Expert Opinion on Pharmacotherapy

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ieop20

Pharmacological management of human

respiratory syncytial virus infection

Alexis M. Kalergis , Jorge A. Soto , Nicolás M. S. Gálvez , Catalina A. Andrade ,

Ayleen Fernandez , Karen Bohmwald & Susan M. Bueno

To cite this article: Alexis M. Kalergis , Jorge A. Soto , Nicolás M. S. Gálvez , Catalina A.
Andrade , Ayleen Fernandez , Karen Bohmwald & Susan M. Bueno (2020): Pharmacological
management of human respiratory syncytial virus infection, Expert Opinion on Pharmacotherapy,
DOI: 10.1080/14656566.2020.1806821

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Published online: 18 Aug 2020.

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EXPERT OPINION ON PHARMACOTHERAPY
https://doi.org/10.1080/14656566.2020.1806821

REVIEW

Pharmacological management of human respiratory syncytial virus infection

Alexis M. Kalergis a,,b,, Jorge A. Sotoa,, Nicolás M. S. Gálvez a,
, Catalina A. Andradea,, Ayleen Fernandeza,,
Karen Bohmwalda, and Susan M. Bueno a,
a,
Millennium Institute on Immunology and Immunotherapy, Departamento De Genética Molecular Y Microbiología, Facultad De Ciencias
Biológicas, Pontificia Universidad Católica De Chile, Santiago, Chile; b,Departamento De Endocrinología, Facultad De Medicina, Pontificia
Universidad Católica De Chile, Santiago, Chile

ABSTRACT ARTICLE HISTORY

Introduction: Human respiratory syncytial virus (hRSV) is the primary viral cause of respiratory diseases, Received 3 January 2020
leading to bronchiolitis and pneumonia in vulnerable populations. The only current treatment against Accepted 4 August 2020
this virus is palliative, and no efficient and specific vaccine against this pathogen is available. KEYWORDS
Areas covered: The authors describe the disease symptoms caused by hRSV, the economic and social Human respiratory syncytial
impact of this infection worldwide, and how this infection can be modulated using pharmacological virus; virus infection;
treatments, preventing and limiting its dissemination. The authors discuss the use of antibodies as prophylactic drugs;
prophylactic tools -such as palivizumab- and the use of nonspecific drugs to decrease the symptoms pharmacologic treatment
associated with the infection -such as bronchodilators, corticoids, and antivirals. They also discuss
current vaccine candidates, new prophylactic treatments, and new antivirals options, which are cur­
rently being tested.
Expert opinion: Today, many researchers are focused on developing different strategies to modulate
the symptoms induced by hRSV. However, to achieve this, understanding how current treatments are
working and their shortcomings needs to be further elucidated.

1. Introduction of the virion surface, with the two first described as major
antigenic proteins, inducing an anti-hRSV antibody response
The number one cause of hospitalizations for children under
[13,15,16]. Furthermore, it has been reported that the
two years old and elderly are respiratory illness caused by
G protein is necessary for viral attachment through its binding
infectious pathogens such as viruses and bacteria [1]. Among
to negatively charged cell-surface carbohydrates, such as gly­
the viruses causative of acute lower respiratory tract infection
cosaminoglycans [17]. However, the G protein is not essential
(ALRTI), human respiratory syncytial virus (hRSV) remains the
for the infection of target cells in in vitro assays, while in vivo
most prevalent one [2–4]. hRSV was first isolated the year
studies suggest that this protein is required in order to achieve
1956, was recently renamed human orthopneumovirus, and
immune evasion [18–20]. Interestingly, new reports regarding
was also reassigned into the Pneumoviridae family and the
the role of the G protein during the viral infection has shown
Orthopneumovirus genus [5]. hRSV is an enveloped virus,
that the CX3C motif presented in this protein is essential for
with a single-stranded (ss), negative-sensed and non-
hRSV-infection [21]. This effect was evaluated by blocking the
segmented RNA genome, of about 15.2 kb [4, 6]. This virus
CX3CR1 receptor with a monoclonal antibody, observing
replicates mainly in the cytoplasm of epithelial cells, where the
a decrease in the viral infection in human airways epithelial
viral RNA-dependent RNA-polymerase (L protein) is required
cells (HAE) when the receptor was blocked [21]. Mutations in
for the synthesis of its ssRNA anti-genome (+). This positive
the cysteine residues found inside of the CX3C motif showed
sensed genome will serve as a template for the synthesis of
an effect that compromises the function of the G protein [22].
new genomic ssRNA and viral proteins [7,8]. The viral tran­
The F protein is required for cellular infection, as seen in both
scription starts as soon as the fusion with the target cell occurs
in vitro and in vivo assays [23]. Since the F protein plays
-with viral antigens being detected as early as 9 hours post-
a significant role in the infective cycle of hRSV, this molecule
infection and new virions being released within 11 to 13 hours
has been chosen throughout the years as the main target for
post-infection, as reported by different in vitro studies [9–11].
the development of drugs to reduce or inhibit this virus infec­
The released viral particles exhibit a pleiomorphic form and
tive capacities [24,25]. Several cell surface molecules had been
a diameter ranging between 60 and 350 nm [12].
described to interact with the F protein, such as TLR4 and
hRSV’s genome encodes for eleven proteins, nine of them
nucleolin, among others [26]. The SH protein has been reported
structural, and the rest of them non-structural [13,14]. The
to form ionic channels in the membranes of infected cells, while
fusion glycoprotein (F), the attachment glycoprotein (G), and
also being involved in the activation of the inflammasome [27].
the small hydrophobic protein (SH) are the main components

