Introduction
Methods
Study Objective
Literature Searches
Evaluation of Data
Compliance with Ethics Guidelines
Results
Past and Present Preventative and Therapeutic Interventions
Prevention of RSVH
RSV-IGIV
RSV-IGIV (n = 250) | Placebo (n = 260) | Reduction | P value | |
---|---|---|---|---|
Incidence of RSVH (%) | 8.0 | 13.5 | 41% | 0.047 |
Total days of hospitalization per 100 children | 60 | 129 | 53% | 0.045 |
Total days of RSVH requiring increased supplemental oxygen per 100 children | 34 | 85 | 60% | 0.007 |
Number of hospital days with moderate or severe LRI (LRI score ≥ 3a) per 100 children | 49 | 106 | 54% | 0.049 |
Total days of ICU or mechanical ventilation for RSV per 100 children | 28 | 50 | – | – |
Palivizumab
Prematurity With or Without CLD/BPD
Author | RCT | Study design | Study population | RSVH (%) | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Preterm < 29 wGA | Preterm 29-32 wGA | Preterm 32-35 wGA | Preterm ≤ 35 wGA | ||||||||
Untreated | Prophylax | Untreated | Prophylax | Untreated | Prophylax | Untreated | Prophylax | ||||
+ | Multicenter, randomized, double-blind, placebo-controlled | 1502 children with prematurity (≤ 35 wGA) or BPD | 10.0 | 2.0a | 7.7 | 1.6b | 10.1 | 1.8b | 8.1 | 1.8c | |
Pedraz [65] Spain | − | Multicenter, comparing 2 untreated cohorts to 2 prophylaxed cohorts | 3502 preterm infants ≤ 32 wGA (11.3% CLD [prophylaxed cohort]; 4.8% CLD [non-prophylaxed cohort]) | 13.0 | 5.4d | 9.9 | 2.5d | 10.4f | 3.7ef | ||
Blanken (MAKI) [25] Netherlands | + | Multicentre, randomized, double-blind, placebo-controlled | 429 otherwise healthy infants 33-35 wGA | 5.1 | 0.9m | ||||||
Figueras-Aloy [66] Spain | − | Multicenter, 2-cohort | 5441 preterm infants 32–35 wGA (excluded CHD and other serious comorbidities) | 4.1 | 1.3c | ||||||
Faldella [64] Italy | − | Single center follow-up of infants admitted to NICU soon after birth | 225 preterm infants ≤ 32 wGA | 9.9h | 1.9g | ||||||
− | Burgundy region, comparing untreated cohorts to prophylaxed cohorts over up to 5 RSV seasons | 69 preterm infants ≤ 32 wGA with BPD (included 2 infants with CHD) 339 preterm infants ≤ 30 wGA without BPD (included 9 infants with CHD) | 0.2–16.7j | 0–2.0ij | |||||||
Feltes [80] USA | + | Multicenter, randomized, double-blind, placebo-controlled | 1287 children aged ≤ 24 months old with HS-CHD | ||||||||
Medrano López [81] Spain | − | Multicenter, epidemiologic, covering 4 RSV seasons | 2613 children ≤ 24 months old with HS-CHDp | ||||||||
Weighted mean rate [95% CI] | 12.5 [11.5–13.5] | 4.8 [4.1–5.4] | 9.5 [8.7–10. 4] | 2.4 [1.9–2.8] | 4.8 [4.2–5.2] | 1.4 [1.1–1.6] | 9.1–10.2 [8.1–9.6; 9.3–11.0] | 2.9–3.0 [2.3–3.2; 2.5–3.4] |
Author | RCT | Study design | Study population | RSVH (%) | |||||
---|---|---|---|---|---|---|---|---|---|
CLD/BPD | CHD | Preterm and CHD/BPD/other comorbidities | |||||||
Untreated | Prophylax | Untreated | Prophylax | Untreated | Prophylax | ||||
+ | Multicenter, randomized, double-blind, placebo-controlled | 1502 children with prematurity (≤ 35 wGA) or BPD | 12.8 | 7.9b | |||||
