Current Vaccine Platforms in Enhancing T-Cell Response.

The induction of T cell-mediated immunity is crucial in vaccine development. The most effective vaccine is likely to employ both cellular and humoral immune responses. The efficacy of a vaccine depends on T cells activated by antigen-presenting cells. T cells also play a critical role in the duration and cross-reactivity of vaccines. Moreover, pre-existing T-cell immunity is associated with a decreased severity of infectious diseases. Many technical and delivery platforms have been designed to induce T cell-mediated vaccine immunity. The immunogenicity of vaccines is enhanced by controlling the kinetics and targeted delivery. Viral vectors are attractive tools that enable the intracellular expression of foreign antigens and induce robust immunity. However, it is necessary to select an appropriate viral vector considering the existing anti-vector immunity that impairs vaccine efficacy. mRNA vaccines have the advantage of rapid and low-cost manufacturing and have been approved for clinical use as COVID-19 vaccines for the first time. mRNA modification and nanomaterial encapsulation can help address mRNA instability and translation efficacy. This review summarizes the T cell responses of vaccines against various infectious diseases based on vaccine technologies and delivery platforms and discusses the future directions of these cutting-edge platforms.

Biodistribution and immunity of adenovirus 5/35 and modified vaccinia Ankara vector vaccines against human immunodeficiency virus 1 clade C.

Previously, we developed a chimeric adenovirus type 5 with type 35 fiber (Ad5/35), which has high tropism to dendritic cells and low hepatoxicity. For further clinical use, we constructed two recombinant vectors expressing human immunodeficiency virus 1 (HIV-1) clade C gag (Ad5/35-Cgag and MVA-Cgag). The biodistribution of the two viral vectors in a mouse model and immunity in monkeys were assessed. The mice received a single intramuscular injection with the vectors alone. The gag gene in the tissues were periodically detected using a real-time quantitative polymerase chain reaction. The distribution of Ad5/35 was also detected using an in vivo imaging system, followed by luciferase-expressing Ad5/35 administration. We found that Ad5/35-Cgag DNA and luciferase activity were detectable until 8 weeks post-administration, whereas MVA-Cgag was undetectable 72 h post-administration. Furthermore, viral administration did not increase serum aspartate aminotransferase and alanine aminotransferase levels in either mouse or monkey models. Moreover, intramuscular administration of Ad5/35-Cgag induced the gag-specific antibody level and IFNγ-secreting PBMCs, the boost with MVA-Cgag further increased the responses and lasted more than 20 weeks from the initial administration. These data demonstrate that Ad5/35 and MVA vectors are safe for in vivo use, and prime-boost with Ad5/35-MVA vaccines is suitable for clinical use against HIV-1 clade C.

Prophylactic and therapeutic vaccine against Pseudomonas aeruginosa keratitis using bacterial membrane vesicles.

PURPOSE: Pseudomonas aeruginosa (P. aeruginosa) infection is one of the major causes of keratitis. However, effective prophylactic and therapeutic vaccines against P. aeruginosa keratitis have yet to be developed. In this study, we explored the use of P. aeruginosa membrane vesicles (MVs) as a prophylactic vaccine as well as the use of immune sera derived from P. aeruginosa MV-immunized animals as a treatment for P. aeruginosa corneal infections in C57BL/6 mice. METHODS: C57BL/6 mice were intramuscularly immunized with P. aeruginosa MVs; the mouse corneas were then scarified and topically infected with several P. aeruginosa strains, followed by determination of corneal clinical score and corneal bacterial load. Next, immune sera derived from P. aeruginosa MV-immunized ICR mice were administered intraperitoneally to naïve C57BL/6 mice, followed by topical P. aeruginosa challenge. Finally, the immune sera were also used as a topical treatment in the mice with established P. aeruginosa corneal infections. RESULTS: P. aeruginosa-specific IgG and IgA antibodies induced by intramuscular immunization were detected not only in the sera but also in the eye-wash solution. Both active and passive immunization significantly inhibited P. aeruginosa corneal infection. Finally, topical treatment with immune sera in the mice with established P. aeruginosa corneal infections notably decreased the corneal clinical score and corneal bacterial load. CONCLUSIONS: P. aeruginosa keratitis can be attenuated by vaccination of P. aeruginosa MVs and topical application of P. aeruginosa MV-specific immune sera.

