 Wuhan (USAWA1), Beta (B.1.351), Delta (B.1.617.2) and Omicron (B.1.1.529) viruses. Heterologous boosting of rVSV-Wuhan with rVSV-Delta induced strong nAb responses against Delta and Omicron viruses, with the rVSV-Trivalent vaccine consistently inducing effective nAbs against all the SARS-CoV-2 variants tested. All rVSV-msp-S-Gtc vaccines also elicited an immunodominant Spike-specific CD8+ T cell response. Conclusion(s): rVSV vaccines targeting SARS-CoV-2 variants of concern can be considered as an effective booster vaccine in the global fight against COVID-19.
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Background: The continuous evolution of SARS-CoV-2 in the diverse immune landscape (natural, vaccine, hybrid) is giving rise to novel immune escape mutations. So far, the resulting new variants (BA.1, BA.2, BA.2.12.1) were observed to cause mild infections, however, BA.5 infections are associated with an increased risk of hospitalization.1 Therefore it is essential to investigate the pathogenesis of BA.5. Method(s): Here we compared the pathogenicity of Pre-Omicron (B.1.351) and Omicron (BA.1, BA.2.12.1, and BA.5) variants in wild-type C57BL/6J mice and K18-hACE2 mice. The virus replication kinetics was also studied in human Calu3, pulmonary alveolar type 2 (AT2) cells, and airway organoids (HAO). Cell-to-cell spread of virus was measured by syncytia formation assay and immunohistochemistry (IHC) of infected lungs. Result(s): In the results, infection in C57BL/6J mice showed severe weight loss ( >15%) for B.1.351 infected mice and moderate ( >5%) for BA.5 infected. C57BL/6J mice showed higher virus replication of B.1.351 followed by BA.5, BA.1, and BA.2.12.1. At the peak of virus replication (2 days) plaque-forming units from lung extract of BA.5 infected mice were two, and three logs higher compared to BA.1 and BA.2.12.1 respectively. BA.5 infection was lethal to 80% of infected K18-hACE2 mice, whereas the mice looked normal after infection with BA.1 and BA.2.12.1. BA.5 infected mice showed high virus replication in brain tissue. Surprisingly the syncytia formation assay and IHC for BA.5 was comparable to that of B.1.351, indicating the higher cell-to-cell spread of BA.5 and B.1.351 compared to BA.1 and BA.2.12.1, which is one of the measures of pathogenicity. Calu3 and HAO showed the same trend of virus replication as was observed in-vivo experiments however AT2 cells were found to be resistant to BA.5 replication. Conclusion(s): These results suggest that the BA.5 variant (lineage) of Omicron has the potential to regain the pathogenicity as it shows increased virulence compared to other Omicron sub-variants. Lethal infection of BA.5 in K18-hACE2 mice may be attributed to catastrophic encephalitis and increased cell-to-cell spread.
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Background: At the global level, the dynamics of the COVID-19 pandemic have been driven by several epidemiological waves, determined by the emergence of new SARS-CoV-2 variants from the original viral lineage from Wuhan, China. While the SARS-CoV-2 dynamic has been described globally, there is a lack of data from Sub-Saharan African. Method(s): A laboratory-based survey was conducted in Cameroon, from March 1, 2020 to March 30, 2022, through an assessment of the evolutionary patterns of SARS-CoV-2 lineages across the four COVID-19 waves in the country. Data on full-length sequencing from all four sequencing laboratories were consecutively entered into the GISAID platform. These data were downloaded, and the molecular phylogeny of the SARS-CoV-2 sequences was performed using Nexstrain. The Mann-Whitney U test was used to calculate the correlation between the duration of each outbreak and the number of confirmed cases and between hospitalised cases and CFR, with a p value < 0.05 considered statistically significant. Result(s): A total of 3,881 samples were successfully processed, of which 38.9% (n=1,509) using PCR mutation assay, 41.5% (n=1,612) using targeted sequencing, and 19.6% (n=760) using whole-genome sequencing. The mean age of the study population was 36 years (min-max: 2-86), and 45% were within the age range 26-45. Regarding gender distribution, 50.9% were male, and 49.1% were female. Phylogenetic analysis of the 760 whole-genome sequences generated from March 2020 to March 2022 revealed that the greater proportion of SARS-CoV-2 circulating in Cameroon belonged to the viral sub-lineages of the original strain from Wuhan (74%), 15% Delta variant, 6% Omicron variant, 3% Alpha variant and 2% Beta variant.The pandemic was driven by SARS-CoV-2 lineages of origin in Wave 1 (16 weeks, 2.3% CFR), the Alpha and Beta variants in Wave 2 (21 weeks, 1.6% CFR), Delta variants in Wave 3 (11 weeks, 2.0% CFR), and Omicron variants in Wave 4 (8 weeks, 0.73% CFR), with a declining trend over time (p=0.01208). Conclusion(s): In a nutshell, the SARS-CoV-2 epidemic in Cameroon appears to have been driven by the SARS-CoV-2 lineage of origin in Wave 1, the cointroduction of the Alpha and Beta variants in Wave 2, the Delta variant in Wave 3, and the Omicron variant in Wave 4, with an overall declining trend in the wave duration, confirmed cases and hospitalisations over time.The SARS-CoV-2 lineage of origin and the Delta variant appeared to be the drivers of COVID-19 severity in Cameroon.
