Immunological determinants of disease caused by respiratory syncytial virus

doi:10.1016/0966-842X(96)10032-9

Trends in Microbiology

Volume 4, Issue 7, July 1996, Pages 290-294

https://doi.org/10.1016/0966-842X(96)10032-9 Get rights and content

Abstract

Various disease syndromes caused by respiratory syncytial virus (RSV) may have a common mechanism of pathogenesis mediated by cytokines produced by type 2 T helper cells. The nature of the immune response to RSV is determined by the pattern of cytokines produced sequentially by many different cell types. Vaccination can influence the types of cytokine produced by selectively activating T cell subpopulations and inducing an immune response that clears the virus with minimal immunopathology.

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In summary the immunological data suggested we were driving protective Th1 immune responses in multiple animal models by delivering a RSV vaccine targeting the F antigen to the skin with SEP. Such an observation is important in consideration of the immunopathology of RSV in experimental models which has been associated with Th2 responses [11–15]. Together, the results from this preclinical development program support the continued advancement of this pGX2303 vaccine candidate paired with skin surface EP delivery device.
Respiratory syncytial virus (RSV) is a massive medical burden in infants, children and the elderly worldwide, and an effective, safe RSV vaccine remains an unmet need. Here we assess a novel vaccination strategy based on the intradermal delivery of a SynCon® DNA-based vaccine encoding engineered RSV-F antigen using a surface electroporation device (SEP) to target epidermal cells, in clinically relevant experimental models. We demonstrate the ability of this strategy to elicit robust immune responses. Importantly we demonstrate complete resistance to pulmonary infection at a single low dose of vaccine in the cotton rat RSV/A challenge model. In contrast to the formalin-inactivated RSV (FI-RSV) vaccine, there was no enhanced lung inflammation upon virus challenge after DNA vaccination. In summary the data presented outline the pre-clinical development of a highly efficacious, tolerable and safe non-replicating vaccine delivery strategy.
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Significant progress has been achieved for the development of novel anti-viral drugs in the recent years. Large numbers of these newly developed drugs belong to three groups of compounds, nucleoside analogues, thymidine kinase-dependent nucleotide analogues and specific viral enzyme inhibitors. It has been found that the natural products, like plant extract, plant-derived compounds (phytochemicals) and so on, as well as traditional medicines, like Ayurvedic, traditional Chinese medicine (TCM), Chakma medicines and so on, are the potential sources for potential and novel anti-viral drugs based on different in vitro and in vivo approaches. In this chapter some of these important approaches utilised in the drug discovery process of potential candidate(s) for anti-viral agents are being discussed. The key conclusion is that natural products are one of the most important sources of novel anti-viral agents.
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Respiratory syncytial virus (RSV), an important pathogen of the lower respiratory tract, is responsible for severe illness both in new born and young children and in elderly people. However, development of a RSV vaccine has been hampered by the outcome of the infant trials in the 1960s with a formalin-inactivated RSV (FI-RSV) preparation. Previous studies in mice indicated that G protein immunization resulted in antibody and Th2-type response and failed to induce MHC I-restricted CD8⁺ T-cell response. Vaccines designed to induce CD8⁺ T-cell along with antibody response might be ideal. In the present report, a fusion protein G1F/M2 containing a RSV-G protein fragment (G: 125–225 amino acid) and a CD8⁺ T-cell epitope from RSV-M2 protein was investigated. G1F/M2 was cloned, expressed in E. coli, purified and renaturated. In BALB/c mice, G1F/M2 induced not only humoral immunity but also cellular immunity. In addition, interestedly, G1F/M2 elicited balanced IgG1/IgG2a response. These results suggest that the fusion protein G1F/M2 is potential as a RSV subunit vaccine.
Identification of an H-2D<sup>b</sup>-restricted CD8+ cytotoxic T lymphocyte epitope in the matrix protein of respiratory syncytial virus
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Cytotoxic T lymphocytes (CTL) play a significant role in the clearance of respiratory syncytial virus (RSV) infection in humans and mice. Identification of class I MHC-restricted CTL epitopes is critical in elucidating mechanisms of CTL responses against viral infections. However, only four H-2^d-restricted epitopes have been reported in mice. Because of the diversity of transgenic and knockout mice available to study immune responses, new epitopes in additional strains of mice must be identified. We therefore attempted to discover novel CTL epitopes in C57Bl/6 mice. Our efforts revealed a new H-2D^b-restricted CTL epitope from the RSV M protein, corresponding to aa 187–195 (NAITNAKII). Also, M187–195-specific CTLs were activated with kinetics similar to the immunodominant BALB/c epitope, M2 82–90. This is the first RSV-specific CTL epitope described in a strain of mice other than BALB/c. Furthermore, identification of this H-2^b-restricted CTL epitope provides access to genetically modified H-2^b mice for more detailed studies of CTL mechanisms in RSV infection.
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Trends in Microbiology

ReviewImmunological determinants of disease caused by respiratory syncytial virus

Abstract

J. Pediatr. (St Louis)

J. Pediatr. (St Louis)

J. Pediatr. (St Louis)

J. Biol. Chem.

J. Biol. Chem.

J. Pediatr. (St Louis)

Microb. Pathog.

Clin. Infect. Dis.

Am. J. Epidemiol.

Am. J. Epidemiol.

J. Infect. Dis.

Arch. Allergy Appl. Immunol.

Pediatr. Pulmonol.

Int. Immunol.

J. Immunol.

Thorax

Annu. Rev. Immunol.

J. Exp. Med.

J. Immunol.

Review
Immunological determinants of disease caused by respiratory syncytial virus