scholarly journals Single-dose respiratory mucosal delivery of next-generation viral-vectored COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2

2021 ◽  
Author(s):  
Sam Afkhami ◽  
Michael R. D'Agostino ◽  
Ali Zhang ◽  
Hannah D. Stacey ◽  
Art Marzok ◽  
...  
Keyword(s):  
Single Dose ◽  
First Generation ◽  
Next Generation ◽  
Vaccine Strategy ◽  
Intranasal Immunization ◽  
Mucosal Delivery ◽  
Cell Immunity ◽  
Generation Vaccine ◽  
Vectored Vaccine ◽  
Resident Memory T Cells

The emerging SARS-CoV-2 variants of concern (VOC) increasingly threaten the effectiveness of current first-generation COVID-19 vaccines that are administered intramuscularly and are designed to only target the spike protein. There is thus a pressing need to develop next-generation vaccine strategies to provide more broad and long-lasting protection. By using adenoviral vectors (Ad) of human and chimpanzee origin, we developed Ad-vectored trivalent COVID-19 vaccines expressing Spike-1, Nucleocapsid and RdRp antigens and evaluated them following single-dose intramuscular or intranasal immunization in murine models. We show that respiratory mucosal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the three-arm immunity, consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells, and mucosal trained innate immunity. We further show that single-dose intranasal immunization provides robust protection against not only the ancestral strain of SARS-CoV-2, but also two emerging VOC, B.1.1.7 and B.1.351. Our findings indicate that single-dose respiratory mucosal delivery of an Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy against current and future VOC. This strategy has great potential to be used not only to boost first-generation vaccine-induced immunity but also to expand the breadth of protective T cell immunity at the respiratory mucosa.

scholarly journals A next generation vaccine against human rabies based on a single dose of a chimpanzee adenovirus vector serotype C

2020 ◽  
Vol 14 (7) ◽  
pp. e0008459 ◽  
Author(s):  
Federico Napolitano ◽  
Rossella Merone ◽  
Adele Abbate ◽  
Virginia Ammendola ◽  
Emma Horncastle ◽  
...  
Keyword(s):  
Single Dose ◽  
Adenovirus Vector ◽  
Human Rabies ◽  
Next Generation ◽  
Generation Vaccine

scholarly journals Correction: A next generation vaccine against human rabies based on a single dose of a chimpanzee adenovirus vector serotype C

2021 ◽  
Vol 15 (4) ◽  
pp. e0009348
Author(s):  
Federico Napolitano ◽  
Rossella Merone ◽  
Adele Abbate ◽  
Virginia Ammendola ◽  
Emma Horncastle ◽  
...  
Keyword(s):  
Single Dose ◽  
Adenovirus Vector ◽  
Human Rabies ◽  
Next Generation ◽  
Generation Vaccine

scholarly journals Building momentum for malaria vaccine research and development: key considerations

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Chetan E. Chitnis ◽  
David Schellenberg ◽  
Johan Vekemans ◽  
Edwin J. Asturias ◽  
Philip Bejon ◽  
...  
Keyword(s):  
Research And Development ◽  
Malaria Control ◽  
First Generation ◽  
Malaria Vaccine ◽  
Next Generation ◽  
Vaccine Research ◽  
Medium Term ◽  
Vaccine Candidates ◽  
Malaria Vaccines ◽  
Generation Vaccine

AbstractTo maintain momentum towards improved malaria control and elimination, a vaccine would be a key addition to the intervention toolkit. Two approaches are recommended: (1) promote the development and short to medium term deployment of first generation vaccine candidates and (2) support innovation and discovery to identify and develop highly effective, long-lasting and affordable next generation malaria vaccines.

scholarly journals Self-assembling nanoparticles presenting receptor binding domain and stabilized spike as next-generation COVID-19 vaccines

2020 ◽  
Author(s):  
Linling He ◽  
Xiaohe Lin ◽  
Ying Wang ◽  
Ciril Abraham ◽  
Cindy Sou ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibody ◽  
Binding Domain ◽  
Heptad Repeat ◽  
High Yield ◽  
Receptor Binding Domain ◽  
Next Generation ◽  
Vaccine Strategy ◽  
Self Assembling ◽  
Cell Immunity

