Evaluation of BioThrax® and AV7909 anthrax vaccines in adults 66 years of age or older.

BACKGROUND: Multiple Anthrax vaccines are licensed or in development for post-exposure prophylaxis in individuals 18 to 65 years of age. No information exists on anthrax vaccines in populations over the age of 65. It is critical that we assess the capacity of anthrax vaccines to generate a protective immune response in older individuals. In this study, we compared BioThrax® to a formulation containing a CpG adjuvant (AV7909). METHODS: We conducted a Phase 2 clinical study to evaluate safety and immunogenicity of three vaccination schedules of the AV7909 vaccine candidate and one vaccination schedule of BioThrax® vaccine in adults over 65 years of age. A total of 305 subjects were enrolled to assess safety and immunogenicity by seroprotection rates, toxin neutralizing antibody titers, and anti-Protective Antigen ELISA titers. RESULTS: Compared to BioThrax, AV7909 elicited a more robust immune response in older subjects, especially with three doses of AV7909 at Days 1, 15, and 29, or two doses at Days 1 and 29. These trends were true with both seroprotection rates as defined by the percentage of subjects with 50 percent neutralization factors greater than 0.56, and geometric mean antibody titers. The responses to both AV7909 and BioThax were lower in older subjects compared to those aged 18-50. CONCLUSION: The immunogenicity data suggest that the CpG adjuvant in the AV7909 vaccine helps to elicit a more robust immune response in subjects over the age of 65. Alternative dosing strategies may be considered in this population given the high seroprotection rates with Day 1 and 29, or Day 1, 15, and 29 regimens. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03518125.

Severe Illnesses Associated With Outbreaks of Respiratory Syncytial Virus and Influenza in Adults.

BACKGROUND: Recent reports have described the contribution of adult respiratory syncytial virus (RSV) infections to the use of advanced healthcare resources and death. METHODS: Data regarding patients aged ≥18 years admitted to any of Maryland's 50 acute-care hospitals were evaluated over 12 consecutive years (2001-2013). We examined RSV and influenza (flu) surveillance data from the US National Respiratory and Enteric Virus Surveillance System and the Centers for Disease Control and Prevention and used this information to define RSV and flu outbreak periods in the Maryland area. Outbreak periods consisted of consecutive individual weeks during which at least 10% of RSV and/or flu diagnostic tests were positive. We examined relationships of RSV and flu outbreaks to occurrence of 4 advanced medical outcomes (hospitalization, intensive care unit admission, intubated mechanical ventilation, and death) due to medically attended acute respiratory illness (MAARI). RESULTS: Occurrences of all 4 MAARI-related hospital advanced medical outcomes were consistently greater for all adult ages during RSV, flu, and combined RSV-flu outbreak periods compared to nonoutbreak periods and tended to be greatest in adults aged ≥65 years during combined RSV-flu outbreak periods. Rate ratios for all 4 MAARI-related advanced medical outcomes ranged from 1.04 to 1.38 during the RSV, flu, or combined RSV-flu outbreaks compared to the nonoutbreak periods, with all 95% lower confidence limits >1. CONCLUSIONS: Both RSV and flu outbreaks were associated with surges in MAARI-related advanced medical outcomes (hospitalization, intensive care unit admission, intubated mechanical ventilation, and death) for adults of all ages.

Clinical Development of Therapeutic Agents for Hospitalized Patients With Influenza: Challenges and Innovations.

