Publications by authors named "Jinyan Liu"

106 Publications

Protective efficacy of rhesus adenovirus COVID-19 vaccines against mouse-adapted SARS-CoV-2.

J Virol 2021 Sep 15:JVI0097421. Epub 2021 Sep 15.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice. We have developed a series of SARS-CoV-2 vaccines using rhesus adenovirus serotype 52 (RhAd52) vectors, which exhibits a lower seroprevalence than human and chimpanzee vectors, supporting their development as novel vaccine vectors or as an alternative Ad vector for boosting. We sought to test these vaccines using a recently reported mouse-adapted SARS-CoV-2 (MA10) virus to i) evaluate the protective efficacy of RhAd52 vaccines and ii) further characterize this mouse-adapted challenge model and probe immune correlates of protection. We demonstrate RhAd52 vaccines elicit robust SARS-CoV-2-specific antibody responses and protect against clinical disease and viral replication in the lungs. Further, binding and neutralizing antibody titers correlated with protective efficacy. These data validate the MA10 mouse model as a useful tool to screen and study novel vaccine candidates, as well as the development of RhAd52 vaccines for COVID-19.
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http://dx.doi.org/10.1128/JVI.00974-21DOI Listing
September 2021

Virus Induced Lymphocytes (VIL) as a novel viral antigen-specific T cell therapy for COVID-19 and potential future pandemics.

Sci Rep 2021 07 27;11(1):15295. Epub 2021 Jul 27.

Intima Bioscience, Inc., New York, NY, USA.

The a priori T cell repertoire and immune response against SARS-CoV-2 viral antigens may explain the varying clinical course and prognosis of patients having a mild COVID-19 infection as opposed to those developing more fulminant multisystem organ failure and associated mortality. Using a novel SARS-Cov-2-specific artificial antigen presenting cell (aAPC), coupled with a rapid expansion protocol (REP) as practiced in tumor infiltrating lymphocytes (TIL) therapy, we generate an immune catalytic quantity of Virus Induced Lymphocytes (VIL). Using T cell receptor (TCR)-specific aAPCs carrying co-stimulatory molecules and major histocompatibility complex (MHC) class-I immunodominant SARS-CoV-2 peptide-pentamer complexes, we expand virus-specific VIL derived from peripheral blood mononuclear cells (PBMC) of convalescent COVID-19 patients up to 1000-fold. This is achieved in a clinically relevant 7-day vein-to-vein time-course as a potential adoptive cell therapy (ACT) for COVID-19. We also evaluate this approach for other viral pathogens using Cytomegalovirus (CMV)-specific VIL from donors as a control. Rapidly expanded VIL are enriched in virus antigen-specificity and show an activated, polyfunctional cytokine profile and T effector memory phenotype which may contribute to a robust immune response. Virus-specific T cells can also be delivered allogeneically via MHC-typing and patient human leukocyte antigen (HLA)-matching to provide pragmatic treatment in a large-scale therapeutic setting. These data suggest that VIL may represent a novel therapeutic option that warrants further clinical investigation in the armamentarium against COVID-19 and other possible future pandemics.
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http://dx.doi.org/10.1038/s41598-021-94654-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316478PMC
July 2021

Durable Humoral and Cellular Immune Responses Following Ad26.COV2.S Vaccination for COVID-19.

medRxiv 2021 Jul 7. Epub 2021 Jul 7.

Janssen Vaccines & Prevention, Leiden, The Netherlands.

Interim immunogenicity and efficacy data for the Ad26.COV2.S vaccine for COVID-19 have recently been reported . We describe here the 8-month durability of humoral and cellular immune responses in 20 individuals who received one or two doses of 5Ã-10 vp or 10 vp Ad26.COV2.S and in 5 participants who received placebo . We evaluated antibody and T cell responses on day 239, which was 8 months after the single-shot vaccine regimen (N=10) or 6 months after the two-shot vaccine regimen (N=10), although the present study was not powered to compare these regimens . We also report neutralizing antibody responses against the parental SARS-CoV-2 WA1/2020 strain as well as against the SARS-CoV-2 variants D614G, B.1.1.7 (alpha), B.1.617.1 (kappa), B.1.617.2 (delta), P.1 (gamma), B.1.429 (epsilon), and B.1.351 (beta).
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http://dx.doi.org/10.1101/2021.07.05.21259918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282116PMC
July 2021

Long Noncoding RNAs: Novel Important Players in Adipocyte Lipid Metabolism and Derivative Diseases.

Front Physiol 2021 8;12:691824. Epub 2021 Jun 8.

Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Obesity, a global public health issue, is characterized by excessive adiposity and is strongly related to some chronic diseases including cardiovascular diseases and diabetes. Extra energy intake-induced adipogenesis involves various transcription factors and long noncoding RNAs (lncRNAs) that control lipogenic mRNA expression. Currently, lncRNAs draw much attention for their contribution to adipogenesis and adipose tissue function. Increasing evidence also manifests the pivotal role of lncRNAs in modulating white, brown, and beige adipose tissue development and affecting the progression of the diseases induced by adipose dysfunction. The aim of this review is to summarize the roles of lncRNAs in adipose tissue development and obesity-caused diseases to provide novel drug targets for the treatment of obesity and metabolic diseases.
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http://dx.doi.org/10.3389/fphys.2021.691824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217837PMC
June 2021

TRAIL promotes epithelial-to-mesenchymal transition by inducing PD-L1 expression in esophageal squamous cell carcinomas.

J Exp Clin Cancer Res 2021 Jun 24;40(1):209. Epub 2021 Jun 24.

Biotherapy Center & Cancer Center, the First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Henan, 450052, Zhengzhou, China.

Background: Tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL) was initially considered an immunity guard; however, its function remains controversial. Besides immune cells, lung and colon cancer cells have also been reported to express TRAIL, which can promote tumor invasion and metastasis. However, the biological function and underlying mechanism of action of TRAIL in esophageal squamous cell carcinoma (ESCC) remain poorly elucidated.

Methods: The ESCC cells stemness, migration, and proliferation ability was assessed by sphere formation, Transwell, and CCK8 assay. The stemness- and epithelial-mesenchymal transition (EMT)- related genes expression levels were analyzed by Western blot and RT-qPCR. The signal activation was conducted by Western blot. The xenograft mouse experiments and lung metastasis model were performed to confirm our findings in vitro.

Results: Herein, we found that TRAIL is a negative predictor in patients with ESCC. To further investigate the biological function of TRAIL, we established TRAIL knockdown and overexpression ESCC cell lines and found that TRAIL induced EMT and promoted tumor aggressiveness. Furthermore, we demonstrated that TRAIL- overexpressing cells upregulated PD-L1 expression, which was dependent on the p-ERK/STAT3 signaling pathway. We obtained similar results when using recombinant human TRAIL. Finally, we validated the biological role and mechanism of action of TRAIL in vivo.

Conclusions: These findings demonstrate that TRAIL promotes ESCC progression by enhancing PD-L1 expression, which induces EMT. This may explain the failure of TRAIL preclinical trials.
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http://dx.doi.org/10.1186/s13046-021-01972-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223376PMC
June 2021

Protective efficacy of Ad26.COV2.S against SARS-CoV-2 B.1.351 in macaques.

Nature 2021 08 23;596(7872):423-427. Epub 2021 Jun 23.

Bioqual, Rockville, MD, USA.

The emergence of SARS-CoV-2 variants that partially evade neutralizing antibodies poses a threat to the efficacy of current COVID-19 vaccines. The Ad26.COV2.S vaccine expresses a stabilized spike protein from the WA1/2020 strain of SARS-CoV-2, and has recently demonstrated protective efficacy against symptomatic COVID-19 in humans in several geographical regions-including in South Africa, where 95% of sequenced viruses in cases of COVID-19 were the B.1.351 variant. Here we show that Ad26.COV2.S elicits humoral and cellular immune responses that cross-react with the B.1.351 variant and protects against B.1.351 challenge in rhesus macaques. Ad26.COV2.S induced lower binding and neutralizing antibodies against B.1.351 as compared to WA1/2020, but elicited comparable CD8 and CD4 T cell responses against the WA1/2020, B.1.351, B.1.1.7, P.1 and CAL.20C variants. B.1.351 infection of control rhesus macaques resulted in higher levels of virus replication in bronchoalveolar lavage and nasal swabs than did WA1/2020 infection. Ad26.COV2.S provided robust protection against both WA1/2020 and B.1.351, although we observed higher levels of virus in vaccinated macaques after B.1.351 challenge. These data demonstrate that Ad26.COV2.S provided robust protection against B.1.351 challenge in rhesus macaques. Our findings have important implications for vaccine control of SARS-CoV-2 variants of concern.
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http://dx.doi.org/10.1038/s41586-021-03732-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373608PMC
August 2021

Protective efficacy of rhesus adenovirus COVID-19 vaccines against mouse-adapted SARS-CoV-2.

bioRxiv 2021 Jun 15. Epub 2021 Jun 15.

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice.

Importance: We have developed a series of SARS-CoV-2 vaccines using rhesus adenovirus serotype 52 (RhAd52) vectors, which exhibits a lower seroprevalence than human and chimpanzee vectors, supporting their development as novel vaccine vectors or as an alternative Ad vector for boosting. We sought to test these vaccines using a recently reported mouse-adapted SARS-CoV-2 (MA10) virus to i) evaluate the protective efficacy of RhAd52 vaccines and ii) further characterize this mouse-adapted challenge model and probe immune correlates of protection. We demonstrate RhAd52 vaccines elicit robust SARS-CoV-2-specific antibody responses and protect against clinical disease and viral replication in the lungs. Further, binding and neutralizing antibody titers correlated with protective efficacy. These data validate the MA10 mouse model as a useful tool to screen and study novel vaccine candidates, as well as the development of RhAd52 vaccines for COVID-19.
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http://dx.doi.org/10.1101/2021.06.14.448461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219099PMC
June 2021

Low-dose Ad26.COV2.S protection against SARS-CoV-2 challenge in rhesus macaques.

