Monoclonal Antibodies for Prevention of Respiratory Syncytial Virus Infection : The Pediatric Infectious Disease Journal

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Monoclonal Antibodies for Prevention of Respiratory Syncytial Virus Infection

Rodriguez-Fernandez, Rosa MD, PhD*,†; Mejias, Asuncion MD, PhD, MsCS*; Ramilo, Octavio MD*

Author Information
The Pediatric Infectious Disease Journal 40(5S):p S35-S39, May 2021. | DOI: 10.1097/INF.0000000000003121
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Abstract

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants and represents around 60% of all lower respiratory tract infections in children younger than 5 years of age.1,2 RSV can also affect other vulnerable groups such as the elderly and immunocompromised patients.3 Globally, it is estimated that RSV causes about 34 million episodes of acute lower respiratory infections in children under the age of 5, representing approximately 3.4 million hospitalizations per year and about 66,000–199,000 deaths worldwide.1,2 In low middle–income countries, RSV represents the second cause of infant mortality, only after malaria.4,5 In the United States, RSV is responsible for 1 in 13 visits to pediatric offices, 1 in 38 visits to the emergency department and 1 of 334 hospitalizations in children under 5 years. In the first year of life, approximately 70% of infants have been infected with RSV at least once, and seropositivity is approximately 100% by 2 years of age.2,6

High-risk groups for severe RSV infection are well defined, including children with prematurity, chronic lung disease and congenital heart disease (CHD). Vulnerable patients, such as children with Down syndrome and immunodeficiencies, are also at high risk. Nevertheless, previously healthy term infants under 3 months of age represent the largest group of hospitalized children with severe RSV infection.7,8

The underlying mechanisms by which this infection causes such significant morbidity are not yet well defined, but it is thought that lung immaturity coupled with a dysregulated immune response play a significant role. In fact, a blood interferon signature characterized by decreased expression of IFN-related genes, has been identified in infants under 6 months of age hospitalized with RSV infection, which was associated with a more prolonged hospitalization and increased days of supplemental oxygen.9,10

It is estimated that almost half of infants hospitalized for RSV bronchiolitis develop long-term pulmonary sequelae, including recurrent wheezing during childhood. It is has been proposed that that preventing RSV infection can also prevent these long-term pulmonary sequelae.11–14

RSV was discovered in 1956 and despite the high disease burden and the global impact of this virus, especially in infants, currently there are no licensed vaccines, although there are several candidates at different stages of development.15,16 Palivizumab, a monoclonal antibody against the F protein of RSV, is the only licensed product for prevention of RSV in high-risk children. However, in recent years, we have witnessed a major effort to develop new strategies for the prevention of RSV infections including vaccines and enhanced monoclonal antibodies (mAb).17,18 This manuscript will summarize recent advances in the development of new monoclonal antibodies directed to RSV. Vaccines have been recently reviewed elsewhere.15

VIRAL STRUCTURE

RSV is a negative, single-stranded RNA orthopneumovirus that belongs to the Paramyxoviridae family and Pneumovirinae subfamily. It has 2 antigenic subgroups, A and B that can cocirculate each season. RSV genome contains 10 genes that encode 11 proteins. Two of these surface proteins are crucial for infectivity and viral pathogenesis, the fusion (F) protein F and the attachment (G) protein, since they are capable of inducing neutralizing antibodies. The F protein allows the virus to enter into epithelial cells and induces the fusion of both the viral and the cellular membranes, inducing the production of the characteristic syncytia. Different cellular receptors for the RSV F protein have been identified including heparan sulfate, ICAM-1, TLR-4 and nucleolin.19–22 The G protein is responsible for the attachment of RSV to the cells of the ciliated respiratory epithelium. The cellular receptors that adhere to the G protein are heparan sulfate, surfactant protein A, annexin II and CX3CR1.23–25

