Analysis of cell-mediated immune responses in support of dengue vaccine development efforts

ABSTRACT Dengue virus infections can cause hemorrhagic fever, shock, encephalitis, and even death. Worldwide, approximately 2.5 billion people live in dengue-infested regions with about 100 million new cases each year, although many of these infections are believed to be silent. There are four antigenically distinct serotypes of dengue virus; thus, immunity from one serotype will not cross-protect from infection with the other three. The difficulties that hamper vaccine development include requirements of the natural conformation of the envelope glycoprotein to induce neutralizing immune responses and the necessity of presenting antigens of all four serotypes. Currently, the only way to meet these requirements is to use a mixture of four serotypes of live attenuated dengue viruses, but safety remains a major problem. In this study, we have developed the basis for a tetravalent dengue vaccine using a novel complex adenovirus platform that is capable of expressing multiple antigens de novo. This dengue vaccine is constructed as a pair of vectors that each expresses the premembrane and envelope genes of two different dengue virus serotypes. Upon vaccination, the vaccine expressed high levels of the dengue virus antigens in cells to mimic a natural infection and induced both humoral and cellular immune responses against multiple serotypes of dengue virus in an animal model. Further analyses show the humoral responses were indeed neutralizing against all four serotypes. Our studies demonstrate the concept of mimicking infections to induce immune responses by synthesizing dengue virus membrane antigens de novo and the feasibility of developing an effective tetravalent dengue vaccine by vector-mediated expression of glycoproteins of the four serotypes.

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Principles and Challenges in anti-COVID-19 Vaccine Development

International Archives of Allergy and Immunology ◽

10.1159/000514225 ◽

2021 ◽

pp. 1-11

Author(s):

Zuzana Strizova ◽

Jitka Smetanova ◽

Jirina Bartunkova ◽

Tomas Milota

Keyword(s):

Clinical Trials ◽

Immune Responses ◽

Vaccine Development ◽

Viral Vector ◽

Health It ◽

Therapeutic Approaches ◽

Clinical Phase ◽

Adaptive Immune ◽

Limited Efficacy ◽

Safe Vaccine

The number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients keeps rising in most of the European countries despite the pandemic precaution measures. The current antiviral and anti-inflammatory therapeutic approaches are only supportive, have limited efficacy, and the prevention in reducing the transmission of SARS-CoV-2 virus is the best hope for public health. It is presumed that an effective vaccination against SARS-CoV-2 infection could mobilize the innate and adaptive immune responses and provide a protection against severe forms of coronavirus disease 2019 (COVID-19) disease. As the race for the effective and safe vaccine has begun, different strategies were introduced. To date, viral vector-based vaccines, genetic vaccines, attenuated vaccines, and protein-based vaccines are the major vaccine types tested in the clinical trials. Over 80 clinical trials have been initiated; however, only 18 vaccines have reached the clinical phase II/III or III, and 4 vaccine candidates are under consideration or have been approved for the use so far. In addition, the protective effect of the off-target vaccines, such as <i>Bacillus</i> Calmette-Guérin and measles vaccine, is being explored in randomized prospective clinical trials with SARS-CoV-2-infected patients. In this review, we discuss the most promising anti-COVID-19 vaccine clinical trials and different vaccination strategies in order to provide more clarity into the ongoing clinical trials.

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COVID-19: Mechanisms of Vaccination and Immunity

Vaccines ◽

10.3390/vaccines8030404 ◽

2020 ◽

Vol 8 (3) ◽

pp. 404 ◽

Cited By ~ 1

Author(s):

Daniel E. Speiser ◽

Martin F. Bachmann

Keyword(s):

Immune Responses ◽

Clinical Management ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Public Life ◽

High Affinity ◽

Vaccination Strategies ◽

Detailed Evaluation ◽

Pros And Cons

Vaccines are needed to protect from SARS-CoV-2, the virus causing COVID-19. Vaccines that induce large quantities of high affinity virus-neutralizing antibodies may optimally prevent infection and avoid unfavorable effects. Vaccination trials require precise clinical management, complemented with detailed evaluation of safety and immune responses. Here, we review the pros and cons of available vaccine platforms and options to accelerate vaccine development towards the safe immunization of the world’s population against SARS-CoV-2. Favorable vaccines, used in well-designed vaccination strategies, may be critical for limiting harm and promoting trust and a long-term return to normal public life and economy.

