bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alternative lineage B cells utilizing fatty acid oxidation predict response to third dose COVID vaccination in solid organ transplant recipients
Authors: Thompson Elizabeth A , Roznik Katerina , Karaba Andrew , Cascino Katherine , Dhakal Santosh , Sena Laura , Biavatti Luca , Abedon Aura T , Alejo Jennifer L , Klein Sabra L , Warren Daniel , Quin Caroline X , Mitchel Jonathan , Garonzik-Wang Jacqueline , Leone Robert , Boyarsky Brian , Segev Dorry L , Tobian Aaron A R , Werbel William , Cox Andrea L , Bailey Justin R 
Published: January 2023

Abstract
Solid organ transplant recipients (SOTRs) demonstrate reduced seroconversion and increased breakthrough infection rates following standard two dose mRNA vaccination against SARs-CoV-2. However, within a prospective cohort of SOTRs, the majority of patients (72%) developed a positive anti-Spike (S) IgG following a third vaccine dose, compared to only 15% following two doses. Those who failed to respond to vaccination uniformly received mycophenolate mofetil (MMF). To better understand mechanisms underlying divergent vaccine responses, both global and S-specific B cells were evaluated using flow cytometry to assess immunologic and metabolic phenotypes. Prior to the third dose, 76% of SOTRs demonstrated detectable S-specific B cells even though only 15% had positive anti-S IgG titers. However, B cells were skewed towards a non-class switched phenotype in SOTRs compared to healthy controls. Response to a third dose was predicted by expanded populations of germinal center (GC)-like B cells and CD11c+ alternative lineage B cells with upregulation of carnitine palmitoyltransferase 1a (CPT1a), the rate limiting enzyme for fatty acid oxidation (FAO), a preferred energy source of GC B cells. SOTRs receiving high dose MMF demonstrated significantly lower expression of CPT1a compared to healthy controls, indicating an energetic deficit associated with MMF and failure to respond. Further, in vitro treatment of B cells with MMF reduced the ability to oxidize fatty acids and induced an accumulation of intracellular lipid droplets. Together, these data define alternative lineage B cells present in those who respond to a third vaccine dose, outlining FAO as a metabolic pathway that could be targeted to improve vaccine responses.
Pan-coronavirus neutralizing S2 human monoclonal antibodies and utility of direct respiratory administration as combination therapy with S1 antibodies against SARS-CoV-2
Authors: Kobie James , Park Jun-Gyu , Sarkar Sanghita , Basu Madhubanti , Loos Andreas , Woo Jennifer , Ye Chengjin , Truong Vu , Bowen Richard , Walter Mark R , Martinez-Sobrido Luis , Piepenbrink Michael 
Published: January 2023

Abstract
To determine if pan-coronavirus neutralizing antibodies are induced by SARS-CoV-2 infection, human monoclonal antibodies (mAb) targeting the highly conserved S2 domain of the Spike glycoprotein were cloned from B cells isolated from convalescent patients with rationally designed SARS-CoV-2 stabilized S2 and SARS-CoV/SARS-CoV-2 S1S2 chimera recombinant protein probes. mAbs emerged capable of binding SARS-CoV-2, including the variants of concern (Beta, Gamma, Delta, and Omicron), SARS-CoV and MERS-CoV. The most potent neutralizing mAb with greatest breadth, 1249A8, recognizes all beta-coronaviruses tested including high affinity for SARS-CoV-2, SARS-CoV, and MERS-CoV. The 1249A8 lineage appears to have developed from a pre-existing OC43-specific memory B cell that was expanded as result of SARS-CoV-2 infection, and further expanded following COVID-19 vaccination. Treating K18 hACE2 transgenic mice with 1249A8 intraperitoneally prior to co-infection with SARS-CoV-2 Wa-1 and Beta VoC strains prevented weight loss and death, with viral titers below detectable levels by 4 days post-infection. 1249A8 delivered as a single 4mg/kg intranasal (i.n.) dose to hamsters 12 hours following infection with SARS-CoV-2/Delta significantly protected them from weight loss, with therapeutic activity enhanced when combined with an S1-specific neutralizing mAb. As little as 2 mg/kg of 1249A8 i.n. 20 hours following infection with SARS-CoV/Urbani protected hamsters from weight loss. 1249A8 recognizes a highly conserved region near HR2 of the S2 domain of Spike. These results indicate that potent pan-coronavirus neutralizing mAbs with therapeutic potential can be induced in humans and can inform pan-coronavirus vaccine development.
Supported in-part by Aridis Pharmaceuticals and NIH (R01AI161175).
Persistence of immune memory to SARS-CoV-2 vaccine in lymphoid tissue
Authors: Davis-Porada Julia , Rybkina Ksenia , Poon Maya M L , Caron Daniel P , Jensen Isaac J , Kubota Masaru , Lam Nora , Lee Yoon Seung , Matsumoto Rei , Morrison-Colvin Rory , Szabo Peter A , Ural Basak B , Wells Steven B , Farber Donna L 
Published: January 2023