Cell 2021 06 1;184(13):3467-3473.e11. Epub 2021 Jun 1.

Bioqual, Rockville, MD 20852, USA.

We previously reported that a single immunization with an adenovirus serotype 26 (Ad26)-vector-based vaccine expressing an optimized SARS-CoV-2 spike (Ad26.COV2.S) protected rhesus macaques against SARS-CoV-2 challenge. To evaluate reduced doses of Ad26.COV2.S, 30 rhesus macaques were immunized once with 1 × 10, 5 × 10, 1.125 × 10, or 2 × 10 viral particles (vp) Ad26.COV2.S or sham and were challenged with SARS-CoV-2. Vaccine doses as low as 2 × 10 vp provided robust protection in bronchoalveolar lavage, whereas doses of 1.125 × 10 vp were required for protection in nasal swabs. Activated memory B cells and binding or neutralizing antibody titers following vaccination correlated with protective efficacy. At suboptimal vaccine doses, viral breakthrough was observed but did not show enhancement of disease. These data demonstrate that a single immunization with relatively low dose of Ad26.COV2.S effectively protected against SARS-CoV-2 challenge in rhesus macaques, although a higher vaccine dose may be required for protection in the upper respiratory tract.
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http://dx.doi.org/10.1016/j.cell.2021.05.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166510PMC
June 2021

Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans.

Nature 2021 08 9;596(7871):268-272. Epub 2021 Jun 9.

Janssen Vaccines & Prevention, Leiden, The Netherlands.

The Ad26.COV2.S vaccine has demonstrated clinical efficacy against symptomatic COVID-19, including against the B.1.351 variant that is partially resistant to neutralizing antibodies. However, the immunogenicity of this vaccine in humans against SARS-CoV-2 variants of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from the COV1001 phase I-IIa clinical trial against the original SARS-CoV-2 strain WA1/2020 as well as against the B.1.1.7, CAL.20C, P.1 and B.1.351 variants of concern. Ad26.COV2.S induced median pseudovirus neutralizing antibody titres that were 5.0-fold and 3.3-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020 on day 71 after vaccination. Median binding antibody titres were 2.9-fold and 2.7-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020. Antibody-dependent cellular phagocytosis, complement deposition and natural killer cell activation responses were largely preserved against the B.1.351 variant. CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the WA1/2020, B.1.1.7, B.1.351, P.1 and CAL.20C variants. These data show that neutralizing antibody responses induced by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. These findings have implications for vaccine protection against SARS-CoV-2 variants of concern.
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http://dx.doi.org/10.1038/s41586-021-03681-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357629PMC
August 2021

Immunogenicity of COVID-19 mRNA Vaccines in Pregnant and Lactating Women.

JAMA 2021 06;325(23):2370-2380

Harvard Medical School, Boston, Massachusetts.

Importance: Pregnant women are at increased risk of morbidity and mortality from COVID-19 but have been excluded from the phase 3 COVID-19 vaccine trials. Data on vaccine safety and immunogenicity in these populations are therefore limited.

Objective: To evaluate the immunogenicity of COVID-19 messenger RNA (mRNA) vaccines in pregnant and lactating women, including against emerging SARS-CoV-2 variants of concern.

Design, Setting, And Participants: An exploratory, descriptive, prospective cohort study enrolled 103 women who received a COVID-19 vaccine from December 2020 through March 2021 and 28 women who had confirmed SARS-CoV-2 infection from April 2020 through March 2021 (the last follow-up date was March 26, 2021). This study enrolled 30 pregnant, 16 lactating, and 57 neither pregnant nor lactating women who received either the mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccines and 22 pregnant and 6 nonpregnant unvaccinated women with SARS-CoV-2 infection.

Main Outcomes And Measures: SARS-CoV-2 receptor binding domain binding, neutralizing, and functional nonneutralizing antibody responses from pregnant, lactating, and nonpregnant women were assessed following vaccination. Spike-specific T-cell responses were evaluated using IFN-γ enzyme-linked immunospot and multiparameter intracellular cytokine-staining assays. Humoral and cellular immune responses were determined against the original SARS-CoV-2 USA-WA1/2020 strain as well as against the B.1.1.7 and B.1.351 variants.

