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      New Rabies Vaccines for Use in Humans

      review-article
      Vaccines
      MDPI
      rabies virus, vaccines, post-exposure prophylaxis (PEP), pre-exposure prophylaxis (PrEP)

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          Abstract

          Although vaccines are available, rabies still claims more than 55,000 human lives each year. In most cases, rabies vaccines are given to humans after their exposure to a rabid animal; pre-exposure vaccination is largely reserved for humans at high risk for contacts with the virus. Most cases of human rabies are transmitted by dogs. Dog rabies control by mass canine vaccination campaigns combined with intensive surveillance programs has led to a decline of human rabies in many countries but has been unsuccessful in others. Animal vaccination programs are also not suited to control human rabies caused by bat transmission, which is common in some Central American countries. Alternatively, or in addition, more widespread pre-exposure vaccination, especially in highly endemic remote areas, could be implemented. With the multiple dose regimens of current vaccines, pre-exposure vaccination is not cost effective for most countries and this warrants the development of new rabies vaccines, which are as safe as current vaccines, but achieve protective immunity after a single dose, and most importantly, are less costly. This chapter discusses novel rabies vaccines that are in late stage pre-clinical testing or have undergone clinical testing and their potential for replacing current vaccines.

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          Most cited references65

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          Adenoviruses as vaccine vectors

          Adenoviruses have transitioned from tools for gene replacement therapy to bona fide vaccine delivery vehicles. They are attractive vaccine vectors as they induce both innate and adaptive immune responses in mammalian hosts. Currently, adenovirus vectors are being tested as subunit vaccine systems for numerous infectious agents ranging from malaria to HIV-1. Additionally, they are being explored as vaccines against a multitude of tumor-associated antigens. In this review we describe the molecular biology of adenoviruses as well as ways the adenovirus vectors can be manipulated to enhance their efficacy as vaccine carriers. We describe methods of evaluating immune responses to transgene products expressed by adenoviral vectors and discuss data on adenoviral vaccines to a selected number of pathogens. Last, we comment on the limitations of using human adenoviral vectors and provide alternatives to circumvent these problems. This field is growing at an exciting and rapid pace, thus we have limited our scope to the use of adenoviral vectors as vaccines against viral pathogens.
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            Stool microbiota and vaccine responses of infants.

            Oral vaccine efficacy is low in less-developed countries, perhaps due to intestinal dysbiosis. This study determined if stool microbiota composition predicted infant oral and parenteral vaccine responses. The stool microbiota of 48 Bangladeshi infants was characterized at 6, 11, and 15 weeks of age by amplification and sequencing of the 16S ribosomal RNA gene V4 region and by Bifidobacterium-specific, quantitative polymerase chain reaction. Responses to oral polio virus (OPV), bacille Calmette-Guérin (BCG), tetanus toxoid (TT), and hepatitis B virus vaccines were measured at 15 weeks by using vaccine-specific T-cell proliferation for all vaccines, the delayed-type hypersensitivity skin-test response for BCG, and immunoglobulin G responses using the antibody in lymphocyte supernatant method for OPV, TT, and hepatitis B virus. Thymic index (TI) was measured by ultrasound. Actinobacteria (predominantly Bifidobacterium longum subspecies infantis) dominated the stool microbiota, with Proteobacteria and Bacteroidetes increasing by 15 weeks. Actinobacteria abundance was positively associated with T-cell responses to BCG, OPV, and TT; with the delayed-type hypersensitivity response; with immunoglobulin G responses; and with TI. B longum subspecies infantis correlated positively with TI and several vaccine responses. Bacterial diversity and abundance of Enterobacteriales, Pseudomonadales, and Clostridiales were associated with neutrophilia and lower vaccine responses. Bifidobacterium predominance may enhance thymic development and responses to both oral and parenteral vaccines early in infancy, whereas deviation from this pattern, resulting in greater bacterial diversity, may cause systemic inflammation (neutrophilia) and lower vaccine responses. Vaccine responsiveness may be improved by promoting intestinal bifidobacteria and minimizing dysbiosis early in infancy. Copyright © 2014 by the American Academy of Pediatrics.
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              Structural Analysis Reveals that Toll-like Receptor 7 Is a Dual Receptor for Guanosine and Single-Stranded RNA.

              Toll-like receptor 7 (TLR7) is a single-stranded RNA (ssRNA) sensor in innate immunity and also responds to guanosine and chemical ligands, such as imidazoquinoline compounds. However, TLR7 activation mechanism by these ligands remain largely unknown. Here, we generated crystal structures of three TLR7 complexes, and found that all formed an activated m-shaped dimer with two ligand-binding sites. The first site conserved in TLR7 and TLR8 was used for small ligand-binding essential for its activation. The second site spatially distinct from that of TLR8 was used for a ssRNA-binding that enhanced the affinity of the first-site ligands. The first site preferentially recognized guanosine and the second site specifically bound to uridine moieties in ssRNA. Our structural, biochemical, and mutagenesis studies indicated that TLR7 is a dual receptor for guanosine and uridine-containing ssRNA. Our findings have important implications for understanding of TLR7 function, as well as for therapeutic manipulation of TLR7 activation.
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                Author and article information

                Journal
                Vaccines (Basel)
                Vaccines (Basel)
                vaccines
                Vaccines
                MDPI
                2076-393X
                20 June 2019
                June 2019
                : 7
                : 2
                : 54
                Affiliations
                The Wistar Institute, Philadelphia, PA 19104, USA; ertl@ 123456wistar.org ; Tel.: +1-215-898-3863
                Article
                vaccines-07-00054
                10.3390/vaccines7020054
                6631309
                31226750
                9253c005-7d1c-489c-b377-4cd42f1c656d
                © 2019 by the author.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 03 June 2019
                : 19 June 2019
                Categories
                Review

                rabies virus,vaccines,post-exposure prophylaxis (pep),pre-exposure prophylaxis (prep)

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