BACKGROUND: Since 1999, the US Food and Drug Administration approved neuraminidase and endonuclease inhibitors to treat uncomplicated outpatient influenza but not severe hospitalized influenza. After the 2009 pandemic, several influenza hospital-based clinical therapeutic trials were unsuccessful, possibly due to certain study factors. Therefore, in 2014, the US Health and Human Services agencies formed a Working Group (WG) to address related clinical challenges. METHODS: Starting in 2014, the WG obtained retrospective data from failed hospital-based influenza therapeutic trials and nontherapeutic hospital-based influenza studies. These data allowed the WG to identify factors that might improve hospital-based therapeutic trials. These included primary clinical endpoints, increased clinical site enrollment, and appropriate baseline enrollment criteria. RESULTS: During 2018, the WG received retrospective data from a National Institutes of Health hospital-based influenza therapeutic trial that demonstrated time to resolution of respiratory status, which was not a satisfactory primary endpoint. The WG statisticians examined these data and believed that ordinal outcomes might be a more powerful primary endpoint. Johns Hopkins' researchers provided WG data from an emergency-department (ED) triage study to identify patients with confirmed influenza using molecular testing. During the 2013-2014 influenza season, 4 EDs identified 1074 influenza-patients, which suggested that triage testing should increase enrollment by hospital-based clinical trial sites. In 2017, the WG received data from Northwestern Memorial Hospital researchers regarding 703 influenza inpatients over 5 seasons. The WG applied National Early Warning Score (NEWS) at patient baseline to identify appropriate criteria to enroll patients into hospital-based therapeutic trials. CONCLUSIONS: Data received by the WG indicated that hospital-based influenza therapeutic trials could use ordinal outcome analyses, ED triage to identify influenza patients, and NEWS for enrollment criteria.

Association of influenza outbreaks with advanced pediatric medical support.

Retrospective data evaluated increases in advanced medical support for children with medically attended acute respiratory illness (MAARI) during influenza outbreak periods (IOP). Advanced support included hospitalisation, intensive care unit admission, or mechanical ventilation, for children aged 0-17 years hospitalised in Maryland's 50 acute-care hospitals over 12 influenza seasons. Weekly numbers of positive influenza tests in the Maryland area defined IOP for each season as the fewest consecutive weeks, including the peak week containing at least 85% of positive tests with a 2-week buffer on either side of the IOP. Peak IOP (PIOP) was defined as four consecutive weeks containing the peak week with the most number of positive influenza tests. Off-PIOP was defined as the 'shoulder' weeks during each IOP. Non-influenza season (NIS) was the remaining weeks of that study season. Rate ratios of mean daily MAARI-related admissions resulting in advanced medical support outcomes during PIOP or Off-PIOP were compared with the NIS and were significantly elevated for all 12 study seasons combined. The results suggest that influenza outbreaks are associated with increased advanced medical support utilisation by children with MAARI. We feel that this data may help preparedness for severe influenza epidemics or pandemic.

Evaluation of anthrax vaccine safety in 18 to 20 year olds: A first step towards age de-escalation studies in adolescents.

BACKGROUND/OBJECTIVES: Anthrax vaccine adsorbed (AVA, BioThrax(®)) is recommended for post-exposure prophylaxis administration for the US population in response to large-scale Bacillus anthracis spore exposure. However, no information exists on AVA use in children and ethical barriers exist to performing pre-event pediatric AVA studies. A Presidential Ethics Commission proposed a potential pathway for such studies utilizing an age de-escalation process comparing safety and immunogenicity data from 18 to 20 year-olds to older adults and if acceptable proceeding to evaluations in younger adolescents. We conducted exploratory summary re-analyses of existing databases from 18 to 20 year-olds (n=74) compared to adults aged 21 to 29 years (n=243) who participated in four previous US government funded AVA studies. METHODS: Data extracted from studies included elicited local injection-site and systemic adverse events (AEs) following AVA doses given subcutaneously at 0, 2, and 4 weeks. Additionally, proportions of subjects with ≥4-fold antibody rises from baseline to post-second and post-third AVA doses (seroresponse) were obtained. RESULTS: Rates of any elicited local AEs were not significantly different between younger and older age groups for local events (79.2% vs. 83.8%, P=0.120) or systemic events (45.4% vs. 50.5%, P=0.188). Robust and similar proportions of seroresponses to vaccination were observed in both age groups. CONCLUSIONS: AVA was safe and immunogenic in 18 to 20 year-olds compared to 21 to 29 year-olds. These results provide initial information to anthrax and pediatric specialists if AVA studies in adolescents are required.