Pedraz [65] Spain | − | Multicenter, comparing 2 untreated cohorts to 2 prophylaxed cohorts | 3502 preterm infants ≤ 32 wGA (11.3% CLD [prophylaxed cohort]; 4.8% CLD [non-prophylaxed cohort]) | 19.7 | 5.5g | 13.25 | 3.95e | ||
Blanken (MAKI) [25] Netherlands | + | Multicentre, randomized, double-blind, placebo-controlled | 429 otherwise healthy infants 33-35 wGA | ||||||
Figueras-Aloy [66] Spain | − | Multicenter, 2-cohort | 5441 preterm infants 32–35 wGA (excluded CHD and other serious comorbidities) | ||||||
Faldella [64] Italy | − | Single center follow-up of infants admitted to NICU soon after birth | 225 preterm infants ≤ 32 wGA | ||||||
− | Burgundy region, comparing untreated cohorts to prophylaxed cohorts over up to 5 RSV seasons | 69 preterm infants ≤ 32 wGA with BPD (included 2 infants with CHD) 339 preterm infants ≤ 30 wGA without BPD (included 9 infants with CHD) | 46.2 | 3.8–11.8i | |||||
Feltes [80] USA | + | Multicenter, randomized, double-blind, placebo-controlled | 1287 children aged ≤ 24 months old with HS-CHD | 9.7 (cyanotic: 7.9) (other [acyanotic]: 11.8) | 5.3b (cyanotic: 7.9n) (other [acyanotic]: 11.8o) | ||||
Medrano López [81] Spain | − | Multicenter, epidemiologic, covering 4 RSV seasons | 2613 children ≤ 24 months old with HS-CHDp | 7.9 | 3.3i | ||||
Weighted mean rate [95% CI] | 17.6 [16.5–18.6] | 6.2 [5.5–6.9] | 8.5 [7.6–9.4] | 4.0 [3.3–4.6] | 13.9 [12.7–14.9] | 4.0-4.1 [3.3–4.6; 3.5–4.8] |
Congenital Heart Disease
HS-CHD, n (%)a | 485 (44.1%) |
---|---|
Primary diagnosis, n (%) | |
Patent ductus arteriosus | 237 (21.5) |
Ventricular septal defect | 184 (16.7) |
Atrial septal defect | 126 (11.4) |
Single ventricle (including hypoplastic left or right ventricle) | 67 (6.1) |
Tetralogy of Fallot | 63 (5.7) |
Atrioventricular canal defect (endocardial cushion defect) | 55 (5.0) |
Pulmonary stenosis | 45 (4.1) |
Coarctation of the aorta | 35 (3.2) |
Heart murmurb | 22 (3.2) |
Transposition of the great arteries | 28 (2.5) |
Pulmonic atresia with ventricular septal defect | 16 (1.5) |
Aortic stenosis | 14 (1.3) |
Tricuspid atresia | 14 (1.3) |
Peripheral pulmonic stenosisb | 8 (1.2) |
Truncus arteriosusb | 7 (1.0) |
Double-outlet right ventricular with transposed great arteries | 10 (0.9) |
Pulmonary atresia with the intact septum | 5 (0.5) |
Ebstein’s anomaly | 5 (0.5) |
Other | 160 (14.5) |
Current status of cardiac defect, n (%) | |
Uncorrected, no surgery planned | 260 (23.6) |
Uncorrected, surgery planned for future | 143 (13.0) |
Partially corrected | 207 (18.8) |
Fully corrected with residual effect | 84 (7.6) |
Fully corrected with no residual effect | 224 (20.3) |
Resolved without surgeryb | 57 (8.3) |
Unknownb | 79 (11.5) |
Other | 47 (4.3) |
Down Syndrome
Cystic Fibrosis
Other Significant Underlying Medical Conditions
Underlying medical disorder | RSV hospitalization rate (%) |
---|---|
Cardiac (n = 22) | 4.55 |
Pulmonary (n = 127) | 1.73 |
Neuromuscular (n = 78) | 6.90 |
Other (n = 163) | 0.78 |
Multiple (n = 57) | 2.01 |
Immunocompromised (n = 17a) | 11.8 |
Airway anomalies (n = 178) | 2.70 |
Down syndrome (n = 193) | 1.84 |
Cystic fibrosis (n = 117) | 1.14 |
Safety
Guidelines
Motavizumab
Prevention of Long-Term Outcomes with Antibodies
Treatment of RSV LRTI
Future Approaches
Advances in RSV Vaccine Development