CONTACT Dr. Alexis M. Kalergis [email protected] Facultad De Ciencias Biológicas, Pontificia Universidad Católica De Chile. Av. Libertador Bernardo
O’Higgins Nº 340, Santiago 8331010, Chile
© 2020 Informa UK Limited, trading as Taylor & Francis Group
2 A. M. KALERGIS ET AL.

The words used in the search for information included (but

Article highlights were not limited to): respiratory syncytial virus, bronchodilator
● hRSV generates an inadequate non-protective immunology memory,
against RSV, corticoids against RSV, antivirals against RSV,
causing frequent reinfections in children, leading to hospitalization antibodies against RSV and vaccine candidate against RSV.
due to bronchiolitis, pneumonia, and -in critical cases- neurological
manifestations.
● Palivizumab is a monoclonal antibody against F protein of hRSV, and
is the only FDA-approved prophylactic approach.
● Bronchodilators and corticosteroids are common pharmacological
3. Symptoms, complications, and hospitalization
measures used to mitigate disease symptoms, and ribavirin is the costs associated with hRSV
only antiviral currently approved by the FDA used to palliate hRSV
disease. As previously mentioned, hRSV causes respiratory illness
● The development of novel therapies to treat hRSV have focused on mainly in the upper and lower respiratory tract, which can
the development of antibodies and antivirals that could modulate
the essential mechanisms for the replicative and infective cycle, the
progress into more severe manifestations, such as bronchiolitis
survival, or the latency processes of this virus. and pneumonia [30]. Bronchiolitis is characterized as the
● Development of hRSV vaccines prototypes are promising approaches inflammation of the bronchiolar epithelium and the subse­
to treat hRSV. Among these are the generation of genetically mod­
ified virus, subunit vaccines, Virus like-particles (VLPs), and recombi­
quent obstruction of the airway, lasting up to 5 days.
nant live-attenuated vaccines. Wheezing or asthma can be developed after the episode of
● rBCG-N-hRSV is a live-attenuated vaccine that promotes a robust bronchiolitis is resolved. Pneumonia is characterized as the
immune cellular and humoral response in humans as shown recently
in a phase I clinical trial.
inflammation of the alveoli, resulting in a more severe disease
as compared to bronchiolitis, which can last up to 2 weeks
This box summarizes key points contained in the article. [31,32]. Among the most commonly described risk factors for
the development of hRSV-associated ALRTI, premature birth,
maternal smoking, immunosuppression, and chronic lung and
heart illnesses are found [33,34]. Data from a study published
The remaining structural proteins can be found inside the the year 2015 shows that hRSV-associated ALRTI episodes
viral particle: the matrix protein (M), the M2-1 and M2-2 pro­ result in millions of hospital admissions and around thousands
teins, the nucleoprotein (N), the phosphoprotein (P), and the of hospital deaths in young children with or without risk
L protein. NS1 and NS2 are the two non-structural proteins factors [30,34]. As this virus elicits an inadequate immunologi­
found in hRSV’s genome and are quickly expressed during the cal memory, reinfections are frequent during both childhood
infective cycle, as they are found at the beginning of the viral and adulthood, although the severity of hRSV infections is
genome [16,28,29]. Upon expression of these non-structural mild in healthy adults [35]. According to the literature, this
proteins, a decrease in Stat2 has been registered leading to decrease in the severity is related to an increase of neutraliz­
the interference of type I IFN pathways on infected cells [28,29]. ing antibodies titers developed throughout life [35].
The replicative cycle of hRSV begins with the viral attach­ Furthermore, the immune system maturity and physiological
ment to its host cell surface-mediated by the G protein, as characteristics of the airway (such as pulmonary capacity) are
stated above. Next, the plasma membrane of the host cell also factors that decrease the severity of hRSV disease in adult
fuses with the virion envelope – composed of plasma mem­ subjects [36–38].
brane from the cell from which it was originated-, a process The elderly are also considered high-risk populations, par­
that is mediated by the F protein. Then, the hRSV nucleocap­ ticularly as their immune system is senescent, and the immune
sid -composed of the viral genome associated with N, P, L, and response elicited against hRSV is inefficient [39,40]. Moreover,
M proteins- is released into the host cell cytoplasm, where the in these individuals, hRSV infections cause high morbidity and
replication and the transcription of the viral genome will start. mortality, as co-infections with other respiratory viral agents -
Eventually, viral particles will be assembled in the surface of such as influenza A- can be detected every winter season [41].
infected cells, and budding of new infective viruses will start, Remarkably, neurologic manifestations have also been
repeating the cycle from this point [15,16]. described in some hRSV-related cases, although they are
detected less frequently than other side symptoms such as
heart problems or hepatic complications [42–44]. hRSV infec­
2. Methodology and literature search
tion has been associated with encephalopathies and encepha­
This manuscript is based on a literature search which went as litis [43–45]. Despite the low reported frequency of these
follows: For the abstract, the search engine used was PubMed. neurological manifestations, elevated levels of IL-6, IL-8, TNF-
While using this platform no date restrictions were made and α, CCL2, and CCL4 have been described in cerebrospinal fluid
words employed for the search included (but were not limited (CSF) [46,47]. Although studies associated with neurological
to): respiratory syncytial virus, pharmacological treatments, complications are few, the causes or the risk factors associated
drugs, antibodies, and vaccine against RSV. As for the main with these neurological complications remain unknown up to
text, the search engines used were PubMed, Google Scholar date [48]. It has been proposed that inflammation caused by
and WHO websites. For the first two platforms, no restrictions hRSV infection in the lungs may promote central nervous
of date were made, although for sections regarding treat­ system (CNS) alterations [47–50]. Interestingly, it has been
ments -such as vaccine and antibodies against RSV- the latest reported that hRSV is able to infect neurons innervating the
reports were used in order to have an updated review. While lung tissue, therefore suggesting that hRSV could be playing
using the WHO website, the latest reports were considered. a role in such neurological alterations [51].
 EXPERT OPINION ON PHARMACOTHERAPY 3