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Porcine Reproductive and Respiratory Syndrome Virus: Immune Escape and Application of Reverse Genetics in Attenuated Live Vaccine Development

Vaccines ◽

10.3390/vaccines9050480 ◽

2021 ◽

Vol 9 (5) ◽

pp. 480

Author(s):

Honglei Wang ◽

Yangyang Xu ◽

Wenhai Feng

Keyword(s):

Immune Responses ◽

Reverse Genetics ◽

Vaccine Development ◽

Immune Escape ◽

Rna Virus ◽

Economic Losses ◽

Respiratory Syndrome Virus ◽

Live Vaccines ◽

Host Immune Responses ◽

Inactivated Vaccines

Porcine reproductive and respiratory syndrome virus (PRRSV), an RNA virus widely prevalent in pigs, results in significant economic losses worldwide. PRRSV can escape from the host immune response in several processes. Vaccines, including modified live vaccines and inactivated vaccines, are the best available countermeasures against PRRSV infection. However, challenges still exist as the vaccines are not able to induce broad protection. The reason lies in several facts, mainly the variability of PRRSV and the complexity of the interaction between PRRSV and host immune responses, and overcoming these obstacles will require more exploration. Many novel strategies have been proposed to construct more effective vaccines against this evolving and smart virus. In this review, we will describe the mechanisms of how PRRSV induces weak and delayed immune responses, the current vaccines of PRRSV, and the strategies to develop modified live vaccines using reverse genetics systems.

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Bacterial Flagellar Filament: A Supramolecular Multifunctional Nanostructure

International Journal of Molecular Sciences ◽

10.3390/ijms22147521 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7521

Author(s):

Marko Nedeljković ◽

Diego Emiliano Sastre ◽

Eric John Sundberg

Keyword(s):

Immune Responses ◽

Basal Body ◽

Vaccine Development ◽

Bacterial Species ◽

High Variability ◽

Bacterial Survival ◽

Bacterial Flagellum ◽

Capping Proteins ◽

Flagellar Filament ◽

Flagellar Assembly

The bacterial flagellum is a complex and dynamic nanomachine that propels bacteria through liquids. It consists of a basal body, a hook, and a long filament. The flagellar filament is composed of thousands of copies of the protein flagellin (FliC) arranged helically and ending with a filament cap composed of an oligomer of the protein FliD. The overall structure of the filament core is preserved across bacterial species, while the outer domains exhibit high variability, and in some cases are even completely absent. Flagellar assembly is a complex and energetically costly process triggered by environmental stimuli and, accordingly, highly regulated on transcriptional, translational and post-translational levels. Apart from its role in locomotion, the filament is critically important in several other aspects of bacterial survival, reproduction and pathogenicity, such as adhesion to surfaces, secretion of virulence factors and formation of biofilms. Additionally, due to its ability to provoke potent immune responses, flagellins have a role as adjuvants in vaccine development. In this review, we summarize the latest knowledge on the structure of flagellins, capping proteins and filaments, as well as their regulation and role during the colonization and infection of the host.

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Overview of Plant-Derived Vaccine Antigens: Dengue Virus

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3401k ◽

2011 ◽

Vol 14 (3) ◽

pp. 400 ◽

Cited By ~ 7

Author(s):

Ravindra B Malabadi ◽

Advaita Ganguly ◽

Jaime A Teixeira da Silva ◽

Archana Parashar ◽

Mavanur R Suresh ◽

...

Keyword(s):

Infectious Diseases ◽

Dengue Virus ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Low Cost ◽

Current Status ◽

Human Immune Deficiency Virus ◽

Dengue Vaccine ◽

New Methods ◽

Vaccine Antigens

ABSTRACT - This review highlights the advantages and current status of plant-derived vaccine development with special reference to the dengue virus. There are numerous problems involved in dengue vaccine development, and there is no vaccine against all four dengue serotypes. Dengue vaccine development using traditional approaches has not been satisfactory in terms of inducing neutralizing antibodies. Recently, these issues were addressed by showing a very good response to inducing neutralizing antibodies by plant-derived dengue vaccine antigens. This indicates the feasibility of using plant-derived vaccine antigens as a low-cost method to combat dengue and other infectious diseases. The application of new methods and strategies such as dendritic cell targeting in cancer therapy, severe acute respiratory syndrome, tuberculosis, human immune deficiency virus, and malaria might play an important role. These new methods are more efficient than traditional protocols. It is expected that in the near future, plant-derived vaccine antigens or antibodies will play an important role in the control of human infectious diseases. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Recent Advances in Nanovaccines Using Biomimetic Immunomodulatory Materials