Results: This study enrolled 103 women aged 18 to 45 years (66% non-Hispanic White) who received a COVID-19 mRNA vaccine. After the second vaccine dose, fever was reported in 4 pregnant women (14%; SD, 6%), 7 lactating women (44%; SD, 12%), and 27 nonpregnant women (52%; SD, 7%). Binding, neutralizing, and functional nonneutralizing antibody responses as well as CD4 and CD8 T-cell responses were present in pregnant, lactating, and nonpregnant women following vaccination. Binding and neutralizing antibodies were also observed in infant cord blood and breast milk. Binding and neutralizing antibody titers against the SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern were reduced, but T-cell responses were preserved against viral variants.

Conclusion And Relevance: In this exploratory analysis of a convenience sample, receipt of a COVID-19 mRNA vaccine was immunogenic in pregnant women, and vaccine-elicited antibodies were transported to infant cord blood and breast milk. Pregnant and nonpregnant women who were vaccinated developed cross-reactive antibody responses and T-cell responses against SARS-CoV-2 variants of concern.
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http://dx.doi.org/10.1001/jama.2021.7563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120446PMC
June 2021

Indoleamine 2,3-Dioxygenase 1 Inhibitor-Loaded Nanosheets Enhance CAR-T Cell Function in Esophageal Squamous Cell Carcinoma.

Front Immunol 2021 22;12:661357. Epub 2021 Mar 22.

Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

In chimeric antigen receptor (CAR)-T cell therapy, the role and mechanism of indoleamine 2, 3 dioxygenase 1 (IDO1) in enhancing antitumor immunity require further study. IDO1 is one of the most important immunosuppressive proteins in esophageal squamous cell carcinoma (ESCC). However, the IDO1 inhibitor, epacadostat, has failed in phase III clinical trials; its limited capacity to inhibit IDO1 expression at tumor sites was regarded as a key reason for clinical failure. In this study, we innovatively loaded the IDO1 inhibitor into hyaluronic acid-modified nanomaterial graphene oxide (HA-GO) and explored its potential efficacy in combination with CAR-T cell therapy. We found that inhibition of the antitumor effect of CAR-T cells in ESCC was dependent on the IDO1 metabolite kynurenine. Kynurenine could suppress CAR-T cell cytokine secretion and cytotoxic activity. Inhibiting IDO1 activity significantly enhanced the antitumor effect of CAR-T cells and . Our findings suggested that IDO1 inhibitor-loaded nanosheets could enhance the antitumor effect of CAR-T cells compared with free IDO1 inhibitor. Nanosheet-loading therefore provides a promising approach for improving CAR-T cell therapeutic efficacy in solid tumors.
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http://dx.doi.org/10.3389/fimmu.2021.661357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019778PMC
March 2021

Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19.

JAMA 2021 04;325(15):1535-1544

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Importance: Control of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines.

Objective: To evaluate the immunogenicity of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses.

Design, Setting, And Participants: Twenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S.

Interventions: Participants were randomized to receive 1 or 2 intramuscular injections with 5 × 1010 viral particles or 1 × 1011 viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group).

Main Outcomes And Measures: Humoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses.

Results: Twenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced.

Conclusion And Relevance: In this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine.

Trial Registration: ClinicalTrials.gov Identifier: NCT04436276.
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http://dx.doi.org/10.1001/jama.2021.3645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953339PMC
April 2021

A Double-Blind, Randomized, Placebo-Controlled Phase 1 Study of Ad26.ZIKV.001, an Ad26-Vectored Anti-Zika Virus Vaccine.

Ann Intern Med 2021 05 16;174(5):585-594. Epub 2021 Feb 16.

Beth Israel Deaconess Medical Center, Boston, Massachusetts (K.E.S., D.G.K., R.A.L., P.A., J.L., L.P., D.H.B.).

Background: Zika virus (ZIKV) may cause severe congenital disease after maternal-fetal transmission. No vaccine is currently available.

Objective: To assess the safety and immunogenicity of Ad26.ZIKV.001, a prophylactic ZIKV vaccine candidate.

Design: Phase 1 randomized, double-blind, placebo-controlled clinical study. (ClinicalTrials.gov: NCT03356561).

Setting: United States.

Participants: 100 healthy adult volunteers.

Intervention: Ad26.ZIKV.001, an adenovirus serotype 26 vector encoding ZIKV M-Env, administered in 1- or 2-dose regimens of 5 × 10 or 1 × 10 viral particles (vp), or placebo.

Measurements: Local and systemic adverse events; neutralization titers by microneutralization assay (MN50) and T-cell responses by interferon-γ enzyme-linked immunospot and intracellular cytokine staining; and protectivity of vaccine-induced antibodies in a subset of participants through transfer in an exploratory mouse ZIKV challenge model.

