Jin Wang

Bio: Jin Wang is an academic researcher from Sun Yat-sen University. The author has contributed to research in topics: Virology & Antibody. The author has an hindex of 3, co-authored 7 publications receiving 21 citations.

Ubiquitin-Modified Proteome of SARS-CoV-2-Infected Host Cells Reveals Insights into Virus-Host Interaction and Pathogenesis.

Abstract: The outbreak of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed a serious threat to global public health. The mechanism of pathogenesis and the host immune response to SARS-CoV-2 infection are largely unknown. In the present study, we applied a quantitative proteomic technology to identify and quantify the ubiquitination changes that occur in both the virus and the Vero E6 cells during SARS-CoV-2 infection. By applying label-free, quantitative liquid chromatography with tandem mass spectrometry proteomics, 8943 lysine ubiquitination sites on 3086 proteins were identified, of which 138 sites on 104 proteins were quantified as significantly upregulated, while 828 sites on 447 proteins were downregulated at 72 h post-infection. Bioinformatics analysis suggested that SARS-CoV-2 infection might modulate host immune responses through the ubiquitination of important proteins, including USP5, IQGAP1, TRIM28, and Hsp90. Ubiquitination modification was also observed on 11 SAR-CoV-2 proteins, including proteins involved in virus replication and inhibition of the host innate immune response. Our study provides new insights into the interaction between SARS-CoV-2 and the host as well as potential targets for the prevention and treatment of COVID-19.

The worldwide seroprevalence of DENV, CHIKV and ZIKV infection: A systematic review and meta-analysis.

Abstract: Background As the three major arthropod-borne viruses, dengue virus (DENV), chikungunya virus (CHIKV), and zika virus (ZIKV) are posing a growing threat to global public health and socioeconomic development. Our study aimed to systematically review the global seroprevalences of these arboviruses from existing publications. Methods Articles published between Jan 01, 2000 and Dec 31, 2019 in the databases of Embase, Pubmed and Web of Science were searched and collected. Countries or areas with known local presence of Aedes vector mosquitoes were included. Random effects model was utilized to estimate the pooled seroprevalences and the proportion of inapparent infection. Results Out of 1375, a total of 133 articles involving 176,001 subjects were included for our analysis. The pooled seroprevalences of DENV, CHIKV and ZIKV were 38%, 25% and 18%, respectively; and their corresponding proportions of inapparent infections were 80%, 40% and 50%. The South-East Asia Region had the highest seroprevalences of DENV and CHIKV, while the Region of the Americas had the highest seroprevalence of ZIKV. The seroprevalences of DENV and CHIKV were similar when comparing developed and developing countries, urban and rural areas, or among different populations. In addition, we observed a decreased global seroprevalences in the new decade (2010–2019) comparing to the decade before (2000–2009) for CHIKV. For ZIKV, the positive rates tested with the nucleic acid detection method were lower than those tested with the antibody detection method. Lastly, numerous cases of dual seropositivity for CHIKV and DENV were reported. Conclusions Our results revealed a varied prevalence of arbovirus infections in different geographical regions and countries, and the inapparent infection accounted an unneglected portion of infections that requires more attention. This study will shed lights on our understanding of the true burden of arbovirus infections and promote appropriate vaccination in the future.

The Emergence and Spread of Novel SARS-CoV-2 Variants.

Abstract: Since severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) began to spread in late 2019, laboratories around the world have widely used whole genome sequencing (WGS) to continuously monitor the changes in the viral genes and discovered multiple subtypes or branches evolved from SARS-CoV-2. Recently, several novel SARS-CoV-2 variants have been found to be more transmissible. They may affect the immune response caused by vaccines and natural infections and reduce the sensitivity to neutralizing antibodies. We analyze the distribution characteristics of prevalent SARS-CoV-2 variants and the frequency of mutant sites based on the data available from GISAID and PANGO by R 4.0.2 and ArcGIS 10.2. Our analysis suggests that B.1.1.7, B.1.351, and P.1 are more easily spreading than other variants, and the key mutations of S protein, including N501Y, E484K, and K417N/T, have high mutant frequencies, which may have become the main genotypes for the spread of SARS-CoV-2.

Epidemiologic Characteristics, Transmission Chain, and Risk Factors of Severe Infection of COVID-19 in Tianjin, a Representative Municipality City of China

Abstract: This study was performed to describe the epidemiologic characteristics of coronavirus disease 2019 (COVID-19) and explore risk factors for severe infection. Data of all 131 confirmed cases in Tianjin before February 20 were collected. By February 20, a total of 14/16 districts reported COVID-19 cases, with Baodi district reporting the most cases (n = 56). A total of 22 (16.8%) cases had a Wuhan-related exposure. Fever was the most common symptom (82.4%). The median duration of symptom onset to treatment was [1.0 (0.0-4.0) days], the duration of symptom onset to isolation [2.0 (0.0-6.0) days], and the duration of symptom onset to diagnosis [5.0 (2.0-8.0) days]. The analysis of the transmission chain showed two cluster infections with 62 cases infected. Transmission from a family member constituted 42%, usually at the end of transmission chain. Compared with patients with non-severe infections, patients with severe infections were more likely to be male (46.2 vs. 77.3%, P = 0.009) and had a Wuhan-related exposure (14.0 vs. 40.9%, P = 0.004). Multivariate logistic regression showed that male (OR 3.913, 95% CI 1.206, 12.696; P = 0.023) was an independent risk factor for severe infection. This study provides evidence on the epidemic of COVID-19 by analyzing the epidemiological characteristics of confirmed cases in Tianjin. Self-quarantine at an outbreak's early stage, especially for those with high-risk exposures, is conducive to prevent the transmission of infection. Further investigation is needed to confirm the risk factors for severe COVID-19 infection and investigate the mechanisms involved.