Since up to date no licensed vaccines for this virus are

commercially available, in the following sections we will
describe the current strategies considered for the develop­
ment of pharmacological treatments and the prevention of
hRSV infections and their symptoms.

4. Prophylactic measures against hRSV

The most common prophylactic approach used against hRSV
is the passive transference of antibodies that modulate viral
infection in the host. Several antibodies have been evaluated
for this purpose, being the first tested a polyclonal pool of Figure 1. Current pharmacological treatments administrated to hRSV-
IVIG-hRSV antibodies (RespiGam, Massachusetts Public Health infected children. The figure shows the four main pharmacological possible
Biologic Laboratories, and MedImmune, Inc, Gaithersburg, treatments applied to hRSV-infected children. Palivizumab is the only one admini­
strated to the high-risk population (premature children and children with heart-
MDe) [52]. This treatment was approved by the Food and related diseases). The bronchodilators, corticosteroids, and antivirals are mainly
Drug Administration (FDA) in 1996 for the use in hRSV high- used in hRSV-infected children as palliative treatments, and thus they should
risk populations, in order to prevent high morbidity and mor­ reduce the inflammation and the obstruction of the airways seen in this disease.
tality in these children [53]. These specifics polyclonal IVIG-
hRSV antibodies were initially evaluated on children with car­
diac illness and in preterm infants, exhibiting a decrease in the out later to evaluate different concentrations and number of
number of hospitalization days and in the symptoms induced dose administration, and the respective prophylactic effects
associated with this disease, when a high dose −750 mg/kg- [57–59]. Studies performed in children with risk factors (such
was administrated [52]. Since this polyclonal IVIG-hRSV pool of as being premature), evaluated the efficacy and the dose
antibodies could be administered in multiples doses, they had administration of this drug, concluding that about five doses
a higher chance to achieve increased protective capacity, from this monoclonal antibody were necessary to decrease the
resulting in fewer respiratory problems in children, when disease symptoms induced by hRSV in children under two
compared to a single dose of administration. These increased years of age [58,59]. Remarkably, a dose of 150 mg/kg was
protective capacities were independent of the recurrence of described as an effective dose for administration [60]. These
hRSV infection [54]. Despite the positive results associated studies also showed that palivizumab was efficient as
with this treatment, currently, the use of monoclonal antibo­ a prophylactic method, therefore it protects against the most
dies is the most commonly chosen strategy against this viral severe symptoms of hRSV-infection and overall decreases the
pathogen, and multiples studies and technologies are being disease caused by this virus [57–59].
evaluated to increase the efficiency of these drugs.
Nowadays, there is only one prophylactic antibody -called
4.2. Motavizumab
palivizumab- approved for human use by the FDA, which will
be addressed in the following section [55]. Accordingly, drugs This drug is also a monoclonal humanized antibody that tar­
other than palivizumab that have been tested for use in gets the F protein of hRSV, just as palivizumab does. The main
humans will also be reported in further sections. difference of Motavizumab with palivizumab is a change of
thirteen amino acids in the variable region of its structure,
although this keeps its capacity to recognize the F protein of
4.1. Palivizumab – the first line of defense against hRSV
hRSV [61,62].
The current first line of defense against hRSV infection is Motavizumab exhibited enhanced capacities to decrease
a drug called palivizumab, also known as MEDI-493 (Synagis, the pathology induced by hRSV as compared to palivizumab,
MedImmune, Inc, Gaithersburg, MD), as shown in Figure 1. in both animal models [61,63] and humans [64,65]. However,
This drug is a humanized IgG monoclonal antibody that recog­ despite the excellent results reported for the administration of
nizes the F protein of hRSV, blocking the fusion of the viral motavizumab and its extraordinary capacity to neutralize the
particle with the membrane of the target cell [55]. This anti­ entry of the virus into the host cell, a phase III clinical trial
body was first tested in vivo in cotton rats, where palivizumab showed that the use of this antibody promoted the appear­
was administrated one day prior to hRSV infection, exhibiting ance of multiple adverse events, such as rashes and skin-
a decrease in the pulmonary damage as compared with the allergies [65]. As a result, this antibody was not approved by
animals that were not treated with this antibody. Its protective the FDA for human use since further adverse events could
capacities were also tested in different animal models, and emerge [65].
eventually, clinical trials were performed to evaluate its impact Since many of the antibodies generated against the
on humans [55]. F protein did not show protective capacities, the G protein
The first study performed in humans considered a cohort of has gained interest for the development of these therapies.
children with less than 35 weeks of gestation, where the A study performed in 2015 compared two monoclonal anti­
authors could determine that a monthly administration of bodies against the F- and G- proteins of hRSV, showing
palivizumab decreased the symptoms associated with hRSV- a better effect in the anti-G-monoclonal antibody than for
infection in this study group [56]. Several studies were carried the anti-F monoclonal antibody [66]. Reports suggest that
4 A. M. KALERGIS ET AL.