Clinical and immune responses to inactivated influenza A(H1N1)pdm09 vaccine in children.

BACKGROUND: As the influenza A H1N1 pandemic emerged in 2009, children were found to experience high morbidity and mortality and were prioritized for vaccination. This multicenter, randomized, double-blind, age-stratified trial assessed the safety and immunogenicity of inactivated influenza A(H1N1)pdm09 vaccine in healthy children aged 6 months to 17 years. METHODS: Children received 2 doses of approximately 15 or 30 µg hemagglutin antigen 21 days apart. Reactogenicity was assessed for 8 days after each dose, adverse events through day 42, and serious adverse events or new-onset chronic illnesses through day 201. Serum hemagglutination inhibition titers were measured on days 0 (prevaccination), 8, 21, 29 and 42. RESULTS: A total of 583 children received the first dose and 571 received the second dose of vaccine. Vaccinations were generally well-tolerated and no related serious adverse events were observed. The 15 µg dosage elicited a seroprotective hemagglutination inhibition (≥ 1:40) in 20%, 47% and 93% of children in the 6-35 month, 3-9 year and 10-17 year age strata 21 days after dose 1 and in 78%, 82% and 98% of children 21 days after dose 2, respectively. The 30 µg vaccine dosage induced similar responses. CONCLUSIONS: The inactivated influenza A(H1N1)pdm09 vaccine exhibited a favorable safety profile at both dosage levels. While a single 15 or 30 µg dose induced seroprotective antibody responses in most children 10-17 years of age, younger children required 2 doses, even when receiving dosages 4- to 6-fold higher than recommended. Well-tolerated vaccines are needed that induce immunity after a single dose for use in young children during influenza pandemics.

Surge in Hospitalizations Associated With Mechanical Ventilator Use During Influenza Outbreaks.

OBJECTIVE: Information on surges in critical care services including mechanical ventilator use during seasonal influenza outbreaks is limited. To potentially facilitate preparedness plans for future pandemics, we retrospectively quantitated surges in all-cause mechanical ventilator use during peak influenza for 12 consecutive years in all certified hospitals in Maryland. METHODS: Influenza testing data obtained for the Centers for Disease Control and Protection, Health and Human Services region 3, included defined peak influenza outbreak periods (PIOP), non-influenza time periods (non-ITP), and proportions of circulating influenza types for all study years. Procedure codes for mechanical ventilator use and diagnostic codes for medically attended acute respiratory illness (MAARI) were reviewed for every Maryland hospitalization. Daily counts of hospitalizations associated with ventilator use or MAARI during PIOP compared to non-ITP were analyzed using Poisson regression adjusted for month and year. RESULTS: Ventilator use increased during PIOP by 7% (95% CI, 5-10) over non-ITP (P < .0001) for all study years. These annual surges correlated with influenza season intensity, as measured by MAARI-related hospitalizations (correlation coefficient = 0.91, P < .0001). CONCLUSIONS: Surges in ventilator use were temporally associated with PIOP and were positively correlated with influenza season intensity, as measured by hospitalizations associated with acute respiratory illness. This information may assist resource planning for future pandemics. (Disaster Med Public Health Preparedness. 2014;x:1-7).

Relationship of influenza vaccine match and use rate to medically attended acute respiratory illnesses in older residents of Maryland. November 13, 2012.