Abstract
Immunization with novel mRNA vaccines against SARS-CoV-2 administered worldwide protects against COVID-19 through the generation of neutralizing antibodies directed against the viral spike protein. While immune responses generated from vaccines have been evaluated in blood, the cellular stores of memory T and B cells are maintained in tissues. Using tissues from vaccinated, but previously uninfected organ donors, we surveyed lymphoid and barrier sites for the presence of SARS-CoV-2 vaccine specific memory B and T cells. Fluorescently labeled, full length Spike and RBD probes were used to identify vaccine specific memory B cells, while vaccine specific T cells were identified by expression of activation induced markers following stimulation with peptide pools spanning the entire spike protein. All donors were confirmed negative for anti-nucleocapsid antibodies and positive for anti-spike and anti-RBD antibodies via ELISA. Spike specific T cells were identified in the blood, spleen, lung, and lung associated lymph nodes (LLN), but not bone marrow (BM). In all tissues, these vaccine specific T cells were primarily CD4 and exhibited a mixed central- and effector-memory phenotype; in the LLN the majority (up to 55%) were T-follicular helper cells (CXCR5+/PD-1+). Spike and RBD specific memory B cells were detected in blood, lung, spleen, BM, and LLN. These vaccine specific B cells in the LLN specifically expressed the tissue residency marker CD69, but only a minority had features of germinal center B cells. These results indicate that memory B and T cells generated from mRNA vaccination localize primarily to lymphoid organs, including those draining the lung, which is important for understanding their longevity and protective capacity.
Supported by grants from NIH (U19 AI128949, PO1 AI106697, T32 GM007367)
Evaluation of the long-term anti-Spike immune response following a novel coronavirus vaccine (CORVax): electroporation of SARS-CoV-2 Spike plasmid DNA plus IL12 plasmid DNA
Authors: Jensen Shawn M , Afentoulis Michael , Wegmann Keith , Canton David A , Twitty Christopher G , Fox Bernard A 
Published: January 2023