New vaccine production platforms used in developing SARS-CoV-2 vaccine candidates.

The threat of the current coronavirus disease pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is accelerating the development of potential vaccines. Candidate vaccines have been generated using existing technologies that have been applied for developing vaccines against other infectious diseases. Two new types of platforms, mRNA- and viral vector-based vaccines, have been gaining attention owing to the rapid advancement in their methodologies. In clinical trials, setting appropriate immunological endpoints plays a key role in evaluating the efficacy and safety of candidate vaccines. Updated information about immunological features from individuals who have or have not been exposed to SARS-CoV-2 continues to guide effective vaccine development strategies. This review highlights key strategies for generating candidate SARS-CoV-2 vaccines and considerations for vaccine development and clinical trials.

Intradermal Delivery of Antigens Enhances Specific IgG and Diminishes IgE Production: Potential Use for Vaccination and Allergy Immunotherapy.

Skin is protected by a tough but flexible multilayered barrier and is a front line for immune responses against invading particles. For many years now, skin has been a tissue where certain vaccines are injected for the prevention of infectious disease, however, the detailed mechanisms of the skin immune response are not yet well understood. Using thin and small injection needles, we carefully injected OVA into a restricted region of mouse skin, i.e., intradermal (ID), and examined the antibody response in comparison with subcutaneous (SC) injection or epicutaneous patch administration of OVA. Epicutaneous patches induced a high IgE response against OVA, but IgG production was low. High IgG production was induced by both ID and SC injection, moreover, ID injection induced higher IgG production without any adjutants. Furthermore, OVA-specific IgE production was diminished by ID injection. We found that ID injection could efficiently stimulate skin resident DCs, drive Th1-biased conditions and diminish IgE production. The ID injection response was regulated by Langerin+ dermal DCs, because OVA was taken up mainly by these cells and, after transiently deleting them, the IgE response was no longer diminished and IgG1 production was enhanced. We also tested whether ID injection might be an effective allergy treatment by attempting to inhibit ongoing IgE production in mice with experimentally induced high serum IgE levels. Multiple ID injections of OVA were shown to prevent elevation of serum OVA-specific IgE after repeated allergen challenge. In contrast, SC OVA injection could only transiently inhibit the OVA-specific IgE production. These findings indicated that ID injection results in higher induction of antigen-specific IgG, and thus may be useful for vaccine delivery with little or no adjuvant components. Moreover, the observed diminishment of IgE and induction of Th1-biased immune responses suggest that ID may be a useful injection route for allergy immunotherapy.

Developments in Viral Vector-Based Vaccines.

Viral vectors are promising tools for gene therapy and vaccines. Viral vector-based vaccines can enhance immunogenicity without an adjuvant and induce a robust cytotoxic T lymphocyte (CTL) response to eliminate virus-infected cells. During the last several decades, many types of viruses have been developed as vaccine vectors. Each has unique features and parental virus-related risks. In addition, genetically altered vectors have been developed to improve efficacy and safety, reduce administration dose, and enable large-scale manufacturing. To date, both successful and unsuccessful results have been reported in clinical trials. These trials provide important information on factors such as toxicity, administration dose tolerated, and optimized vaccination strategy. This review highlights major viral vectors that are the best candidates for clinical use.

Adenovirus type 5 with modified hexons induces robust transgene-specific immune responses in mice with pre-existing immunity against adenovirus type 5.

