Immunotherapy: ALLOGENEIC UMBILICAL CORD BLOOD REGULATORY T CELLS DECREASE INFLAMMATION AND PRESERVE ANTI-TUMOR ACTIVITY OF CAR T CELLS

Background & Aim: With larger accessibility and increased number of patients being treated with CART cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood derived (UCB) regulatory T cells (Tregs) can resolve uncontrolled inflammation and can treat acute and immune mediated lung injury in a xenogenic model as well as in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Tregs including: i) lack of plasticity when exposed to inflammatory micro-environments;ii) no requirement for HLA matching;iii) long shelf life of cryopreserved Tregs;and iv) immediate product availability for on demand treatment, makes them an attractive source for treating acute inflammatory syndromes. Therefore, we hypothesized that add-on therapy with UCB derived Tregs may resolve uncontrolled inflammation responsible for CART cell therapy associated toxicity. Methods, Results & Conclusion(s): UCB Tregs were added in 1:1 ratio to CART cells, where no interference in their ability to kill CD19+ Raji cells, was detected at different ratios : 8:1 (80.4% vs. 81.5%);4:1 (62.0% vs. 66.2%);2:1 (50.1% vs. 54.7%);1:1 (35.4% vs. 44.1%) (Fig 1A). In a xenogenic B cell lymphoma model, multiple injections of Tregs were administered after CART injection (Fig 1B), which did not impact distribution of CD8+ T effector cells (Fig 1C) or CART cells cells (Fig 1D) in different organs. No decline in the CAR T levels was observed in the Tregs recipients (Fig 1E). Specifically, no difference in tumor burden was detected between the two arms (Fig 2A). No tumor was detected in CART+Tregs in liver (Fig 2B) or bone marrow (Fig 2C). A corresponding decrease in multiple inflammatory cytokines in peripheral blood was observed in CART+Tregs when compared to CART alone (Fig 2D). Here we show "proof of concept" for add-on therapy with Tregs to mitigate hyper-inflammatory state induced by CART cells without interference in their on-target anti-tumor activity. The timing of Tregs administration after CART cells have had sufficient time for forming synapse with tumor cells allows for preservation of their anti-tumor cytotoxicity, such that the infused Tregs home to the areas of tissue damage to bind to the resident antigen presenting cells which in turn collaborate with Tregs to resolve inflammation. Such differential distribution of cells allow for a Treg "cooling blanket" and lays ground for clinical study. [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy

Boosting the Immune System with Vitamin D: Special Focus on Prevention of COVID-19 and Complications

In addition to the classical functions of the musculoskeletal system and calcium homeostasis, the function of vitamin D as an immune modulator is well established. The vitamin D receptors and enzymes that metabolize vitamin D are ubiquitously expressed in most cells in the body, including T and B lymphocytes, antigen-presenting cells, monocytes, macrophages and natural killer cells that trigger immune and antimicrobial responses. Many in vitro and in vivo studies revealed that vitamin D promotes tolerogenic immunological action and immune modulation. Vitamin D adequacy positively influences the expression and release of antimicrobial peptides, such as cathelicidin, defensin, and anti-inflammatory cytokines, and reduces the expression of proinflammatory cytokines. Evidence suggestss that vitamin D's protective immunogenic actions reduce the risk, complications, and death from COVID-19. On the contrary, vitamin D deficiency worsened the clinical outcomes of viral respiratory diseases and the COVID-19-related cytokine storm, acute respiratory distress syndrome, and death. The study revealed the need for more preclinical studies and focused on well-designed clinical trials with adequate sizes to understand the role of vitamin D on the pathophysiology of immune disorders and mechanisms of subduing microbial infections, including COVID-19.Copyright © 2023 Bentham Science Publishers.