Ad26.COV2.S breakthrough infections induce high titers of neutralizing antibodies against Omicron and other SARS-CoV-2 variants of concern

Abstract: •Ad26.COV2.S neutralizing antibodies persist 6 months post-vaccination•Breakthrough infection boosts binding antibodies, ADCC, and neutralization•Boosted neutralizing antibodies cross-react with SARS-CoV-2 variants including Omicron•Vaccination and infection synergistically contribute to high levels of immunity The Janssen (Johnson & Johnson) Ad26.COV2.S non-replicating viral vector vaccine has been widely deployed for COVID-19 vaccination programs in resource-limited settings. Here we confirm that neutralizing and binding antibody responses to Ad26.COV2.S vaccination are stable for 6 months post-vaccination, when tested against multiple SARS-CoV-2 variants. Secondly, using longitudinal samples from individuals who experienced clinically mild breakthrough infections 4 to 5 months after vaccination, we show dramatically boosted binding antibodies, Fc effector function, and neutralization. These high titer responses are of similar magnitude to humoral immune responses measured in convalescent donors who had been hospitalized with severe illness, and are cross-reactive against diverse SARS-CoV-2 variants, including the neutralization-resistant Omicron (B.1.1.529) variant that currently dominates global infections, as well as SARS-CoV-1. These data have implications for population immunity in areas where the Ad26.COV2.S vaccine has been widely deployed, but where ongoing infections continue to occur at high levels. The Janssen (Johnson & Johnson) Ad26.COV2.S non-replicating viral vector vaccine has been widely deployed for COVID-19 vaccination programs in resource-limited settings. Here we confirm that neutralizing and binding antibody responses to Ad26.COV2.S vaccination are stable for 6 months post-vaccination, when tested against multiple SARS-CoV-2 variants. Secondly, using longitudinal samples from individuals who experienced clinically mild breakthrough infections 4 to 5 months after vaccination, we show dramatically boosted binding antibodies, Fc effector function, and neutralization. These high titer responses are of similar magnitude to humoral immune responses measured in convalescent donors who had been hospitalized with severe illness, and are cross-reactive against diverse SARS-CoV-2 variants, including the neutralization-resistant Omicron (B.1.1.529) variant that currently dominates global infections, as well as SARS-CoV-1. These data have implications for population immunity in areas where the Ad26.COV2.S vaccine has been widely deployed, but where ongoing infections continue to occur at high levels. A phase 3 clinical trial of Ad26.COV2.S in eight countries demonstrated 85% protection against severe disease,1Sadoff J. Gray G. Vandebosch A. Cárdenas V. Shukarev G. Grinsztejn B. Goepfert P.A. Truyers C. Fennema H. Spiessens B. et al.Safety and efficacy of single-dose Ad26.COV2.S vaccine against covid-19.N. Engl. J. Med. 2021; 384: 2187-2201Crossref PubMed Scopus (806) Google Scholar including in South Africa, where the trial coincided with the emergence of the Beta (B.1.351) variant, which was shown to have increased resistance to neutralizing antibodies.2Tegally H. Wilkinson E. Giovanetti M. Iranzadeh A. Fonseca V. Giandhari J. Doolabh D. Pillay S. San E.J. Msomi N. et al.Detection of a SARS-CoV-2 variant of concern in South Africa.Nature. 2021; 592: 438-443Crossref PubMed Scopus (596) Google Scholar,3Wibmer C.K. Ayres F. Hermanus T. Madzivhandila M. Kgagudi P. Oosthuysen B. Lambson B.E. de Oliveira T. Vermeulen M. van der Berg K. et al.SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma.Nat. Med. 2021; 27: 622-625Crossref PubMed Scopus (509) Google Scholar As a result, Ad26.COV2.S was made available to South African health care workers (HCWs) in early 2021 through the Sisonke open-label, phase 3b clinical trial. Globally, this vaccine has also been used widely in several countries, including the United States and European Union member states, with 5.38, 15.68, and 16.16 million doses administered in these regions, respectively, by the beginning of November 2021. Subsequently, South Africa has experienced a third and fourth wave of infection, driven by the Delta (B.1.617.2) and Omicron (B.1.1.529) variants, respectively, with reports of Ad26.COV2.S breakthrough infections (BTIs) occurring. Infections following mRNA vaccination result in boosted neutralizing antibody titers,4Bates T.A. McBride S.K. Winders B. Schoen D. Trautmann L. Curlin M.E. Tafesse F.G. Antibody response and variant cross-neutralization after SARS-CoV-2 breakthrough infection.JAMA. 2021; https://doi.org/10.1001/jama.2021.22898Crossref Scopus (29) Google Scholar, 5Collier A.-R.Y. Brown C.M. Mcmahan K. Yu J. Liu J. Jacob-Dolan C. Chandrashekar A. Tierney D. Ansel J.L. Rowe M. et al.Immune responses in fully vaccinated individuals following breakthrough infection with the SARS-CoV-2 Delta variant in Provincetown, Massachusetts.medRxiv. 2021; https://doi.org/10.1101/2021.10.18.21265113https://www.medrxiv.org/content/10.1101/2021.10.18.21265113v1Crossref Scopus (0) Google Scholar, 6Walls A.C. Sprouse K.R. Joshi A. Bowen J.E. Franko N. Navarro M.J. Stewart C. McCallum M. Goecker E.A. Degli-Angeli E.J. et al.Delta breakthrough infections elicit potent, broad and durable neutralizing antibody responses.bioRxiv. 2021; https://doi.org/10.1101/2021.12.08.471707https://www.biorxiv.org/content/10.1101/2021.12.08.471707v1Crossref Scopus (0) Google Scholar but less is known about the immunological consequences of BTI after Ad26.COV2.S vaccination. With the emergence in late November 20217Viana R. Moyo S. Amoako D.G. Tegally H. Scheepers C. Althaus C.L. Anyaneji U.J. Bester P.A. Boni M.F. Chand M. et al.Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in Southern Africa.medRxiv. 2021; https://doi.org/10.1101/2021.12.19.21268028https://www.medrxiv.org/content/10.1101/2021.12.19.21268028v1Crossref Scopus (0) Google Scholar of the Omicron variant, which now dominates global infections and has more spike mutations in key neutralizing epitopes than any variant to date, a key question is whether Ad26.COV2.S-vaccinated individuals who experienced breakthrough infections in the previous Delta-driven wave would have substantial neutralizing responses against this variant. Here, we evaluated the durability and breadth of vaccine-elicited humoral responses in 19 HCWs vaccinated with Ad26.COV.2S in February-March 2021 (Figure 1A ). Second, we characterized the humoral response to BTI in a subset of six individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR-confirmed infections 4 to 5 months (median number of months: 4.4; interquartile range [IQR]: 4.1–4.8) following vaccination. Five of these participants were followed longitudinally 2 to 6 months post-vaccination, whereas for the sixth BTI participant only 2- and 6-month post-vaccination samples were available (Table S1). These BTIs occurred between June and August 2021, during the third wave of SARS-CoV-2 infections in South Africa. This wave was driven by the more transmissible Delta variant, which accounted for between 40% and 95% of genomes sequenced in South Africa over this period.8Tegally H. Wilkinson E. Althaus C.L. Giovanetti M. San J.E. Giandhari J. Pillay S. Naidoo Y. Ramphal U. Msomi N. et al.Rapid replacement of the beta variant by the delta variant in South Africa.medRxiv. 