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Background: COVID-19 vaccines that expand immunity against emerging variants of concern (VOC) are needed to protect against ongoing viral evolution. We investigated the impact of boosting nonhuman primates pre-immune to the original WA-1 strain with updated VOC vaccines on the breadth and magnitude of mucosal and systemic antibody (Ab) and T cell (Tc) responses. Method(s): Cynomolgus macaques were primed with 2 doses of WA-1 Spike protein encoded by either an IL-12 adjuvanted DNA vaccine administered by gene gun (GG) or a self-amplifying RNA vaccine (repRNA) delivered intramuscularly (IM) with a cationic nanocarrier (LIONTM/IM, HDT Bio) or by GG (FIG 1). A booster dose was administered at week 17 with DNA or repRNA vaccines expressing B.1.351 (Beta) and B.1.617 (Delta) Spike receptor-binding domains (RBDs) fused to influenza HA2 stem domain (SHARP, designed by AIR/ JP) followed by a final Beta + Delta + WA-1 SHARP boost at week 34. Blood and bronchoalveolar lavages (BAL) were collected before and after each dose. Binding and neutralizing Ab to VOCs, including Omicron strains, were measured by ELISA and pseudovirus neutralization assays. Tc responses to Spike protein (WA-1 peptides) were measured by ELISpot. Immune responses were compared between groups and between blood vs lung using non-parametric statistical tests. Result(s): Two doses of WA-1 DNA or repRNA vaccines induced broad Ab against all VOC with the repRNA vaccine inducing the highest titers. Boosting with VOC SHARP significantly increased mucosal and systemic Ab responses against all VOCs tested including Omicron. After final boost, all groups had comparable binding and neutralization Ab titers and Tc responses regardless of method of delivery (GG or LIONTM/IM) or formulation (DNA or repRNA). Tc responses were significantly higher in the BAL vs PBMC after WA-1 Spike doses (p=0.0420) and VOC SHARP boosters (p=0.0009). Conclusion(s): The WA-1 strain primed for broad responses against VOCs that were significantly boosted with updated SHARP vaccines including responses against Omicron, even though this strain was not included in any dose. This suggests that sequential immunization with updated vaccines may broaden mucosal and systemic immunity against future VOCs. The repRNA vaccine initially induced the strongest responses, but there were no differences between RNA and DNA following additional booster doses, a result that supports development of a more cost-effective, room temperature stable DNA vaccine for worldwide boosters. (Figure Presented).
