Respiratory syncytial virus-neutralizing serum antibody titers in infants following palivizumab prophylaxis with an abbreviated dosing regimen.
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ABSTRACT: Background
Monthly injections of palivizumab during the respiratory syncytial virus (RSV) season in at-risk infants reduces RSV-associated hospitalizations. However, the additive effect of naturally acquired immunity remains unclear. The objective of this study was to assess total neutralizing serum antibodies (NAb) against RSV in at-risk infants who had received an abbreviated course of palivizumab prophylaxis.Methods
Serum samples were collected from infants enrolled in the RSV Immunoprophylaxis Program in British Columbia, Canada over 2 consecutive RSV seasons (2013 to 2015). Infants in this program had received an abbreviated course of palivizumab in accordance with the provincial guidelines. Data were compared to adults and infants less than 12 months of age who did not receive palivizumab. Anti-RSV NAb titers were measured using an RSV microneutralization assay.Findings
Infants who received palivizumab had anti-RSV NAb titers at the end of the RSV season that persisted beyond what is expected from the pharmacokinetics of palivizumab alone. Moreover, 54% of the control infants who did not receive palivizumab and all tested adults had protective anti-RSV NAb titers.Conclusions
Based on our observations, we hypothesize that naturally acquired NAb provide additive protection, which may significantly reduce the need for additional doses of palivizumab in infants at risk of severe RSV infections.
SUBMITTER: Claydon J
PROVIDER: S-EPMC5402955 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionPalivizumab is indicated for the prevention of respiratory syncytial virus (RSV) infection in high-risk children. Previous palivizumab utilization studies examined prior authorization claims but did not examine utilization within insured populations as a whole. This study describes outpatient palivizumab utilization trends and characterizes high-risk infants receiving palivizumab within Medicaid- and commercially insured populations.MethodsInfants born July 1, 2003 through June 30, 2013 were identified in the MarketScan® Multistate Medicaid and Commercial claims databases. Infants with ≥ 18 months of continuous medical insurance enrollment with pharmacy benefits after birth and evidence of chronic lung disease of prematurity (CLDP), congenital heart disease (CHD), or preterm birth without CLDP or CHD were studied. Palivizumab use and demographic and clinical characteristics were measured in infant subgroups. Outpatient palivizumab utilization rates were calculated for each seasonal year (July-June) and for each infant subgroup.ResultsIn total, 29,350 (2.1%) Medicaid-insured and 9589 (2.5%) commercially insured infants received palivizumab and had CLDP, CHD, or were born at < 37 weeks gestational age (wGA). Infants with CLDP (82%) and those < 29 wGA (78%) had the highest utilization. Decreases in utilization rates between the 2003-2004 and 2012-2013 seasons were seen among Medicaid-insured infants born at 29-36 wGA (all P < .0001), and commercially insured infants born at 31-32 wGA (P < .0001), 33-34 wGA (P = .055), 35-36 wGA (P < .0001), and with CHD (P = .003). Utilization by month was consistent across subgroups among Medicaid- and commercially insured infants, with most doses administered from November to March.ConclusionPalivizumab use is targeted to a small percentage of infants who are at highest risk of hospitalization for RSV disease. Utilization declined in recent years in both Medicaid- and commercially insured infant groups. Most palivizumab doses were administered from November to March, with most infants receiving ≤ 5 doses.FundingAstraZeneca.
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Project description:BackgroundInfection with respiratory syncytial virus (RSV) is common among young children insured through Medicaid in the United States. Complete and timely dosing with palivizumab is associated with lower risk of RSV-related hospitalizations, but up to 60% of infants who receive palivizumab in Medicaid population do not receive full prophylaxis. The purpose of this study was to evaluate the association of partial palivizumab prophylaxis with the risk of RSV hospitalization among high-risk Medicaid-insured infants.MethodsClaims data from 12 states during 6 RSV seasons (October 1st to April 30th in the first year of life in 2003-2009) were analyzed. Inclusion criteria were birth hospital discharge before October 1st, continuous insurance eligibility from birth through April 30th, ? one palivizumab administration from August 1st to end of season, and high-risk status (?34 weeks gestational age or chronic lung disease of prematurity [CLDP] or hemodynamically significant congenital heart disease [CHD]). Fully prophylaxed infants received the first palivizumab dose by November 30th with no gaps >35 days up to the first RSV-related hospitalization or end of follow-up. All other infants were categorized as partially prophylaxed.ResultsOf the 8,443 high-risk infants evaluated, 67% (5,615) received partial prophylaxis. Partially prophylaxed infants were more likely to have RSV-related hospitalization than fully prophylaxed infants (11.7% versus 7.9%, p< 0.001). RSV-related hospitalization rates ranged from 8.5% to 24.8% in premature, CHD, and CLDP infants with partial prophylaxis. After adjusting for potential confounders, logistic regression showed that partially prophylaxed infants had a 21% greater odds of hospitalization compared with fully prophylaxed infants (odds ratio 1.21, 95% confidence interval 1.09-1.34).ConclusionsRSV-related hospitalization rates were significantly higher in high-risk Medicaid infants with partial palivizumab prophylaxis compared with fully prophylaxed infants. These findings suggest that reduced and/or delayed dosing is less effective.