2021; https://doi.org/10.1101/2021.09.23.21264018https://www.medrxiv.org/content/10.1101/2021.09.23.21264018v1Crossref Scopus (0) Google Scholar BTIs were thus most likely caused by the Delta variant, though sequencing data for these participants were not available. Participants, of whom 16 of 19 were female, had a median age of 34 (IQR: 30–40 years) and all presented with mild disease (Table S1). All 19 participants were SARS-CoV-2 naive prior to vaccination, as confirmed by nucleocapsid ELISA (Figure 1B). We first assessed the durability of vaccine-elicited antibody responses in individuals who were confirmed to have remained uninfected up to 6 months post-vaccination, by nucleocapsid ELISA (Figure 1B). Spike binding responses against the original D614G variant were measured at 2, 4, and 6 months post-vaccination. No significant reduction in binding was observed over this period (Figure 1C), as has been previously reported.9Stephenson K.E. Le Gars M. Sadoff J. de Groot A.M. Heerwegh D. Truyers C. Atyeo C. Loos C. Chandrashekar A. McMahan K. et al.Immunogenicity of the Ad26.COV2.S vaccine for COVID-19.JAMA. 2021; 325: 1535-1544Crossref PubMed Scopus (119) Google Scholar, 10Barouch D.H. Stephenson K.E. Sadoff J. Yu J. Chang A. Gebre M. McMahan K. Liu J. Chandrashekar A. Patel S. et al.Durable humoral and cellular immune responses 8 months after Ad26.COV2.S vaccination.N. Engl. J. Med. 2021; 385: 951-953Crossref PubMed Scopus (74) Google Scholar, 11Sadoff J. Le Gars M. Cardenas V. Shukarev G. Vaissiere N. Heerwegh D. Truyers C. de Groot A.M. Scheper G. Hendriks J. et al.Durability of antibody responses elicited by a single dose of Ad26.COV2.S and substantial increase following late boosting.medRxiv. 2021; https://doi.org/10.1101/2021.08.25.21262569https://www.medrxiv.org/content/10.1101/2021.08.25.21262569v1Crossref PubMed Scopus (0) Google Scholar We also used a spike-pseudotyped lentivirus neutralization assay to measure longitudinal neutralization titers against the ancestral D614G variant (which differs from the vaccine spike protein by a single D614G mutation), six SARS-CoV-2 variants with increased transmissibility and/or immune escape mutations, and SARS-CoV-1. The SARS-CoV-2 variants included Beta, Delta, Gamma (P.1), and Omicron, as well as C.1.2, and A.VOI.V2, isolated in South Africa and Angola, respectively, which share common mutations with variants of concern (VOCs) and are of local relevance to the Southern African region.12de Oliveira T. Lutucuta S. Nkengasong J. Morais J. Paixão J.P. Neto Z. Afonso P. Miranda J. David K. Inglês L. et al.A novel variant of interest of SARS-CoV-2 with multiple spike mutations detected through travel surveillance in Africa.medRxiv. 2021; https://doi.org/10.1101/2021.03.30.21254323https://www.medrxiv.org/content/10.1101/2021.03.30.21254323v1Crossref Scopus (0) Google Scholar,13Scheepers C. Everatt J. Amoako D.G. Tegally H. Wibmer C.K. Mnguni A. Ismail A. Mahlangu B. Lambson B.E. Richardson S.I. et al.Emergence and phenotypic characterization of C.1.2, a globally detected lineage that rapidly accumulated mutations of concern.medRxiv. 2021; https://doi.org/10.1101/2021.08.20.21262342https://www.medrxiv.org/content/10.1101/2021.08.20.21262342v3Crossref PubMed Scopus (0) Google Scholar For the ancestral D614G variant, geometric mean titers (GMTs) were stable up to 6 months post-vaccination (GMTs of 104, 117, and 96 at 2, 4, and 6 months post-vaccination), consistent with previous studies10Barouch D.H. Stephenson K.E. Sadoff J. Yu J. Chang A. Gebre M. McMahan K. Liu J. Chandrashekar A. Patel S. et al.Durable humoral and cellular immune responses 8 months after Ad26.COV2.S vaccination.N. Engl. J. Med. 2021; 385: 951-953Crossref PubMed Scopus (74) Google Scholar,11Sadoff J. Le Gars M. Cardenas V. Shukarev G. Vaissiere N. Heerwegh D. Truyers C. de Groot A.M. Scheper G. Hendriks J. et al.Durability of antibody responses elicited by a single dose of Ad26.COV2.S and substantial increase following late boosting.medRxiv. 2021; https://doi.org/10.1101/2021.08.25.21262569https://www.medrxiv.org/content/10.1101/2021.08.25.21262569v1Crossref PubMed Scopus (0) Google Scholar (Figures 1D and 2A ). Where detectable, titers against the six variants were similarly stable over 6 months, showing no significant differences over time (Figure 2A), as observed in two previous studies.10Barouch D.H. Stephenson K.E. Sadoff J. Yu J. Chang A. Gebre M. McMahan K. Liu J. Chandrashekar A. Patel S. et al.Durable humoral and cellular immune responses 8 months after Ad26.COV2.S vaccination.N. Engl. J. Med. 2021; 385: 951-953Crossref PubMed Scopus (74) Google Scholar,14Jongeneelen M. Kaszas K. Veldman D. Huizingh J. van der Vlugt R. Schouten T. Zuijdgeest D. Uil T. van Roey G. Guimera N. et al.Ad26.COV2.S elicited neutralizing activity against delta and other SARS-CoV-2 variants of concern.bioRxiv. 2021; https://doi.org/10.1101/2021.07.01.450707Crossref Scopus (0) Google Scholar However, for all variants tested, titers were 1.9- to 4.2-fold lower at 2 months post-vaccination compared with the D614G variant, as reported elsewhere10Barouch D.H. Stephenson K.E. Sadoff J. Yu J. Chang A. Gebre M. McMahan K. Liu J. Chandrashekar A. Patel S. et al.Durable humoral and cellular immune responses 8 months after Ad26.COV2.S vaccination.N. Engl. J. Med. 2021; 385: 951-953Crossref PubMed Scopus (74) Google Scholar,14Jongeneelen M. Kaszas K. Veldman D. Huizingh J. van der Vlugt R. Schouten T. Zuijdgeest D. Uil T. van Roey G. Guimera N. et al.Ad26.COV2.S elicited neutralizing activity against delta and other SARS-CoV-2 variants of concern.bioRxiv. 2021; https://doi.org/10.1101/2021.07.01.450707Crossref Scopus (0) Google Scholar, 15Alter G. Yu J. Liu J. Chandrashekar A. Borducchi E.N. Tostanoski L.H. McMahan K. Jacob-Dolan C. Martinez D.R. Chang A. et al.Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans.Nature. 2021; : 1-5https://doi.org/10.1038/s41586-021-03681-2Crossref Scopus (125) Google Scholar, 16Tada T. Zhou H. Samanovic M.I. Dcosta B.M. Cornelius A. Mulligan M.J. Landau N.R. Comparison of neutralizing antibody titers elicited by mRNA and adenoviral vector vaccine against SARS-CoV-2 variants.bioRxiv. 2021; https://doi.org/10.1101/2021.07.19.452771Crossref Scopus (0) Google Scholar, 17Tada T. Zhou H. Dcosta B.M. Samanovic M.I. Cornelius A. Herati R.S. Mulligan M.J. Landau N.R. Neutralization of Mu and C.1.2 SARS-CoV-2 variants by vaccine-elicited antibodies in individuals with and without previous history of infection.bioRxiv. 