mAbs present a compelling alternative for addressing viral infections, given their remarkable specificity toward pathogens and ability to provide passive immune responses (36). The primary objective is to target a highly neutralizing, sensitive epitope situated on the RSV pre-F protein (37–39). Furthermore, the latest generation of RSV antibodies undergoes Fc mutation modification, which can prolong their half-life. There are 5 mAbs with activity against RSV, including palivizumab, motavizumab, nirsevimab, clesrovimab, and TM001.

(1) Palivizumab. Palivizumab (Synagis) is the first humanized mAb approved by the FDA for the prophylaxis of high-risk of hospital admission infants during bronchiolitis season (40, 41). Palivizumab is administered intramuscularly at 15 mg/kg every month during five months of the first RSV season to prevent serious RSV LRTI in children (42). Palivizumab binds antigenic site A, a highly conserved region on the RSV fusion (F) protein, and can block the membrane fusion process by binding to RSV fusion proteins on the surface of the virus, and can also prevent the fusion process between cells infected with RSV (43). The intervention is restricted to a narrow subset of the pediatric population, infants with a gestational age below 35 weeks and infants up to 6 months of age at the time of RSV season onset. This leaves millions of infants at risk of severe or potentially fatal disease every year, without protection from RSV. Two clinical trials are currently underway to investigate the preventive efficacy of palivizumab against RSV in children under two years of age (NCT01006629/phase 2/3; NCT01466062/phase 3). In light of the advent of novel long-acting mAbs, it is pertinent to deliberate upon the necessity of conducting additional experiments to verify the protective effect on children over 6 month old in this regard.

Motavizumab, which is alternatively referred to as MEDI-524 or Numax, is a second-generation mAb that is developed from palivizumab through affinity maturation techniques (44). It has been found to effectively reduce the disease burden of RSV in high-risk infants (35). This mAb has been the subject of five clinical trials. A randomized, double-blind, placebo-controlled trial (NCT00121108/phase 3) (15) indicated that motavizumab led to a relative reduction of 87% in the proportion of infants hospitalized due to RSV when compared to the placebo group. Moreover, the incidence of adverse events (AEs) was lower among subjects administered motavizumab than among those who received placebo, and no fatalities associated with motavizumab were reported. There was no statistically significant difference observed in the occurrence of severe adverse events (SAEs) or hypersensitivity events between the two groups. When comparing the administration of motavizumab alone to a combined regimen of motavizumab and palivizumab, it was observed that the rates of AEs and the antidrug antibodies (ADAs) associated with the sequential administration of the combined regimen to high-risk children were similar between the two groups (16).

Nirsevimab, a human mAb designed to target site Ø of the F protein and that features a YTE mutation in the Fc portion to prolong its serum half-life, when administered as a singular dosage, offers comprehensive protection throughout a RSV season (45). In November 2022, the EMA and the EU granted approval for the use of Beyfortus (nirsevimab) in newborns and infants to aid in the prevention of RSV LRTIs during their initial RSV pandemic season.

The mean half-life of MEDI8897 ranged from 85 to 117 days among different dosage cohorts, accompanied by a bioavailability of 77% following subsequent to the administration of a 300-mg i.m. dose (NCT02114268/phase1) (17). The incidences of ADA and AEs in the intervention group were comparable to those observed in the placebo group. Subsequent phase 2 (NCT02878330) (18) and phase 3 trials (NCT03979313) (20) demonstrated that nirsevimab exhibited efficacies of 70.1% (95% CI, 52.3 to 81.2) and 74.5% (95% CI, 49.6 to 87.1) in treating LRTIs in drug-treated patients, respectively. Additionally, the efficacy of nirsevimab in preventing hospitalization due to RSV in premature infants was found to be 78.4% (95% CI, 51.9 to 90.3) and 62.1% (95% CI, -8.6 to 86.8), respectively. SAEs were similar between the two groups. In addition, the safety profiles of nirsevimab in infants diagnosed with congenital heart disease (CHD) or chronic lung disease (CLD) were comparable to those observed in preterm infants receiving palivizumab(NCT03959488/phase 2/3) (19).

