Tauopathy Analysis in P301S Mouse Model of Alzheimer Disease Immunized with DNA and MVA Poxvirus-Based Vaccines Expressing Human Full-Length 4R2N or 3RC Tau Proteins

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive memory loss and cognitive decline that has been associated with an accumulation in the brain of intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein, and extracellular senile plaques formed by β-amyloid peptides. Currently, there is no cure for AD and after the failure of anti β-amyloid therapies, active and passive tau immunotherapeutic approaches have been developed in order to prevent, reduce or ideally reverse the disease. Vaccination is one of the most effective approaches to prevent diseases and poxviruses, particularly modified vaccinia virus Ankara (MVA), are one of the most promising viral vectors used as vaccines against several human diseases. Thus, we present here the generation and characterization of the first MVA vectors expressing human tau genes; the full-length 4R2N tau protein or a 3RC tau fragment containing 3 tubulin-binding motifs and the C-terminal region (termed MVA-Tau4R2N and MVA-Tau3RC, respectively). Both MVA-Tau recombinant viruses efficiently expressed the human tau 4R2N or 3RC proteins in cultured cells, being detected in the cytoplasm of infected cells and co-localized with tubulin. These MVA-Tau vaccines impacted the innate immune responses with a differential recruitment of innate immune cells to the peritoneal cavity of infected mice. However, no tau-specific T cell or humoral immune responses were detected in vaccinated mice. Immunization of transgenic P301S mice, a mouse model for tauopathies, with a DNA-Tau prime/MVA-Tau boost approach showed no significant differences in the hyperphosphorylation of tau, motor capacity and survival rate, when compared to non-vaccinated mice. These findings showed that a well-established and potent protocol of T and B cell activation based on DNA/MVA prime/boost regimens using DNA and MVA vectors expressing tau full-length 4R2N or 3RC proteins is not sufficient to trigger tau-specific T and B cell immune responses and to induce a protective effect against tauopathy in this P301S murine model. In the pursuit of AD vaccines, our results highlight the need for novel optimized tau immunogens and additional modes of presentation of tau protein to the immune system.

An Overview of Nanocarrier-Based Adjuvants for Vaccine Delivery

“…Viral vector such as adenovirus [ 27 ], modified vaccinia virus Ankara (MVA) [ 45 ], canary pox vector [ 46 ], pox virus [ 47 ], measles virus [ 44 ], herpes simplex virus (HSV) [ 48 ], alpha virus [ 49 ] have been pursued for vaccine delivery against various diseases. Among them, adenovirus and vaccinia virus are the most widely used vectors.…”

“…All these studies indicated that the adenovirus expresses a foreign gene as antigen/immunogen for the purpose of vaccine and thus it functions as both carrier and adjuvant. Several other viral vectors such as lentiviral [ 40 , 41 , 42 ], modified vaccinia virus Ankara (MVA) [ 43 ], cytomegalovirus (CMV) [ 23 ], poxvirus [ 22 , 24 ], measles virus [ 25 , 45 ], vesicular stomatitis virus [ 15 , 18 ], HSV and alphavirus [ 27 ] are also under different phases of clinical trials. Lentiviral and integrase defective lentiviral vector has been used widely in the vaccination strategies and several preclinical and phase I/II studies are currently undergoing [ 63 , 64 , 65 ].…”

Alzheimer’s disease in elderly COVID-19 patients: potential mechanisms and preventive measures

“…Since available treatments for AD show at best modest therapeutic effects, researchers have undertaken intensive efforts to develop vaccines able to halt AD progression by removing Aβ from the brain [ 67 ]. However, following promising results in mice, a clinical trial examining the effectiveness of vaccination with full length Aβ42 was stopped after 6% of patients with mild to moderate AD developed meningoencephalitis [ 68 ].…”

Current Advances of Plant-Based Vaccines for Neurodegenerative Diseases

“…Similarly, peptide-based vaccines employing specific epitopes or peptides that mimic the structure of epitopes (mimotopes) are currently being developed to prevent and/or treat NDDs by harnessing the activity of the immune system (active immunization) [ 35 , 36 , 37 ]. As an example, in recent years a variety of vaccine designs for NDDs have been described, including MultiTEP-based vaccines, virus-like particle (VLP)-based vaccines, DNA-based vaccines, modified vaccinia virus Ankara (MVA) poxvirus-based vaccines, and synthetic peptide vaccines [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”