RSV Prevention Research Articles

A Single Dose Monoclonal Antibody (mAb) Immunoprophylaxis Strategy to Prevent RSV Disease in All Infants: Results of the First in Infant Study with MEDI8897

BackgroundRSV is the most common cause of lower respiratory tract infection (LRTI) among infants making prevention of RSV disease a public health priority. A significant unmet need exists for RSV prevention in healthy infants. Our goal is to develop a mAb with an extended half-life (t½) capable of protecting infants for an entire RSV season by using a single intramuscular (IM) dose. This study was conducted to evaluate the safety profile, pharmacokinetics (PK), RSV neutralizing antibody titers, and anti-drug antibody (ADA) responses for MEDI8897 in healthy preterm infants born between 32 and 35 weeks gestational age.MethodsInfants were randomized 4:1 to receive a single IM injection of MEDI8897 10mg (n = 8), 25mg (n = 31), 50mg (n = 32) or placebo (n = 18) and followed for 360 days. Enrollment occurred during the 2,015 RSV seasons in the US, South Africa, and Chile. Blood was collected at multiple timepoints. Infants who met criteria for a medically-attended (MA) LRTI had nasal swabs obtained for RSV testing by RT-PCR.ResultsA total of 85/89 (95.5%) infants completed the study. Adverse events (AEs) were reported in 17/18 (94.4%) placebo and 66/71 (93.0%) MEDI8897 recipients. Five serious AEs (three LRTIs, two febrile seizures) were reported in three MEDI8897 recipients. No events were consistent with hypersensitivity reactions. The estimated MEDI8897 serum t½ ranged from 62.5 to 72.9 days. On day 151, 87% of the infants who received the 50mg dose of MEDI8897 had serum concentrations above the target EC90 level of 6.8 µg/ml, and 93.3% showed a ≥3-fold rise from baseline in serum anti-RSV neutralizing antibody titers. ADA was detected in 28.2% of MEDI8897 recipients, but when present was not associated with any safety findings. ADA was detected at day 361 only in 26.5% of subjects. MA-LRTI was reported in 5 (7%) MEDI8897 recipients through 150 days after dosing. The one subject with an MA-LRTI caused by RSV had received a 10mg dose of MEDI8897.ConclusionIn healthy preterm infants, the safety profile of MEDI8897 was favorable. The extended t½ of MEDI8897 with the corresponding increase in RSV neutralizing antibody levels was confirmed and supports protection from RSV disease during a typical 5-month season with a single 50mg IM dose.This study was sponsored by MedImmune.Disclosures J. B. Domachowske, Medimmune: Investigator, Research grant; Regeneron: Investigator, Research grant; Pfizer: Investigator, Research grant; Glaxo Smith Kline: Investigator, Research grant; Novavax: Investigator, Research grant; Janssen: Investigator, Research grant; A. Khan, MedImmune: Employee and Shareholder, Salary and stock; M. T. Esser, MedImmune: Employee and Shareholder, Salary and stock; K. M. Jensen, MedImmune: Employee and Shareholder, Salary and stock; T. Takas, MedImmune: Employee and Shareholder, Salary and stock; T. Villafana, MedImmune: Employee and Shareholder, Salary and stock; F. Dubovsky, MedImmune: Employee and Shareholder, Salary and stock; M. P. Griffin, MedImmune: Employee and Shareholder, Salary and stock

Use of Oral Ribavirin for the Treatment of RSV Infections in Hematopoietic Cell Transplant (HCT) Recipients