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The genetic evolution of SARS-CoV-2 began in February 2020, with G614 spike protein strains superseding D614 strains globally. Since then with each subsequent mutations, the SARS-CoV-2 variants of concern, namely Alpha, Beta, Gamma, Delta and Omicron, superseded the previous one to become the dominant strain during the pandemic. By the end of November 2022, the Omicron variant and its descendent lineages account for 99.9% of sequences reported globally. All five VOCs have mutations located in the RBD of the spike protein, resulting in increased affinity of the spike protein to the ACE2 receptors resulting in enhanced viral attachment and its subsequent entry into the host cells. In vitro studies showed the mutations in spike protein help increase the viral fitness, enhancing both transmissibility and replication. In general, Alpha, Beta, Gamma, and Delta variants, were reported with higher transmissibility of 43-90%, around 50%, 170-240%, or 130-170% than their co-circulating VOCs, respectively. The Omicron however was found to be 2.38 times and 3.20 times more transmissible than Delta among the fully-vaccinated and booster-vaccinated households. Even the SARS-Cov-2 Omicron subvariants appear to be inherently more transmissible than the ones before. With the broader distribution, enhanced evasion, and improved transmissibility, SARS-CoV-2 variants infection cause severe diseases due to immune escape from host immunity and faster replication. Reports have shown that each subsequent VOC, except Omicron, cause increased disease severity compared with those infected with other circulating variants. The Omicron variant infection however, appears to be largely associated with a lower risk of hospitalisation, ICU admission, mechanical ventilation, and even a shorter length of hospital stay. It has been shown that the relatively much slower replication of the Omicron variants in the lung, resulted in a less severe disease.Copyright © 2022, Malaysian Society of Pathologists. All rights reserved.
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Coronavirus disease 2019 (COVID-19) outbreak started in Wuhan, China when people started with the symptoms of respiratory disorder. The onset of this disease have symptoms like fever, dry cough, fatigue, and difficulty in breathing. The nature of SARS-CoV-2 seems highly contagious as it also can be spread with asymptomatically infected individuals. It has been more than a year which this outbreak have been announced as a pandemic by World Health Organization (WHO) due to major public health crisis and uncontrollable around the globe. Some countries have taken initiatives in inventing vaccines and step up in the clinical trial process since a vaccine is an all-powerful tool which it always been a saviour in fighting infectious disease. In searching for the vaccine, researchers had studied the previously published article of SARS-CoV or MERS as in the beginning, in light, there will be a suitable vaccine to fight this pandemic situation. Recent research on the vaccine has been tested to seek the right vaccine for COVID-19. This study is to focus on the current vaccine development against COVID-19 and to explore the potential vaccines' characteristics that have been studied by the previous proven research findings. This review was done based on the research articles and reviews published until the end of April 2021 through established scientific search engines and related scientific platforms based on the inclusion criteria with its related keywords like coronavirus, SARS-CoV-2, COVID-19 Vaccine, clinical trials, and COVID-19 vaccine development. This review summarized a few vaccine candidates that have entered clinical trials and some supported evidence from Phase I until Phase III clinical trial studies that have been published and reported. In this review, 12 vaccine candidates have the potential to against SARS-CoV-2. Thus, their vaccine platform, characteristic as well as its efficacy studies have been discussed.Copyright © RJPT All right reserved.
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The year 2020 was the most challenging period due to the havoc caused by the outbreak of novel coronavirus SARS-CoV-2. Scientists and researchers all around the world have endeav-ored every possible approach to find solutions in context to therapeutics and vaccines to control the spread of this life-threatening virus. The acceleration instigated by the outbreak of SARS-CoV-2 and its mutated strains has leveraged the use of numerous platform technologies for the development of vaccines against this unfathomable disease. Vaccines could play an important role in miti-gating the effects of COVID-19 and reducing the ongoing health crisis. Various innovative plat-forms like proteins, nucleic acids, viruses, and viral vectors have been exploited to fabricate vaccines depicting almost 90% of efficacy like BNT162b2, AZD1222, Ad5-nCoV, etc. Some of these vaccines are multipotent and have shown potent activity against newly emerged malicious strains of SARS-CoV-2 like B.1.351 and B.1.1.7. In this review article, we have gathered key findings from various sources of recently popularized vaccine candidates, which will provide an overview of potential vaccine candidates against this virus and will help the researchers to investi-gate possible ways to annihilate this menace and design new moieties.Copyright © 2022 Bentham Science Publishers.