Results: All regimens were well tolerated, with no safety concerns identified. In both 2-dose regimens, ZIKV neutralizing titers peaked 14 days after the second vaccination, with geometric mean MN50 titers (GMTs) of 1065.6 (95% CI, 494.9 to 2294.5) for 5 × 10 vp and 956.6 (595.8 to 1535.8) for 1 × 10 vp. Titers persisted for at least 1 year at a GMT of 68.7 (CI, 26.4-178.9) for 5 × 10 vp and 87.0 (CI, 29.3 to 258.6) for 1 × 10 vp. A 1-dose regimen of 1 × 10 vp Ad26.ZIKV.001 induced seroconversion in all participants 56 days after the first vaccination (GMT, 103.4 [CI, 52.7 to 202.9]), with titers persisting for at least 1 year (GMT, 90.2 [CI, 38.4 to 212.2]). Env-specific cellular responses were induced. Protection against ZIKV challenge was observed after antibody transfer from participants into mice, and MN50 titers correlated with protection in this model.

Limitation: The study was conducted in a nonendemic area, so it did not assess safety and immunogenicity in a flavivirus-exposed population.

Conclusion: The safety and immunogenicity profile makes Ad26.ZIKV.001 a promising candidate for further development if the need reemerges.

Primary Funding Source: Janssen Vaccines and Infectious Diseases.
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http://dx.doi.org/10.7326/M20-5306DOI Listing
May 2021

Low-Dose Ad26.COV2.S Protection Against SARS-CoV-2 Challenge in Rhesus Macaques.

bioRxiv 2021 Jan 27. Epub 2021 Jan 27.

We previously reported that a single immunization with an adenovirus serotype 26 (Ad26) vector-based vaccine expressing an optimized SARS-CoV-2 spike (Ad26.COV2.S) protected rhesus macaques against SARS-CoV-2 challenge. In this study, we evaluated the immunogenicity and protective efficacy of reduced doses of Ad26.COV2.S. 30 rhesus macaques were immunized once with 1×10 , 5×10 , 1.125×10 , or 2×10 vp Ad26.COV2.S or sham and were challenged with SARS-CoV-2 by the intranasal and intratracheal routes. Vaccine doses as low as 2×10 vp provided robust protection in bronchoalveolar lavage, whereas doses of 1.125×10 vp were required for protection in nasal swabs. Activated memory B cells as well as binding and neutralizing antibody titers following vaccination correlated with protective efficacy. At suboptimal vaccine doses, viral breakthrough was observed but did not show evidence of virologic, immunologic, histopathologic, or clinical enhancement of disease compared with sham controls. These data demonstrate that a single immunization with a relatively low dose of Ad26.COV2.S effectively protected against SARS-CoV-2 challenge in rhesus macaques. Moreover, our findings show that a higher vaccine dose may be required for protection in the upper respiratory tract compared with the lower respiratory tract.
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http://dx.doi.org/10.1101/2021.01.27.428380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852276PMC
January 2021

Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma.

Nat Med 2021 03 21;27(3):515-525. Epub 2021 Jan 21.

Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.

Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient ( NCT01970358 ). All patients were alive and six were without evidence of active disease. We observed long-term persistence of neoantigen-specific T cell responses following vaccination, with ex vivo detection of neoantigen-specific T cells exhibiting a memory phenotype. We also found diversification of neoantigen-specific T cell clones over time, with emergence of multiple T cell receptor clonotypes exhibiting distinct functional avidities. Furthermore, we detected evidence of tumor infiltration by neoantigen-specific T cell clones after vaccination and epitope spreading, suggesting on-target vaccine-induced tumor cell killing. Personal neoantigen peptide vaccines thus induce T cell responses that persist over years and broaden the spectrum of tumor-specific cytotoxicity in patients with melanoma.
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http://dx.doi.org/10.1038/s41591-020-01206-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273876PMC
March 2021

NF1 and PTEN gene polymorphisms and the susceptibility to soft tissue sarcomas in a Chinese population: A case-control study.

Exp Mol Pathol 2021 02 8;118:104603. Epub 2021 Jan 8.

Department of Bone and soft tissue cancer, The Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, Henan province 450008, China.

The aim of this study was to assess the association between NF1 and PTEN gene polymorphisms and the risk of soft tissue sarcomas (STSs). This case-control study collected peripheral blood from 136 patients with STSs and 124 healthy controls. Six single nucleotide polymorphisms (SNPs) of the NF1 gene and five SNPs of the PTEN gene were investigated and genotyped using the SNaPshot assay. The association between the polymorphisms and the risk of STSs was estimated using unconditional logistic regression analysis. The results showed that individuals with the TC/CC genotype for NF1 rs2905789 displayed a significantly increased risk of STSs compared with individuals with wild-type TT (OR = 1.702, 95% CI = 1.002-2.890, P = 0.049). There were no significant differences in the distribution of the genotype or the allele frequencies of the polymorphisms of the NF1 and PTEN genes between the STSs patients and the controls in a Chinese population. Therefore, this study's results suggest that individuals carrying the TC/CC genotype for NF1 rs2905789 may be susceptible to STSs.
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http://dx.doi.org/10.1016/j.yexmp.2021.104603DOI Listing
February 2021

Correlates of protection against SARS-CoV-2 in rhesus macaques.