Abstract
The global SARS-CoV-2 (CoV2) pandemic has focused efforts to generate effective vaccines that induce potent and persistent immunity. Recently, we described a novel vaccine approach using electroporation (EP) of a plasmid encoding a prefusion stabilized CoV2 spike protein (CORVax) plus plasmid Interleukin-12 (IL-12). IL-12 is an effective vaccine adjuvant that increases Th1 and Th2 antibodies in the serum. Here we examine the persistence of anti-Spike antibodies present in the serum of mice one year following CORVax vaccination.
C57BL/6 and BALB/c were vaccinated intramuscular (IM) and/or intradermal (ID) with a plasmid encoding the CoV2 spike protein with or without plasmid-encoded murine IL-12. Mice received plasmid EP immediately following injection. Splenocytes and serum were harvested at various time points to interrogate virus-specific cellular responses as well anti-spike antibody titers.
Anti-Spike IgG antibodies were elicited by EP of CORVax (IC50 = 1/2112), as well as EP of CORVax combined with IL-12 (IC50 = 1/4214) approximately 40 days after the booster vaccination. These anti-Spike IgG titers decayed over time but were still present 1 year after vaccination: CORVax (IC50 = 1/351 day 146, IC50 = 1/208 day 383); CORVax + IL12 (IC50 = 1/590 day 146, IC50 = 1/266 day 383).
Our data shows that EP of CORVax induces IgG responses to CoV2 Spike and the CoV2 Spike receptor binding domain. At one year following vaccination the anti-Spike IgG titers were higher in mice that received CORVax plus IL-12, however the rate at which the titers waned from their initial peak was comparable whether the mice received IL-12 or not. Additional studies are ongoing to determine whether the addition of IL-12 will enhance an anti-Spike memory response.
Generous support from The Chiles Foundation, Nancy Lematta, and the Providence Medical Foundation.
Efficacy of pediatric SARS-CoV-2 vaccines against high-dose B.1.617.2 challenge one year after vaccination of infant rhesus macaques
Authors: Milligan Emma C , Olstad Katherine , Cano Patricio , Munt Jenny , Lindesmith Lisa , Scobey Trevor , Mallory Michael , Edwards Darin , Carfi Andrea , Corbett Kizzmekia , Graham Barney S , Tomai Mark A , Iyer Smita S , Baric Ralph , Reader Rachel , Van Rompay Koen , Dittmer Dirk P , Permar Sallie , De Paris Kristina 
Published: January 2023

Abstract
To advance SARS-CoV-2 vaccines in infants younger than 5 years, we tested the efficacy of two SARS-CoV-2 vaccine platforms against challenge with the delta variant one year after immunization of infant rhesus macaques (RM).
Infant RMs (n=8/ group; 2 month-old) were immunized intramuscularly at weeks 0 and 4 with 30 mg stabilized prefusion SARS-CoV-2 S-2P spike (S) protein (Washington strain) encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or 15 mg S protein mixed with 3M-052 in stable emulsion (Protein). At 1 year, vaccinated and age-matched unvaccinated RM (n=8) were challenged intranasally (106 pfu) and intratracheally (2×106 pfu) with B.1.617.2. Lung pathology was blindly assessed on day 7. Viral RNA copies of the N gene (vRNA) were measured by qPCR in nasal and pharyngeal swabs.
Severe lung pathology was observed in 7 of 8 controls compared to 1 of 8 or 0 of 8 RM in the mRNA-LNP or protein group, respectively. On days 2 and 4, vRNA copies/ml were significantly higher in pharyngeal swabs of control RM (day 2: 4.2p&gt;
Supported by grants from NIH PO1 AI117915
Respiratory humoral and cellular immune responses following COVID-19 mRNA vaccination
Authors: Tang Jinyi , Zeng Cong , Cox Thomas M , Li Chaofan , Son Young Min , Cheon In Su , Behl Supriya , Justin Taylor J , Chakaraborty Rana , Johnson Aaron J , Shiavo Dante N , Utz James P , Reisenauer Janani S , Midthun David E , Mullon John J , Edell Eric S , Vassallo Robert S , Kern Ryan , Liu Shan-lu , Sun Jie 
Published: January 2023