Impact of Azithromycin and 8-Hydroxychloroquine in 2019 Novel Coronavirus (COVID-19) Pandemic: A Systematic Review

As we know novel coronavirus is an emergent nuisance in this stipulated period. Corona virus is a group of enveloped viruses, with non-segmented, single stranded & positive sense RNA genomes. Human Corona virus is mainly subdivided into four categories such as 229E, NL63, OC43, HKU1. Epidemiologically it has a greater prevalence in the modern era. The features encountered in the clinical course of the disease are multifarious spanning from cough, sneezing, fever, breathlessness. It may take 2-14 days for a person to notice symptoms after infection. Azithromycin and 8 Hydroxychloroquine both plays an instrumental role for management of COVID-19. Azithromycin is a macrolide antibiotic and it binds with a 50s ribosome then inhibits bacterial protein synthesis. On the other hand 8-Hydroxychloroquine was approved by United State in the year of 1955 .Basically it is used as a antimalarial drugs . Briefly, in inflammatory conditions it binds with toll like receptor & blocks them. 8- hydroxychloroquine increases lysosomal pH in antigen presenting cells . In inflammatory conditions it blocks toll like receptors on plasmacytoid dendritic cells. In our review we focused on the role of Azithromycin, and 8-hydroxychloroquine in Covid-19 .Copyright © 2021 International Journal of Pharma and Bio Sciences. All rights reserved.

A multiscale mechanistic model of human dendritic cells for in-silico investigation of immune responses and novel therapeutics discovery.

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) with the unique ability to mediate inflammatory responses of the immune system. Given the critical role of DCs in shaping immunity, they present an attractive avenue as a therapeutic target to program the immune system and reverse immune disease disorders. To ensure appropriate immune response, DCs utilize intricate and complex molecular and cellular interactions that converge into a seamless phenotype. Computational models open novel frontiers in research by integrating large-scale interaction to interrogate the influence of complex biological behavior across scales. The ability to model large biological networks will likely pave the way to understanding any complex system in more approachable ways. We developed a logical and predictive model of DC function that integrates the heterogeneity of DCs population, APC function, and cell-cell interaction, spanning molecular to population levels. Our logical model consists of 281 components that connect environmental stimuli with various layers of the cell compartments, including the plasma membrane, cytoplasm, and nucleus to represent the dynamic processes within and outside the DC, such as signaling pathways and cell-cell interactions. We also provided three sample use cases to apply the model in the context of studying cell dynamics and disease environments. First, we characterized the DC response to Sars-CoV-2 and influenza co-infection by in-silico experiments and analyzed the activity level of 107 molecules that play a role in this co-infection. The second example presents simulations to predict the crosstalk between DCs and T cells in a cancer microenvironment. Finally, for the third example, we used the Kyoto Encyclopedia of Genes and Genomes enrichment analysis against the model's components to identify 45 diseases and 24 molecular pathways that the DC model can address. This study presents a resource to decode the complex dynamics underlying DC-derived APC communication and provides a platform for researchers to perform in-silico experiments on human DC for vaccine design, drug discovery, and immunotherapies.

Impact Of Plant Based Vaccines On Covid-19

Human life has always been under a constant threat to emerging deadly viruses, Covid-19 is the newest. This deadliest virus become pandemic within a short span of time and brought great amount of concern to fight against it and overcome dynamic challenges. It demands the speedy manufacture of vaccines and drugs at the industrial level. A conventional vaccine is effective but has risk of being infected with foreign agents;to overcome this problem plant based vaccine is superior alternative. The VLPs are generated by recombinant technology and consumed orally and functionally plant cell distributes the antigen. The process consumes time, cost effective, easily conveyed and mucosal immunity induction. Benefit of plant counteract, they are free from any corruption and has minute risk of anomalous responses. VLPs are more stable than conventional vaccines and have immense potential to treat diseases. It contains few bioethical issues, such as transferring of allergens to humans. It requires the safe sites and skilled staff for the smooth administration of operations. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Novel checkpoint modifier lowers T cell activation threshold and enhances and broadens vaccine-induced responses to chronic viral infections