Recently, McLellan et al (2013) resolved the 2 conformational forms of the RSV F protein F: the prefusion (or preF) and the postfusion (or postF) forms. This discovery represents a genuine revolution for designing drugs and vaccines against RSV. The preF conformation initiates the fusion and induces higher potency neutralizing antibodies compared with the postF form. Antibodies that bind only to the preF protein are more efficient in neutralizing RSV than antibodies against the postF form.25,26 Currently, the F protein is the preferred target for the development of monoclonal antibodies (mAbs), vaccines and antivirals because it has 6 antigenic sites that induce the production of neutralizing antibodies and it is well conserved between RSV subtypes A and B. In contrast, the G protein is not well conserved between RSV strains A and B, it is heavily glycosylated and induces less potent neutralizing antibodies. For these reasons, currently the G protein is not considered a major therapeutic target.25,27–31

ANTI-RSV ANTIBODIES

Polyclonal Antibodies

The first strategy developed to provide passive immunization for prevention of severe RSV infection was the administration of intravenous polyclonal gammaglobulin with high titers of neutralizing antibodies against RSV (RSV-IGIV). This polyclonal antibody preparation was administered at a dose of 750 mg/kg once a month, 5 doses, during the RSV season to high-risk children. This preventive strategy was associated with a 40% reduction of RSV hospitalizations, as well as reductions in days of hospitalization and of days of supplementary oxygen by 50%. This preparation had limitations as it had a risk of fluid overload and interfered with vaccination schedules.32 Nevertheless, it established the proof of principle for the value of passive immunization to prevent severe RSV infections.

Monoclonal Antibodies

The next step advancing passive immunization against RSV was the development of mAb against RSV, specifically palivizumab.17,33 Compared with polyclonal gammaglobulins, palivizumab has greater neutralizing activity, and it does not risk fluid overload and altering the immunization calendar. This strategy has been focused on selected high-risk groups for RSV infection, mostly related to its high cost: namely premature infants, patients with chronic lung disease of prematurity (CLD) and patients with CHD. Currently, efforts are directed to the development of new, equally or more efficacious mAbs that are more cost effective and, even, reach the entire target infant population.17 Most anti-RSV mAbs are IgG antibodies directed against viral epitopes in the protein F (Table 1). Monoclonal antibodies against RSV include the following.

TABLE 1. - Anti-RSV Antibodies
Antibodies Class Name Development Phase CV Target Population Results
Monoclonal antibodies with standard half life Palivizumab Approved and marketed PreF & PostF protein (site II) High-risk infants Reduction in hospitalization rates by 55%
Motavizumab Phase III Not approved PreF & PostF protein (site II) High-risk infants Decrease in RSV-MALRI compared with palivizumab
MPE 8 Preclinical PreF RSV site IV and hMPV Prophylaxis Efficacious for HRSV and HMPV
TLR3D3 Preclinical G protein Treatment More potent than palivizumab, decrease airway inflammation
Monoclonals antibodies with extended half life Motavizumab-YTE Phase II interrupted PreF & PostF protein (site II) High-risk infants Half life up to 4 times longer than motavizumab
REGN-2222 (Suptavumab) Phase III. Interrupted PreF protein (site V) Premature and healthy infants Did not met the primary endpoint
MEDI-8897 (Nirsevimab) Phase IIb/III Pre F protein. (site Ø) Healthy and high-risk infants Relative risk reduction in MALRI-RSV of 70%
MK-1654 Phase I/IIa PreF and PostF (site IV) Healthy and high-risk infants Half-life of ~ 70-85

Palivizumab

In 1998, the FDA approved the use of palivizumab for RSV prophylaxis in high-risk children. It is a humanized mAb directed against the F (fusion) glycoprotein and is composed of a complement-determining region derived from a murine mAb of and a human IgG1 mAb produced by recombinant DNA technology. This mAb binds the antigenic site II of the F protein of the RSV A and B subtypes. It binds the F protein in both its preF and postF forms. Palivizumab has a half life of 28 days and, therefore, is administered once a month during the RSV season at a dose of 15 mg/kg intramuscularly (IM).17