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Passive immunization with mAbs has been employed in COVID-19. We performed a systematic review of the literature assessing the endogenous humoral immune response against SARS-CoV-2 in patients treated with mAbs. Administration of mAbs in seronegative patients led to a reduction in both antibody titres and neutralizing activity against the virus.Copyright © 2022
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The Omicron variant of SARS-CoV-2 is a new variant of concern after Alpha, Beta, Gamma and Delta variants. The amino acid mutations in the viral antigens, especially in the receptor binding region (RBD) of spike protein, were significantly more than those of other variants, which lead to the significant increase of infectivity, transmissibility and immune escape of Omicron variant. In addition, those spike mutations impaired the protective effect of vaccination. When compared to the infection of other variants, the latency of Omicron variant infection was significantly shortened, and the pathogenicity decreased markedly, which is in consistence with the fact that the vast majority of infected individuals showed no symptoms or only mild disease. Exacerbations in patients infected by Omicron variant were often associated with the progress of underlying disease. Early detection and medical isolation of infected persons, careful personal protection measures to cut off transmission routes, and active vaccination to protect susceptible people are key measures to prevent the spread of Omicron variant epidemic. A small number of patients infected with Omicron variant may develop so-called long COVID-19, post-COVID-19 syndrome, or post-COVID-19 condition, which means that long-term follow-up is needed in those patients. Effective anti-Omicron variant therapy can shorten the course of infection, promote the recovery from infection, and also contribute to the control of infection. Therefore, the development of antiviral drugs with ideal cost-benefit ratio and convenient administration is one of the research hotspot in the future.Copyright © 2022 Authors. All rights reserved.
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), and SARS-CoV-2 variants pose an increased risk to global health. Therefore, monitoring of SARS-CoV-2 variants of concern (VOCs) is of high importance for the implementation of disease control methods, for timely public health decisions, and the development of vaccines against SARS-CoV-2 variants. In this study, which was performed before the delta and omicron variants of concern became dominant, a total of 111 SARS-CoV-2 positive samples from our hospital staff in Cologne, Germany, collected from March 2020 to May 2021 were analysed for VOCs. For determination of VOCs, mutation genotyping analysis (MGA) using mutation-specific simple (MSS) probes based on quantitative reverse transcription-polymerase chain reaction (RT-qPCR) of ten spike protein variants (SPVs) was performed. The MGA focuses on the detection of the spike protein mutation (SPM) of SPVs belonging to VOCs. By successful determination of SPV, the work concludes that 24.66 % of the samples belong to VOC B.1.1.7 and 1.37 % of the samples belong to VOC B.1.351. Based on these results, MGA proves to be a suitable alternative to sequencing technologies as it is a rapid, cost-effective, widely available, and feasible method that allows high sample throughput for the determination of circulating and monitored SARS-CoV-2 VOCs. With focus on the novel variants such as SARS-CoV-2 omicron BA.4 and BA.5 similar approaches could be used for a rapid initial screening, while, however, due to the increasing number of single nucleotide polymorphisms that determine the variants of concern in depth screening becomes more cost efficient by next generation sequencing.Copyright © 2022 AEPress, s.r.o.. All rights reserved.
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Critically ill patients infected with SARS-CoV-2 display adaptive immunity, but it is unknown if they develop cross-reactivity to variants of concern (VOCs). We profiled cross-immunity against SARS-CoV-2 VOCs in naturally infected, non-vaccinated, critically ill COVID-19 patients. Wave-1 patients (wild-type infection) were similar in demographics to Wave-3 patients (wild-type/alpha infection), but Wave-3 patients had higher illness severity. Wave-1 patients developed increasing neutralizing antibodies to all variants, as did patients during Wave-3. Wave-3 patients, when compared to Wave-1, developed more robust antibody responses, particularly for wild-type, alpha, beta and delta variants. Within Wave-3, neutralizing antibodies were significantly less to beta and gamma VOCs, as compared to wild-type, alpha and delta. Patients previously diagnosed with cancer or chronic obstructive pulmonary disease had significantly fewer neutralizing antibodies. Naturally infected ICU patients developed adaptive responses to all VOCs, with greater responses in those patients more likely to be infected with the alpha variant, versus wild-type.