2021; https://doi.org/10.1101/2021.10.19.463727Crossref Scopus (0) Google Scholar (Figure 2A). For the Beta and Delta variants, in particular, half of non-BTI vaccinees showed no detectable neutralization at 6 months post-vaccination (Figure 2C). As expected, titers against SARS-CoV-1 were low, with GMTs of 28 and 21 at 2 and 4 months, respectively, and undetectable at 6 months post-vaccination (Figure 2A). We next assessed the breadth and magnitude of humoral immune responses following BTI. In all participants, BTI occurred between 3 and 5 months post-vaccination. Prior to BTI, the nucleocapsid binding responses in both the BTI and non-BTI participants were negative, and only detected following BTI (Figure 1B). There were also no significant differences in D614G spike binding responses between the BTI and non-BTI participants prior to 3 to 4 months post-vaccination (Figure 1C). However, following infection, there was a 3.3-fold increase in spike responses, which peaked at approximately 2 weeks post-infection (5 months post-vaccination) and remained constant until 1 month post-infection (6 months post-vaccination) (Figure 1C). We also assessed the impact of BTI on Fc effector functions, which have been implicated in protection from severe coronavirus disease 2019 (COVID-19) disease, and which generally retain activity against VOCs.18Zohar T. Loos C. Fischinger S. Atyeo C. Wang C. Slein M.D. Burke J. Yu J. Feldman J. Hauser B.M. et al.Compromised humoral functional evolution tracks with SARS-CoV-2 mortality.Cell. 2020; 183: 1508-1519.e12Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar,19Richardson S.I. Manamela N.P. Motsoeneng B.M. Kaldine H. Ayres F. Makhado Z. Mennen M. Skelem S. Williams N. Sullivan N.J. et al.A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity.medRxiv. 2021; https://doi.org/10.1101/2021.11.05.21265853https://www.medrxiv.org/content/10.1101/2021.11.05.21265853v1Crossref Scopus (0) Google Scholar We examined whether levels of antibody-dependent cellular cytotoxicity (ADCC), measured by ability to cross-link FcγRIIIa were boosted following BTI. Similar to binding, ADCC against D614G remained stable up to 3 to 4 months post-vaccination, with a rapid 3.1-fold increase in activity after BTI (Figure 1E). These responses peaked (geomean RLU: 712) at approximately 2 weeks post-infection (5 months post-vaccination), but declined slightly (geomean RLU: 558) by 1 month post-infection (6 months post-vaccination) (Figure 1E). Both before and after infection, ADCC was cross-reactive against D614G, Beta, and Delta variants, showing only slight decreases against VOCs relative to D614G across all time points (geomean RLUs of 712, 626, and 702 against D614G, Beta, and Delta, respectively, at 2 weeks post-infection). This illustrates the resilience of Fc effector function against VOCs in Ad26.CoV2.S BTI participants. Neutralization titers against D614G closely mirrored the spike binding and ADCC response, with no significant differences in titers between the BTI and non-BTI participants prior to 3 to 4 months post-vaccination, but with a dramatic increase in titers for all participants (407-fold increase from 102 to 41,528 GMT) following infection (Figures 1D and 2B). This increase in neutralization titers is similar in magnitude to what was previously reported for a single individual with Ad26.CoV2.S BTI.10Barouch D.H. Stephenson K.E. Sadoff J. Yu J. Chang A. Gebre M. McMahan K. Liu J. Chandrashekar A. Patel S. et al.Durable humoral and cellular immune responses 8 months after Ad26.COV2.S vaccination.N. Engl. J. Med. 2021; 385: 951-953Crossref PubMed Scopus (74) Google Scholar We observed extremely high neutralization titers at approximately 2 weeks post-infection (5 months post-vaccination), which declined by approximately 4.7-fold 1 month thereafter (Figure 1D). Neutralization titers after BTI were also significantly higher against six SARS-CoV-2 variants relative to non-BTI participants (40- to 154-fold difference in GMT), and SARS-CoV-1 (9-fold difference in GMT) (Figures 2B and 3). This includes the highly neutralization-resistant Omicron variant, against which titers ranged from 161 to 1,858 (GMT of 843) for the BTI participants (Figure 3). Thus, in contrast to vaccine-elicited responses, BTI after a single dose of Ad26.COV2.S resulted in neutralization of all SARS-CoV-2 variants, with a GMT >800 against Omicron, and >3,000 against all other SARS-CoV-2 variants (Figures 2B, 2C, and 3). Overall our data confirm durable vaccine-elicited humoral immune responses 6 months after a single dose of Ad26.COV2.S, consistent with other studies.10Barouch D.H. Stephenson K.E. Sadoff J. Yu J. Chang A. Gebre M. McMahan K. Liu J. Chandrashekar A. Patel S. et al.Durable humoral and cellular immune responses 8 months after Ad26.COV2.S vaccination.N. Engl. J. Med. 2021; 385: 951-953Crossref PubMed Scopus (74) Google Scholar,14Jongeneelen M. Kaszas K. Veldman D. Huizingh J. van der Vlugt R. Schouten T. Zuijdgeest D. Uil T. van Roey G. Guimera N. et al.Ad26.COV2.S elicited neutralizing activity against delta and other SARS-CoV-2 variants of concern.bioRxiv. 2021; https://doi.org/10.1101/2021.07.01.450707Crossref Scopus (0) Google Scholar, 15Alter G. Yu J. Liu J. Chandrashekar A. Borducchi E.N. Tostanoski L.H. McMahan K. Jacob-Dolan C. Martinez D.R. Chang A. et al.Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans.Nature. 2021; : 1-5https://doi.org/10.1038/s41586-021-03681-2Crossref Scopus (125) Google Scholar, 16Tada T. Zhou H. Samanovic M.I. Dcosta B.M. Cornelius A. Mulligan M.J. Landau N.R. Comparison of neutralizing antibody titers elicited by mRNA and adenoviral vector vaccine against SARS-CoV-2 variants.bioRxiv. 2021; https://doi.org/10.1101/2021.07.19.452771Crossref Scopus (0) Google Scholar, 17Tada T. Zhou H. Dcosta B.M. Samanovic M.I. Cornelius A. Herati R.S. Mulligan M.J. Landau N.R. Neutralization of Mu and C.1.2 SARS-CoV-2 variants by vaccine-elicited antibodies in individuals with and without previous history of infection.bioRxiv. 2021; https://doi.org/10.1101/2021.10.19.463727Crossref Scopus (0) Google Scholar Moreover, despite relatively modest titers after vaccination, we observed significantly boosted binding antibodies, ADCC, and neutralization activity following BTI. This boost resulted in neutralization titers in BTI participants at 1 month post-infection (GMT 8,249) that were higher than those elicited by a two-dose Pfizer-BioNTech (BNT162b2) vaccine regimen (GMT: 1,128) 2 month post-vaccination, or those observed in convalescent donors who had previously been hospitalized with moderate (GMT: 993) or severe disease (GMT: 3,747) (Figure S1). Though we note that these comparisons differ by number of antigen exposures and timing, among other variables, this illustrates the extremely high level of boosting observed in BTIs. Similar to BTI individuals, we have previously confirmed that ADCC, binding, and neutralization are also significantly boosted following vaccination in individuals who were previously infected,20Keeton R. Richardson S.I. Moyo-Gwete T. Hermanus T. Tincho M.B. Benede N. Manamela N.P. Baguma R. Makhado Z. Ngomti A. et al.Prior infection with SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant dependent manner.Cell Host Microbe. 2021; 29: 1611-1619.e5Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar but not to the same levels we report here for BTI (GMT of 1,372 versus 8,249 for neutralization, respectively) (Figure S1). Whether this is a result of increased affinity maturation broadening the response against variants, or rather the boosting of vaccine-elicited cross-reactive memory B cells to higher titers, remains to be determined and will be the focus of future work. These data add to previous reports of BTI following mRNA vaccination, which results in >30-fold increased neutralization potency, suggesting broad relevance across multiple vaccine modalities.4Bates T.A. McBride S.K. Winders B. Schoen D. Trautmann L. Curlin M.E. Tafesse F.G. Antibody response and variant cross-neutralization after SARS-CoV-2 breakthrough infection.JAMA. 2021; https://doi.org/10.1001/jama.2021.22898Crossref Scopus (29) Google Scholar,5Collier A.