antibodies against the G protein will be good candidates for is quite controversial, since there are not enough reports to
the development of therapies against hRSV [67]. support its administration for the treatment of the symptoms
caused by hRSV [78,82].

5. Pharmacological measures currently used to

palliate hRSV disease 5.2. Corticosteroids use during hRSV infections
There are several drugs -other than antibodies- that can be Corticosteroids are steroid hormones commonly used when
used to decrease the symptoms from the illness caused by patients exhibit severe symptoms of allergies or inflammatory
hRSV, and in most cases, they are the main option to treat the problems, in order to suppress the excessive immune
bronchiolitis and pneumonia resulting from this infection [68]. response elicited in these subjects [83,84].
However, the vast majority of the drugs used to reduce these The use of corticosteroids can be considered as a treatment
more severe symptoms have not been completely proven to when infants infected with hRSV exhibits symptoms such as
be efficient. Some of the pharmacological measures used bronchiolitis or wheezing -as shown in Figure 1- although
against hRSV are discussed below, and their targets and the some studies suggest that there is no clinical improvement
symptoms treated are found in Table 1 and will be discussed from this treatment [73,85,86]. Corticosteroids activate the
in the following section. glucocorticoid receptors found in the muscle cells from the
lungs and in some immune cells such as macrophages, den­
dritic cells, and T lymphocytes [87,88]. The route of adminis­
5.1. Bronchodilators used during hRSV infections tration of the corticosteroids (oral, intravenous, or inhaled)
Bronchodilators are non-steroid drugs that work by relaxing does not seem to significantly impact the effectiveness of
the muscle cells in the airway [69,70]. Therefore, these mole­ these treatments, and therefore they are not recommended
cules are generally used in patients with symptoms of asthma for patients infected with hRSV. In a study performed in infants
or with obstruction of the airways, which are common features infected with hRSV and diagnosed with bronchiolitis, corticos­
seen during infections with hRSV, as described above [71,72]. teroids administration was not able to diminish the long term
In this line, bronchodilators are also considered for the treat­ consequences produced by hRSV [78,86,89,90].
ment of this infection Figure 1 [73]. Different clinical trials have
shown that the use of bronchodilators in children suffering
5.3. Antivirals used against hRSV
from bronchiolitis results in a general improvement of the
health status, at least in the short time [74,75]. Despite this, There are several drugs currently being used as antiviral thera­
the use of these drugs in patients afflicted with hRSV is not pies, depending on the pathogenic agent that must be faced.
recommended [68,76]. They work in different ways and consider several approaches,
Bronchodilators can be categorized into different types although their ultimate goal is to inhibit the replication cycle
according to the way they perform their actions. Two exam­ of the virus [91]. Ribavirin is a guanosine analog and is the
ples of widely used bronchodilators are β2-adrenoreceptor main antiviral treatment used to manage the most severe
(AR) agonists and epinephrine. The β2-AR agonist can also symptoms caused by hRSV (as shown in Figure 1), as this
be sub-classified into short-acting β2-AR agonist and long- drug is able to suppress the replication of hRSV effectively
acting β2-AR agonist. Their target -as their name suggests- [92]. Treatment with Ribavirin was originally recommended to
are the β2-AR found in type I and II alveolar cells, macro­ patients who suffered from severe illness or that were more
phages, and neutrophils, among other cells [69,77]. susceptible to develop complications from the disease caused
Interestingly, the use of β2-AR agonist is not enough to by hRSV, therefore being considered as risk populations [93].
increase the oxygen intake levels in patients infected with This antiviral is currently used in high-risk children, as it has
hRSV [78,79]. Epinephrine works as an α-adrenergic agonist been proven to modulate the bronchiolitis caused by hRSV
and β-adrenergic agonist combined, and it targets the α- and [94]. However, the use of this drug remains controversial, due
β-adrenergic receptors located in the muscle cells at the to its route of administration, cost and the irregular course the
bronchioles [80,81]. Use of epinephrine to treat bronchiolitis disease might take. However, when Ribavirin is administered

Table 1. Current drugs used as pharmacological treatment.