Abstract
Vaccination is the key for controlling COVID-19 pandemic. SARS-CoV-2 mRNA vaccines have been demonstrated to induce robust and persistent humoral and cellular immunity in the circulation, but the vaccine-induced immune responses in the respiratory tract remain largely elusive. Here, we examined SARS-CoV-2 S-specific antibody, B and T cell immune responses in the bronchoalveolar lavage (BAL) fluid and blood from unvaccinated, COVID-19 vaccinees or COVID-19 convalescents that recovered from prior moderate to severe SARS-CoV-2 infection. We found that mRNA vaccination induced significant SARS-CoV-2 S-specific CD4+ and CD8+ T cell responses in the blood but not in the BAL. Similarly, mRNA vaccination failed to provoke detectable SARS-CoV-2 S RBD-specific B cell responses in the BAL despite marked RBD-specific B cells were observed in the blood of COVID-19 vaccinees. In contrast, robust SARS-CoV-2 S-specific B and T cell responses were present in the BAL of COVID-19 convalescents. Furthermore, significant neutralizing antibody responses were only observed in the BAL from convalescents but not vaccinees, while both COVID-19 vaccinee and convalescent groups mounted marked neutralizing antibody responses in the blood. Thus, despite their induction of robust circulating humoral and cellular immunity, the current COVID-19 vaccines provoke relatively weak cellular and neutralizing antibody responses in the lower respiratory tract. Our results indicate that a mucosal booster vaccine may be needed to establish robust immunity in the respiratory mucosa, which could provide a strong first line of defense against SARS-CoV-2 re-infection.
Development of a Cell-based ELISA assay to assess memory IgG produced in vitro by B cells specific for spike protein of SARS-CoV-2
Authors: Scapigliati Giuseppe , Zarletti Gianpaolo , Tiberi Massimo , De Molfetta Veronica , Toppi Elisa , Bossù Paola 
Published: January 2023

Abstract
Knowledge of antibody-mediated immune response to SARS-CoV-2 is crucial to understand the virus immunogenicity, establish seroprevalence and determine possible risks for infection/reinfection. An antibody presence, indicative of an humoral immune response, can be evidenced at early/intermediated stages after infection and antibodies are mainly detected by ELISA-based platforms. However, a major drawback of ELISA systems is a decrease of serum antibody titers during time. On the other hand, circulating antigen-specific memory B cells (MBC) may be present for long time after immunization/infection. The spike S1 protein has been shown to be a serological marker for Covid-19, and we describe a novel, simple and robust Cell-ELISA assay specifically designed to measure viral spike S1 protein by detecting specific IgG produced in vitro by MBC in PBMC (doi:10.3390/v12111274). By applying the Cell-ELISA assay to a cohort of 150 asympto/symptomatic individuals, age ranging from 8–100 years, we detected individuals resulted negative in ELISA but positive in Cell-ELISA, thus showing the presence of MBC that produce in vitro antibodies against SARS-CoV-2 at levels that are undetectable in the serum. These data may challenge the negative results obtained from the serological screening and indicate a previous antigen exposure in the possible absence of serum IgG. We also detected a presence of MBC specific for S1 protein for &gt;10 months after viral infection (doi:10.3390/v13091704), suggesting a potent antigenicity, and evaluated the relative amount of in vitro secreted IgG in positive subjects. The proposed assay could be a candidate tool to monitor the presence of an effective IgG antibody memory after SARS-CoV-2 infection and vaccination.
Longitudinal measurement of human immune responses to SARS-CoV-2 vaccines through serum immunoglobulins
Authors: Heatherton Kara , Carey Charleve , Hawkins William , Lacey Stephanie 
Published: January 2023

Abstract

Introduction
The novel SARS-CoV-2 (COVID-19) vaccines generate antibodies to the viral spike protein. The mRNA vaccines Moderna Inc. and Pfizer-BioNTech and adenovirus vaccine Johnson & Johnson (J&J) work through generation of humoral immune responses, particularly immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies. We assessed IgG and IgM response in vaccinated patients longitudinally.

Methods
Blood was drawn from 106 subjects over the course of five time points ranging from pre-to post-vaccine inoculation of Moderna, Pfizer, or J&J. Blood was collected into serum separating tubes (SST). SSTs were spun at 1200rcf for 15 minutes; the serum was isolated and used for testing. Levels of IgG and IgM were measured in geometric mean titers, then analyzed through multiple t-tests across vaccines and demographics.