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Introduction/ Background: May 2021, Kisumu County was affected by a COVID- 19 Delta variant outbreak. For non-resilient health systems with data channels based on paper, such outbreaks are a major challenge. A public-private partnership was initiated in Kisumu, Kenya. This partnership emphasizes digital mobile solutions that have a high potential for scalability. Methods: The partnership was between Kisumu County, KEMRI, PharmAccess, and healthcare facilities to roll out the implementation research. All those accessing tests as per the case definition of the MoH case definition were eligible for inclusion. We digitalized the Ministry of Health COVID-19 Case Identification Form, gathered data in healthcare facilities on digital tools, and shared aggregated results via a co-created (semi-) live dashboard to all relevant stakeholders. We performed descriptive analyses on the data. Additionally, semi-structured interviews with key stakeholders on the experiences of the project will provide qualitative insights. Results: As of November 2021, 32 healthcare facilities are connected to the dashboard, over 23,000 COVID-19 tests have been done with more than 2,800 positive cases: 52% Delta variant, 45% Alpha variant, and 4% Beta variant. All key staff are connected to the digital tools and actively use them for decision-making. Geomapping of cases has shown to be useful for disease surveillance, especially case-tracking. Proper training and technical support for the digital tools and dashboard, co-creation with all users, and having a strong roll-out plan are key for success. Impact: Public-private partnerships offer the possibility of scaling up diagnostic capacity and using technology to track the epidemic in real-time guiding efficient allocation of limited resources in an evidence-based manner, a good step towards epidemic preparedness. Better decision making and targeted action can be taken because of this digitalized systems approach. Conclusion: Digital platforms have a key role to play in epidemics tracking and preparedness. From these outcomes, the digital platform we developed during this study is being scaled up to 14 more counties of Kenya to be used to track the epidemic in a population of over 15 million people.
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Objective To evaluate the in vitro cross-neutralization of serum antibodies in human and mice immunized with inactivated SARS-CoV-2 vaccine against Delta and Beta variants. Methods Human serum samples after a second and a third dose of inactivated SARS-CoV-2 vaccine and mouse serum samples after a two-dose vaccination were collected. The neutralizing antibodies in the samples against SARS-CoV-2 strains of prototype, Delta and Beta variants were detected using micro-neutralization assay in biosafety level III laboratory. The seroconversion rates and geometric mean titers (GMTs) of antibodies were calculated. Results The seroconversion rates of antibodies in human serum samples against different SARSCoV-2 strains were all above 95%. After two-dose vaccination, the GMTs of neutralizing antibodies against the prototype, Delta and Beta strains were 109, 41 and 15, respectively. The GMTs decreased by 2. 7 folds and 7. 3 folds for the Delta and Beta variants as compared with the prototype strain. After the booster vaccination, the GMTs of neutralizing antibodies against the prototype, Delta and Beta strains were 446,190 and 86, respectively. The GMTs of neutralizing antibodies against Delta and Beta variants decreased by 2. 3 folds and 5. 2 folds as compared with that against the prototype strain. The seroconversion rates of antibodies against different SARS-CoV-2 strains in mouse serum samples were all 100%. The GMTs of neutralizing antibodies against the prototype, Delta and Beta strains were 2 037, 862 and 408, respectively. The GMTs decreased by 2.4 folds and 5.0 folds for the Delta and Beta variants. Conclusions Inactivated SARS-CoV-2 vaccine could induce a certain level of neutralizing antibodies against Delta and Beta variants in both human and mouse models. Moreover, a third dose of vaccine induced higher levels of neutralizing antibodies against Delta and Beta variants in human. This study provided valuable data for the clinical application and protective evaluation of the inactivated SARS-CoV-2 vaccine.
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The ongoing COVID-19 pandemic has hit long-term care facilities (LTCF), with outbreaks affecting both residents and health care workers (HCWs). Elderly persons have been prioritized in the implementation of vaccination programs. Here we investigated a COVID-19 outbreak, caused by the Beta variant (B.1.351) in a LTCF where residents and HCWs had received 2 doses of Comirnaty vaccine (Pfizer/BioNTech) until one month before the outbreak. Samples from 14 residents (SARS-CoV-2 PCR-negative: n = 8, PCR-positive: n = 6) and 10 HCWs (PCR-negative: n = 10) were collected at a median of 54 days following the second vaccine dose. IgG antibodies to SARS-CoV-2 spike glycoprotein and neutralizing antibody (NAb) titers were measured. Additionally, functional responses of PBMCs to SARS-CoV-2 spike and nucleocapsid proteins were investigated. We observed that Comirnaty induced higher IgG concentrations and NAb titers in HCWs compared to residents. PBMCs of HCWs responded vigorously to stimulation with SARS-CoV-2 spike glycoprotein, with the secretion of interferon gamma, granzyme B and perforin-1 into supernatants. In comparison, only 3 of 9 samples from residents showed positive cellular responses to spike glycoprotein. Group-level cellular responses directed at SARS-CoV-2 nucleoprotein remained low both in HCWs and in residents. Only 2 of 2 PCR-positive residents showed a positive response consistent with exposure to SARS-CoV-2 breakthrough infection. Our results show that elderly persons are at increased risk for breakthrough infection after vaccination. Weak vaccine-directed responses in the elderly need to be addressed in vaccination protocols.