  • - The IMPACT study a randomized, placebo-controlled clinical trial demonstrated for the first time the safety and efficacy of palivizumab. The study evaluated 1502 premature infants ≤35 weeks gestational age (wGA) and children with CLD of prematurity (former bronchopulmonary dysplasia, BPD) and showed a 55% reduction in RSV hospitalizations. Specifically, in premature infants without BPD, the reduction in RSV hospitalizations was 78% and in infants with BPD was 39%. In addition, infants who received prophylaxis with palivizumab had significantly shorter duration of RSV-associated hospitalizations, shorter duration of supplemental oxygen administration, lower rates of PICU admissions and lower disease severity scores compared with infants included in the placebo arm.17
  • - In 2003, the Cardiac Study in which 1287 children <24 months of age with CHD were randomized to palivizumab or placebo showed a 45% decrease in RSV hospitalizations in the palivizumab arm.34
  • - In 2013, the Maki Study trial conducted in the Netherlands in 429 late preterm infants (33–35 wGA), prophylaxis with palivizumab was associated with an 82% reduction in RSV hospitalizations and 61% reduction in the number of wheezing days during the first year of life.12

Since its approval in 1998, the American Academy of Pediatrics (AAP) has updated the RSV prophylaxis guidelines on several occasions. In its latest update in 2014, due in part to the high cost of prophylaxis with palivizumab, the AAP limited RSV prophylaxis to premature infants born at <29 wGA, infants <32 wGA with BPD, and infants under 12 months of age with CHD.35 A number of studies evaluated the impact of these changes in AAP recommendations in the premature population and showed an increase in RSV hospitalizations severity in premature infants 29 to 34–35 weeks GA no longer receiving RSV prophylaxis.36

Motavizumab

Motavizumab (MEDI-524) is a second-generation recombinant IgG1 mAb, derived from palivizumab and also directed against site II of the F protein.37 Motavizumab differs from palivizumab by 13 aminoacids and has more potent neutralization activity against RSV than palivizumab. Because of data derived from preclinical studies, it was thought that motavizumab would be more efficacious than palivizumab. There were a number of clinical trials that evaluated motavizumab in high-risk infants.

  • In 2010, a noninferiority trial compared motavizumab vs palivizumab in 6635 preterm infants and children under 2 years of age with CLD. The study showed that motavizumab was noninferior to palivizumab in reducing RSV hospitalizations. Furthermore, motavizumab was superior to palivizumab at preventing RSV-associated medically attended lower respiratory infections (RSV-MALRI). However, motavizumab was associated with a 2.1% increase in cutaneous hypersensitivity reactions compared with palivizumab.38
  • A subsequent study in 2011 evaluated the safety and tolerability of motavizumab compared with palivizumab in 1236 children with CHD ≤24 months. RSV hospitalization rates and MALRIs were not significantly different between the palivizumab and motavizumab groups. Safety profiles were also not different with the exception of skin rashes that were more frequent in the group that received motavizumab (19.3 vs. 16.2%).39
  • Finally, in 2015, a phase-3 randomized placebo-controlled study conducted in 2127 Native American Navajo full-term infants under 6 months of age showed a 87% decrease in RSV hospitalization rates in the motavizumab group.40

In 2010, FDA decided not to grant the license to motavizumab because it was not superior to palivizumab and was associated with a higher frequency of hypersensitivity skin reactions.

Motavizumab-YTE

Both palivizumab and motavizumab have a half life of 19–27 days and, therefore, require monthly administration to maintain adequate protective levels during the RSV season. MEDI-557 (motavizumab-YTE) was a third generation humanized mAb derived from motavizumab, in which 3 amino acid substitutions (M252Y/S254T/T256E [YTE]) were introduced in the IgG1 Fc region, which allowed to extend its half life. A randomized, double blind, phase I study to assess the safety, tolerability and pharmacokinetics of this mAb showed that the clearance of motavizumab-YTE was significantly reduced and the half life up to 4 times longer than motavizumab. Further development of this mAb has also been suspended, but the YTE technology has served as a platform that has been applied to other mAbs.41

MEDI-8897 (Nirsevimab)

MEDI-8897 is a recombinant human IgG1 mAb with high neutralizing activity and prolonged half life because of the YTE substitution. It is directed to the antigenic site Ø that is exclusive to the preF conformation of the RSV F protein. It was derived from the human mAb D25. This mAb has shown in vitro and in vivo to be more potent than palivizumab, and it has an extended half life with a favorable safety profile. The theoretical benefits of prolonged half-life antibodies include improving efficacy, avoiding compliance problems and reducing costs so they could be used not only in high-risk patients but also in healthy full-term infants entering their first RSV season.42