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Project description:ObjectiveThe aim of this study was to assess the safety and effectiveness of palivizumab for the prevention of lower respiratory tract infection (LRI) caused by respiratory syncytial virus (RSV) in children with immunocompromised conditions or Down syndrome.MethodsIn this multicenter, post-marketing surveillance study (December 2013 to December 2015), children aged ≤24 months with immunocompromised conditions or Down syndrome (without hemodynamically significant congenital heart disease) receiving palivizumab immunoprophylaxis during two RSV seasons were observed until 30 days after the final palivizumab injection. Safety [adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), serious ADRs (SADRs)] and effectiveness (frequency, incidence, and duration of hospitalization due to RSV infections) were assessed.ResultsOf 304 patients receiving palivizumab, 167 (54.9%) had immunocompromised conditions, and 138 (45.4%) had Down syndrome; 260 (85.5%) completed palivizumab immunoprophylaxis. The annual mean (±standard deviation) number of doses was 5.3 (±2.4) per season. Overall, 220 AEs occurred in 99 patients (32.6%), including 89 SAEs in 53 patients (17.4%). Of these, 33 AEs in 25 patients (8.22%) were considered ADRs, and 13 ADRs in 11 patients (3.62%) were considered SADRs. In four patients, five SADRs (nephroblastoma and asthma in the same patient, septic shock, device-related infection, and drug-induced liver injury) were previously unreported; however, none were considered drug-related. During the observation period, five RSV infections occurred and two patients required hospitalization.ConclusionPalivizumab was generally safe and effective for the prevention of LRI caused by RSV in newborns, infants, and children with immunocompromised conditions or Down syndrome up to the age of 24 months.
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Project description:ImportanceInfection with the respiratory syncytial virus (RSV) is the leading cause of hospitalizations in children, accounting for more than 90,000 hospitalizations every year in the United States. For children who are at risk for severe RSV infections, the American Academy of Pediatrics recommends immunoprophylaxis with a series of up to 5 injections of the antibody palivizumab administered monthly, beginning on November 1 of each year. However, many practitioners initiate injections at the onset of RSV season as indicated by local surveillance.ObjectivesTo evaluate the effectiveness of current regimens for palivizumab injections across different cities and to design an optimized regimen.Design, setting, and participantsWe performed a mathematical modeling study of the risk for hospitalization due to RSV infection. The model accounted for the pharmacokinetics of the antibody, the timing of the injections, and seasonal patterns of RSV, including geographic and year-to-year variability. We used the model to estimate the efficacy of current regimens, including the American Academy of Pediatrics recommendation, and to design a more effective injection regimen, the optimized fixed start (OFS), which uses city-specific initiation dates. Participants were the approximately 700,000 individuals who had specimens tested for RSV by National Respiratory and Enteric Virus Surveillance System laboratories in 18 US cities from July 1, 1994, through June 30, 2011 (a total of 725,741 tests).InterventionsDifferent palivizumab injection regimens.Main outcomes and measuresThe primary outcome measure was reduction in hospitalizations due to RSV infections. The secondary measures were cost (number of palivizumab doses) and duration of protection (in days).ResultsThe American Academy of Pediatrics-recommended 5-injection regimen is expected to reduce hospitalization risk by a median of 2.7% (range, -2.2% to 6.1%) compared with the conventional regimen based on RSV surveillance. The 5-injection OFS regimen is expected to further reduce risk by a median of 6.8% (range, 4.9% to 14.8%), and the 4-injection OFS regimen is expected to achieve efficacy comparable to that of the conventional 5-injection regimen while reducing costs by 20%.Conclusions and relevanceModified palivizumab regimens can improve protection for children at risk for severe outcomes of RSV infection and thereby lower rates of hospitalization due to RSV.
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Project description:BackgroundNeutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.e., seasonal variation) are necessary.MethodsFive decades of clinical trial literature were leveraged to build a model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinical endpoints. The MBMA was validated by backward translation to animal challenge experiments and forward translation to predict results of a recent RSV mAb trial. MBMA predictions were evaluated against a human trial of 70 participants who received either placebo or one of four dose-levels of MK-1654 and were challenged with RSV [NCT04086472]. The MBMA was used to perform clinical trial simulations and predict efficacy of MK-1654 in the infant target population.FindingsThe MBMA established a quantitative relationship between RSV SNA and clinical endpoints. This relationship was quantitatively consistent with animal model challenge experiments and results of a recently published clinical trial. Additionally, SNA elicited by increasing doses of MK-1654 in humans reduced RSV symptomatic infection rates with a quantitative relationship that approximated the MBMA. The MBMA indicated a high probability that a single dose of ≥ 75 mg of MK-1654 will result in prophylactic efficacy (> 75% for 5 months) in infants.InterpretationAn MBMA approach can predict efficacy of neutralizing antibodies against RSV and potentially other respiratory pathogens.
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Project description:Palivizumab can reduce hospitalizations due to respiratory syncytial virus (RSV), but many eligible infants fail to receive the full 5-dose series. The efficacy of clinical decision support (CDS) in fostering palivizumab receipt has not been studied. We sought a comprehensive solution for identifying eligible patients and addressing barriers to palivizumab administration.We developed workflow and CDS tools targeting patient identification and palivizumab administration. We randomized 10 practices to receive palivizumab-focused CDS and 10 to receive comprehensive CDS for premature infants in a 3-year longitudinal cluster-randomized trial with 2 baseline and 1 intervention RSV seasons.There were 356 children eligible to receive palivizumab, with 194 in the palivizumab-focused group and 162 in the comprehensive CDS group. The proportion of doses administered to children in the palivizumab-focused intervention group increased from 68.4% and 65.5% in the two baseline seasons to 84.7% in the intervention season. In the comprehensive intervention group, proportions of doses administered declined during the baseline seasons (from 71.9% to 62.4%) with partial recovery to 67.9% during the intervention season. The palivizumab-focused group improved by 19.2 percentage points in the intervention season compared to the prior baseline season (p < 0.001), while the comprehensive intervention group only improved 5.5 percentage points (p = 0.288). The difference in change between study groups was significant (p = 0.05).Workflow and CDS tools integrated in an EHR may increase the administration of palivizumab. The support focused on palivizumab, rather than comprehensive intervention, was more effective at improving palivizumab administration.
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