Pharmaceutics ◽

10.3390/pharmaceutics11100534 ◽

2019 ◽

Vol 11 (10) ◽

pp. 534 ◽

Cited By ~ 12

Author(s):

Vijayan ◽

Mohapatra ◽

Uthaman ◽

Park

Keyword(s):

Immune Responses ◽

Targeted Delivery ◽

Vaccine Development ◽

Polymeric Nanoparticles ◽

Vital Role ◽

Effective Control ◽

Therapeutic Vaccines ◽

Hiv Therapy ◽

Recent Advances ◽

Wide Range

The development of vaccines plays a vital role in the effective control of several fatal diseases. However, effective prophylactic and therapeutic vaccines have yet to be developed for completely curing deadly diseases, such as cancer, malaria, HIV, and serious microbial infections. Thus, suitable vaccine candidates need to be designed to elicit appropriate immune responses. Nanotechnology has been found to play a unique role in the design of vaccines, providing them with enhanced specificity and potency. Nano-scaled materials, such as virus-like particles, liposomes, polymeric nanoparticles (NPs), and protein NPs, have received considerable attention over the past decade as potential carriers for the delivery of vaccine antigens and adjuvants, due to their beneficial advantages, like improved antigen stability, targeted delivery, and long-time release, for which antigens/adjuvants are either encapsulated within, or decorated on, the NP surface. Flexibility in the design of nanomedicine allows for the programming of immune responses, thereby addressing the many challenges encountered in vaccine development. Biomimetic NPs have emerged as innovative natural mimicking biosystems that can be used for a wide range of biomedical applications. In this review, we discuss the recent advances in biomimetic nanovaccines, and their use in anti-bacterial therapy, anti-HIV therapy, anti-malarial therapy, anti-melittin therapy, and anti-tumor immunity.

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A Combined Adjuvant TF–Al Consisting of TFPR1 and Aluminum Hydroxide Augments Strong Humoral and Cellular Immune Responses in Both C57BL/6 and BALB/c Mice

Vaccines ◽

10.3390/vaccines9121408 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1408

Author(s):

Qiao Li ◽

Zhihua Liu ◽

Yi Liu ◽

Chen Liang ◽

Jiayi Shu ◽

...

Keyword(s):

Immune Responses ◽

Vaccine Development ◽

Inbred Mouse ◽

Effective Vaccine ◽

Mouse Strains ◽

Cellular Immune Responses ◽

Recombinant Hbsag ◽

Cellular Immune

TFPR1 is a novel adjuvant for protein and peptide antigens, which has been demonstrated in BALB/c mice in our previous studies; however, its adjuvanticity in mice with different genetic backgrounds remains unknown, and its adjuvanticity needs to be improved to fit the requirements for various vaccines. In this study, we first compared the adjuvanticity of TFPR1 in two commonly used inbred mouse strains, BALB/c and C57BL/6 mice, in vitro and in vivo, and demonstrated that TFPR1 activated TLR2 to exert its immune activity in vivo. Next, to prove the feasibility of TFPR1 acting as a major component of combined adjuvants, we prepared a combined adjuvant, TF–Al, by formulating TFPR1 and alum at a certain ratio and compared its adjuvanticity with that of TFPR1 and alum alone using OVA and recombinant HBsAg as model antigens in both BALB/c and C57BL/6 mice. Results showed that TFPR1 acts as an effective vaccine adjuvant in both BALB/c mice and C57BL/6 mice, and further demonstrated the role of TLR2 in the adjuvanticity of TFPR1 in vivo. In addition, we obtained a novel combined adjuvant, TF–Al, based on TFPR1, which can augment antibody and cellular immune responses in mice with different genetic backgrounds, suggesting its promise for vaccine development in the future.