-R.Y. Brown C.M. Mcmahan K. Yu J. Liu J. Jacob-Dolan C. Chandrashekar A. Tierney D. Ansel J.L. Rowe M. et al.Immune responses in fully vaccinated individuals following breakthrough infection with the SARS-CoV-2 Delta variant in Provincetown, Massachusetts.medRxiv. 2021; https://doi.org/10.1101/2021.10.18.21265113https://www.medrxiv.org/content/10.1101/2021.10.18.21265113v1Crossref Scopus (0) Google Scholar,21Hacisuleyman E. Hale C. Saito Y. Blachere N.E. Bergh M. Conlon E.G. Schaefer-Babajew D.J. DaSilva J. Muecksch F. Gaebler C. et al.Vaccine breakthrough infections with SARS-CoV-2 variants.N. Engl. J. Med. 2021; 384: 2212-2218Crossref PubMed Scopus (294) Google Scholar Affinity maturation following SARS-CoV-2 infection can lead to the development of broader and more potent neutralizing antibodies.22Muecksch F. Weisblum Y. Barnes C.O. Schmidt F. Schaefer-Babajew D. Wang Z. Lorenzi J.C. Flyak A.I. DeLaitsch A.T. Huey-Tubman K.E. et al.Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations.Immunity. 2021; 54: 1853-1868.e7Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar,23Wang Z. Muecksch F. Schaefer-Babajew D. Finkin S. Viant C. Gaebler C. Hoffmann H.H. Barnes C.O. Cipolla M. Ramos V. et al.Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection.Nature. 2021; : 1-10https://doi.org/10.1038/s41586-021-03696-9Crossref Scopus (219) Google Scholar We have previously shown that the sequence of the spike in a prior infection influenced the breadth and potency of neutralizing antibodies following vaccination with Ad26.COV2.S.20Keeton R. Richardson S.I. Moyo-Gwete T. Hermanus T. Tincho M.B. Benede N. Manamela N.P. Baguma R. Makhado Z. Ngomti A. et al.Prior infection with SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant dependent manner.Cell Host Microbe. 2021; 29: 1611-1619.e5Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Whether spike identity in BTIs (here, likely a heterologous exposure to the Delta variant after priming with ancestral sequence) similarly contributes to the selection of cross-reactive B cells is not yet known.24Tang J. Grubbs G. Lee Y. Huang C. Ravichandran S. Forgacs D. Golding H. Ross T.M. Khurana S. Antibody affinity maturation and cross-variant activity following SARS-CoV-2 mRNA vaccination: impact of prior exposure and sex.eBioMedicine. 2021; 74: 103748Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Taken together, these findings suggest a strongly synergistic effect of vaccination and infection, which will contribute to higher levels of protective community immunity in areas with high burden of infection, and may have contributed to the low hospitalization rates seen during the Omicron-driven fourth wave in South Africa.25Madhi S. Kwatra G. Myers J.E. Jassat W. Dhar N. Mukendi C.K. Nana A. Blumberg L. Welch R. Ngorima-Mabhena N. Mutevedzi P.C. South African population immunity and severe covid-19 with Omicron variant.medRxiv. 2021; https://doi.org/10.1101/2021.12.20.21268096https://www.medrxiv.org/content/10.1101/2021.12.20.21268096v1Crossref Scopus (0) Google Scholar As homologous and heterologous boosters are deployed, this effect may be further enhanced.26Gray G.E. Collie S. Garrett N. Goga A. Champion J. Zylstra M. Reddy T. Yende N. Seocharan I. Takalani A. et al.Vaccine effectiveness against hospital admission in South African health care workers who received a homologous booster of Ad26.COV2 during an Omicron COVID19 wave: preliminary results of the Sisonke 2 study.medRxiv. 2021; https://doi.org/10.1101/2021.12.28.21268436https://www.medrxiv.org/content/10.1101/2021.12.28.21268436v1Crossref Scopus (0) Google Scholar Overall, this study provides insight into the magnitude and quality of humoral immune responses elicited by BTIs after an adenovirus-based vaccine, with implications for public health interventions in regions that have experienced high levels of SARS-CoV-2 transmission. This study is limited by the relatively small number of BTIs that were characterized. We also note that the median age of the BTI participants was higher than that of the non-BTI participants (BTI participants median age: 39 years, IQR: 32–59 years; non-BTI participants median age: 33 years, IQR: 29–36 years), which may impact comparisons between the two groups.11Sadoff J. Le Gars M. Cardenas V. Shukarev G. Vaissiere N. Heerwegh D. Truyers C. de Groot A.M. Scheper G. Hendriks J. et al.Durability of antibody responses elicited by a single dose of Ad26.COV2.S and substantial increase following late boosting.medRxiv. 2021; https://doi.org/10.1101/2021.08.25.21262569https://www.medrxiv.org/content/10.1101/2021.08.25.21262569v1Crossref PubMed Scopus (0) Google Scholar,27Wei J. Stoesser N. Matthews P.C. Ayoubkhani D. Studley R. Bell I. Bell J.I. Newton J.N. Farrar J. Diamond I. et al.Antibody responses to SARS-CoV-2 vaccines in 45,965 adults from the general population of the United Kingdom.Nat. Microbiol. 2021; 6: 1140-1149Crossref PubMed Scopus (82) Google Scholar We do not have sequencing data to determine the variant responsible for BTI, and it is possible that the infecting viral sequence may impact the quality of the response, as we have previously shown.20Keeton R. Richardson S.I. Moyo-Gwete T. Hermanus T. Tincho M.B. Benede N. Manamela N.P. Baguma R. Makhado Z. Ngomti A. et al.Prior infection with SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant dependent manner.Cell Host Microbe. 2021; 29: 1611-1619.e5Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar,28Moyo-Gwete T. Madzivhandila M. Makhado Z. Ayres F. Mhlanga D. Oosthuysen B. Lambson B.E. Kgagudi P. Tegally H. Iranzadeh A. et al.Cross-reactive neutralizing antibody responses elicited by SARS-CoV-2 501Y.V2 (B.1.351).N. Engl. J. Med. 2021; 384: 2161-2163Crossref PubMed Scopus (53) Google Scholar We note that the pseudotyped virus neutralization assay used here can only assess the effectiveness of neutralizing antibodies against the spike protein in preventing viral entry into host cells, and cannot detect any effects antibodies may have on viral replication or cell-to-cell spread.29Lu Y. Wang J. Li Q. Hu H. Lu J. Chen Z. Advances in neutralization assays for SARS-CoV-2.Scand. J. Immunol. 2021; 94: e13088Crossref Scopus (14) Google Scholar,30Khoury D.S. Wheatley A.K. Ramuta M.D. Reynaldi A. Cromer D. Subbarao K. O'Connor D.H. Kent S.J. Davenport M.P. Measuring immunity to SARS-CoV-2 infection: comparing assays and animal models.Nat. Rev. Immunol. 2020; 20: 727-738Crossref PubMed Scopus (44) Google Scholar Inherent differences between the pseudotyped viruses and authentic, replication-competent SARS-CoV-2 viruses, such as spike density and geometry on the virion surface, may also result in differences in sensitivity.29Lu Y. Wang J. Li Q. Hu H. Lu J. Chen Z. Advances in neutralization assays for SARS-CoV-2.Scand. J. Immunol. 2021; 94: e13088Crossref Scopus (14) Google Scholar,30Khoury D.S. Wheatley A.K. Ramuta M.D. Reynaldi A. Cromer D. Subbarao K. O'Connor D.H. Kent S.J. Davenport M.P. Measuring immunity to SARS-CoV-2 infection: comparing assays and animal models.Nat. Rev. Immunol. 2020; 20: 727-738Crossref PubMed Scopus (44) Google Scholar However, neutralization titers from pseudovirus and replication-competent SARS-CoV-2 assays generally correlate well.31Schmidt F. Weisblum Y. Muecksch F. Hoffmann H.H. Michailidis E. Lorenzi J.C.C. Mendoza P. Rutkowska M. Bednarski E. Gaebler C. et al.Measuring SARS-CoV-2 neutralizing antibody activity using pseudotyped and chimeric viruses.J. Exp.