Background. Vaccines aim to induce immune responses that prevent disease. They may also clear chronic infections or reduce tumor progression. Vaccine adjuvants augment immune responses, in general, by providing stimulatory signals. Our focus has been on a different type of adjuvant that enhances vaccine-induced T cell responses by modulating the herpes virus entry mediator (HVEM) pathway. The B and T cell attenuator (BTLA) is expressed on naive T cells and, upon binding to HVEM on antigen presenting cells, dampens signaling through the T cell receptor. HVEM binds with a different domain to the co-stimulator LIGHT. Within a trimolar BTLA-LIGHT/HVEM complex, inhibition prevails. Herpes simplex virus (HSV-1) glycoprotein D (gD) attaches to the BTLA binding site of HVEM and as it has higher binding affinity outcompetes BTLA binding and allows for co-stimulation through LIGHT. This results in enhanced signaling through the T cell receptor and thereby augments and broadens CD8+ T cell responses as we showed with chimpanzee adenovirus (AdC) vector vaccines for several viral antigens. Methods. Immunogenicity in rodents was evaluated following one or two immunizations with AdC vectors expressing antigens of HIV (gag), HPV-16 (E7/6/5), HBV (core & pol), influenza virus (nucleoprotein) and SARS-CoV2 (nucleoprotein), with or without gD. Vaccine-induced CD8+ T cell responses, including their magnitude, functions, duration, and breadth were characterized. Vaccine efficacy was also evaluated. Results. Vaccination with gD-antigen fusion proteins increased CD8+ T cell frequencies to all of the antigens tested (Fig) and improved efficacy. Addition of gD increased stimulation of CD8+ T cells to subdominant epitopes and thereby enhanced breadth of responses. Conclusion. Checkpoint modification of the HVEM pathway with a gD-antigen fusion protein produces potent, prolonged, and broad responses of CD8+ T cells to immunodominant and subdominant epitopes. The latter is especially important for chronic viral infections, where, due to exhaustion of T cells to dominant epitopes therapeutic efficacy of vaccines may rely on expansion of T cells to subdominant epitopes. Clinical studies to evaluate therapeutic vaccination for chronic HBV are planned. (Figure Presented).

Downregulation of the Protein C Signaling System Is Associated with COVID-19 Hypercoagulability-A Single-Cell Transcriptomics Analysis.

Because of the interface between coagulation and the immune response, it is expected that COVID-19-associated coagulopathy occurs via activated protein C signaling. The objective was to explore putative changes in the expression of the protein C signaling network in the liver, peripheral blood mononuclear cells, and nasal epithelium of patients with COVID-19. Single-cell RNA-sequencing data from patients with COVID-19 and healthy subjects were obtained from the COVID-19 Cell Atlas database. A functional protein-protein interaction network was constructed for the protein C gene. Patients with COVID-19 showed downregulation of protein C and components of the downstream protein C signaling cascade. The percentage of hepatocytes expressing protein C was lower. Part of the liver cell clusters expressing protein C presented increased expression of ACE2. In PBMC, there was increased ACE2, inflammatory, and pro-coagulation transcripts. In the nasal epithelium, PROC, ACE2, and PROS1 were expressed by the ciliated cell cluster, revealing co-expression of ACE-2 with transcripts encoding proteins belonging to the coagulation and immune system interface. Finally, there was upregulation of coagulation factor 3 transcript in the liver and PBMC. Protein C could play a mechanistic role in the hypercoagulability syndrome affecting patients with severe COVID-19.

The Mosaic of Autoimmunity

Introduction: Lupus nephritis (LN) is one of the most common manifestations affecting 45% of patients with systemic lupus erythematosus (SLE). Here we present a case of rapid progression of LN in the setting of recent COVID-19 infection, suggesting a possible synergistic cascade of cytokines contributing to rapid disease flare up. Case Description: 52-year-old hispanic lady with past medical history of hypertension and newly diagnosed SLE presented to the clinic with chief complaint of generalized anasarca, fatigue and low back ache. She was found to have a hemoglobin of 8.8 along with severe leukopenia. Urinalysis was positive for large amount of blood, protein with a protein: creatinine ratio of 9 gm. ANA titer was positive along with low levels of C3 complement and normal levels of C4 complement. Creatinine of 2.3 which was 4 times higher than her baseline. Labs from 2 months ago showed creatinine of 0.57. Of note, the patient was diagnosed with COVID-19 a month ago. She had a renal biopsy and was diagnosed with stage IV LN and was started on dialysis. Discussion(s): LN usually has an indolent course with people developing ESRD within 5 years of diagnosis of lupus. This case strikes out as a rapid progression of LN with progression to ESRD within less than 3 months of diagnosis of SLE. COVID-19 a few months before she was diagnosed with Lupus is a possible source of a cytokine storm. Suggested mechanisms of induction of autoimmunity include both molecular mimicry as well as bystander activation whereby the infection may lead to activation of antigen presenting cells that may in turn activate pre-primed auto-reactive T-cells, thus leading to pro-inflammatory mediators, which in turn may lead to tissue damage. Strategies to prevent rapid progression to ESRD in these patients needs to be studied and better understood. Perhaps patients with autoimmune conditions like SLE need more robust management of diseases like COVID-19 which is known to alter and activate the immunological cascade. As per recent literature exaggerated extrafollicular B cell response characteristic of active SLE also characterizes the B cell response to COVID-19. Understanding and targeting the B cell pathway could potentially help dampen a severe response and disease progression. Overlap including racial preponderance of disease severity also needs to be studied further.