Clesrovimab is a mAb with an extended half-life and the same YTE mutation as that in nirsevimab and is designed to target site IV of the RSV F protein, although it partially targets site V and preferentially binds to pre-F. MK-1654 was tested in two phase 1 clinical trials conducted among Japanese adults. A single intramuscular injection of MK-1654 produced a dose-dependent increase in RSV serum-neutralizing antibody (SNA) titers (46). The antibody exhibited a half-life ranging from 73 to 88 days, with an estimated bioavailability of 69% at the 300-mg intramuscular dose. There was no significant difference in safety events between the MK1654 and placebo groups. Orito et al. (47) proved that the bioavailability of MK-1654 in healthy adults was 86% and 77% for the 100 mg i.m. and 300 mg i.m. doses, respectively. The registration numbers were not found in clinicaltrials.gov. Currently, this mAb is being tested in 7 trials in infants.

LAVs are promising options for young children due to their intranasal administration, ability to induce both local mucosal and systemic responses, and immunogenicity when maternal antibodies are present, thereby enabling the immunization of vulnerable infants at high risk of severe illness (48). Enhanced comprehension of the RSV genome and reverse genetics has facilitated the logical development of LAV candidates through the elimination or alteration of proteins that are recognized to exert a noteworthy influence on the control of RNA biosynthesis or hinder the host immune reactions, such as NS2, M2-2, SH, L, and G proteins, which resulting in limited viral replication (49, 50). LAVs offer a valuable needle-free option for the active intranasal immunization of older infants who may not receive adequate protection from maternal vaccines or monoclonal antibodies.

RSV ΔNS2/Δ1313/I1314L was developed by deleting the NS2 gene and the amino acid S1313 from the L polymerase protein. Consequently, a phenotypically stable variant was obtained, which displays temperature sensitivity under physiological conditions (51). In children who were seronegative for RSV, administration of a 106 plaque forming unit (PFU) dose of RSV/ΔNS2/Δ1313/I1314L was found to be both well tolerated and capable of inducing an immune response. Following the RSV season, it was observed that vaccinated individuals experienced a significant increase in RSV titers (1:955) compared to placebo recipients (1:69), indicating the effectiveness of the vaccine (NCT01893554) (21). Both RSV/ΔNS2/Δ1313/I1314L and RSV/276 vaccine recipients (NCT03227029) (22) experienced upper respiratory illness and/or fever post vaccination, with generally mild symptoms. It is noteworthy that the incidence of cough was significantly higher in subjects that received RSV/276 than in those that received RSV/ΔNS2/Δ1313/I1314L (48% vs. 12%). Lower respiratory illnesses and SAEs were not observed. The two groups demonstrated a ≥4-fold elevation in serum RSV neutralizing titers and anti-RSV F IgG titers by 60% and 92%, respectively.

MV-012-968 is a live attenuated vaccine that is free of adjuvants. This vaccine, modifications were made to it’s NS1 and NS2 proteins, as well as the G proteins, with the SH deletion and ablation of secreted G protein. Currently, the safety and immunogenicity of MV-012-968 is being assessed in phase 1 and phase 2 clinical trials, but the results were not published.

RSV LID ΔM2-2 is a candidate vaccine for RSV that involves the deletion of RSV M2-2. The attenuation of LIDΔM2-2 leads to an increase in viral gene transcription and antigen expression, and a decrease in RNA replication. The vaccine virus was found to be shed by 95% of individuals who received the LIDΔM2-2 (105 PFU) vaccine (median peak titers, 3.8 log10 PFU/mL; 6.3 log10 copies/mL)(NCT02237209) (23). Additionally, 90% of vaccine recipients demonstrated a serum-neutralizing antibody (SNA) increase of at least fourfold. It is noteworthy that both the vaccine and placebo groups experienced a high prevalence of respiratory symptoms and fever. Notably, one vaccine recipient exhibited grade 2 rhonchi in conjunction with vaccine shedding, rhinovirus, and enterovirus. Following the RSV season, vaccine recipients (8/19) demonstrated a marked increase in RSV antibody titers compared to placebo recipients (2/9), without experiencing medically attended RSV disease.

LID/ΔM2-2/1030s is produced by eliminating of the RSV M2-2 protein and introducing of a genetically stabilized temperature-sensitive mutation, known as 1030s, in the RSV polymerase protein. LID/ΔM2-2/1030s vaccine (105 PFU) (52) exhibited 85% shedding of the vaccine and a ≥4-fold increase in serum-neutralizing antibodies. Respiratory symptoms and fever were commonly reported by vaccine recipients (60%) and placebo recipients (27%). Notably, a vaccinated individual experienced grade 2 wheezing caused by Rhinovirus but did not concurrently shed LID Δ M2-2/1030s.