COVID-19 in Children: Expressions of Type I/II/III Interferons, TRIM28, SETDB1, and Endogenous Retroviruses in Mild and Severe Cases.

Abstract: Children with the new coronavirus disease 2019 (COVID-19) have milder symptoms and a better prognosis than adult patients. Several investigations assessed type I, II, and III interferon (IFN) signatures in SARS-CoV-2 infected adults, however no data are available for pediatric patients. TRIM28 and SETDB1 regulate the transcription of multiple genes involved in the immune response as well as of human endogenous retroviruses (HERVs). Exogenous viral infections can trigger the activation of HERVs, which in turn can induce inflammatory and immune reactions. Despite the potential cross-talks between SARS-CoV-2 infection and TRIM28, SETDB1, and HERVs, information on their expressions in COVID-19 patients is lacking. We assessed, through a PCR real time Taqman amplification assay, the transcription levels of six IFN-I stimulated genes, IFN-II and three of its sensitive genes, three IFN-lIIs, as well as of TRIM28, SETDB1, pol genes of HERV-H, -K, and -W families, and of env genes of Syncytin (SYN)1, SYN2, and multiple sclerosis-associated retrovirus (MRSV) in peripheral blood from COVID-19 children and in control uninfected subjects. Higher expression levels of IFN-I and IFN-II inducible genes were observed in 36 COVID-19 children with mild or moderate disease as compared to uninfected controls, whereas their concentrations decreased in 17 children with severe disease and in 11 with multisystem inflammatory syndrome (MIS-C). Similar findings were found for the expression of TRIM-28, SETDB1, and every HERV gene. Positive correlations emerged between the transcriptional levels of type I and II IFNs, TRIM28, SETDB1, and HERVs in COVID-19 patients. IFN-III expressions were comparable in each group of subjects. This preserved induction of IFN-λs could contribute to the better control of the infection in children as compared to adults, in whom IFN-III deficiency has been reported. The upregulation of IFN-I, IFN-II, TRIM28, SETDB1, and HERVs in children with mild symptoms, their declines in severe cases or with MIS-C, and the positive correlations of their transcription in SARS-CoV-2-infected children suggest that they may play important roles in conditioning the evolution of the infection.