BackgroundThe benefit of aerosolized ribavirin (AR) in reducing the risk of progression of RSV infections and RSV-associated mortality in HCT recipients has been recognized, yet there is a paucity of data assessing the use of oral ribavirin (OR) in this patient population. We evaluated outcomes associated with the use of OR compared with AR in HCT recipients.MethodsRetrospective review of all HCT recipients with RSV infection treated with OR or AR during three RSV seasons (September 2014 – February 2017). An established immunodeficiency Scoring Index (ISI) was applied to identify patients at high risk for progression and death based on host risk factors. Mortality, progression to lower respiratory infection (LRI), and need for ICU admission was compared among recipients of AR and OR.ResultsA total of 107 patients were treated with OR (n = 42, 39%) or AR (n = 65, 61%). Recipients of AR and OR were equally likely to be high-risk by ISI scoring (11% vs. 10%, P = 1.00). Fifty-three patients (50%) presented with upper respiratory infection (URI) of whom 13 (25%) progressed to LRI. There was no difference in the rate of progression to LRI between patients who received AR and OR (28% vs. 19%, P = 0.53). No difference was found in 30-day mortality rates based on treatment strategy (8% AR vs. 5% OR, P = 0.70). Interestingly, 90-day mortality was found to be significantly lower among patients who received OR vs. AR (20% vs. 5%, P = 0.04). No differences in rates of ICU admission and requirement for mechanical ventilation were found between the two groups. For the 99 inpatients at time of diagnosis, median (interquartile range) length of stay was 7 (5 – 19) days, and was similar for patients on either treatment modality. Eight patients were treated for RSV on an outpatient basis and all received OR.ConclusionHCT patients with RSV had similar outcomes when treated with AR and OR. OR may be a safe and effective alternative to AR for prevention and treatment of RSV in HCT patients with significantly reduced cost.Disclosures R. Chemaly, Gilead: Consultant and Investigator, Consulting fee and Research grant. Ansun: Investigator, Research grant. GSK: Investigator, Research grant.

Identification of Respiratory Syncytial Virus Nonstructural Protein 2 Residues Essential for Exploitation of the Host Ubiquitin System and Inhibition of Innate Immune Responses.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in young children worldwide. The RSV nonstructural protein 2 (NS2) is a multifunctional protein that primarily acts to antagonize the innate immune system by targeting STAT2 for proteasomal degradation. We investigated the structural determinants of NS2 important for interaction with the host ubiquitin system to degrade STAT2 during infection. We found that NS2 expression enhances ubiquitination of host proteins. Bioinformatics analysis provided a platform for identification of specific residues that limit NS2-induced ubiquitination. Combinations of multiple mutations displayed an additive effect on reducing NS2-induced ubiquitination. Using a reverse genetics system, we generated recombinant RSV (rRSV) containing NS2 ubiquitin mutations, which maintained their effect on ubiquitin expression during infection. Interestingly, STAT2 degradation activity was ablated in the NS2 ubiquitin mutant rRSV. In addition, NS2 ubiquitin mutations decreased rRSV replication, indicating a correlation between NS2's ubiquitin function and antagonism of innate immune signaling to enhance viral replication. Our approach of targeting NS2 residues required for NS2 inhibition of immune responses provides a mechanism for attenuating RSV for vaccine development. RSV has been circulating globally for more than 60 years, causing severe respiratory disease in pediatric, elderly, and immunocompromised populations. Production of a safe, effective vaccine against RSV is a public health priority. The NS2 protein is an effective target for prevention and treatment of RSV due to its antagonistic activity against the innate immune system. However, NS2-deleted RSV vaccine candidates rendered RSV overattenuated or poorly immunogenic. Alternatively, we can modify essential NS2 structural features to marginally limit viral growth while maintaining immune responses, providing the necessary balance between antigenicity and safety required for an effective vaccine. We coupled bioinformatics analysis with reverse genetics to introduce mutations into RSV's negative-sense genome. In this way we constructed rRSV NS2 ubiquitin mutants that limited NS2's ability to antagonize the innate immune system, thereby attenuating rRSV growth and increasing innate immune responses.

Relative Importance and Additive Effects of Maternal and Infant Risk Factors on Childhood Asthma.