Target Populations for RSV Vaccines
Infants and Young Children
Pregnant Women
Other Vaccine Candidates
Advances in Prophylaxis
Antibodies
Therapeutic Drugs to Treat RSV Infection
Fusion inhibitors | GS-5806, MDT-637 (VP-14637); JNJ-2408068 (R-170591); TMC353121; BMS-433771; BTA-C585; P13 and C15; JNJ-53718678; AK-0529; RFI-641 |
---|---|
Single domain, trivalent antibody fragment derived from Camelidae (Nanobody) | ALX-0171 |
L (“large”)-protein inhibitors | JNJ-64041575a; BI-D; AZ-27 |
N-protein targeting RSV inhibitor | RSV604 |
Other potential targets include: N-P protein–protein interaction; SH-protein; M2-1 protein |
Limitations
Key statements/findings | Level of evidencea |
---|---|
Palivizumab | |
Currently, the only product licensed for prophylaxis against RSV | Level 1 studies: 5 |
Preterm infants < 35 wGA: 68% (range 64–100%) reduction in RSVH (absolute risk reduction: 0.2–14.7%) | Risk of biasb: low Qualityc: high |
Children with CLD/BPD: 65% (range 38–72%) reduction in RSVH (absolute risk reduction: 4.9–14.2%) | |
Children with CHD: 53% (range 45–58%) reduction in RSVH (absolute risk reduction: 4.4–4.6%) | |
Limited data in other comorbidities | |
Significantly reduced subsequent wheezing episodes | Level 1 studies: 1 Risk of biasb: low Qualityc: high |
Ribavirin | |
Licensed for treatment of severe RSV infection | Level 1 studies: 4 |
Lack of evidence supporting its efficacy and concerns over toxicity | Risk of biasb: unclear Qualityc: low |
Strongest evidence in immunocompromised infants | |
Future therapies | |
There are currently around 28 RSV vaccines in preclinical development and WHO estimates the availability of an RSV vaccine within 5–10 years | N/A |
Nanoparticle and subunit vaccines are the most promising for pregnant women, whereas live-attenuated, vector-based and subunit vaccines are optimal for the pediatric population | N/A |
Several new antibodies targeting the RSV fusion (F) protein are showing promise (e.g. MEI8897) and entering phase 3 trials | N/A |
Recent efforts to develop RSV antiviral drugs have focused primarily on fusion inhibitors or virus gene silencing; a number are in development and could become available for clinical use within a few years | N/A |
Key areas for research 1. Currently approved therapies More up-to-date research and published, prospective RCTs are needed to determine: The effectiveness of palivizumab in reducing RSVH and improving outcomes in children with underlying medical conditions, such as Down syndrome, cystic fibrosis, congenital airway anomalies, immunocompromising or neuromuscular disease The ultimate impact of palivizumab on longer-term sequelae, such as recurrent wheezing 2. Future therapies for prevention and treatment Continued research is needed on: Receptive strategies, such as pre- versus post-natal prophylaxis Establishing whether there is a causal link between RSV infection and asthma, possibly via a follow-on to a phase 3 vaccine or prophylaxis trial The optimal timing of therapy with antiviral drugs Whether the combination of antiviral drugs and immunomodulatory therapies might improve outcomes, as suggested by Prince et al. [216] |