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Introduction SARS-CoV-2 variants of concern (VOCs) represent an alarming threat as they may escape vaccination effectiveness. Broad-spectrum antivirals could complement and further enhance preventive benefits achieved through SARS-CoV-2 vaccination campaigns. Aim Testing the antiviral activity of Echinacea purpurea against VOCs and exploring underlying modes-of-action. Method A hydroethanolic extract of freshly harvested E. purpurea herb and roots (Echinaforce®, EF extract) was tested to inhibit infection of VOCs B1.1.7 (alpha), B.1.351.1 (beta), P.1 (gamma), B1.617.2 (delta), AV.1 (Scottish) and B1.525 (eta). Molecular dynamics (MD) were used to study interaction of EF phytochemical markers with known pharmacological viral and host cell targets. Results EF broadly inhibited propagation of all tested SARS-CoV-2 VOCs at EC50 < 12.0 ;jg/ml. Treatment of epithelial cells with 20 jg/ml EF prevented sequential infection with SARS-CoV-2 (Hu-1). MD analyses showed for alkylamides, caftaric acid and feruoyl-tartaric constant binding affinity to spike proteins of all VOCs and to TMPRSS-2, a serine protease required for virus endocytosis. Conclusion EF extract exhibits virucidal activity against all tested SARS-CoV-2 VOCs and protects epithelial cells from infection.
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The novel coronavirus and its emerging variants have continued to affect 50.4 million people worldwide, increasing the need for safe and effective vaccines. According to the World Health Organization guidelines, the efficacy of a vaccine should be at least 30% in all age groups and protect for a longer duration without any life-threatening adverse effects. At present, there are 319 vaccines in various stages of development, of which 16 are authorized for emergency use. Of these 16 vaccines, five vaccines are based on adenoviral vectors. This review is focused on understanding the safety and efficacy of the approved adenoviral vector vaccines for COVID-19, particularly highlighting the interim analysis of phase 3 clinical trials of AZD1222, Gam-Covid-Vac, Ad26.COV2.S, and AD5-nCOV vaccine. The efficacy of AZD1222, Gam-Covid-Vac, Ad26.COV2.S, and AD5-nCOV vaccine were found to be 70.4%, 95%, 66%, and 65.7%, respectively. Some serious adverse events such as deep vein thrombosis and thrombosis with thrombocytopenia syndrome were observed among AZD1222 and Ad26.COV2.S vaccinated individuals. Meanwhile, Gam-Covid-Vac and AD5-nCOV vaccines did not report any significant adverse events. In addition, we have also focused on the efficacy of these vaccines against SARS-CoV-2 variants such as B.1.1.7, B.1.351, and P.1. Although the efficacy of these approved vaccines against novel SARS-CoV-2 variants, pediatric and geriatric population and long-term efficacy remains uncertain, they are reasonably efficient in preventing mortality due to COVID-19.