The effectiveness of seasonal influenza vaccine may be influenced by mismatches to circulating influenza viruses. The relationship of these vaccine mismatches to the occurrence of medically attended acute respiratory illnesses (MAARI)-related emergency department (ED) visits and hospitalizations for all Maryland residents aged 50 years or older was examined for seven years (2001-2008). Also, relationships of individual circulating influenza types or subtypes to these MAARI-encounters were investigated. Anonymous, retrospective discharge data from all Maryland hospitals were utilized to determine daily numbers of MAARI-related ED visits and hospitalizations. Rate ratios (RR) of these MAARI-related encounters were then determined between intense influenza outbreak periods and non-influenza season time periods for each year using a Poisson regression model. Center for Disease Control end of season data reports were used to estimate each season's 'match' of each trivalent influenza vaccine component to subsequent circulating influenza viruses in the United States. The overall vaccine match proportion for the three vaccine viruses was then multiplied by reported vaccination rates of Maryland residents aged 50 years or older to determine an 'estimated influenza vaccine impact factor' (EIVIF) for each year. Correlation coefficients (CC) were then calculated comparing RR of MAARI-encounters to the corresponding EIVIF data. Finally, yearly RR of MAARI-encounters were compared to corresponding rates of individual circulating influenza types or subtypes circulating in the Maryland area. Consistent trends were observed whereby increased EIVIF proportions were correlated with decreased RR of MAARI-related ED visits and hospitalizations. This correlation reached statistical significance when comparing EIVIF to RR of MAARI-related ED visits (CC=-0.77, P=0.04). Also, the proportion of A/H3N2 viruses circulating each season was significantly positively correlated to that season's RR of MAARI-related ED visits (CC=0.89) and hospitalizations (CC=0.92); both P<0.01. Our data suggest increased protective effects of influenza immunization on reducing MAARI-related ED visits and hospitalizations in older individuals when the vaccine is well matched to the circulating strains. A/H3N2 viruses were clearly associated with more frequent MAARI-related ED visits and hospitalizations than A/H1N1 and B viruses.

Successful use of volunteers to conduct school-located mass influenza vaccination clinics.

OBJECTIVE: To determine the feasibility of using volunteers to assist in school-located mass vaccination clinics for influenza. METHODS: A set of elementary school-based mass vaccination clinics was implemented in Carroll County, Maryland by the local health department in the 2005-2006 school year. In addition to using health department personnel, fiscal restraints necessitated using medical volunteers and lay volunteers to assist health professionals. The medical volunteers included physicians, nurses, and pharmacists, and were responsible for administering intranasal vaccine (live, attenuated influenza vaccine [LAIV]). We assessed the performance, as measured by the number of vaccinations administered, and effort expended by these volunteers. RESULTS: A total of 5319 (44%) of the 12,090 elementary school children in the county received LAIV. Of the estimated 3547 (66%) children eligible and consenting to receive a second dose, 3124 (88%) received it. In total, 8806 doses of LAIV were administered. Health department nurses worked 42 person-days and were assisted by medical and allied health professionals volunteering 87 person-days without compensation, totaling 581 person-hours spent in this effort. CONCLUSIONS: A mass school-located influenza vaccination program using medical and lay volunteers guided by health department nurses is feasible. Several issues were identified to improve future clinics and help make the program sustainable.

Pediatrician attitudes concerning school-located vaccination clinics for seasonal influenza.

OBJECTIVE: Vaccinating all children aged 6 months to 18 years every year has potentially large ramifications for office-based primary care pediatricians. We determined the degree to which pediatricians support routine annual influenza vaccination outside the medical home, especially in school-located mass influenza vaccination clinics. METHODS: Internet-based survey sent in May and June 2009 to all 623 currently practicing primary care general pediatricians who were members of the Maryland Chapter of the American Academy of Pediatrics. RESULTS: Of those surveyed, 193 (31%) responded. Approximately 67% reported they vaccinated more than half the children in their practice with at least one dose in the 2008-2009 influenza season, and about half anticipated that, in their office, they would not attain ≥75% coverage of all patients older than 5 months of age. Approximately 27% of respondents predicted they would likely have difficulty obtaining sufficient vaccine to cover commercially insured patients, and 32% were likely to have difficulty getting sufficient vaccine to cover Medicaid, underinsured, and uninsured patients because of ordering or distribution problems. Approximately 78% of respondents cited borderline or poor reimbursement for influenza vaccinations, and 53% had unused vaccine at the end of the 2008-2009 influenza season. Ninety-six percent of respondents supported school-located influenza vaccination programs in their community for their patients. CONCLUSIONS: These results indicate awareness by primary care pediatricians in Maryland of the potential difficulties involved in implementing universal influenza vaccinations in their practice and their support of school-located vaccination programs managed by the local health department in their community.