Nature 2021 02 4;590(7847):630-634. Epub 2020 Dec 4.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Recent studies have reported the protective efficacy of both natural and vaccine-induced immunity against challenge with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in rhesus macaques. However, the importance of humoral and cellular immunity for protection against infection with SARS-CoV-2 remains to be determined. Here we show that the adoptive transfer of purified IgG from convalescent rhesus macaques (Macaca mulatta) protects naive recipient macaques against challenge with SARS-CoV-2 in a dose-dependent fashion. Depletion of CD8 T cells in convalescent macaques partially abrogated the protective efficacy of natural immunity against rechallenge with SARS-CoV-2, which suggests a role for cellular immunity in the context of waning or subprotective antibody titres. These data demonstrate that relatively low antibody titres are sufficient for protection against SARS-CoV-2 in rhesus macaques, and that cellular immune responses may contribute to protection if antibody responses are suboptimal. We also show that higher antibody titres are required for treatment of SARS-CoV-2 infection in macaques. These findings have implications for the development of SARS-CoV-2 vaccines and immune-based therapeutic agents.
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http://dx.doi.org/10.1038/s41586-020-03041-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906955PMC
February 2021

Renoprotective effects of Tilianin in diabetic rats through modulation of oxidative stress via Nrf2-Keap1 pathway and inflammation via TLR4/MAPK/NF-κB pathways.

Int Immunopharmacol 2020 Nov 22;88:106967. Epub 2020 Sep 22.

Department of Nephrology, Jining First People's Hospital, Jining 272000, China. Electronic address:

The present study was undertaken to assess the protective effects of Tilianin (TN) on type-2 diabetes-induced renal dysfunction in experimental rats. Diabetes was induced by injecting Nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg) by i.p. and then the rats were treated with TN (10 and 20 mg/kg) daily by oral gavage for 28 days. TN treatment significantly decreases the BUN, creatinine, 24-hour urinary protein, urea, uric acid, and albumin protein levels. The protein of expression of Nrf2, NQO1, and HO-1 was augmented while the expression of Keap-1 decreased significantly. TN also reduces the oxidative/nitrosative status by lowering MDA content, NO, and MPO levels. TN exerted anti-inflammatory effects by suppressing TLR4/NF-κB/MAPK signaling cascades and inhibiting MyD88, TRAF6, IκBα, p38MAPK, JNK, and ERK2 in the diabetic rats. Histopathological findings supported the biochemical and molecular results. The results showed that TN modulated Nrf2-Keap1 and TLR4/MAPK/NF-κB signaling pathways and provided significant protection against diabetes-induced renal dysfunction.
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http://dx.doi.org/10.1016/j.intimp.2020.106967DOI Listing
November 2020

Construction and Characterization of KRAS Immune Lipid Magnetic Balls for Colorectal Cancer Circulating Tumor Cells.

Cancer Manag Res 2020 13;12:10067-10075. Epub 2020 Oct 13.

Department of Medical Oncology, No. 2 Hospital of Baoding, Baoding City, People's Republic of China.

Objective: The purpose of this study was to prepare and characterize a lipid magnetic ball modified with KRAS antibodies on the surface and to isolate circulating tumor cells of colorectal cancer with mutations.

Methods: The microemulsion method was used to form lipid bilayers to encapsulate Fe3O4 nanoparticles with superparamagnetism to form lipid magnetic balls, and antibodies were formed on the surface to form immune lipid magnetic balls.

Results: Compared with traditional EpCAM antibody-modified lipid magnetic balls, it can effectively improve the capture ability of colorectal cancer circulating tumor cells with mutation, the capture rate reaches 92.9%, and the capture results are consistent with clinical diagnosis and pathology.

Conclusion: Our results showed that antibody-modified lipid magnetic balls can be used in the diagnosis and treatment of colorectal cancer.
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http://dx.doi.org/10.2147/CMAR.S258565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568589PMC
October 2020

Origin of rebound virus in chronically SIV-infected Rhesus monkeys following treatment discontinuation.

