**2.1 Ribavirin**

*The Burden of Respiratory Syncytial Virus Infection in the Young*

however the mechanism of the VED remains unclear [12].

as it is highly conserved between the two antigenic subgroups.

nucleocapsid associated proteins N, P, L, M2–1, and M2–2, the matrix (M)

respiratory distress, resulting in an emergency department visit or hospital admission [9]. Males are more severely affected than females, and for reasons that are not fully elucidated, Native Americans and Alaskan Native children are more likely than children of other ethnicities to have severe infection requiring hospitalization.

There is no vaccine approved for RSV prophylaxis in the general population. In 1966, the first vaccine for RSV, a formalin-inactivated (FI-RSV) type, was developed. However, it resulted in vaccine-enhanced disease (VED). Among vaccinated infant, 80% developed severe bronchiolitis or pneumonia and two died, compared to only 5% for the placebo group [11]. There was increased eosinophilic and neutrophilic infiltration and mononuclear cells in the lung parenchyma found in the autopsies of two infants that died, which suggests a Th2-biased immune response,

To date, supportive care is the main treatment option for RSV admission [9, 10].

RSV is composed of 10 genes encoding 11 proteins: small hydrophobic (SH) protein,

protein, nonstructural proteins NS1 and NS2, glycoprotein (G), and fusion (F) protein. The SH, N, M2–2, NS2, G, and F proteins are the most commonly manipulated proteins in vaccine production (**Figure 1**). The SH protein inhibits cell apoptosis through inhibition of the TNF-α pathway [13]. The N protein initiates encapsidation of the genome, the M2–2 protein mediates the balance between transcription and RNA replication, and the NS2 protein inhibits host interferon (IFN) response [14, 15]. G protein mediates viral attachment to the host cell, while F protein enables fusion of the virus [16, 17]. RSV A and RSV B, the two antigenic subtypes, differ in their amino acid sequence of the G protein and reactivity to antibodies, resulting in differences in disease severity [18]. Targeting the F protein is of particular interest,

In this chapter, we will discuss the current and candidate antiviral drugs and prophylactic agents against RSV infection and some of the ongoing clinical trials of RSV vaccines. Evaluation of drugs typically proceeds in a methodical order, from studies in healthy adults, to hospitalized adults, to older seropositive children, to

*Current and future options for RSV treatment or prophylaxis. No RSV vaccine is currently on the market, but diverse vaccine candidates, targeting different proteins within the RSV virion, are undergoing clinical trials.*

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**Figure 1.**

Ribavirin, a synthetic guanosine analogue antiviral agent, was first synthesized in the 1970s. It is believed that ribavirin is phosphorylated intracellularly and can then disrupt purine metabolism by inhibiting inosine monophosphate dehydrogenase, thereby inhibiting nucleic acid synthesis. Furthermore, it promotes antiviral cytokine production and Type 1 T-cell mediated immune responses. Starting in 1993, the American Academy of Pediatrics (AAP) Committee on Infectious Diseases supported the use of Ribavirin for severe RSV infections. However, in 1996, the recommendation changed to "may be considered" [19]. Currently, the use of aerosolized Ribavirin is limited to immunocompromised patients with RSV due to the inconvenient route of delivery, which requires prolonged aerosol administration; risks for potential toxicity, such as teratogenic effects during pregnancy; cost of therapy; and need for hospital admission. The safety of oral ribavirin in moderately to severely immunocompromised adults with PCR-proven RSV infection was examined in a retrospective cohort study. The main outcome of this study was the rate of adverse events, and authors conclude that ribavirin is well tolerated in immunocompromised adults [20]. However, the rate of progression of disease from URTI to the LRTI was not measured. In another retrospective study, immunosuppressed patients were given either oral, intravenous, aerosol or a combination of these treatments and showed that ribavirin therapy reduces progression from RSV URTI to LRTI [21]. In a similar study, Khanna et al. reported that 32% of patients who were treated with ribavirin progressed to LRTI compared to 68% of the untreated group [22]. Their study showed that oral ribavirin therapy was likely as effective as aerosolized therapy. However, because of the sample size and retrospective nature, neither of these studies could determine the precise role of ribavirin therapy in this patient population. In addition, ribavirin is being used for Hepatitis C infection, in conjunction with an interferon agent [23]. Furthermore, a recent study showed that ribavirin inhibited Zika virus replication and Zika virus-induced cell death in mammalian cells [24].
