1. Dendrimers and Gene Delivery 5274 2. Surface-Engineered Dendrimers in Gene Delivery 5276 2.1. Lipid-Modified Dendrimers 5276 2.2. Fluorinated Dendrimers 5278 2.3. Amino Acid-Modified Dendrimers 5280 2.4. Saccharide-Modified Dendrimers 5281 2.5. Proteinand Peptide-Modified Dendrimers 5283 2.6. Polymer-Modified Dendrimers 5285 2.7. Nanoparticle-Modified Dendrimers 5285 2.8. Cationic-Moiety-Modified Dendrimers 5287 2.9. Other Ligand-Modified Dendrimers 5289 2.9.1. Hormone-Modified Dendrimers 5289 2.9.2. Folic Acid-Modified Dendrimers 5289 2.9.3. Photosensitizer-Modified Dendrimers 5289 2.9.4. Fluorophore-Modified Dendrimers 5289 2.9.5. Aminoglycoside-Modified Dendrimers 5289 3. Conclusions and Perspectives 5289 Author Information 5289 Corresponding Author 5289 Author Contributions 5289 Notes 5289 Biographies 5290 Acknowledgments 5290 Abbreviations Used 5290 References 5291

Surface-engineered dendrimers in gene delivery.

Rabies is a zoonotic, fatal and progressive neurological infection caused by rabies virus of the genus Lyssavirus and family Rhabdoviridae. It affects all warm-blooded animals and the disease is prevalent throughout the world and endemic in many countries except in Islands like Australia and Antarctica. Over 60,000 peoples die every year due to rabies, while approximately 15 million people receive rabies post-exposure prophylaxis (PEP) annually. Bite of rabid animals and saliva of infected host are mainly responsible for transmission and wildlife like raccoons, skunks, bats and foxes are main reservoirs for rabies. The incubation period is highly variable from 2 weeks to 6 years (avg. 2-3 months). Though severe neurologic signs and fatal outcome, neuropathological lesions are relatively mild. Rabies virus exploits various mechanisms to evade the host immune responses. Being a major zoonosis, precise and rapid diagnosis is important for early treatment and effective prevention and control measures. Traditional rapid Seller's staining and histopathological methods are still in use for diagnosis of rabies. Direct immunofluoroscent test (dFAT) is gold standard test and most commonly recommended for diagnosis of rabies in fresh brain tissues of dogs by both OIE and WHO. Mouse inoculation test (MIT) and polymerase chain reaction (PCR) are superior and used for routine diagnosis. Vaccination with live attenuated or inactivated viruses, DNA and recombinant vaccines can be done in endemic areas. This review describes in detail about epidemiology, transmission, pathogenesis, advances in diagnosis, vaccination and therapeutic approaches along with appropriate prevention and control strategies.

https://tandfonline.com/doi/pdf/10.1080/01652176.2017.1343516

Rabies – epidemiology, pathogenesis, public health concerns and advances in diagnosis and control: a comprehensive review

https://lib.dr.iastate.edu/cgi/viewcontent.cgi?article=1309&context=cbe_pubs

Nanoneuromedicines for degenerative, inflammatory, and infectious nervous system diseases.

The present study describes the generation of a new Orf virus (ORFV) recombinant, D1701-V-RabG, expressing the rabies virus (RABV) glycoprotein that is correctly presented on the surface of infected cells without the need of replication or production of infectious recombinant virus. One single immunization with recombinant ORFV can stimulate high RABV-specific virus-neutralizing antibody (VNA) titers in mice, cats, and dogs, representing all nonpermissive hosts for the ORFV vector. The protective immune response against severe lethal challenge infection was analyzed in detail in mice using different dosages, numbers, and routes for immunization with the ORFV recombinant. Long-term levels of VNA could be elicited that remained greater than 0.5 IU per ml serum, indicative for the protective status. Single applications of higher doses (10(7) PFU) can be sufficient to confer complete protection against intracranial (i.c.) challenge, whereas booster immunization was needed for protection by the application of lower dosages. Anamnestic immune responses were achieved by each of the seven tested routes of inoculation, including oral application. Finally, in vivo antibody-mediated depletion of CD4-positive and/or CD8-posititve T cell subpopulations during immunization and/or challenge infection attested the importance of CD4 T cells for the induction of protective immunity by D1701-V-RabG. This report demonstrates another example of the potential of the ORFV vector and also indicates the capability of the new recombinant for vaccination of animals.