BackgroundEnvironmental exposures that occur in utero and during early life may contribute to the development of childhood asthma through alteration of the human microbiome. The objectives of this study were to estimate the cumulative effect and relative importance of environmental exposures on the risk of childhood asthma.MethodsWe conducted a population-based birth cohort study of mother-child dyads who were born between 1995 and 2003 and were continuously enrolled in the PRIMA (Prevention of RSV: Impact on Morbidity and Asthma) cohort. The individual and cumulative impact of maternal urinary tract infections (UTI) during pregnancy, maternal colonization with group B streptococcus (GBS), mode of delivery, infant antibiotic use, and older siblings at home, on the risk of childhood asthma were estimated using logistic regression. Dose-response effect on childhood asthma risk was assessed for continuous risk factors: number of maternal UTIs during pregnancy, courses of infant antibiotics, and number of older siblings at home. We further assessed and compared the relative importance of these exposures on the asthma risk. In a subgroup of children for whom maternal antibiotic use during pregnancy information was available, the effect of maternal antibiotic use on the risk of childhood asthma was estimated.ResultsAmong 136,098 singleton birth infants, 13.29% developed asthma. In both univariate and adjusted analyses, maternal UTI during pregnancy (odds ratio [OR] 1.2, 95% confidence interval [CI] 1.18, 1.25; adjusted OR [AOR] 1.04, 95%CI 1.02, 1.07 for every additional UTI) and infant antibiotic use (OR 1.21, 95%CI 1.20, 1.22; AOR 1.16, 95%CI 1.15, 1.17 for every additional course) were associated with an increased risk of childhood asthma, while having older siblings at home (OR 0.92, 95%CI 0.91, 0.93; AOR 0.85, 95%CI 0.84, 0.87 for each additional sibling) was associated with a decreased risk of childhood asthma, in a dose-dependent manner. Compared with vaginal delivery, C-section delivery increased odds of childhood asthma by 34% (OR 1.34, 95%CI 1.29, 1.39) in the univariate analysis and 11% after adjusting for other environmental exposures and covariates (AOR 1.11, 95%CI 1.06, 1.15). Maternal GBS was associated with a significant increased risk of childhood asthma in the univariate analysis (OR 1.27, 95%CI 1.19, 1.35), but not in the adjusted analysis (AOR 1.03, 95%CI 0.96, 1.10). In the subgroup analysis of children whose maternal antibiotic use information was available, maternal antibiotic use was associated with an increased risk of childhood asthma in a similar dose-dependent manner in the univariate and adjusted analyses (OR 1.13, 95%CI 1.12, 1.15; AOR 1.06, 95%CI 1.05, 1.08 for every additional course). Compared with infants with the lowest number of exposures (no UTI during pregnancy, vaginal delivery, at least five older siblings at home, no antibiotics during infancy), infants with the highest number of exposures (at least three UTIs during pregnancy, C-section delivery, no older siblings, eight or more courses of antibiotics during infancy) had a 7.77 fold increased odds of developing asthma (AOR: 7.77, 95%CI: 6.25, 9.65). Lastly, infant antibiotic use had the greatest impact on asthma risk compared with maternal UTI during pregnancy, mode of delivery and having older siblings at home.ConclusionEarly-life exposures, maternal UTI during pregnancy (maternal antibiotic use), mode of delivery, infant antibiotic use, and having older siblings at home, are associated with an increased risk of childhood asthma in a cumulative manner, and for those continuous variables, a dose-dependent relationship. Compared with in utero exposures, exposures occurring during infancy have a greater impact on the risk of developing childhood asthma.

Phase 1 Study Evaluating Safety, Tolerability, Pharmacokinetics and Immunogenicity of REGN2222 in Healthy Adults: A New Human Monoclonal RSV-F Antibody for RSV Prevention

Phase 1 Study Evaluating Safety, Tolerability, Pharmacokinetics and Immunogenicity of REGN2222 in Healthy Adults: A New Human Monoclonal RSV-F Antibody for RSV Prevention

Respiratory syncytial virus infections in pediatric transplant recipients: A Canadian Paediatric Surveillance Program study.

The incidence and spectrum of severity of RSV infections in SOT or HSCT recipients is not known. From September 2010 through August 2013, pediatricians were surveyed monthly by the CPSP for SOT or HSCT recipients with RSV infection within two yr post-transplant. There were 24 completed case report forms that fit the inclusion criteria (10 HSCT and 14 SOT recipients). Six of 24 cases (25%) remained outpatients, and 11 (46%) were managed on an inpatient ward, while seven (29%) required intensive care of which five required mechanical ventilation and two died of RSV infection. Ten of 23 cases (43%) were nosocomial with these data not recorded for one case. Many transplant recipients recover uneventfully from RSV infection in the first two yr post-transplant. However, severe disease and death also occur. Larger studies are required to establish risk factors for poor outcomes. Prevention of nosocomial RSV should be a priority in transplant recipients.