Drug Target Treated symptom Reference
Bronchodilators β2-adrenoreceptor agonist β2-adrenergic receptor Asthma [66](Cazzola 2012)
Bronchiolitis [68](Celli 2004)
[69](Bateman 2008)
[71](Spina 1989)
Epinephrine α- and β-adrenergic receptor Asthma [68](Celli 2004)
Bronchiolitis [69](Bateman 2008)
[74](Barr 2000)
[75](Blumenthal 1969)
Corticoids Glucocorticoid receptor Bronchiolitis [79](Lee 2011)
Wheezing [80](Cade 2000)
[81](Barnes 2003)
[82](Schwiebert 1996)
Inhibitors of the replication cycle of the virus RNA and DNA Bronchiolitis [86](Jafri 2003)
 EXPERT OPINION ON PHARMACOTHERAPY 5

in an aerosol-format, this treatment is capable of decreasing and humoral response, being able to improve viral clearance
viral loads detected and improve the overall health of hRSV- in murine models [115,116,118]. Reports also suggest that this
infected subjects [95,96]. response is mainly triggered by polarization of CD4+ T cells
Up to date, the mechanisms underlying the effectiveness of toward a Th1-like profile, accompanied by the secretion of
Ribavirin during an hRSV infection have not been elucidated. antiviral cytokines such as IFN-γ, and the activation of cyto­
However, it has been described that this drug -as an analog of toxic CD8+ T cells. These protective results were also validated
guanosine- is able to impact the synthesis of new RNA mole­ by adoptive transfer assays, where the authors showed that
cules from this virus, prompting the generation of errors in the a transfer of both CD4+ and CD8+ T cells was required to
transcription and therefore generating non-viable viral parti­ achieve a proper clearance of the virus [115,116].
cles [97,98]. Ribavirin has been reported to induce the expres­ This vaccine prototype was also able to promote an enhanced
sion of IFN-stimulated response genes. Ribavirin is the only humoral immune response, promoting the secretion of antibodies
current treatment approved by the FDA as an antiviral against against the N protein of hRSV, along with antibodies against other
hRSV, although it is not recommended to use routinely, as viral proteins [118]. Interestingly, the antibodies secreted exhibited
adverse effects have been reported -such as anemia, arrhyth­ a high neutralizing effect, leading to decreased viral loads. These
mia, and chest pain [99–101]. antibodies were also capable of promoting protection in passive
transfer assays, showing even better protective capacities than
palivizumab [118]. Finally, a recent study using this vaccine
6. Emergent therapies to treat hRSV
under current Good Manufacturing Practice (cGMP) and a single
So far, we have described the limited treatments that are and low dose of immunization (5x105 CFU) showed a protective
currently being used in order to face hRSV infection. Since role of both cellular and humoral immune response against hRSV
these treatments are not always optimal, we still require new [117]. These results were evaluated fifty days after immunization,
studies for the generation of novel prophylactic and therapeu­ showing that vaccinated mice exhibited better protectives para­
tic approaches to control the disease caused by this virus. In meters than non-vaccinated mice. This vaccine candidate was
the following section, we will discuss different drugs and efficient not only in the induction of an immune response against
vaccines that have been developed and tested in animal hRSV but also against M. tuberculosis antigens [117].
models and have undergone clinical trials -in order to elicit GlaxoSmithKline (GSK) generated two recombinant versions
their safety, immunogenicity, and effectiveness, among other of the F protein -hRSV F-020 and hRSV-F024- as vaccine proto­
characteristics-, that will aid in the prevention and reduction types, and they are currently being evaluated in clinical trials.
of the incidence of hospitalizations caused by hRSV. These recombinant F proteins were designed using the pre-
fusion conformation of this protein, as this conformation exhi­
bits more epitopes for antibody-binding, than its post-fusion
6.1. Development of hRSV vaccines
conformation [120]. Clinical trials performed with a cohort of
Since the discovery of hRSV in 1956, different vaccine prototypes healthy male adults reported some secondary effects, although
have been developed [102]. The first vaccine tested in humans in they were transient and of minor-to-medium intensity, after
1960 was a formalin-inactivated hRSV (FI-hRSV), which promoted vaccine administration. When trials were performed in
an exacerbation of the original disease caused by hRSV. a cohort of women of fertile age, the authors could report
Immunization with this drug triggered severe clinical manifesta­ that vaccination was safe and that it was able to promote the
tions that were not reported in ordinary cases of hRSV, such as high induction of antibodies with neutralizing capacities.
mucus secretion, collapse of the airways, and a pro-inflammatory Remarkably, women pregnant in this cohort gave birth to chil­
cytokines secretion that lead to the infiltration of several immune dren without congenital complications or any other diseases
cells into the lungs [28,103,104]. The use of this FI-hRSV vaccine that could be associated with the vaccine. Only two sponta­
resulted in an increased number of hospitalized children and even neous abortions were found in these patients, although no
the death of two of them, retiring this vaccine prototype from the relation to the vaccine could be established [121–123].
field [28,103,104]. Nowadays, several efforts to develop a vaccine LIDcpΔM2-2 is the name of a live-attenuated vaccine candi­
are being held, exploring different methodologies for this aim, date that has been tested to modulate the incidence of hRSV.
such as the generation of genetically modified virus [105–107], This drug was generated through the deletion of the M2-2
subunit vaccines [108–110], Virus like-particles (VLPs) [111–114], protein of hRSV in a wild-type serotype A virus, followed by five
and recombinant live-attenuated vaccines [28,115–118]. cold passages to further attenuate it. This vaccine exhibited low
Interestingly, these vaccine prototypes are promising approaches, protectives effects and low titers of neutralizing antibodies,
as published in several reports performed in animal models. when it was tested in children who were seronegative for hRSV.
Among the most promising vaccines candidates evaluated In light of these results, this vaccine prototype was withdrawn as
nowadays stands out a live-attenuated vaccine based in a possible candidate to prevent hRSV infection [124–126].
a recombinant Mycobacterium bovis Bacillus Calmette-Guerin DS-Cav1 is the name of a vaccine currently in phase I clinical
(rBCG) that expresses the nucleoprotein of hRSV (rBCG- trials, that consists of a stabilized F protein in its pre-fusion
N-hRSV). This vaccine prototype was already tested in conformation. During clinical trials, antibody titers were of better
a phase 1 clinical trial with positive results [119]. Different quality, after four weeks post-immunization, than the ones pro­
studies performed with this rBCG-N-hRSV vaccine showed duced with earlier hRSV immunogens [127]. Further studies are
that a double immunization (dose 1 × 108 CFU) with this required to evaluate its efficacy and the reduction of the disease
prototype was able to promote a robust immune cellular severity that this vaccine prototype could induce.
6 A. M. KALERGIS ET AL.