Association of Vitamin D with Coronavirus Disease 2019 (Covid-19): A Review

Nutrition is essential for the function of the immune system and this relationship is currently being studied. In particular, vitamin D is a crucial immunonutrient that can also be obtained through the diet. Although the primary function of vitamin D appears to be calcium homeostasis, this vitamin also serves for immunomodulatory functions. The link between vitamin D deficiency and susceptibility to infections originated more than a century ago when vitamin D was used for the treatment of tuberculosis. The importance of vitamin D in cases of respiratory infection is supported by the fact that low levels of vitamin D are common in populations and low levels have been associated with a significantly increased risk of pneumonia. Vitamin D supplementation can improve innate immunity as well as adaptive immunity. The rapid global spread of COVID-19 has renewed interest in the possible role of vitamin D in modulating the immune response to respiratory infections. Copyright © 2021, SILAE (Italo-Latin American Society of Ethnomedicine). All rights reserved.

MECHANISMS OF FORMATION OF HYBRID IMMUNITY IN PEOPLE WHO RECOVERED FROM COVID-19 AND WERE VACCINATED WITH SARS-CoV-2 PEPTIDE ANTIGENS

The relevance of the current epidemic situation of a new coronavirus infection is determined by new strains of the virus and the registration of cases of re-infection in COVID-19 survivors earlier. In this regard, the questions about the expediency and nature of vaccination of those who have been ill attract close attention, moreover it has affected the formation of the concept of “hybrid immunity”. The aim of this study was to analyze changes in the parameters of the immune system, reflecting their regulatory and functional potential, in response to the introduction of the peptide vaccine EpiVacCorona to persons who have suffered from the new coronavirus infection. To study the features of the formation of hybrid immunity, a retrospective analysis of the observation of 43 study participants was carried out. The inclusion criteria were data confirming COVID-19 in mild and moderate forms of the course in the period from six months to a year ago, a low level or absence of antibodies to the nucleocapsid protein SARS-CoV-2, a negative PCR result for the presence of the SARS-CoV-2 virus, the absence of comorbid pathology. The subpopulation composition, regulatory and functional potential of the immune system were determined by flow cytofluorimetry using a set of monoclonal antibodies corresponding to the goals. 21 days after the administration of a single dose of EpiVacCorona, antibodies to the vaccine peptide antigens were registered in all study participants at the highest coefficient of positivity values for the SARS-CoV-2-IgG-Vector test system used. In addition, there was a fourfold increase in the number of specific IgG to the N protein. A specific immune response to recombinant SARS-CoV-2 antigens was accompanied by a decrease in the circulation of the number of monocytes expressing TLR4, T helper cells expressing the interaction coreceptor with antigen-presenting cells, unconnected B memory with an increase in the number of B lymphocytes expressing the CD40 T-B coreceptor interaction molecule. The remaining differences in the functioning of the immune system identified in patients with COVID-19 before the vaccination in comparison with the control data have not changed. The differences consist in a decrease in the proportion of monocytes expressing HLA-DR, an increase in the expression of interaction molecules on T and B lymphocytes, an increase in the number of Treg, B1 cells, activated B lymphocytes with a decrease in the proportion of suppressor Breg and B memory. The totality of the presented data demonstrates that the COVID-19 infection that preceded vaccination in mild and moderate clinical course contributes to the formation of immunological memory, which made it possible to form a secondary immune response even to a single injection of peptide antigens of the virus.