Nat Commun 2020 10 27;11(1):5412. Epub 2020 Oct 27.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Viral rebound following antiretroviral therapy (ART) discontinuation in HIV-1-infected individuals is believed to originate from a small pool of CD4+ T cells harboring replication-competent provirus. However, the origin and nature of the rebound virus has remained unclear. Recent studies have suggested that rebound virus does not originate directly from individual latent proviruses but rather from recombination events involving multiple proviruses. Here we evaluate the origin of rebound virus in 16 ART-suppressed, chronically SIV-infected rhesus monkeys following ART discontinuation. We sequence viral RNA and viral DNA in these animals prior to ART initiation, during ART suppression, and following viral rebound, and we compare rebound viral RNA after ART discontinuation with near full-length viral DNA from peripheral blood and lymph node mononuclear cells (PBMC and LNMC) during ART suppression. Sequences of initial rebound viruses closely match viral DNA sequences in PBMC and LNMC during ART suppression. Recombinant viruses are rare in the initial rebound virus populations but arise quickly within 2-4 weeks after viral rebound. These data suggest that intact proviral DNA in PBMC and LNMC during ART suppression is likely the direct origin of viral rebound in chronically SIV-infected rhesus monkeys following ART discontinuation.
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http://dx.doi.org/10.1038/s41467-020-19254-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591481PMC
October 2020

Point mutation in facilitates immune escape of B cell lymphoma from CAR-T cell therapy.

J Immunother Cancer 2020 10;8(2)

Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

Background: Tumor relapse due to mutation in can hinder the efficacy of chimeric antigen receptor (CAR)-T cell therapy. Herein, we focused on lymphoma patients whose B cells exhibited a point mutation in of B cells after CAR-T cell infusion.

Methods: The CAR-T and CD19 B cells from peripheral blood or bone marrow were assessed using flow cytometry. Genome sequencing was conducted to identify the molecular characteristics of CAR-T and CD19 B cells from pre-relapse and postrelapse samples. CD19 in CARs comprising single chain fragments variable (scFV) antibody with FMC63 or 21D4 was constructed. The cytotoxic efficacy of CAR-T cells was also evaluated via in vitro and in vivo experiments.

Results: A patient with high-grade B cell lymphoma exhibited complete response, but the lymphoma relapsed in her left breast at 6 months after CAR (FMC63)-T cell infusion. A mutation was found in exon 3 of (p.163. R-L) in malignant B cells of the patient. In two lymphoma patients who exhibited resistance to CAR-T cell therapy, a mutation was detected in exon 3 of (p.174. L-V). Functional analysis revealed that FMC63 CAR-T cells exhibited antitumor ability against wild-type CD19 cells but were unable to eradicate these two types of mutated CD19 cells. Interestingly, 21D4 CAR-T cells were potentially capable of eradicating these mutated CD19 cells and exhibiting high antitumor capacity against CD19 cells with loss of exon 1, 2, or 3.

Conclusions: These findings suggest that point mutation can facilitate immune escape from CAR-T cell therapy and that alternative CAR-T cells can effectively eradicate the mutated B cells, providing an individualized therapeutic approach for lymphoma patients showing relapse.
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http://dx.doi.org/10.1136/jitc-2020-001150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539592PMC
October 2020

PD-1 abrogates the prolonged persistence of CD8 CAR-T cells with 4-1BB co-stimulation.

Signal Transduct Target Ther 2020 08 25;5(1):164. Epub 2020 Aug 25.

Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.

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http://dx.doi.org/10.1038/s41392-020-00277-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447768PMC
August 2020

Sequencing and phylogenetic characterization of a novel Polerovirus from Nicotiana tabacum.

Virus Genes 2020 Oct 30;56(5):657-661. Epub 2020 Jul 30.

Key Laboratory of Tobacco Pest Monitoring Controlling & Integrated Management, Tobacco Research Institute of Chinese Academy of Agricultural Sciences, Qingdao, 266101, China.

In this study, we reported the complete genome of a novel Polerovirus, named Tobacco yellow virus (TYV), which can be transmitted by Myzus persicae. TYV had a single-stranded RNA genome of 5735 nucleotides in length and contained six putative open reading frames (ORFs). Phylogenetic analysis with whole genome nucleotide sequences and amino acid sequences deduced from the conserved domain of the RNA-dependent RNA polymerase, clustered TYV with Potato leafroll virus from the genus Polerovirus with high bootstrap values. However, TYV clustered with Brassica yellow virus using amino acid sequences deduced from the conserved domain of the coat protein. Taken together with the identities between ORFs in TYV and related ORFs in species from Polerovirus, our results strongly suggested TYV is a novel species of the genus Polerovirus.
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http://dx.doi.org/10.1007/s11262-020-01782-0DOI Listing
October 2020

Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques.

Nature 2020 10 30;586(7830):583-588. Epub 2020 Jul 30.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic. For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in non-human primates. Fifty-two rhesus macaques (Macaca mulatta) were immunized with Ad26 vectors that encoded S variants or sham control, and then challenged with SARS-CoV-2 by the intranasal and intratracheal routes. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs after SARS-CoV-2 challenge. Titres of vaccine-elicited neutralizing antibodies correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in non-human primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials.
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http://dx.doi.org/10.1038/s41586-020-2607-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581548PMC
October 2020

COVID-19: immunopathogenesis and Immunotherapeutics.