rationale behind the use of this antibody considers that an

interaction between this antibody and the N-hRSV protein
could neutralize the negative effects reported by this protein
and promote an efficient immunity. The vast majority of
antibodies generated for therapeutic purposes are focused
on the F protein of the virus, however this protein under­
goes conformational changes from a pre-fusion to a post-
fusion state, hampering the production of these drugs. The
N protein could be an excellent new target, given its con­
servation and biological importance for viral replication

Figure 2. Targets for novel therapies against hRSV-infection. At the left of 8. New antiviral treatments against hRSV
the figure, all the proteins of hRSV are depicted. At the center of the figure,
a representation of the viral particle of hRSV is found. Different arrows, going hRSV inhibitors are also being studied and generated in order to
from the different viral proteins, show the new candidate targets currently
studied for the development of different pharmacological therapies such as provide an option for the use of Ribavirin, which cannot be used
vaccines and prophylactic monoclonal antibodies. Also, the gray boxes show routinely. ALN-RSV01 is the name of a synthetic, double-
other pharmacological therapies focused on antiviral molecules that affect stranded, partially complementary small interfering RNA
different processes vital for the viral infection.
(siRNA) against the n gene, that is currently used as a drug to
impair hRSV replication [138]. A phase 2 clinical trial was held
Different vaccine prototypes have been developed. These the year 2007 for this antiviral, with a cohort of subjects of at
prototypes can be found in Figure 2, and are currently being least 18 years old, with lung transplant (LTx) and diagnosed with
evaluated in clinical trials, among which we can highlight hRSV. This report shows that ALN-RSV01 is safe and well-
MEDI-559 [128], the ΔSH prototype [129], hRSV cps2 [130] tolerated and exhibits an antiviral protector effect [138–140].
and the ΔNS2 Δ1313/1314 L prototype [131] and rBCG- Presatovir or GS-5806 is another drug that is currently
N-hRSV(clinical trials NCT03213405). being tested against hRSV. This drug is a small orally adminis­
tered molecule that targets the F protein, inhibiting the fusion
of the virus with its target cells. Results obtained from a study
using healthy volunteers showed that Presatovir significantly
7. New prophylactic treatments against hRSV
reduced hRSV viral loads and clinical signs and symptoms
Nowadays, the primary focus of prophylactic treatments is the [141,142]. Remarkably, clinical trials associated with this drug
development of antibodies that could recognize the two major considering its evaluation in healthy adult men with LTx or
antigenic proteins found in hRSV, the F and G proteins, as shown hematopoietic cell transplant, showed a significant reduction
in Figure 2 [13,15,16]. MEDI-8897 and REGN-2222 are also mono­ in the total weight of mucus generated, the total symptom
clonal antibodies that are currently being tested and that share score, and no serious adverse events were registered
as a target the F protein of hRSV, recognizing the protein in its [143,144]. Bioinformatics analyses have also been able to
pre-fusion conformation [132–134]. Both of these antibodies are detect different possible targets of interest to generate anti­
currently undergoing clinical trials in either phase II and phase III virals against hRSV (as shown in Figure 2). Three main cate­
[135], respectively. So far, results associated with these studies gories were chosen, depending on their mechanism of action:
have shown a good range of tolerance and low immunogenicity. N protein inhibitors, RNA-dependent RNA polymerase (L pro­
The final goal with these antibodies is to induce a reduction in tein) inhibitors, and F protein inhibitors [145]. Within these
the symptoms of ALRTI -and hopefully prevent it- in patients with categories, different antivirals targeting these three proteins
a single or double intramuscular (IM) dose. Interestingly, efforts can be found. Among those proved to be tolerable in volun­
to develop antibodies targeting the G protein of hRSV are still in teers infected with hRSV are: EDP-983, which targets the
progress, as the characterization of the sequence identity of this N protein; lumicitabine (ALS-008176), which targets the
protein has reached only 60% of advance. Without the complete L protein; and JNJ-53,718,678 and sisunatovir (RV521), which
sequence identity of this protein, it is difficult to know the targets the F protein [142,146–149]. Bioinformatics analyses
possible targets that antivirals can aim for [136]. can open doors to further advances in the study of novel
Finally, another candidate to use as a therapeutic target drugs with enhanced effects to protect against hRSV, which
that is currently under evaluation is the N protein of hRSV, as can also be used with fewer limitations.
it has been demonstrated that this protein is able to affect
the proper assembly of an immunological synapses [137].
9. Conclusion
The suggested mechanism associated to this considers the
recently reported capacity of the N protein to migrate As discussed in this work, hRSV-associated infections result in
toward the surface of infected cells, where it can generate millions of hospitalizations around the world, affecting mainly
clusters of N proteins near the contact zone of the peptide- children, elderly and immunosuppressed patients, causing not
MHC complex and the TCR (T Cell Receptor) [137]. Since this only ALRTI but also, in some extreme cases, non-pulmonary
is a novel target, it is not surprising that a new monoclonal related symptoms such as encephalopathies and encephalitis.
antibody against this protein has already been generated Nowadays, prophylactic treatments against hRSV are mainly
and its currently being evaluated in preclinical studies. The limited to palivizumab, the only FDA-approved antibody
 EXPERT OPINION ON PHARMACOTHERAPY 7