ABSTRACTWe present a comprehensive vaccine strategy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by combining antigen optimization and nanoparticle display. We first developed a receptor binding domain (RBD)-specific antibody column for purification and displayed the RBD on self-assembling protein nanoparticles (SApNPs) using the SpyTag/SpyCatcher system. We then identified the heptad repeat 2 (HR2) stalk as a major cause of spike metastability, designed an HR2-deleted glycine-capped spike (S2GΔHR2), and displayed S2GΔHR2 on three SApNPs with high yield, purity, and antigenicity. Compared to the RBD, the RBD-ferritin SApNP elicited a more potent murine neutralizing antibody (NAb) response on par with the spike. S2GΔHR2 elicited two-fold-higher NAb titers than the proline-capped spike (S2P), while S2GΔHR2 SApNPs derived from multilayered E2p and I3-01v9 60-mers elicited up to 10-fold higher NAb titers. The S2GΔHR2-presenting I3-01v9 SApNP also induced critically needed T-cell immunity, thereby providing a next-generation vaccine candidate to battle the COVID-19 pandemic.ONE-SENTENCE SUMMARYThe receptor binding domain and stabilized SARS-CoV-2 spike were displayed on nanoparticles as vaccine antigens and elicited potent immune responses.

The Inheritors’ Coming of Age

2018 ◽  
Author(s):  
Elisabeth Schimpfössl
Keyword(s):  
First Generation ◽  
Second Generation ◽  
Coming Of Age ◽  
Next Generation ◽  
Privileged Status ◽  
The Rich

Chapter 7 focuses on the upbringing of the second generation of the Russian bourgeoisie. As the first generation of wealthy Russians grows older, they are becoming more aware of their own mortality and are preparing to hand over their wealth to the next generation. It seems that rich Russians are yet to find a convincing narrative to justify their children’s legitimate entitlement to wealth that does not contradict their own everyday ideology of being self-made. Nevertheless, a two-pronged approach is emerging. First, in line with the shift toward new modesty, children are being encouraged to cultivate a habitus of privilege, as Sherman suggests in the case with wealthy US Americans, which makes them appear morally worthy in an environment marked by extreme inequality. Second, via their philanthropy the rich are supporting institutions and scholars in an effort to strengthen a dynamic capitalist environment in which privileged status is respected.

scholarly journals T Cell Immunity against Influenza: The Long Way from Animal Models Towards a Real-Life Universal Flu Vaccine

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 199
Author(s):  
Anna Schmidt ◽  
Dennis Lapuente
Keyword(s):  
T Cells ◽  
T Cell ◽  
Animal Models ◽  
Respiratory Tract ◽  
Memory T Cells ◽  
Real Life ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
Flu Vaccine ◽  
Resident Memory T Cells

Current flu vaccines rely on the induction of strain-specific neutralizing antibodies, which leaves the population vulnerable to drifted seasonal or newly emerged pandemic strains. Therefore, universal flu vaccine approaches that induce broad immunity against conserved parts of influenza have top priority in research. Cross-reactive T cell responses, especially tissue-resident memory T cells in the respiratory tract, provide efficient heterologous immunity, and must therefore be a key component of universal flu vaccines. Here, we review recent findings about T cell-based flu immunity, with an emphasis on tissue-resident memory T cells in the respiratory tract of humans and different animal models. Furthermore, we provide an update on preclinical and clinical studies evaluating T cell-evoking flu vaccines, and discuss the implementation of T cell immunity in real-life vaccine policies.

The Next Generation of Service Agreements for Publicly Owned Waste-to-Energy Facilities: Pinellas County Case Study

2007 ◽  
Author(s):  
Paul J. Stoller ◽  
Anthony LoRe ◽  
William Crellin ◽  
Robert Hauser
Keyword(s):  
First Generation ◽  
Lessons Learned ◽  
Waste To Energy ◽  
Next Generation ◽  
Procurement Process ◽  
Pinellas County ◽  
The Past ◽  
Operation And Maintenance ◽  
Service Agreement

This paper discusses one of the key lessons learned from administering the first generation of service agreements for public owners of waste-to-energy (WTE) facilities over the past 22 years and how those experiences were incorporated into a new service agreement for the operation and maintenance of Pinellas County’s 24 year old, 3,000 tpd WTE Facility to better protect the county’s interests. Additionally, a major issue raised by the operating companies during the competitive procurement process for continue operation of the facility is discussed and how that concern was addressed in the new service agreement is also presented. Capitalized words or terms used in this paper are defined within the new service agreement.

scholarly journals Prime-boost vaccination regimens with INO-4800 and INO-4802 augment and broaden immune responses against SARS-CoV-2 in nonhuman primates

2021 ◽  
Author(s):  
Jewell N Walters ◽  
Blake Schouest ◽  
Ami Patel ◽  
Emma L Reuschel ◽  
Katherine Schultheis ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Nonhuman Primates ◽  
First Generation ◽  
Rhesus Macaques ◽  
Natural Infection ◽  
Next Generation ◽  
Synthetic Dna ◽  
One Year ◽  
Global Population