D46/NS2/N/ΔM2-2-HindIII, a recombinant LAVs with an M2-2 deletion, was derived from the earlier candidate LID/ΔM2-2. All 21 individuals who received D46/NS2/N/ΔM2-2-HindIII (105 PFUs) (NCT03102034, NCT03099291) (24) were found to be infected with the vaccine, with 20 of them (95%) exhibiting vaccine shedding. Notably, 95% and 100% of the vaccine recipients experienced a ≥4-fold increase in serum RSV-neutralizing antibodies and anti-RSV fusion immunoglobulin G, respectively. Additionally, both vaccinees (76%) and placebo recipients (18%) reported mild upper respiratory tract symptoms and/or fever.

These two vaccines serve as the initial attenuated candidates for RSV immunization in young children (53). Both vaccines exhibited high attenuation in adults and RSV-seropositive children while also exhibiting favorable tolerability and immunogenicity in RSV-seronegative children. Notably, the replication of rA2cp248/404/1030 Delta SH was found to be restricted in RSV-seronegative children, with a mean peak titer of 10 (2.5) PFUs/mL, compared to 10 (4.3) PFUs/mL for rA2cp248/404 Delta SH. Although rA2cp248/404/1030 Delta SH was well tolerated in infants, only 44% of the recipients who were administered two 10 (5.3) PFU doses of the vaccine exhibited discernible antibody responses.

MEDI-559 (54) was mutated from RSV rA2cp248/404/1030 Δ SH and is currently being assessed in phase 1/2 clinical trials (NCT00767416). RSVcps2 is a newly developed vaccine that was modified from MEDI-559 through the incorporation of five nucleotide changes and one amino acid alteration. This modification resulted in the stabilization of two significant decay mutations, thereby preventing their degradation. Administration of RSVcps2 via the intranasal resulted in a significant proportion of vaccinees (85%) acquiring RSVcps2 infection, with 77% shedding the vaccine virus and 59% developing a≥4-fold increase in RSV-SNA titers (NCT01852266, NCT01968083) (25). The incidence of respiratory tract and/or febrile illness was similar between the vaccine and placebo groups.

The ChAd155-RSV vaccine, which is currently under investigation, is a chimpanzee adenovirus-based vaccine that expresses three distinct proteins, namely, fusion proteins, nucleoproteins, and M2-1 proteins (55). Following the administration of the first dose of GSK3389245A (NCT02927873; phase1/2 trial) (56), all groups (0.5 × 1010, 1.5 × 1010, and 5 × 1010 viral particles) exhibited a dose-dependent escalation in RSV-A Nab titers, with no discernible booster effect observed after the second dose. At the one-year mark, RSV-A Nab titers remained elevated above prevaccination levels. The incidence of AEs was comparable across all groups, with the exception of fever, which was more prevalent in the high dose group. The majority of fevers were mild. There were no SAEs and hospitalizations related to vaccine were reported.

An adenovirus serotype 26 RSV vector encoding a prefusion F (preF) protein (Ad26.RSV.preF) in combination with an RSV preF protein. Previous studies have demonstrated the effectiveness of Ad26.RSV.preF in mitigating lower respiratory tract disease caused by RSV among the elderly population (57, 58). The geometric mean titers for RSV A2 neutralization in children aged 12-24 months who were administered Ad26.RSV.preF (NCT03606512; phase1/2 trial) (59) exhibited a significant increase from 121 (Day 0) to 1608 (Day 29) and further increased to 2235 (Day 57), persisting at elevated levels for a duration of over 7 months. The administration of Ad26.RSV.preF resulted in a lower incidence of RSV infection in children (1, 4.2%) in comparison to the administration of placebo (5, 41.7%). No SAEs related to vaccination were reported.

Parainfluenza virus 5 (PIV5) is a paramyxovirus that has been utilized as a vector-based platform for vaccine development. Two distinct recombinant PIV5 viruses have been developed, one expressing the fusion (F) protein and the other expressing the attachment glycoprotein (G). A phase 1 clinical trial is currently underway to evaluate the safety, tolerability, and immunogenicity of the BLB-201 vaccine in children (NCT05655182).

RSVPreF3 is an adjuvant-free vaccine. There are seven clinical studies on RSVPreF3. In a cohort of healthy nonpregnant females, RSVPreF3(GSK3888550A)(30/60/120 µg) group exhibited a higher incidence of induced local adverse events (AEs) (4%~53.2%) than the placebo group (0% ~ 15.9%). Nonetheless, the majority of the aforementioned events were categorized as mild to moderate. Furthermore, the frequency of unsolicited AE reports was similar between the RSVPreF3 and placebo, and no SAEs associated with the medication were documented (NCT03674177, phase1) (27). Bebia et al. (26) suggest that RSVPreF3 (RSV MAT 009) (60/120 µg) was well tolerated, as no AEs related to the vaccine were observed both in the pregnant women and in their offspring. Furthermore, the level of the maternal nAbs against RSV increased by more than 10 times, even 43 days after labor, with a range of 8.9-10.0 times. The level of nAbs in neonates is at its peak during birth and gradually declines until the 181st day postpartum (NCT04126213/phase2).