against the F protein of the virus. The pharmacological man­ combinations of drugs for symptoms which appear later might
agement of hRSV is based on palliatives drugs, including be a good approach to aid in the control of the disease.
bronchodilators -with insufficient evidence to date of its capa­ Recent reports from the Program for Appropriate Technology
city to decrease the symptoms associated to this disease-; in Health (PATH) indicate an increase in different new designs for
corticoids -that suppress the excessive immune response eli­ the development of vaccines against this virus, using several new
cited during cases of bronchiolitis and wheezing-; and viral proteins as a target for its modulation [150]. For instance,
Ribavirin, the only FDA-approved antiviral therapy that aids the G and SH proteins and the N and M2 proteins of hRSV are
in the control of hRSV, although its routine use is not recom­ among the new candidates. Interestingly these proteins are
mended, being limited to patients with severe illness. Further being considered as new targets of research, suggesting that
studies and the development of new drugs are still required in the scientific community now understands that the develop­
order to effectively control the global burden that this virus ment of new approaches as therapies against hRSV is mandatory.
possesses in high-risk populations. Therefore, we believe that in the near future, we as researchers
will be able to finally generate a vaccine capable of protecting
children of the disease caused by hRSV, by promoting the search
10. Expert opinion
of new technologies in collaborative fields, such as the genera­
Human Respiratory Syncytial Virus (hRSV) is known as one of the tion of new antibodies with therapeutic potential or even new
most important causes of respiratory problems in children and drugs with antiviral potential that will be specific against hRSV or
high-risk populations. However, since its discovery in the year other agents with similar characteristics.
1956, six decades have gone without achieving the develop­ However, in order to move forward and reach this final aim,
ment of an effective vaccine or treatment than can be used in all we still need to understand how the virus is able to modulate -
the populations that are highly vulnerable to this virus. and also evade- the immune system. This new understanding
Currently, palivizumab is the only prophylactic treatment will allow us to explore new molecular targets or will lead us
approved by the FDA for human use, and is only administrated to develop new drugs that could modulate the mechanisms
to high-risk children due to the high costs associated with the that are essential for the replicative and infective cycle, the
administration of its five doses required during the winter sea­ survival, or the latency processes of hRSV.
son. This heavy economic burden difficult its access and avail­ In this line, our laboratory is mainly focused in the understand­
ability to the most economically vulnerable population. ing of the role of the N protein of hRSV during its infection, as it has
The lack of treatments and drugs available today to treat been reported that this protein plays a negative role in the regula­
the symptoms associated with this disease is probably asso­ tion of the immunological synapsis -a process required for the
ciated with the low understanding of most of the molecular proper activation of lymphocytes. As we believe that the N protein
regulation processes that the virus is able to promote in the of hRSV is an interesting therapeutic target to modulate this viral
host. However, great efforts have been performed so far in infection, our group has worked strongly in developing and char­
order to understand these mechanisms and develop new acterizing a vaccine that expresses the N protein of hRSV. So far,
technologies to confront this disease. One of the main targets we have reported successful results in several animal models, with
for the development of therapies and vaccines is the F protein remarkable safety and protective capacities [117]. Just recently, we
of hRSV, as this protein is essential for the fusion of both viral underwent a phase I clinical trial with this vaccine, reaching posi­
and host membranes and, as a consequence, the beginning of tive results soon to be published. All of this allows us, as scientists,
the infective cycle. Moreover, this protein has been thoroughly to be more prepared in the field of basic and applied research
characterized and several of its immunogenic epitopes have against hRSV, focused mainly on the study of the N protein.
been widely studied and used for the design of treatments
and vaccines. Some of the drugs generated against this pro­
Funding
tein are palivizumab, motavizumab, and MEDI-8877 -all of
these drugs used as prophylaxis treatment. The hRSV F-020 This research was funded by FONDECYT 1190830, the Millennium Institute
and hRSV-F024 (GSK) are vaccine candidates that, along with on Immunology and Immunotherapy P09/016-F and COPEC-UC 2019.
the recently withdrawn Novavax vaccine candidate (based in R.1169. AMK is a Helen C. Levitt visiting professor at the Department of
Microbiology and Immunology of the University of Iowa.
nanoparticles associated with the F protein), exhibited low
protective effect during their phase III clinical trials.
Another factor that may negatively impact the effect of the
Declaration of interest
drugs available to treat the symptoms of this disease might be
the inability to identify the stage of the infection. This is relevant JA Soto has received Comisión Nacional de Investigación Científica
y Tecnológica/The National Fund for Scientific and Technological
as, depending on this factor, the use of a specific antivirals may
Development (CONICYT/FONDECYT) POSTDOCTORADO grant No. 3,190,590
not be of actual help. Accordingly, lack of expertise to recognize while NMS Galvez is supported by CONICYT grants No. 21,190,183.
that symptoms as pneumonia can come from different patho­ K Bomhwald is supported by CONICYT/FONDECYT POSTDOCTORADO grant
gens -such as bacteria- might lead to an inefficient use of antiviral No. 3,180,570. AM Kalergis is a Helen C. Levitt Visiting Professor at the
drugs, as these pathogens are not the target for the chosen Department of Microbiology and Immunology of the University of Iowa. The
authors also declare that they have filed a patent application for an anti-N mAb
treatment. The current primary concern during respiratory-
that may be considered as a conflict of interest. The authors have no other
related diseases is to mitigate the immediate severe symptoms. relevant affiliations or financial involvement with any organization or entity
However, symptoms that are develop later like wheezing, are not with a financial interest in or financial conflict with the subject matter or
really the aim of current therapies. Administration of different materials discussed in the manuscript apart from those disclosed.
8 A. M. KALERGIS ET AL.