5ICCN_037: Cost effectiveness of palivizumab for RSV prevention in high-risk infants for the 2012/2013 epidemic season in Moscow

Epigenetic changes have long-lasting effects on gene expression and are related to, and often induced by, the environment in which early development takes place.In particular, the period of development that extends from pre-conception to early infancy is the period of life during which epigenetic DNA imprinting activity is the most active.Epigenetic changes have been associated with modification of the risk for developing a wide range of adulthood, non-communicable diseases (including cardiovascular diseases, metabolic diseases, diseases of the reproductive system, etc.).This paper reviews the molecular basis of epigenetics, and addresses the issues related to the process of developmental programming of the various areas of human health.© 2014 Elsevier Ireland Ltd. All rights reserved.

Pediatric news.

Pediatric news.

G154 Estimation of the “True” Hospital Burden of Paediatric Respiratory Syncytial Virus on the NHS England

Background and AimRespiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infection (LRTI) in infants and young children and the leading cause of severe bronchiolitis between...

RSV prevention and treatment in pediatric lung transplant patients: A survey of current practices among the International Pediatric Lung Transplant Collaborative

RSV infection can be severe after pediatric lung transplantation. Strategies to prevent and treat RSV in this population are underreported. To assess the current practices, we surveyed the members of the IPLTC regarding RSV prevention and treatment strategies. Twenty-eight programs were surveyed; 18 (64.3%) responded at least partially. A median of 53 transplants (range, 8-355) occurred since inception. RSV testing occurs in asymptomatic (6/17) and symptomatic (17/17) patients. Diagnostic method is polymerase chain reaction at 13 sites and DFA at 8. Transplant candidates were received prophylaxis at 10 sites, with nine following national (5) or local (4) guidelines. All use palivizumab IM and/or IV. Recipients were received prophylaxis with palivizumab at eight centers (eight IM, one IV). Fourteen were treated for RSV (seven all patients; seven age-related). Medications include inhaled (6), oral (4), or IV (4) ribavirin, plus IVIG (9), steroids (8), and IV (2) or IM (3) palivizumab. Prevention and treatment barriers include insurance/hospital concerns, such as institutional reluctance to use inhaled ribavirin. RSV prevention and treatment strategies are diverse at pediatric lung transplant programs. Many centers offer prophylaxis (9/17) and treatments (14/17), but strategies are not uniform.

503 RSV Prevention and Treatment in Pediatric Lung Transplant Patients: A Survey of Current Practices among the International Pediatric Lung Transplant Collaborative (IPLTC)

503 RSV Prevention and Treatment in Pediatric Lung Transplant Patients: A Survey of Current Practices among the International Pediatric Lung Transplant Collaborative (IPLTC)

Palivizumab: a performer for prevention of RSV in Austria

Palivizumab: a performer for prevention of RSV in Austria

Palivizumab proves too costly for RSV prevention in Canada

Palivizumab proves too costly for RSV prevention in Canada

Palivizumab “highly cost-effective” for RSV prevention

Palivizumab “highly cost-effective” for RSV prevention

Palivizumab poor performer for prevention of RSV

Palivizumab poor performer for prevention of RSV

Consenso clínico sobre la profilaxis de la infección por virus respiratorio sincitial y el uso del palivizumab en cardiología pediátrica

Background Following the results of the CIVIC study, the SECPCC proposes to revise its recommendations for the prevention of RSV, taking into account the new evidence, as well as the preventive experience of paediatric cardiologists. For this purpose a structured method of professional consensus has been chosen. Objectives To develop a Spanish clinical consensus on preventing infection by RSV under the auspices of the Sociedad Española de Cardiología Pediátrica y Cardiopatías Congénitas. Methods Delphi Consensus modified in two rounds. The study was conducted in four phases: 1) constitution of a Scientific Committee for bibliographic review and submission of the recommendations for discussion, 2) constitution of an Expert Panel with 75 representatives in the speciality, 3) postal survey organised in two rounds and intermediate processing of opinions, and issuing of a report to the panellists, and 4) discussion of the results in a face-to-face meeting of the Scientific Committee. Results Consensus was reached on 54 of the 70 preventive recommendations analysed. With respect to the 16 remaining issues, no consensus was reached, due to differences in professional opinion and the absence of established criteria among the majority of the experts. Conclusions A set of recommendations for RSV prophylaxis in cardiology was developed and updated, rated in accordance with the degree of professional consensus on which they were based. These can be considered valid until such time as new scientific information emerges that warrants a further review.