Genome-wide CRISPR screens identify GATA6 as a proviral host factor for SARS-CoV-2 via modulation of ACE2

Abstract: Abstract The global spread of SARS-CoV-2 led to major economic and health challenges worldwide. Revealing host genes essential for infection by multiple variants of SARS-CoV-2 can provide insights into the virus pathogenesis, and facilitate the development of novel therapeutics. Here, employing a genome-scale CRISPR screen, we provide a comprehensive data-set of cellular factors that are exploited by wild type SARS-CoV-2 as well as two additional recently emerged variants of concerns (VOCs), Alpha and Beta. We identified several host factors critical for SARS-CoV-2 infection, including various components belonging to the Clathrin-dependent transport pathway, ubiquitination, Heparan sulfate biogenesis and host phosphatidylglycerol biosynthesis. Comparative analysis of the different VOCs revealed the host factors KREMEN2 and SETDB1 as potential unique candidates required only to the Alpha variant. Furthermore, the analysis identified GATA6, a zinc finger transcription factor, as an essential proviral gene for all variants inspected. We show that GATA6 directly regulates ACE2 transcription and accordingly, is critical for SARS-CoV-2 cell entry. Analysis of clinical samples collected from SARS-CoV-2 infected individuals shows elevated levels of GATA6, suggesting a role in COVID-19 pathogenesis. Finally, pharmacological inhibition of GATA6 resulted in down-modulation of ACE2 and inhibition of viral infectivity. Overall, we show GATA6 may represent a target for the development of anti-SARS-CoV-2 therapeutic strategies and reaffirm the value of the CRISPR loss-of-function screens in providing a list of potential new targets for therapeutic interventions.