BACKGROUND: Adenovirus type 5 (Ad5) is widely used as a vehicle for vaccine delivery in the treatment of infectious disease and cancer. However, the efficacy of Ad5 vectors has been limited in humans because exposure to Ad5 infections results in most adults having neutralizing antibodies against Ad5. To overcome this limitation, the hexon epitope present in the fifth hypervariable region of Ad5 was modified. METHODS: To evaluate the ability of Ad5 vectors encoding the HIV env protein to induce Ag-specific immune responses in the face of pre-existing anti-Ad5 immunity, mice were administrated intramuscularly with the Ad-Luc vector, and then vaccinated with parental or hexon-modified Ad5 vectors (Ad-HisHIV, Ad-END/AAAHIV or Ad-HIV) at week 8. HIV-specific cell-mediated immune responses were detected through a combination of tetramer assays and intracellular cytokine staining from weeks 8-23. RESULTS: The hexon-modified Ad vector was able to escape from anti-Ad5 neutralizing antibody, and mice with the modified vector generated significantly lower individual neutralizing antibody than those immunized with the parental vector. Furthermore, mice with pre-existing anti-Ad immunity immunized with the modified vector generated significantly stronger cell-mediated anti-env responses than those immunized with the parental vector. CONCLUSIONS: These data demonstrate that Ad5 vector with hexon modification reduce their sensitivity to pre-existing anti-Ad immunity and improve their clinical utility.

Designed recombinant adenovirus type 5 vector induced envelope-specific CD8(+) cytotoxic T lymphocytes and cross-reactive neutralizing antibodies against human immunodeficiency virus type 1.

BACKGROUND: A monoclonal antibody (mAb) 2F5 binds to the membrane-proximal external region (MPER) of the transmembrane subunit gp41 of human immunodeficiency virus type 1 (HIV-1) is known to broadly neutralize HIV-1 strains. The Adenovirus type 5 vector (Ad5) has been widely applied for HIV-1 vaccine, and hexon hypervariable region 5 (HVR5) is exposed on viral surface and easily target host immune responses against Ad5. METHODS: We constructed a recombinant adenovirus type 5 vector (rAd5) with a 2F5-binding epitope (ELDKWA) of MPER on Ad5-HVR5. In addition, we developed rAd5 encoding the HIV-1(IIIB) envelope (Env) gene for the induction of Env-specific cellular immunity. RESULTS: The virus titers of the constructed rAd5 were similar to that of the parental Ad5 vector. Furthermore, high-dose immunization of rAd5 induced Env-specific CD8(+) cells and high levels of anti-ELDKWA antibodies. Moreover, an in vitro HIV-1 neutralization assay indicated that ELDKWA-specific mAbs derived from rAd5-immunized mice neutralized a wide range of HIV-1 strains. CONCLUSIONS: The present study outlines the development of an Ad5-based HIV-1 vaccine targeting the hypervariable regions of Ad5. The constructed rAd5 induced an HIV-1-specific cellular immune response and neutralizing antibodies against various strains of HIV-1 simultaneously.

Actin network formation by unidirectional polycation diffusion.

We show that F-actins form three-dimensional giant network under uni-directional diffusion of polycations, at a dilute actin concentration (0.01 mg/mL) that only bundles are formed by homogeneous mixing with polycations. The mesh size of the actin network depends on polycation concentration and ionic strength, while bundle thickness of network depends only on ionic strength, which indicates that actin network is formed through nucleation-growth mechanism. The mesh size and the bundle thickness are determined by nucleus concentration and nucleus size, respectively. The atomic force microscopy measurement correlates the elasticity of the actin network, E, with the mesh size, xi, as E approximately xi-1, while the bundle thickness, D dependence of E cannot be described by a simple scaling relation. E approximately D6.5 when D is small and E approximately D0.1 when D is large. Our study on the self-assembly of actin network under asymmetric polycation condition would provide the crucial insight into the organization of biopolymers in polarized condition of cell.