Palivizumab for RSV prevention in high-risk children

Palivizumab for RSV prevention in high-risk children

Palivizumab for RSV prevention in high-risk children

Palivizumab for RSV prevention in high-risk children

WITHDRAWN: Immunoglobulin for preventing respiratory syncytial virus infection.

Respiratory Syncytial virus, the most important cause of lower respiratory tract infections in infants and young children in industrialized countries, is associated with increased morbidity in premature infants with or without bronchopulmonary dysplasia as well as those with congenital heart disease. Because of observations that lower rates of disease occur immediately after birth, presumably due to vertical transmission of maternal antibody, and animal studies where protection from pneumonia was observed through administration of immune globulin, the efficacy of passive prophylaxis in premature infants has been studied. This meta-analysis was performed to assess the effects of polyclonal respiratory syncytial virus hyperimmune globulin or monoclonal antibody in preventing RSV hospitalization, receipt of intensive care, mechanical ventilation, and mortality in those with underlying prematurity, bronchopulmonary dysplasia, or congenital heart disease. We searched the Cochrane Acute Respiratory Infections trials register and MEDLINE in March, 1999. In addition, abstracts on these topics were sought from the Pediatric Academies Meetings and the Intersciences Conference on Antimicrobial Agents and Chemotherapy for the years 1994 to 1997, inclusive. Randomized, controlled trials of prevention of RSV using immune globulin, respiratory syncytial virus immune globulin, or monoclonal RSV antibody in children with prematurity, bronchopulmonary dysplasia or congenital heart disease. Two authors independently abstracted data and assessed study quality. Only incidences could be pooled because data for durations was summarized in a manner that did not allow combining results across the studies. Four studies with a total of 2598 subjects were included in the main analysis. All were randomized controlled trials. Two trials were not blinded. Three studies examined RSV hyperimmune globulin and one examined monoclonal RSV antibody. A study of a different monoclonal RSV antibody could not be included because it has not been presented or published. The pooled Peto Odds Ratios favoring prophylaxis were 0.48 (95% CI 0.37, 0.64), 0.47 (0.29, 0.77), and 0.99 (0.48, 2.07) for incidence of hospitalization, incidence of ICU admission, and incidence of mechanical ventilation, respectively. The numbers needed to prevent one hospitalization and one ICU admission are 17 and 50 respectively. RSVIG is effective in preventing RSV hospitalizations and admission to the intensive care unit, but not in preventing mechanical ventilation. There was a non-significant trend towards a higher mortality in children given RSVIG.

Management of infants with bronchopulmonary dysplasia in North America

The in-hospital management of infants with BPD includes minimizing the duration of mechanical ventilation and avoiding the use of high inspired oxygen concentrations while maintaining adequate oxygenation. Fluid restriction, bronchodilators, and diuretic therapy can improve lung function and reduce the need for supplemental oxygen and high ventilator settings, but do not change the ultimate course of these infants. Corticosteroids also improve lung function and accelerate weaning from oxygen and mechanical ventilation, but their use during the first weeks of life is associated with worse neurological outcome. Adequate nutrition plays an important role in lung injury protection and recovery. Infants with severe BPD frequently develop pulmonary hypertension and may benefit from the use of pulmonary vasodilators. Outpatient management must be carefully planned and carried out by experienced multidisciplinary teams. Social and financial issues must be addressed with the family and caregivers. Home oxygen and mechanical ventilation therapy are used frequently after discharge and require specialized staff and equipment. Maintenance of oxygenation and proper nutritional support are critical aspects in the post-discharge management of these infants. Immunizations and RSV prevention are also important to prevent infections in these vulnerable immunocompromised patients.