A New Rabies Vaccine Based on a Recombinant Orf Virus (Parapoxvirus) Expressing the Rabies Virus Glycoprotein

DNA vaccine is a third generation vaccine type based on concepts and techniques of molecular biology. It can closely mimic live infections and induce both antibody and cell mediated immune responses and thus has much potential for treating chronic viral infection and cancer. How do we transport the DNA vaccine to the right target cells in lymphoid tissues and organs? How do we achieve high and robust gene transfection efficiency while simultaneously inducing DC maturation and antigen presentation? These questions pose significant challenges and addressing them may require serious efforts in developing better biomaterials as carriers. This review is dedicated to the discussion of polymers as nanoscale carriers for the DNA vaccine. We summarize recent advances in polymer science and engineering to overcome multilevel hurdles for DNA vaccine delivery and conclude with thoughts on challenges and opportunities that may shape the future of polymers in DNA vaccination.

Polymers for DNA Vaccine Delivery

PURPOSE Delayed onset of, and low magnitude of, protective immune responses are major drawbacks limiting the practical utility of plasmid vaccination against rabies. In this study we evaluated whether nanoformulation with the novel poly(ether imine) (PETIM) dendrimer can enhance the immunogenicity and efficacy of a plasmid-based rabies vaccine. MATERIALS AND METHODS A plasmid vaccine construct (pIRES-Rgp) was prepared by cloning the full-length rabies virus glycoprotein gene into pIRES vector. Drawing upon the results of our previous study, a dendriplex (dendrimer-DNA complex) of pIRES-Rgp was made with PETIM dendrimer (10:1 w/w, PETIM:pIRES-Rgp). In vitro transfection was done on baby hamster kidney (BHK)-21 cells to evaluate expression of glycoprotein gene from pIRES-Rgp and PETIM-pIRES-Rgp. Subsequently, groups of Swiss albino mice were immunized intramuscularly with pIRES-Rgp or PETIM-pIRES-Rgp. A commercially available cell culture rabies vaccine was included for comparison. Rabies virus neutralizing antibody (RVNA) titers in the immune sera were evaluated on days 14, 28, and 90 by rapid fluorescent focus inhibition test. Finally, an intracerebral challenge study using a challenge virus standard strain of rabies virus was done to evaluate the protective efficacy of the formulations. RESULTS Protective levels of RVNA titer (≥0.5 IU/mL) were observed by day 14 in animals immunized with pIRES-Rgp and its dendriplex. Notably, PETIM-pIRES-Rgp produced 4.5-fold higher RVNA titers compared to pIRES-Rgp at this time point. All mice immunized with the PETIM-pIRES-Rgp survived the intracerebral rabies virus challenge, compared with 60% in the group which received pIRES-Rgp. CONCLUSION Our results suggest that nanoformulation with PETIM dendrimer can produce an earlier onset of a high-titered protective antibody response to a plasmid-based rabies vaccine. PETIM dendriplexing appears to be an efficacious nonviral delivery strategy to enhance genetic vaccination.

/pdf/enhancement-of-immunogenicity-and-efficacy-of-a-plasmid-dna-7ahh6u6dil.pdf

Enhancement of immunogenicity and efficacy of a plasmid DNA rabies vaccine by nanoformulation with a fourth-generation amine-terminated poly(ether imine) dendrimer.

Rabies continues to be a significant cause of human and animal mortality, despite the availability of safe and effective prophylactics Apart from limited access, the cost and complex schedules of rabies biologics often impact on the success of post-exposure prophylaxis in humans in the endemic countries Mass vaccination of dogs, critical in rabies control, often fails to achieve its goal in rabies-endemic countries due to logistic, animal and vaccine-related issues DNA vaccination has been proposed as a cheaper and efficient strategy for rabies prophylaxis, and its feasibility has been demonstrated in a number of animal models including companion animals, since 1994 Despite the proven efficacy, the technology suffers from a few drawbacks that limit its large-scale application, such as delayed and weaker immune responses in larger animals Recent advances in the field of vector design and delivery hold promise for enhancement of rabies DNA vaccine efficacy The present article provides an overview of developments in the field of DNA rabies vaccination and its future prospects

/pdf/rabies-dna-vaccines-current-status-and-future-1x7nnafz45.pdf

Padinjaremattathil Thankappan Ullas

Papers

Enhancement of immunogenicity and efficacy of a plasmid DNA rabies vaccine by nanoformulation with a fourth-generation amine-terminated poly(ether imine) dendrimer.

Rabies DNA Vaccines: Current Status and Future