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A Systems Biology Approach Identifies B Cell Maturation Antigen (BCMA) as a Biomarker Reflecting Oral Vaccine Induced IgA Antibody Responses in Humans

Frontiers in Immunology ◽

10.3389/fimmu.2021.647873 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lynda Mottram ◽

Anna Lundgren ◽

Ann-Mari Svennerholm ◽

Susannah Leach

Keyword(s):

Systems Biology ◽

Immune Responses ◽

B Cell ◽

Vaccine Development ◽

Oral Vaccine ◽

Antibody Responses ◽

Cell Maturation ◽

Antigen Specificity ◽

B Cell Maturation ◽

B Cell Maturation Antigen

Vaccines against enteric diseases could improve global health. Despite this, only a few oral vaccines are currently available for human use. One way to facilitate such vaccine development could be to identify a practical and relatively low cost biomarker assay to assess oral vaccine induced primary and memory IgA immune responses in humans. Such an IgA biomarker assay could complement antigen-specific immune response measurements, enabling more oral vaccine candidates to be tested, whilst also reducing the work and costs associated with early oral vaccine development. With this in mind, we take a holistic systems biology approach to compare the transcriptional signatures of peripheral blood mononuclear cells isolated from volunteers, who following two oral priming doses with the oral cholera vaccine Dukoral®, had either strong or no vaccine specific IgA responses. Using this bioinformatical method, we identify TNFRSF17, a gene encoding the B cell maturation antigen (BCMA), as a candidate biomarker of oral vaccine induced IgA immune responses. We then assess the ability of BCMA to reflect oral vaccine induced primary and memory IgA responses using an ELISA BCMA assay on a larger number of samples collected in clinical trials with Dukoral® and the oral enterotoxigenic Escherichia coli vaccine candidate ETVAX. We find significant correlations between levels of BCMA and vaccine antigen-specific IgA in antibodies in lymphocyte secretion (ALS) specimens, as well as with proportions of circulating plasmablasts detected by flow cytometry. Importantly, our results suggest that levels of BCMA detected early after primary mucosal vaccination may be a biomarker for induction of long-lived vaccine specific memory B cell responses, which are otherwise difficult to measure in clinical vaccine trials. In addition, we find that ALS-BCMA responses in individuals vaccinated with ETVAX plus the adjuvant double mutant heat-labile toxin (dmLT) are significantly higher than in subjects given ETVAX only. We therefore propose that as ALS-BCMA responses may reflect the total vaccine induced IgA responses to oral vaccination, this BCMA ELISA assay could also be used to estimate the total adjuvant effect on vaccine induced-antibody responses, independently of antigen specificity, further supporting the usefulness of the assay.

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VLP-Based COVID-19 Vaccines: An Adaptable Technology against the Threat of New Variants

Vaccines ◽

10.3390/vaccines9121409 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1409

Author(s):

Wasim A. Prates-Syed ◽

Lorena C. S. Chaves ◽

Karin P. Crema ◽

Larissa Vuitika ◽

Aline Lira ◽

...

Keyword(s):

Immune Responses ◽

Immune Evasion ◽

Convergent Evolution ◽

Vaccine Development ◽

Receptor Binding Domain ◽

Vaccine Platform ◽

Cellular Immune Responses ◽

Alpha Beta ◽

Cellular Immune ◽

Financial Losses

Virus-like particles (VLPs) are a versatile, safe, and highly immunogenic vaccine platform. Recently, there are developmental vaccines targeting SARS-CoV-2, the causative agent of COVID-19. The COVID-19 pandemic affected humanity worldwide, bringing out incomputable human and financial losses. The race for better, more efficacious vaccines is happening almost simultaneously as the virus increasingly produces variants of concern (VOCs). The VOCs Alpha, Beta, Gamma, and Delta share common mutations mainly in the spike receptor-binding domain (RBD), demonstrating convergent evolution, associated with increased transmissibility and immune evasion. Thus, the identification and understanding of these mutations is crucial for the production of new, optimized vaccines. The use of a very flexible vaccine platform in COVID-19 vaccine development is an important feature that cannot be ignored. Incorporating the spike protein and its variations into VLP vaccines is a desirable strategy as the morphology and size of VLPs allows for better presentation of several different antigens. Furthermore, VLPs elicit robust humoral and cellular immune responses, which are safe, and have been studied not only against SARS-CoV-2 but against other coronaviruses as well. Here, we describe the recent advances and improvements in vaccine development using VLP technology.

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