Mixing NA variants in an antigen presenting cell-targeted DNA vaccine elicits cross-reactive influenza antibody responses

Vaccination is a successful tool against influenza. However, antigenic drift of the virus requires an annual update of the vaccine. A universal vaccine approach which can elicit immune responses reactive to ideally all seasonal as well as zoonotic influenza strains is urgently needed. To explore this we used a flexible DNA vaccine platform, increasing immunogenicity by targeting dimeric vaccine molecules to antigen-presenting cells (APCs). We hypothesize that when including multiple antigen variants from different influenza strains in one heterodimeric APC-targeted mix DNA vaccine, antibody responses can be focused on conserved epitopes which are shared between the different variants. Neuraminidase (NA) is the second most abundant surface protein on the influenza virus after hemagglutinin and has been established as an independent correlate of protection. We have previously shown that an APC-targeted DNA vaccine with NA induced highly protective antibody responses. NA is divided into 9 different subtypes (N1-N9), and two NA-like antigens in bats (N10 and N11). Here, we created a NA mix vaccine which successfully expressed heterodimeric vaccine molecules with 8 different NA variants (N2-N9) that were targeted to MHC class II on APCs. Upon intramuscular DNA immunization and electroporation in mice, the NA mix vaccine induced cross-reactive antibody responses towards N1, which was not included in the vaccine. The NA mix approach has the potential to fill knowledge gaps about NA immunity and would be a great advancement in universal vaccine design for influenza as well as for other emerging and rapidly changing viruses. WS5.4 ;SARS-CoV- 2- specific T cell responses to COVID-19 BNT162b2 vaccination in chronic lymphocytic leukaemia patients Lisa Blixt1,2;David Wullimann2;Soo Aleman1,2;Jeanette Lundin1,2;Puran Chen2;Yu Gao2;Angelica Cuapio2;Mira Akber2;Joshua Lange2;Olga Rivera-Ballesteros2;Marcus Buggert2;Hans-Gustaf Ljunggren2;Anders Hansson;Lotta1,2;Österborg1,2 1Karolinska University Hospital;Stockholm, Sweden;2Karolinska Institutet, Stockholm, Sweden Immunocompromised patients have an increased risk for severe disease and mortality from viral infection. Importantly, disease and treatment reduce humoral and cellular immune responses to vaccination, which offer the best protection from severe COVID-19 disease during the ongoing pandemic. We recently reported from a prospective clinical trial that BNT162b2 vaccination in different immunodeficient groups had significantly lower SARS-CoV- 2- specific antibody titers compared to healthy controls. The seroconversion rate observed was 63% in chronic lymphocytic leukaemia (CLL) patients, with a negative impact of ibrutinib treatment. Whether T cells in the absence of sufficient levels of SARS-CoV- 2- specific antibody titers can confer immunity after BNT162b2 vaccination remains unclear. We measured reactive SARS-CoV- 2- specific T cell responses in uninfected (naive) and previously infected CLL patients following BNT162b2 vaccination. Out of 52 naive CLL patients, 12 (29%) had a specific IFN-γ T cell response compared to 24/41 (59%) in controls after two doses. In previously infected CLL patients, mainly spike-specific CD8 T cells expanded after the third dose, at which 11/12 (92%) had detectable responses, and all 12 (100%) had spike-specific CD4 T cell responses. Relative to the Wuhan reference strain (wild-type) variant, the median reduction of antigen-specific CD8 and CD4 T cells to the B.1.1.529 (Omicron) variant were 51% and 13%, respectively. Collectively, these data indicate that CLL patients respond with T-cells specific to SARS-CoV- 2 spike protein after BNT162b2 vaccination or infection. The increased T-cell response rate after the third dose and ability to recognize the Omicron variant of concern demonstrates the importance of a booster dose in this patient group.

Management of COVID-19-A Review

Coronavirus disease-2019 (COVID-19) has gained much popularity not only in the Wuhan city of China but internationally also;in January 2020, the corona rapidly spread to many countries like the USA, Italy, Russia, India, Singapore, Pakistan, Thailand, Canada, Australia, England, and so on through passengers traveling to other countries. Corona patients can be cured with synthetic drugs, traditional herbal medicines (THM), use of Vitamin D and the quarantine approach. Different allopathic medicines, herbal extracts, and vitamin D have been observed to be useful in the treatment of novel coronavirus, like Remdesivir, hydroxychloroquine, Teicoplanin, Lopinavir+ Ritonavir, Ribavirin + corticosteroids, Glycyrrhizin, Sanguisorbae radix, Acanthopanacis cortex, Sophorae radix, etc. Various antiviral drugs are used to treat COVID-19, alone or in combination with other medications like Interferon-α, Lopinavir + Ritonavir, Arbidol, corticosteroids, etc., and some herbal extracts;also quarantine approach and Vitamin D are used that not only cure the infection but also boost up our immunity. For this review article, different papers were searched on Google Scholar, Scopus, WHO’s website, PubMed, clinicaltrials.gov and other relevant scientific research websites. In this review article, we have discussed the current strategies that are being used to treat COVID-19. Along with allopathic drugs, some herbal extracts can also be used to treat this novel coronavirus, like Glycyrrhizin, Sanguisorbae radix, Acanthopanacis cortex, Sophorae radix, etc. and even vitamin D.