Results
Moderna vaccine recipients had a significantly higher IgG titer following vaccine inoculation (p &lt; 0.0005 for Time Point 1, 2, 3, 4). No significant difference was observed across various demographics (age/gender) within vaccine types (p &gt; 0.05). There was a steady decline in IgG and IgM levels after full inoculations, which were trending towards baseline levels. J&J recipients had little change in IgG and IgM after receiving the vaccine; however, significantly lower IgG than the Moderna (p = 0.0006) and Pfizer (p =0.0071).

Conclusion
With the use of IgG and IgM as immune response indicator, our data shows Moderna outperforming Pfizer at all Time Points following baseline testing, which suggests greater, longer-lasting immunity against COVID-19. With a low sample size for J&J (n = 5), it is unclear what implications the poor IgG response observed in this study indicates about the adenovirus vaccine.
SARS-CoV-2 Spike395–404 is identified as a murine CD8+ T cell epitope in the receptor-binding domain of the SARS-CoV-2 spike protein
Authors: Yang Jihyun , Kim Eunjin , Poo Haryoung 
Published: January 2023

Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of the COVID-19 pandemic. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is considered an important antigen of SARS-CoV-2 vaccines, while the cytotoxic T lymphocyte (CTL) activity is critical for evaluating cell-mediated immune response for vaccine efficacy. Human angiotensin-converting enzyme 2 (hACE2)-expressing transgenic mice with a C57BL/6 genetic background have widely used as an animal model of SARS-CoV-2 study. However, the CTL epitope of SARS-CoV-2 RBD has not yet been identified in C57BL/6 mice and quantifying the CTL activity has used RBD peptide pools with limitations such as expensive and time-consuming synthesis of peptides. In this study, we identified a murine CD8+ T cell epitope of the SARS-CoV-2 spike RBD using C57BL/6 wild-type and hACE2-expressing transgenic (K18-hACE2) mice. Mice were immunized with the adjuvanted SARS-CoV-2 RBD recombinant protein and then the CTL activities were evaluated by determining numbers of the IFN-γ-producing T cells in the splenocytes of the immunized mice upon exposure to overlapping peptide pools or individual peptides via an enzyme-linked immunospot assay and flow cytometry. We found SARS-CoV-2 S395–404 (VYADSFVIRG) as a major histocompatibility complex class I-restricted epitope for the RBD-specific CTL activity in C57BL/6 mice.
Supported by a grant from Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGM9942112).
Differential T cell immunity to SARS-CoV-2 in mRNA-1273 and BNT162b2 vaccinated individuals
Authors: Katsis Katelin , Leick Mark B , Larson Rebecca C , Berger Trisha R , Elder Eva L , Maus Marcela V , Gallagher Kathleen M E 
Published: January 2023