Direct and indirect impact of influenza vaccination of young children on school absenteeism.

Special mass influenza vaccination programs of elementary school-aged children (ESAC) in some or all Maryland Counties were conducted during the falls of 2005-2007. From 3% to 46% of ESAC received live attenuated influenza vaccine during these county programs, which were in addition to routine influenza vaccination efforts conducted in county medical offices. Anonymous, all cause public school absentee data for all grades was available from 11 of Maryland's 24 counties. Binomial regression was used to estimate associations between the percentage of children vaccinated in each county and the degree of increase in absenteeism rates during influenza outbreaks. We estimated that, for every 20% increase in vaccination rates for ESAC during these special programs, a 4% decrease in the rise in absentee rates occurred during influenza outbreak periods in both elementary and upper schools (P<0.05). These results suggest both direct and indirect benefits of influenza vaccination of young children.

Impact of influenza vaccination of schoolchildren on medical outcomes among all residents of Maryland.

Special influenza vaccination programs of elementary school-aged children (ESAC) in some or all of Maryland Counties were conducted during the falls of 2005-2007. Rates of emergency department (E.D.) visits and hospitalizations for medically attended acute respiratory illnesses (MAARI) as well as deaths due to pneumonia and influenza for county residents were determined. The degree to which these rates were modulated during intense influenza outbreak periods (IIOP) in counties who vaccinated a greater percentage of ESAC was estimated using Poisson regression. Notably, for every 20% increase in vaccination rates, MAARI related E.D. visits during IIOP decreased by 8% (95% C.I., 5-12%) in children aged 5-11 years and by 6% (95% C.I., 3-8%) in adults aged 19-49 years (p<0.001), which suggests both a direct and indirect benefit of the vaccination programs. In contrast, MAARI related hospitalizations increased during IIOP by 4% (95% C.I., 3-9%) in adults aged >50 years for every 20% increase in vaccination rates (p<0.023) for which we have no plausible biologic explanation. No significant changes in deaths were noted.

Evaluation of the safety, reactogenicity and immunogenicity of FluBlok trivalent recombinant baculovirus-expressed hemagglutinin influenza vaccine administered intramuscularly to healthy children aged 6-59 months.

BACKGROUND: Recombinant baculovirus-expressed hemagglutinin (rHA [FluBlok]) influenza vaccine is unique in avoiding production in eggs and its rapid production capability. OBJECTIVE: Compare the safety and immunogenicity of trivalent FluBlok to egg-grown trivalent influenza vaccine (TIV) in children. METHODS: Healthy children were randomized to receive two doses of study vaccines. TIV (7.5 microg HA/antigen), FluBlok-22.5 (22.5 microg rHA/antigen), or FluBlok-45 (45 microg rHA/antigen) were given to 115 children ages 6-35 months. TIV (15 microg HA/antigen) or FluBlok-45 was given to 41 children ages 36-59 months. Safety and reactogenicity data were collected post-vaccination. Serum hemagglutination-inhibition antibody (HI) titers were measured before and 28 days after vaccination. RESULTS: No serious vaccine-related adverse events occurred and reactogenicity events to equal volumes of TIV or FluBlok were generally similar. However, in the younger children, selected local and systemic symptoms were recorded significantly more frequently to 0.5 mL FluBlok-45 than to 0.25 mL doses of either the FluBlok-22.5 or 7.5 microg TIV vaccines. In the younger children, the immunogenicity to TIV was generally significantly superior to FluBlok. Serologic responses to FluBlok were higher in the older children than the younger group, but were still somewhat lower compared to TIV. CONCLUSION: These data suggests that FluBlok is as safe but less immunogenic than similar volumes of TIV, particularly in the youngest children. The immunogenicity data is the converse of what has been observed in adults. Further studies examining the immunogenicity of FluBlok in older children are warranted.

Countywide school-based influenza immunization: direct and indirect impact on student absenteeism.