Dysregulated Immune Responses in SARS-CoV-2-Infected Patients: A Comprehensive Overview.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in humans more than two years ago and caused an unprecedented socio-economic burden on all countries around the world. Since then, numerous studies have attempted to identify various mechanisms involved in the alterations of innate and adaptive immunity in COVID-19 patients, with the ultimate goal of finding ways to correct pathological changes and improve disease outcomes. State-of-the-art research methods made it possible to establish precise molecular mechanisms which the new virus uses to trigger multisystem inflammatory syndrome and evade host antiviral immune responses. In this review, we present a comprehensive analysis of published data that provide insight into pathological changes in T and B cell subsets and their phenotypes, accompanying the acute phase of the SARS-CoV-2 infection. This knowledge might help reveal new biomarkers that can be utilized to recognize case severity early as well as to provide additional objective information on the effective formation of SARS-CoV-2-specific immunity and predict long-term complications of COVID-19, including a large variety of symptoms termed the 'post-COVID-19 syndrome'.

mRNA as a Therapeutics: Understanding mRNA Vaccines.

Vaccination is one of the important approaches in the prevention and control of diseases. Although the capacity to present antigens other than the disease-specific antigen in the traditional vaccine composition provides a potential benefit by increasing its protective efficacy, many components that are not needed for the related disease are also transferred. These components can reduce vaccine activity by lowering immunity against protective antigens. The reasons such as the low effectiveness of traditional vaccines and the high cost of production and time-consuming reasons show that it is necessary to develop a new vaccine method for our world, which is struggling with epidemics almost every year. Among nucleic acids, mRNA has many advantages, such as genomic integration, induction of anti-DNA autoantibodies, and immune tolerance induced by long-term antigen expression. mRNA vaccines have become a therapeutic target for reasons such as efficacy, safety, fast and non-expensive production. The fact that mRNA triggers both humoral and cellular immunity and goes only to the cytoplasm, not to the nucleus, makes it highly efficient. The mRNA must cross the lipid bilayer barrier and entry to the cytoplasm where it is translated into protein. There are two main ways of mRNA vaccine delivery for this: ex vivo loading of mRNA into dendritic cells (DCs) and direct injection of mRNA with or without a carrier. Studies continue to understand which delivery system is therapeutically more efficient. Preclinical and clinical trials showed that mRNA vaccines trigger a long-lasting and safe immune response.

The role of antigen-presenting cells in the pathogenesis of COVID-19.

Coronavirus Disease 2019 (COVID-19) is one of the three lethal coronavirus outbreaks in the recent two decades and a serious threat to global health all over the world. The principal feature of the COVID-19 infection is the so-called "cytokine storm" exaggerated molecular response to virus distribution, which plays massive tissue and organ injury roles. Immunological treatments, including monoclonal antibodies and vaccines, have been suggested as the main approaches in treating and preventing this disease. Therefore, a proper investigation of the roles of antigen-presenting cells (APCs) in the aforementioned immunological responses appears essential. The present review will provide detailed information about APCs' role in the infection and pathogenesis of SARS-CoV-2 and the effect of monoclonal antibodies in diagnosis and treatment.

Plant viral nanoparticle-based adjuvants for cancer immunotherapy and COVID-19 vaccines