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Introduction: The rapid emergence of the SARS-CoV-2 Omicron variant that evades many monoclonal antibody therapies illustrates the need for anti-viral treatments with low susceptibility to evolutionary escape. The small molecule PAV-104, identified through a moderate-throughput screen involving cell-free protein synthesis, was recently shown to target a subset of host protein assembly machinery in a manner specific to viral assembly. This compound has minimal host toxicity, including once daily oral dosing in rats that achieves >200-fold of the 90% effective concentration (EC90) in blood. The chemotype shows broad activity against respiratory viral pathogens, including Orthomyxoviridae, Paramyxoviridae, Adenoviridae, Herpesviridae, and Picornaviridae, with low suceptability to evolutionary escape. We hypothesized that PAV-104 would be active against SARSCoV- 2 variants in human airway epithelial cells. Methods: Airway epithelial cells were differentiated from lung transplant tissue at air-liquid interface (ALI) for four weeks prior to challenge with Alpha (Pango lineage designation B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) SARS-CoV-2 variants. Viral replication was determined by quantitative PCR measurement of the SARS-CoV-2 nucleocapsid (N) gene. Dose-dependent virus inhibition and cytotoxicity of PAV-104 in the Calu-3 airway epithelial cell line was determined by PCR and MTT assay. Student's t-tests were used to evaluate statistical significance. Results: Alpha, Beta, Gamma, and Delta variants of SARS-CoV-2 showed comparable infectivity in human primary airway epithelial cells at ALI (N=3 donors), 47- to 550-fold higher than the parent (USA-WA1/2020) strain. PAV-104 reached 50% cytotoxicity in Calu-3 cells at 240 nM (Fig. 1A). Dose-response studies in Calu-3 cells demonstrated PAV-104 has a 6 nM 50% inhibitory concentration (IC50) for blocking replication of SARS-CoV-2 (USA-WA1/2020) (Fig.1B). In primary cells at ALI from 3 donors tested, there was >99% inhibition of infection by SARS-CoV-2 Gamma variant (N=3, MOI 0.1, P <0.01) with 100 nM PAV-104 (Fig. 1C). Addition of 100 nM PAV-104 2-hours post-infection, but not pre-infection, resulted in >99% suppression of viral replication, indicating a post-entry drug mechanism. PAV-104 bound a small subset of the known allosteric modulator 14-3-3, itself implicated in the interactome of SARS-CoV-2. Conclusion: PAV-104 is a host-targeted, orally bioavailable, pan-viral small molecule inhibitor with promising activity against SARS-CoV-2 variants in human primary airway epithelial cells. (Figure Presented).
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Rationale The recent emergence of a novel coronavirus, SARS-CoV-2, has led to the global pandemic of the severe disease COVID-19 in humans. While efforts to quickly identify effective antiviral therapies have focused largely on repurposing existing drugs, the current standard of care, remdesivir, remains the only authorized antiviral intervention of COVID-19 and provides only modest clinical benefits. Thus, new antivirals targeting SARS-CoV-2 are urgently needed. Methods Artificial intelligence algorithm MediKanren was used to query FDA-approved and late-stage drug compounds for potential interactions with SARS-CoV-2 proteins, coronaviruses, and host cell networks for possible antiviral activity. From this, 157 compounds were further tested in an antiviral screen against live SARS-CoV-2 for reduction in viral growth. Select compounds were further assessed for synergistic activity with remdesivir. Both in vitro and cell free systems identified tocopherol succinate compounds that inhibited the RNA-dependent RNA polymerase (RdRp). Validation of antiviral and synergistic activity was performed in primary human airway epithelial cell cultures against multiple SARS-CoV-2 variants.Results Here we show that water-soluble derivatives of α-tocopherol have potent antiviral activity and synergize with remdesivir as inhibitors of the SARS-CoV-2 (RdRp). Through an artificial-intelligence-driven in silico screen and in vitro viral inhibition assay, we identified D-α-tocopherol polyethylene glycol succinate (TPGS) as an effective antiviral against SARS-CoV-2 and β-coronaviruses more broadly that also displays strong synergy with remdesivir. We subsequently determined that TPGS and other water-soluble derivatives of α- tocopherol inhibit the transcriptional activity of purified SARS-CoV-2 RdRp and identified affinity binding sites for these compounds within a conserved, hydrophobic interface between SARS-CoV- 2 nonstructural protein 7 and nonstructural protein 8 that is functionally implicated in the assembly of the SARS-CoV-2 RdRp. Conclusion In summary, solubilizing modifications to α-tocopherol allow it to interact with the SARS-CoV-2 RdRp, making it an effective antiviral molecule alone and even more so in combination with remdesivir. These findings are significant given that many tocopherol derivatives, including TPGS, are considered safe for humans, orally bioavailable, and dramatically enhance the activity of the only approved antiviral for SARS-CoV-2 infection.