In a cohort of pregnant women were randomly assigned to receive the bivalent RSVpreF vaccines (120/240 μg), with or without aluminum hydroxide, or placebo (NCT04032093/phase2b) (28). The study revealed a significant increase in the titer of 50% nAb in the vaccinated group compared to the placebo group. Furthermore, the transfer ratios of neutralizing antibodies through the placenta varied between 1.41 and 2.10. Furthermore, the incidence of AEs observed in both women and infants in the vaccine group was similar to that in the placebo groups. RSVpreF was well tolerated and safe when administered alone or in conjunction with acellular pertussis vaccine adsorbed (Tdap) in the healthy, nonpregnant woman (NCT04071158/phase2b) (29).

A single intramuscular injection of RSVpreF vaccine or placebo was administered to pregnant women at 24 to 36 weeks gestation (NCT04424316/phase3) (30). Within the first 90 days following birth, the vaccine demonstrated an effective rate of 81.8% (99.5% CI, 40.6 to 96.3) in preventing severe lower respiratory tract diseases caused by medication treatment and a 57.1% (99.5% CI, 14.7 to 79.8) effective rate in preventing lower respiratory tract diseases related to respiratory syncytial virus in the vaccine group. Additionally, within the first 180 days following birth, the effective rate of prophylactic treatment for severe lower respiratory tract diseases was 69.4% (97.58% CI, 44.3 to 84.1). No noticeable safety signals were detected in maternal participants or infants and toddlers up to 24 months of age. The frequency of AEs reported within 1 month following injection or birth was similar between the two groups.

The immunogenicity and safety of GSK3003891A (30/60/120 μg) was assessed in healthy nonpregnant women (NCT02956837/phase2) by a single intramuscular injection (31). The results showed that the geometric mean titer (GMT) and PCA concentration increased in a dose-dependent manner. Another comparative analysis was conducted to evaluate the safety and immunogenicity of the RSV F-020/GSK3003895A (NCT02360475/phase2) and RSV F-024/GSK3003891A vaccines (NCT02753413/phase2) (32). In the clinical trial identified as RSV F-020, participants were randomized and subsequently received a single dose of RSV PreF vaccine (30/60 μg without adjuvant or 60 μg with aluminum adjuvant) or Tdap. In the RSV F-024 trial (NCT02753413/phase2), participants were randomly assigned to receive a single dose of RSV PreF (60 μg without adjuvant) or Tdap. The two studies demonstrated comparable reactogenicity profiles between the RSV-PreF and Tdap vaccines. There have been no SAEs associated with vaccine injection.

The pregnant women who received the RSV F vaccine exhibited a significant elevation in RSV-specific antibody levels, exhibiting responses that were comparable to mAbs known for their specificity towards various RSV-neutralizing epitopes. (NCT02247726/phase2) (34). The transference rate of antibodies through the placenta was discovered to range from 90% to 120% across diverse assays for neonates born to immunized females. Offspring born to mothers who received vaccination exhibited RSV-specific antibodies with half-lives of approximately 40 days, and no instances of severe RSV disease were detected in these neonates.

The pregnant woman was administrated an intramuscular injection of the RSV F vaccine, to assess the efficacy and its potential to provide protection to live-born infants (NCT02624947/phase3) (33). Within the initial 90 days of life, the vaccine effectiveness against RSV-associated, clinically significant LRTIs was 39.4%, and the vaccine efficacy for RSV-associated LRTIs with severe hypoxemia was 48.3%. Moreover, the vaccine’s effectiveness in preventing hospitalization due to RSV-associated LRTIs was determined to be 44.4%. The occurrence of local injection site reactions was observed to be greater in female recipients of the vaccine (40.7% vs 9.9%). Among these mAbs and vaccines, the efficacy and safety data can be retrieved in PubMed are listed in Table 3 . Based on the attributes associated with the staging of clinical trials, it is reasonable to accord precedence to the dissemination of clinical research findings derived from extensive sample sizes. For instance, Nirsevimab has successfully concluded Phase III clinical trials, thereby furnishing solely Phase III efficacy and safety data.