Structural Plasticity and Immune Evasion of SARS-CoV-2 Spike Variants

Abstract: The global pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly affected every human life and overloaded the health care system worldwide. Limited therapeutic options combined with the consecutive waves of the infection and emergence of novel SARS-CoV-2 variants, especially variants of concern (VOCs), have prolonged the COVID-19 pandemic and challenged its control. The Spike (S) protein on the surface of SARS-CoV-2 is the primary target exposed to the host and essential for virus entry into cells. The parental (Wuhan-Hu-1 or USA/WA1 strain) S protein is the virus-specific component of currently implemented vaccines. However, S is most prone to mutations, potentially shifting the dynamics of virus-host interactions by affecting S conformational/structural profiles. Scientists have rapidly resolved atomic structures of S VOCs and elucidated molecular details of these mutations, which can inform the design of S-directed novel therapeutics and broadly protective vaccines. Here, we discuss recent findings on S-associated virus transmissibility and immune evasion of SARS-CoV-2 VOCs and experimental approaches used to profile these properties. We summarize the structural studies that document the structural flexibility/plasticity of S VOCs and the potential roles of accumulated mutations on S structures and functions. We focus on the molecular interpretation of structures of the S variants and its insights into the molecular mechanism underlying antibody evasion and host cell-receptor binding.