Reviewer disclosures 12. Jeffree CE, Rixon HWML, Brown G, et al. Distribution of the attach­
ment (G) glycoprotein and GM1 within the envelope of mature
One referee declares affiliation with IMV Inc, a company that in its pipeline respiratory syncytial virus filaments revealed using field emission
has a vaccine for RSV, known as DPX-RSV(A). Peer reviewers on this manu­ scanning electron microscopy. Virology. 2003;306(2):254–267.
script have no other relevant financial relationships or otherwise to disclose. 13. Hacking D, Hull J. Respiratory syncytial virus - viral biology and the
host response. J Infect. 2002 Jul;45(1):18–24.
14. Schmidt A, Couch R, Galasso G, et al. Current research on respira­
tory viral infections: third International Symposium. Antiviral Res.
Authors’contributions
2001;50(3):157–196.
All authors listed have made substantial, direct, and intellectual contribu­ 15. Collins PL, Graham BS. Viral and host factors in human respiratory
tion to the work and approved it for publication. syncytial virus pathogenesis. J Virol. 2008;82(5):2040–2055.
JS: conceptualization, writing original draft, review, editing and revision. 16. Ruuskanen O, Ogra PL. Respiratory syncytial virus. Curr. Probl.
NG: writing original draft, review, editing and revision. Pediatr. 1993;23(2):50–79.
CA: writing original draft 17. Mastrangelo P, Hegele RG. RSV fusion: time for a new model.
KB: writing original draft Viruses. 2013;5(3):873–885.
AF: writing original draft 18. Radu G, Caidi H, Miao C, et al. Prophylactic treatment with a G
SB: editing and revision glycoprotein monoclonal antibody reduces pulmonary inflamma­
AK: conceptualization, revision of original draft, editing and revision of tion in Respiratory Syncytial Virus (RSV)-challenged naive and
final version. formalin-inactivated RSV-immunized BALB/c mice. J Virol. 2010
Sep;84(18):9632–9636.
19. Haynes LM, Caidi H, Radu GU, et al. Therapeutic monoclonal
ORCID antibody treatment targeting respiratory syncytial virus (RSV)
G protein mediates viral clearance and reduces the pathogen­
Alexis M. Kalergis http://orcid.org/0000-0001-7622-5263 esis of RSV infection in BALB/c mice. J Infect Dis. 2009;200
Nicolás M. S. Gálvez http://orcid.org/0000-0003-2046-7882 (3):439–447.
Susan M. Bueno http://orcid.org/0000-0002-7551-8088 20. Harcourt J, Alvarez R, Jones LP, et al. Respiratory Syncytial Virus
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