Abstract

In the aftermath of the COVID-19 pandemic, the evolution of the SARS-CoV-2 into a seasonal pathogen along with the emergence of new variants, underscores the need for dynamic and adaptable responses, emphasizing the importance of sustained vaccination strategies. This observer-blind, double-dummy, randomized immunobridging phase 2 study (NCT05175742) aimed to compare the immunogenicity induced by two doses of 40 μg PTX-COVID19-B vaccine candidate administered 28 days apart, with the response induced by two doses of 30 µg Pfizer-BioNTech COVID-19 vaccine (BNT162b2), administered 21 days apart, in Nucleocapsid-protein seronegative adults 18-64 years of age. Both vaccines were administrated via intramuscular injection in the deltoid muscle. Two weeks after the second dose, the neutralizing antibody (NAb) geometric mean titer ratio and seroconversion rate met the non-inferiority criteria, successfully achieving the primary immunogenicity endpoints of the study. PTX-COVID19-B demonstrated similar safety and tolerability profile to BNT162b2 vaccine. The lowest NAb response was observed in subjects with low-to-undetectable NAb at baseline or no reported breakthrough infection. Conversely, participants who experienced breakthrough infections during the study exhibited higher NAb titers. This study also shows induction of cell-mediated immune (CMI) responses by PTX-COVID19-B. In conclusion, the vaccine candidate PTX-COVID19-B demonstrated favourable safety profile along with immunogenicity similar to the active comparator BNT162b2 vaccine.

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Abstract

The emergence of SARS-CoV-2 variants presents challenges to vaccine effectiveness, underlining the necessity for next-generation vaccines with multiple antigens beyond the spike protein. Here, we investigated a multiantigenic booster containing spike and a chimeric construct composed of nucleoprotein (N) and membrane (M) proteins, comparing its efficacy to a spike-only booster against Omicron BA.5 in K18-hACE2 mice. Initially, mice were primed and boosted with Beta (B.1.351) spike-only mRNA, showing strong spike-specific T cell responses and neutralizing antibodies, albeit with limited cross-neutralization to Omicron variants. Subsequently, a spike-NM multiantigenic vaccine was then examined as a second booster dose for protection in hACE2-transgenic mice. Mice receiving either homologous spike-only or heterologous spike-NM booster had nearly complete inhibition of infectious virus shedding in oral swabs and reduced viral burdens in both lung and nasal tissues following BA.5 challenge. Examination of lung pathology further revealed that both spike-only and spike-NM boosters provided comparable protection against inflammatory infiltrates and fibrosis. Moreover, the spike-NM booster demonstrated neutralization efficacy in a pseudovirus assay against Wuhan-Hu-1, Beta, and Omicron variants akin to the spike-only booster. These findings indicate that supplementing spike with additional SARS-CoV-2 targets in a booster immunization confers equivalent immunity and protection against Omicron BA.5. This work highlights a promising strategy for individuals previously vaccinated with spike-only vaccines, potentially offering enhanced protection against emerging coronaviruses.

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Introduction

In vitro transcription (IVT) reaction for synthesis of mRNA is commonly performed by adding T7 RNA polymerase (RNAP) and a DNA template. Although the reaction is very efficient, T7 RNAP generates additional immunostimulatory dsRNA impurities – abortive, antisense, and loop-back dsRNAs during the transcription initiation and termination.

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Introduction

Here, we developed new lipid nanoparticle (LNP) formulations which can be utilized for therapeutic mRNA/LNP cancer vaccines. Utilizing an in vivo screening model identifying LNP formulations capable of breaking self-tolerance allows the selection of LNP candidates with superior anti-tumor efficacy. In the well characterized mouse syngeneic colorectal cancer (CRC) model expressing model glycoprotein antigens from lymphocytic choriomeningitis virus (LCMV, MC38gp), intramuscular administration of this new LNP formulation as a monotherapy in a therapeutic setting after tumor inoculation significantly delayed tumor growth and cleared tumors in 50% of treated mice. 

The data suggests the possible applicability of our next generation LNP formulations for the development of effective therapeutic mRNA cancer vaccines for multiple solid tumors.

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Introduction

1. Glioblastoma (GBM) is the most prevalent and aggressive primary brain tumor type with an abysmal prognosis. a. GBM features an immunologically dampened tumor microenvironment and limited neoantigen production. b. Novel therapeutic strategies for GBM are urgently needed.
2. A well-characterized GBM-associated mutation can elicit an anti-tumor immune response: The EGFRvIII mutation.
   1. The cancer-driver mutation is detected in approximately 30% of patients at the time of diagnosis and plays a pivotal role in the emergence of GBM.
   2. Its highly immunogenic nature represents an ideal focal point for cutting-edge mRNA-LNP candidate therapeutics.
   3. (CAR)–T cells directed against EGFRvIII have shown promise in a phase 1 study for GBM treatment, paving the way for a vaccination-based approach.

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Introduction

Lipid nanoparticle(LNP)-based mRNA vaccines have recently gained traction as an attractive modality for cancer therapies. However, inducing an effective anti-tumor response often requires the induction of a T cell response breaking self-tolerance mechanisms, a challenge forcurrent therapies. Providence Therapeutics has developed next-generation LNP formulations, which can break self-tolerance and have the potential to be utilized for therapeutic LNP/mRNA cancer vaccines.

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Introduction

Glioblastoma (GBM) is an aggressive primary brain tumor with a dismal prognosis. ​It is characterized by a limited number of neoantigens and a highly immunosuppressive tumor environment. A well-known GBM-associated driver mutation is EGFRvIII, which is detected in approximately 30% of patients at the time of diagnosis and plays a pivotal role in the emergence of GBM. Its high expression on the tumor cell surface makes it an ideal target antigen for vaccine development, as demonstrated by targeting therapies with antibodies and more recently CAR–T cells.

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