RSV: Available Prophylactic Options and Vaccines in Clinical Trials

*Debra T. Linfield and Fariba Rezaee*

## **Abstract**

Respiratory syncytial virus (RSV) is the leading cause of serious lower respiratory infection (ALRI)-related hospitalization in children worldwide, and a source of morbidity and mortality in high-risk adults. There are strong associations between RSV, persistent wheezing and childhood asthma. Despite extensive research, no effective treatment is available aside from supportive care. The trial of a formalininactivated RSV vaccine in the 1960s resulted in priming the severe illness upon natural infection. Palivizumab, a monoclonal antibody approved for RSV prophylaxis in high-risk infants, has only moderately decreased hospital admissions due to RSV infection. Live-attenuated, vector, and protein-based vaccine candidates are being investigated in many clinical trials. Developing a vaccine remains challenging due to finding the right balance between adequate immunogenicity and attenuation of vaccine. Here we review the clinical significance of RSV in infants, young children, high-risk adults, elderly population, pregnant women; clinical manifestations and consequences of RSV infection; the pharmacologic strategies currently available, the current stages of RSV vaccine clinical trials, different strategies, and major hurdles in the development of an effective RSV vaccine.

**Keywords:** respiratory syncytial virus (RSV), pediatric, respiratory infection, palivizumab, antiviral therapy, immuno-prophylaxis, RSV vaccine, clinical trials

#### **1. Introduction**

RSV, a member of the Paramyxoviridae family, is an enveloped, negativesense, single-stranded RNA virus [1]. Especially within the winter months, it is an important cause of morbidity and mortality among young children, the elderly, and immunocompromised individuals [2]. Infection is transmitted by either direct or indirect contact with respiratory droplets, and prior infection does not result in persistent immunity.

RSV accounts for approximately 2.1 million outpatient visits among children younger than 5 years old [3]. Additionally, there are 177,000 hospitalizations and 14,000 deaths among adults older than 65 years due to RSV infection [4, 5] each year in the United States. Human studies have shown strong associations between RSV, persistent wheezing, and childhood asthma [6–8].

Symptoms usually begin 4–6 days after transmission and present with nasal congestion, rhinorrhea, fever, or cough. RSV is one of the leading causes of lower respiratory tract infection (LRTI), and can cause tachypnea, wheeze, hypoxemia, or 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.

To date, supportive care is the main treatment option for RSV admission [9, 10]. 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, however the mechanism of the VED remains unclear [12].

RSV is composed of 10 genes encoding 11 proteins: small hydrophobic (SH) protein, nucleocapsid associated proteins N, P, L, M2–1, and M2–2, the matrix (M) 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, as it is highly conserved between the two antigenic subgroups.

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

**63**

**2.2 ALS-008176**

**2.3 Presatovir**

*RSV: Available Prophylactic Options and Vaccines in Clinical Trials*

and Zika virus-induced cell death in mammalian cells [24].

February 2018, but results have not been published yet.

ALS-008176, a prodrug of a cytidine nucleoside analogue, decreased viral load and more readily cleared RSV than placebo in a randomized, double-blind clinical trial in healthy adults [25]. However, participants' preexisting immune memory, which may promote RSV clearance, was not assessed [26]. A randomized, double-blind Phase I study assessing both a single and multiple ascending dosing in hospitalized infants (Clinicaltrials.gov identifier #NCT02202356) was completed in

During viral entry, the F protein undergoes conformational changes to fuse with the host cell membrane [17]. Presatovir (GS-5806) is an orally bioavailable agent that inhibits these conformational changes, thereby blocking viral fusion [27]. It was found in a Phase 2a trial with healthy adults (Clinicaltrials.gov identifier

seronegative infants/toddlers. For purposes of this chapter, we will highlight the most recent trials where research is ongoing. We will also elucidate many of the complex hurdles that have impeded progress in the development of an effective vaccine.

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

*DOI: http://dx.doi.org/10.5772/intechopen.84851*

**2. Available pharmacologic strategies**

**2.1 Ribavirin**

#### **Figure 1.**

*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.*

seronegative infants/toddlers. For purposes of this chapter, we will highlight the most recent trials where research is ongoing. We will also elucidate many of the complex hurdles that have impeded progress in the development of an effective vaccine.