Signal Transduct Target Ther 2020 07 25;5(1):128. Epub 2020 Jul 25.

Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China.

The recent novel coronavirus disease (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is seeing a rapid increase in infected patients worldwide. The host immune response to SARS-CoV-2 appears to play a critical role in disease pathogenesis and clinical manifestations. SARS-CoV-2 not only activates antiviral immune responses, but can also cause uncontrolled inflammatory responses characterized by marked pro-inflammatory cytokine release in patients with severe COVID-19, leading to lymphopenia, lymphocyte dysfunction, and granulocyte and monocyte abnormalities. These SARS-CoV-2-induced immune abnormalities may lead to infections by microorganisms, septic shock, and severe multiple organ dysfunction. Therefore, mechanisms underlying immune abnormalities in patients with COVID-19 must be elucidated to guide clinical management of the disease. Moreover, rational management of the immune responses to SARS-CoV-2, which includes enhancing anti-viral immunity while inhibiting systemic inflammation, may be key to successful treatment. In this review, we discuss the immunopathology of COVID-19, its potential mechanisms, and clinical implications to aid the development of new therapeutic strategies against COVID-19.
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http://dx.doi.org/10.1038/s41392-020-00243-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381863PMC
July 2020

Characterization of fish collagen from blue shark skin and its application for chitosan- collagen composite coating to preserve red porgy (Pagrus major) meat.

J Food Biochem 2020 08 21;44(8):e13265. Epub 2020 Jun 21.

College of Food Science and Technology, Shanghai Ocean University, Shanghai, China.

Pepsin soluble collagen (PSC) was extracted from blue shark (Prionace glauca) skin and was used for chitosan-collagen composite coating to investigate coating effects on fresh red porgy (Pagrus major) fillet quality during storage at 4°C. Total volatile basic nitrogen (TVB-N), thiobarbituric acid (TBA), pH, K value, drip loss, and sensory evaluation scores were measured as deterioration indexes. Results show that coating by 1% of chitosan solutions containing 0.0%-0.8% of PSC significantly improved most deterioration indexes. Coating by 1% of chitosan solution containing 0.8% of PSC yielded the best results for K value, drip loss, and sensory evaluation, although the other indexes show no clear PSC concentration dependence. These results indicate 1% of chitosan solution containing 0.8% of PSC as the best coating formulation examined in this study. PRACTICAL APPLICATIONS: Aquatic products have high contents of water and protein. Their qualities are likely to decline because of endogenous chemical and enzyme reactions, and also because of the role of spoilage and pathogenic microorganisms during storage. The edible collagen and chitosan coating suggested by this research is biodegradable, biocompatible, cost effective, and is able to meet the requirements for food quality and storage duration. Pepsin soluble collagen (PSC) is an aquatic product processing by-product that makes the maximum use of resources. As described herein, a composite formulation comprising collagen and chitosan improves preservation effects of different types of coatings. A more high-quality and effective edible coating formulation was obtained, thereby extending the red porgy fillet shelf life.
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http://dx.doi.org/10.1111/jfbc.13265DOI Listing
August 2020

Over-Expression and Prognostic Significance of HHLA2, a New Immune Checkpoint Molecule, in Human Clear Cell Renal Cell Carcinoma.

Front Cell Dev Biol 2020 19;8:280. Epub 2020 May 19.

Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

HHLA2, a newly identified B7 family member, regulates T cell functions. However, the expression and prognostic value of HHLA2 in solid tumors is ill defined. This study aimed to reveal the expression landscape of HHLA2 in various solid tumors, and to evaluate its prognostic value in kidney clear cell carcinoma (KIRC). Using The Cancer Genome Atlas (TCGA) database, we investigated the expression pattern of HHLA2 across 22 types of cancer. HHLA2 and CD8 protein expression was determined via immunohistochemistry (IHC). KIRC-specific findings were further analyzed with R software and the prognostic value was validated on tissue microarrays. HHLA2 was widely expressed in cancers at both the mRNA and protein levels. Among all tested tumors, KIRC showed the highest transcript level of HHLA2, and HHLA2 levels were significantly higher in tumor tissues than in matched normal samples, as evidenced by both TCGA and IHC data. HHLA2 was also positively correlated with survival rates in KIRC based on TCGA and clinical data. Receiver operating characteristic curves data showed the prognostic value of HHLA2 for patients with KIRC in TCGA. Moreover, HHLA2 was positively correlated with immune-related genes, while HHLA2 and CD8 expression exhibited a consistent trend in KIRC tumor samples. In conclusion, HHLA2 is highly expressed in KIRC and predicts a favorable survival outcome, highlighting that it may work as a potential target for KIRC therapy.
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http://dx.doi.org/10.3389/fcell.2020.00280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248229PMC
May 2020
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