Duality of Interactions Between TGF-β and TNF-α During Tumor Formation

The tumor microenvironment is essential for the formation and development of tumors. Cytokines in the microenvironment may affect the growth, metastasis and prognosis of tumors, and play different roles in different stages of tumors, of which transforming growth factor β (TGF-β) and tumor necrosis factor α (TNF-α) are critical. The two have synergistic and antagonistic effect on tumor regulation. The inhibition of TGF-β can promote the formation rate of tumor, while TGF-β can promote the malignancy of tumor. TNF-α was initially determined to be a natural immune serum mediator that can induce tumor hemorrhagic necrosis, it has a wide range of biological activities and can be used clinically as a target to immune diseases as well as tumors. However, there are few reports on the interaction between the two in the tumor microenvironment. This paper combs the biological effect of the two in different aspects of different tumors. We summarized the changes and clinical medication rules of the two in different tissue cells, hoping to provide a new idea for the clinical application of the two cytokines.

Broad and Long-lasting Immune Response against SARS-CoV-2 Omicron and Other Variants by PIKA-Adjuvanted Recombinant SARS-CoV-2 Spike (S) Protein Subunit Vaccine (YS-SC2-010)

Recently SARS-CoV-2 Omicron (B.1.1.529) variant was identified in South Africa with numerous mutations in spike protein, and numerous community infections have been reported and raised grave concern around the world. Some studies found that the neutralization effects of several licensed vaccines against Omicron were dramatically reduced, which significantly affected antibody mediated protection, especially for individuals whose immunization were completed after extended period. In this regard, we studied the persistence and neutralization activity toward mutant strains in animal serum immunized with PIKA-adjuvanted recombinant SARS-CoV-2 spike protein subunit vaccine (YS-SC2-010). Here we are reporting that animal serum collected at 596 days after immunization with YS-SC2-010 still retains high and persistent neutralizing activity against all the Variant of Concern (VOC) variants, including Omicron variant. Although it is a blessed event to achieve 20 months long neutralization against Omicron variant after immunization with YS-SC2-010, it was also founded that the neutralization effect of immune serum on Omicron decreased by 6.29 folds as compared to D614G, more significantly when compared with other mutant strains.

ASCVac-1, a Multi-Peptide Chimeric Vaccine, Protects Mice Against Ascaris suum Infection

Control of human ascariasis, the most prevalent neglected tropical disease globally affecting 450 million people, mostly relies on mass drug administration of anthelmintics. However, chemotherapy alone is not efficient due to the high re-infection rate for people who live in the endemic area. The development of a vaccine that reduces the intensity of infection and maintains lower morbidity should be the primary target for infection control. Previously, our group demonstrated that immunization with crude Ascaris antigens in mice induced an IgG-mediated protective response with significant worm reduction. Here, we aimed to develop a multipeptide chimera vaccine based on conserved B-cell epitopes predicted from 17 common helminth proteomes using a bioinformatics algorithm. More than 480 B-cell epitopes were identified that are conserved in all 17 helminths. The Ascaris-specific epitopes were selected based on their reactivity to the pooled sera of mice immunized with Ascaris crude antigens or infected three times with A. suum infective eggs. The top 35 peptides with the strongest reactivity to Ascaris immune serum were selected to construct a chimeric antigen connected in sequence based on conformation. This chimera, called ASCVac-1, was produced as a soluble recombinant protein in an Escherichia coli expression system and, formulated with MPLA, was used to immunize mice. Mice immunized with ASCVac-1/MPLA showed around 50% reduced larvae production in the lungs after being challenged with A. suum infective eggs, along with significantly reduced inflammation and lung tissue/function damage. The reduced parasite count and pathology in infected lungs were associated with strong Th2 immune responses characterized by the high titers of antigen-specific IgG and its subclasses (IgG1, IgG2a, and IgG3) in the sera and significantly increased IL-4, IL-5, IL-13 levels in lung tissues. The reduced IL-33 titers and stimulated eosinophils were also observed in lung tissues and may also contribute to the ASCVac-1-induced protection. Taken together, the preclinical trial with ASCVac-1 chimera in a mouse model demonstrated its significant vaccine efficacy associated with strong IgG-based Th2 responses, without IgE induction, thus reducing the risk of an allergic response. All results suggest that the multiepitope-based ASCVac-1 chimera is a promising vaccine candidate against Ascaris sp. infections.