Abstract
T-cell immunity to SARS-CoV-2 vaccination with either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) mRNA vaccines was quantified through a validated ELISpot assay at various time points. The magnitude and duration of response was compared between these two vaccine cohorts alongside the anti-spike IgG response.
Freshly isolated peripheral blood mononuclear cells were incubated with overlapping peptide pools covering the SARS-CoV-2 spike protein in an IFNg ELISpot assay. Donors T cell responses to spike protein were assessed where possible at pre-vaccination, post second vaccination, and at long-term follow up. Anti-Spike IgG was quantified by serum ELISA.
Following the 2 dose regimens, all donors developed anti-spike T-cell responses. The median decline in T-cell response between the 2nd vaccine dose and long-term follow-up was 35.1%. At long-term follow-up, T-cell responses in BNT162b2 vaccinated individuals were lower than mRNA-1273. Median T-cell responses were 38.5 SFU/2.5×105 (BNT162b2) and 86 SFU/2.5×105 (mRNA-1273). Anti-spike IgG decreased by a median of 89.3% at long-term follow-up. Individuals receiving BNT162b2 had lower serum antibody levels long-term compared to mRNA-1273. The median antibody responses were 205.3 BAU/mL (BNT162b2) and 335 BAU/mL (mRNA-1273).
Both humoral and cellular immunity to SARS-CoV-2 is decreased long-term post-vaccination with either mRNA vaccine, and both are significantly lower in BNT162b2-vaccinated compared to mRNA-1273-vaccinated individuals, with a greater magnitude of difference in the T cell response between vaccines compared to antibody levels. As breakthrough infections continue to rise, understanding the dynamics of these vaccine responses is crucial.
MHC Class I–Dependent Shaping of the NK Cell Ly49 Receptor Repertoire Takes Place Early during Maturation in the Bone Marrow
Authors: Wickström Stina L , Wagner Arnika K , Fuchs Sina , Elemans Marjet , Kritikou Joanna , Mehr Ramit , Kärre Klas , Johansson Maria H , Brauner Hanna 
Published: January 2023

Abstract
MHC class I (MHC I) expression in the host influences NK cells in a process termed education. The result of this education is reflected in the responsiveness of NK cells at the level of individual cells as well as in the repertoire of inhibitory MHC I–specific receptors at the NK cell system level. The presence of MHC I molecules in the host environment gives rise to a skewed receptor repertoire in spleen NK cells where subsets expressing few (one or two) inhibitory receptors are expanded whereas subsets with many (three or more) receptors are contracted. It is not known whether this MHC I–dependent skewing is imposed during development or after maturation of NK cells. In this study, we tested the hypothesis that the NK cell receptor repertoire is shaped already early during NK cell development in the bone marrow. We used mice with a repertoire imposed by a single MHC I allele, as well as a C57BL/6 mutant strain with exaggerated repertoire skewing, to investigate Ly49 receptor repertoires at different stages of NK cell differentiation. Our results show that NK cell inhibitory receptor repertoire skewing can indeed be observed in the bone marrow, even during the earliest developmental steps where Ly49 receptors are expressed. This may partly be accounted for by selective proliferation of certain NK cell subsets, but other mechanisms must also be involved. We propose a model for how repertoire skewing is established during a developmental phase in the bone marrow, based on sequential receptor expression as well as selective proliferation.
CD5 Suppresses IL-15–Induced Proliferation of Human Memory CD8+ T Cells by Inhibiting mTOR Pathways
Authors: Choi Young Joon , Lee Hoyoung , Kim Jong Hoon , Kim So-Young , Koh June-Young , Sa Moa , Park Su-Hyung , Shin Eui-Cheol 
Published: January 2023

Abstract
IL-15 induces the proliferation of memory CD8+ T cells as well as NK cells. The expression of CD5 inversely correlates with the IL-15 responsiveness of human memory CD8+ T cells. However, whether CD5 directly regulates IL-15–induced proliferation of human memory CD8+ T cells is unknown. In the current study, we demonstrate that human memory CD8+ T cells in advanced stages of differentiation respond to IL-15 better than human memory CD8+ T cells in stages of less differentiation. We also found that the expression level of CD5 is the best correlate for IL-15 hyporesponsiveness among human memory CD8+ T cells. Importantly, we found that IL-15–induced proliferation of human memory CD8+ T cells is significantly enhanced by blocking CD5 with Abs or knocking down CD5 expression using small interfering RNA, indicating that CD5 directly suppresses the IL-15–induced proliferation of human memory CD8+ T cells. We also found that CD5 inhibits activation of the mTOR pathway, which is required for IL-15–induced proliferation of human memory CD8+ T cells. Taken together, the results indicate that CD5 is not just a correlative marker for IL-15 hyporesponsiveness, but it also directly suppresses IL-15–induced proliferation of human memory CD8+ T cells by inhibiting mTOR pathways.