Plant virus nanoparticles are recognized as a platform technology for potential applications in nanomedicine. While non-infectious toward mammals, many plant virus nanoparticles are recognized by the immune system and act as potent adjuvants, both in the classical setting of vaccination and cancer immunotherapy. In the context of cancer immunotherapy, we have demonstrated potent efficacy of plant virus, particularly cowpea mosaic virus (CPMV) when applied intratumorally;CPMV signals through and activates multiple toll-like receptors, which primes a potent innate immune activation leading to reprogramming of the tumor microenvironment from an immunosuppressed to immune-activated state. Data in mouse models of melanoma, colon cancer, ovarian cancer, glioma, and breast cancer demonstrate potent efficacy through priming of the innate immune system leading to adaptive and systemic anti-tumor immunity and most importantly immune memory. Efficacy was also replicated in canine patients with melanoma. Given the promise of the plant virus nanotechnology as an adjuvant for cancer immunotherapy, we also have begun to utilize the technology as a vaccination platform for the generation of COVID-19 vaccine candidates. We formulated multivalent COVID-19 vaccine candidates using plant virus nanoparticles displaying SARS-CoV-2 S protein peptide B cell epitopes. The plant virus nanoparticle confers efficient lymphatic trafficking and targeting of antigen-presenting cells;the adjuvant properties of the nanotechnology lead to robust antibody levels against the target, S protein. While other vaccine candidates have advanced through clinical testing, our approach has unique advantages: The high thermal and pH stability of the plant virus nanotechnology alleviates cold chain requirements;further, the stability of the platform technology enables its integration into vaccine delivery devices such as microneedle patches that can be shipped globally and be self-administered. In this presentation, we will discuss our data on the cancer immunotherapy and highlight the potential to pivot the technology for infectious disease vaccines with unique attributes.

Classical Antigen Presenting Cell Activation Correlates with T Cell Immunity and COVID-19 Severity

Background. The initial response of immune cells against respiratory viruses often determines the severity and duration of disease. The early trajectory of the immune response during infection with SARS-CoV-2 remains poorly understood. Dysregulation of innate immune factors that facilitate viral clearance and the adaptive response, such as type I interferons, have been implicated in severe COVID-19. However, collection of biological samples during the first seven days post-symptom onset has posed a logistical challenge, limiting our knowledge surrounding the immune responses that drive protection versus immunopathology. Methods. From March 2020, Military Health System beneficiaries presenting with a positive SARS-CoV-2 test, a COVID-19 like illness, or a high-risk SARS-CoV-2 exposure at nine military medical treatment facilities across the United States were eligible for enrollment in our longitudinal cohort study, which included collection of respiratory sample, sera, plasma, and peripheral blood mononuclear cells (PBMCs). Twenty-five SARS-CoV-2 infected study participants provided samples with in the first seven days of symptom onset, fifteen of whom were hospitalized with COVID-19. We employed multiparameter spectral flow cytometry to comprehensively analyze the early trajectory of the innate and adaptive immune responses. Results. We discovered that early activation of critical antigen presenting cell subsets was impaired upon comparing inpatients with outpatients, correlating with decreased antigen-experienced T cell responses. Specifically, we noted reduced expression of key costimulatory molecules, CD80 and CD86, on conventional dendritic cells that are required for viral antigen-specific T cell priming. Reduction in CD38, a marker of activation was also observed on inpatient dendritic cell subsets. Conclusion. Reduced antigen presenting cell activation and expression of ligands that facilitate T cell engagement may impede the efficient clearance of SARS-CoV-2, coinciding with more severe disease in our cohort. Further analysis of the functional activation of early innate immune responses triggered by SARS-CoV-2 may unveil new immune biomarkers and therapeutic targets to predict and prevent severe disease associated with inadequate T cell immunity.

[Exploration of vaccine immunogenicity]. / L'exploration de l'immunogénicité vaccinale.

The development of new vaccines has traditionally been a long-term job, although recent experience with the emergence of Covid-19 has caused development and production delays to skyrocket. The fact remains that the development of vaccines in the preclinical phases and in phases 1 and 2 of clinical development is based on the study of the specific immune response of the adaptive immune system.

Pulmonary vaccine delivery: An emerging strategy for vaccination and immunotherapy

Vaccination has been known as the most successful health strategy for the prevention of infectious diseases, and their subsequent disability conditions. Conventional vaccination is based on parenteral administration and therefore requires needles, cold-chain storage and distribution. To meet these drawbacks, new strategies such as pulmonary vaccination have brought new insights into immunotherapy and vaccination. Among novel strategies, nanoparticulate vaccine delivery systems play an undeniable role in targeting and depositing of antigenic (nano-)microparticles in particular regions of the respiratory tract, engineering the inhalable powders, altering the release profile and pharmacokinetic features of vaccines. This study aims to review pulmonary immune system, pulmonary vaccine delivery, micro and nanocarriers for pulmonary vaccine delivery, and nanotechnology-based pulmonary vaccines.