Identification of Reticulocyte Binding Domain of Plasmodium ovale curtisi Duffy Binding Protein (PocDBP) Involved in Reticulocyte Invasion

The Plasmodium ovale curtisi (Poc) prevalence has increased substantially in sub-Saharan African countries as well as regions of Southeast Asia. Poc parasite biology has not been explored much to date; in particular, the invasion mechanism of this malaria parasite remains unclear. In this study, the binding domain of the Duffy binding protein of P. ovale curtisi (PocDBP) was characterized as an important ligand for reticulocyte invasion. The homologous region of the P. vivax Duffy binding protein in PocDBP, named PocDBP-RII herein, was selected, and the recombinant PocDBP-RII protein was expressed in an Escherichia coli system. This was used to analyze reticulocyte binding activity using fluorescence-activated cell sorting and immune serum production in rabbits. The binding specificity was proven by treating reticulocytes with trypsin, chymotrypsin and neuraminidase. The amino acid sequence homology in the N-terminal Cys-rich region was found to be ~ 44% between PvDBP and PocDBP. The reticulocyte binding activity of PocDBP-RII was significantly higher than the erythrocyte binding activity and was concentration dependent. Erythrocyte binding was reduced significantly by chymotrypsin treatment and inhibited by an anti-PocDBP-RII antibody. This finding suggests that PocDBP may be an important ligand in the reticulocyte invasion process of P. ovale curtisi.

Poliovirus Vaccination Induces a Humoral Immune Response That Cross Reacts With SARS-CoV-2

Background: Millions have been exposed to SARS-CoV-2, but the severity of resultant infections has varied among adults and children, with adults presenting more serious symptomatic cases. Children may possess an immunity that adults lack, possibly from childhood vaccinations. This retrospective study suggests immunization against the poliovirus may provide an immunity to SARS-CoV-2.Methods: Publicly available data were analyzed for possible correlations between national median ages and epidemiological outbreak patterns across 100 countries. Sera from 204 adults and children, who were immunized with the poliovirus vaccine, were analyzed using an enzyme-linked immunosorbent assay. The effects of polio-immune serum on SARS-CoV-2-induced cytopathology in cell culture were then evaluated.Results: Analyses of median population age demonstrated a positive correlation between median age and SARS-CoV-2 prevalence and death rates. Countries with effective poliovirus immunization protocols and younger populations have fewer and less pathogenic cases of COVID-19. Antibodies to poliovirus and SARS-CoV-2 were found in pediatric sera and in sera from adults recently immunized with polio. Sera from polio-immunized individuals inhibited SARS-CoV-2 infection of Vero cell cultures. These results suggest the anti-D3-pol-antibody, induced by poliovirus vaccination, may provide a similar degree of protection from SARS-CoV-2 to adults as to children.Conclusions: Poliovirus vaccination induces an adaptive humoral immune response. Antibodies created by poliovirus vaccination bind the RNA-dependent RNA polymerase (RdRp) protein of both poliovirus and SARS-CoV-2, thereby preventing SARS-CoV-2 infection. These findings suggest proteins other than “spike” proteins may be suitable targets for immunity and vaccine development.