The enhanced transmissibility and immune evasion associated with emerging SARS-CoV-2 variants demands the development of next-generation vaccines capable of inducing superior protection amid a shifting pandemic landscape. Since a portion of the global population harbors some level of immunity from vaccines based on the original Wuhan-Hu-1 SARS-CoV-2 sequence or natural infection, an important question going forward is whether this immunity can be boosted by next-generation vaccines that target emerging variants while simultaneously maintaining long-term protection against existing strains. Here, we evaluated the immunogenicity of INO-4800, our synthetic DNA vaccine candidate for COVID-19 currently in clinical evaluation, and INO-4802, a next-generation DNA vaccine designed to broadly target emerging SARS-CoV-2 variants, as booster vaccines in nonhuman primates. Rhesus macaques primed over one year prior with the first-generation INO-4800 vaccine were boosted with either INO-4800 or INO-4802 in homologous or heterologous prime-boost regimens. Both boosting schedules led to an expansion of antibody responses which were characterized by improved neutralizing and ACE2 blocking activity across wild-type SARS-CoV-2 as well as multiple variants of concern. These data illustrate the durability of immunity following vaccination with INO-4800 and additionally support the use of either INO-4800 or INO-4802 in prime-boost regimens.

scholarly journals 843 Development and engineering of human sialidase for degradation of immunosuppressive sialoglycans to treat cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A884-A884
Author(s):  
Li Peng ◽  
Lizhi Cao ◽  
Sujata Nerle ◽  
Robert LeBlanc ◽  
Abhishek Das ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
First Generation ◽  
Single Agent ◽  
Mouse Tumor ◽  
Cytokine Release ◽  
Tumor Models ◽  
Cell Immunity ◽  
Mouse Tumor Models

BackgroundSialoglycans, a type of glycans with a terminal sialic acid, have emerged as a critical glyco-immune checkpoint that impairs antitumor response by inhibiting innate and adaptive immunity. Upregulation of sialoglycans on tumors has been observed for decades and correlates with poor clinical outcomes across many tumor types. We previously showed that targeted desialylation of tumors using a bifunctional sialidase x antibody molecule, consisting of sialidase and a tumor-associated antigen (TAA)-targeting antibody, has led to robust single-agent efficacy in mouse tumor models. In addition to tumor cells, most immune cells present substantially more abundant sialoglycans than non-hematological healthy cells, which may also contribute to immunosuppression. Therefore, we studied the impact of immune cell desialylation and evaluated the therapeutic potential of a newly developed sialidase-Fc fusion (Bi-Sialidase), which lacks a TAA-targeting moiety and consists of engineered human neuraminidase 2 (Neu2) and human IgG1 Fc region, in preclinical mouse tumor models.MethodsThe first generation Neu2 variant was further optimized to improve titers and stability to constructed Bi-Sialidase. Bi-Sialidase’s desialylation potency and impact on immune responses were studied in vitro using various human immune functional assays, including T-cell activation, allogeneic mixed lymphocyte reaction, antibody-dependent cellular cytotoxicity, macrophages polarization/activation, neutrophil activation, and peripheral blood mononuclear cell (PBMC) cytokine release assays. We evaluated its antitumor efficacy in mouse tumor models. Bi-Sialidase’s safety profile was characterized by conducting rat and non-human primate (NHP) toxicology studies.ResultsThe optimized Bi-Sialidase achieved a titer of 2.5 g/L from a 15-day fed-batch Chinese hamster ovary cell culture; in contrast, the wild-type and first-generation Neu2 had no production or a low titer (<0.1 g/L) under similar conditions, respectively. We demonstrated that Bi-Sialidase led to dose-dependent desialylation of immune cells and potentiated T-cell immunity, without impacting NK, macrophage, or neutrophil activation by desialylating immune cells. Activated and exhausted T cells upregulated surface sialoglycans and Bi-Sialidase-mediated desialylation reinvigorated exhausted-like T cells as measured by IFNg production. Bi-Sialidase treatment also enhanced DC priming and activation of naïve T cells by desialylating both T cells and DCs. Furthermore, Bi-Sialidase showed single-agent antitumor activity in multiple mouse tumor models, including MC38, CT26, A20, and B16F10. Importantly, Bi-Sialidase did not cause cytokine release in human PBMC assays and was tolerated to up to 100 mg/kg in rats and NHPs, demonstrating a wide safety margin.ConclusionsBi-Sialidase with an optimized Neu2 offers a novel immunomodulatory approach to enhancing T-cell immunity by desialylating immunosuppressive sialoglycans for cancer treatment.

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