  • A phase I placebo-controlled clinical trial was initially conducted in 136 healthy adults who were randomized to receive a single dose of MEDI-8897 or placebo and were followed 360 days. The time to reach the maximum concentrations was 5–9 days and the half life of MEDI-8897 was 85–117 days. The safety profile was similar in both groups.43
  • Subsequently, a cohort of 89 healthy premature infants born at 32–35 wGA were randomized to MEDI-8897 or placebo. The half life of the mAb in these infants ranged from 62.5 to 72.9 days and showed an adequate safety profile with no differences in adverse effects between the placebo and treatment arms.44
  • More recently, a phase 2b randomized, double blind, placebo-controlled study was conducted in 1417 healthy preterm infants born at 29–35 wGA to assess the safety and efficacy of MEDI-8897. The primary and secondary endpoints included the incidence of RSV-MALRI and RSV hospitalizations, respectively, up to 150 days after administration of MEDI-8897.45 Other secondary objectives included assessing the safety profile and pharmacokinetics. Initial results of this study showed a 70.1% (52.3%–81.2%) reduction in RSV-MALRI and 78.4% (51.9%–90.3%) reduction in RSV hospitalizations.46

The long-term goal of MEDI-8897 is to provide passive immunization for the prevention of RSV lower respiratory tract infection to all infants, preterm and full term, using a single, intramuscular dose. Ongoing studies with MEDI-8897 include a comparative study versus palivizumab in preterm infants, and a randomized, double-blind trial comparing MEDI-8897 versus placebo in healthy late preterm and full-term infants.

REGN-2222 (Suptavumab)

REGN-2222 is a human IgG1 mAb that targets the site V, a well-preserved epitope of the RSV preF protein. In vitro, REGN-2222 was 40 times more potent than palivizumab to inhibit the fusion of RSV to cells, and 10–40 times more potent than palivizumab to reduce lung and nasal viral loads in cotton rats. A randomized, double blind, placebo-controlled, phase III clinical trial was conducted in preterm infants born at ≤35 wGA who were ≤6 months old at the time of enrollment and who did not receive palivizumab. Unfortunately, REGN-2222 did not meet the primary endpoint, namely prevention of severe RSV lower respiratory tract infection. Two escape mutations were identified in the predominant circulating RSV B strain during the study that conferred resistance to this mAb. Its clinical development has been interrupted but results from this trial has stimulated the field to actively monitor for the development of RSV mutants, naturally or upon exposure to anti-RSV compounds.47

MK-1654

It is a prolonged half-life human mAb directed against the antigenic site IV, which is present in both forms of the F protein, prefusion and postfusion. The apparent half life of MK-1654 ranges from ~70 to 85 days after an IM or IV dose. Pediatric modeling studies suggest that the half life in infants is shorter than in adults, probably due to childhood growth during treatment.48,49 This mAb is currently being evaluated in phase 1/2a trials.

Other mAb Undergoing Preclinical Studies

(a) TLR3D3 is a native human mAb directed against the RSV G protein, unlike all previously described. In animal models, it has shown to be more potent than palivizumab and to decrease airway inflammation when used as treatment.50 (b). MPE8 is a human mAb directed against the preF protein, capable of neutralizing both human RSV and human metapneumovirus (hMPV), and 2 animal paramyxoviruses.51

SUMMARY

Since palivizumab was approved in 1998 for the prevention of severe RSV infection in premature infants and in those with CLD and CHD, it remains as the only prophylactic agent available. However, the development of newer monoclonal antibodies that will likely be cost effective, safe and easy to administer in a single dose due to their prolonged half life represents an opportunity to extend RSV prevention strategies to full-term infants. We face a paradigm change in the prevention of RSV infection as preventive strategies are not only targeting high-risk groups but rather the entire infant population. In the era of RSV vaccine development,15 prophylaxis with new generation monoclonal antibodies would be a complementary and potentially effective strategy.

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Keywords:

monoclonal antibodies; RSV; prevention

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