Production of equine sera as a potential immunotherapy against COVID-19

Emerging viruses such as the COVID-19-inducing virus, SARSCoV- 2, represent a threat to human health, unless effective vaccines, drugs or alternative treatments, such as passive immunization, become accessible. Animal-derived immunoglobulins, such as equine immunoglobulins might be useful as immunoprophylaxis or immunotherapy against this viral disease. Therapeutic antibodies (Abs) for SARS-CoV-2 were obtained from hyperimmune equine plasma using the Spike protein receptor binding domain (RBD) as an immunogen. The presence of anti-RBD antibodies was evaluated by ELISA and the titres of neutralizing antibodies were determined in viral cell culture. Immunized horses generated high-titre of anti-RBD antibodies with antiviral neutralizing activity on Vero-E6 cells of 1/1,000. To minimize potential adverse effects, the immunoglobulins were digested with pepsin, and purified to obtain the F(ab’)2 fragments with the protocol standardized by Biotecfar C.A for the production of snake antivenom. Pre-immune serum displayed an unexpected anti-RBD reactivity by ELISA (titre up to 1/900) and Western Blot, but no angioneutralizing activity. Modelling of the RBD of equine coronavirus showed that some of the known epitopes of SARS-CoV-2 RBD were structurally conserved in the equine coronavirus protein. This might suggest that some of the reactivity observed in the pre-immune serum to the SARS-CoV-2 RBD might be due to a previous exposure to equine coronavirus.

Antibodies Elicited in Response to a Single Cycle Glycoprotein D Deletion Viral Vaccine Candidate Bind C1q and Activate Complement Mediated Neutralization and Cytolysis

Herpes simplex virus (HSV) prevention is a global health priority but, despite decades of research, there is no effective vaccine. Prior efforts focused on generating glycoprotein D (gD) neutralizing antibodies, but clinical trial outcomes were disappointing. The deletion of gD yields a single-cycle candidate vaccine (∆gD-2) that elicits high titer polyantigenic non-gD antibodies that exhibit little complement-independent neutralization but mediate antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Active or passive immunization with ΔgD-2 completely protects mice from lethal disease and latency following challenge with clinical isolates of either serotype. The current studies evaluated the role of complement in vaccine-elicited protection. The immune serum from the ΔgD-2 vaccinated mice exhibited significantly greater C1q binding compared to the serum from the gD protein vaccinated mice with infected cell lysates from either serotype as capture antigens. The C1q-binding antibodies recognized glycoprotein B. This resulted in significantly greater antibody-mediated complement-dependent cytolysis and neutralization. Notably, complete protection was preserved when the ΔgD-2 immune serum was passively transferred into C1q knockout mice, suggesting that ADCC and ADCP are sufficient in mice. We speculate that the polyfunctional responses elicited by ΔgD-2 may prove more effective in preventing HSV, compared to the more restrictive responses elicited by adjuvanted gD protein vaccines.

Poliovirus Vaccination Induces a Humoral Immune Response that Cross Reacts with SARS-CoV-2

Background: Millions have been exposed to SARS-CoV-2, but the severity of resultant infections has varied among adults and children, with adults presenting more serious symptomatic cases. Children may possess an immunity that adults lack, possibly from childhood vaccinations. This retrospective study suggests immunization against the poliovirus may provide an immunity to SARS-CoV-2. Methods: Publicly available data were analyzed for possible correlations between national median ages and epidemiological outbreak patterns across 100 countries. Sera from 204 adults and children, who were immunized with the poliovirus vaccine, were analyzed using an enzyme-linked immunosorbent assay. The effects of polio-immune serum on SARS-CoV-2-induced cytopathology in cell culture were then evaluated. Results: Analyses of median population age demonstrated a positive correlation between median age and SARS-CoV-2 prevalence and death rates. Countries with effective poliovirus immunization protocols and younger populations have fewer and less pathogenic cases of COVID-19. Antibodies to poliovirus and SARS-CoV-2 were found in pediatric sera and in sera from adults recently immunized with polio. Western blot demonstrated antibodies recognized the RNA-dependent-RNA-polymerase (RdRp) of either virus. Sera from polio-immunized individuals inhibited SARS-CoV-2 infection of Vero cell cultures. These results suggest the anti-D3-pol-antibody, induced by poliovirus vaccination, may provide a similar degree of protection from SARS-CoV-2 to adults as to children. Conclusions: Poliovirus vaccination induces an adaptive humoral immune response. Antibodies created by poliovirus vaccination bind the RdRp protein of both poliovirus and SARS-CoV-2, thereby preventing SARS-CoV-2 infection. These findings suggest proteins other than spike proteins may be suitable targets for immunity and vaccine development.