OBJECTIVE: Live attenuated influenza vaccine was given to 5319 (44%) of the 12090 students enrolled in public elementary schools in Carroll County, Maryland, during the fall of 2005. We examined the impact of this community-based intervention on countywide student absenteeism during the subsequent influenza outbreak. METHODS: This study used existing, anonymous information: census data, community influenza tests, and public school absenteeism data. The intervention group was Carroll County, years 2005-2006. The control group included Carroll County, years 2001-2005, and adjacent Frederick County, years 2001-2006. Weekly student absenteeism was determined during baseline influenza-free periods and influenza outbreak periods for all of the public schools. RESULTS: The absolute change in absenteeism during the influenza outbreak periods over baseline in elementary schools was 0.61% for the intervention group and 1.79% for the control group. Similarly, the change in absenteeism during the influenza outbreak period over baseline for high schools was 0.32% for the intervention group and 1.80% for the control group. Although not statistically significant, trends in middle schools were similar. CONCLUSIONS: Countywide school-based influenza vaccination was associated with reduced absenteeism during an influenza outbreak. The data suggest not only a direct impact on elementary schools but also an indirect impact on high schools. School-based programs provide an efficient method of providing influenza vaccination to children, and protection may extend to unvaccinated community members. Additional research is needed to determine whether school-based vaccination of children reduces morbidity and mortality associated with influenza outbreaks.

Benefits and costs of immunizing children against influenza at school: an economic analysis based on a large-cluster controlled clinical trial.

Current influenza vaccination recommendations focus on immunizing high-risk people; however, influenza mortality and morbidity remain elevated. U.S. policymakers are considering expansion of flu vaccination recommendations to include school-age children (ages 5-18). Children are at risk for flu and propagate epidemic spread. Immunizing children at school offers an efficient approach to covering this population. This study examines the cost consequences of a large multistate, school-based influenza immunization program. The results show that immunization reduces disease among children and adults and is cost-saving to society. An epidemiologically based influenza immunization policy might be an important supplement to the existing risk-based policy.

Persistence of PAR-2 vasodilation despite endothelial dysfunction in BPH/2 hypertensive mice.

This study investigated relaxation of vascular smooth muscle by acetylcholine, bradykinin and protease-activated receptor 2 (PAR-2) to characterise endothelial dysfunction in spontaneously hypertensive mice (BPH/2). We hypothesised that PAR-2 induced vasodilation would be preserved in BPH/2 despite the presence of hypertension and impaired vasodilator responses to acetylcholine and bradykinin. Mean arterial blood pressure (MAP), heart rate and locomotor activity were assessed in conscious mice over 24-h periods by radiotelemetry. Relaxation responses of small mesenteric arteries to acetylcholine, bradykinin and the PAR-2 agonist, 2-furoyl-LIGRLO-amide (2fly), were assessed using wire myographs. MAP and heart rate of BPH/2 were 15 and 18%, respectively, higher than in controls (BPN/3). BPH/2 also exhibited increased locomotor activity. Maximal relaxations of arteries by acetylcholine and bradykinin in BPH/2 were reduced by 25-50% relative to BPN/3. In contrast, relaxation responses to 2fly were only slightly (6%), albeit significantly, reduced. Sodium nitroprusside-induced relaxations were not different between strains. Treatment of BPH/2 arteries with inhibitors of calcium-activated K(+) channels was sufficient to block persistent 2fly- and residual ACh- and bradykinin-induced relaxations, whereas NO synthase inhibitor failed to inhibit these relaxations. In BPH/2 mice, vascular smooth muscle relaxation by PAR-2 is well preserved despite the presence of hypertension and impaired vasodilation responses to acetylcholine and bradykinin.

A double-blind, placebo-controlled, pilot study of bovine lactoferrin supplementation in bottle-fed infants.

BACKGROUND: Lactoferrin has an array of biological activities that include growth, immune modulation, and antimicrobial effects. The aim of this randomized, placebo-controlled, double-blind study was to examine the impact of bovine lactoferrin supplementation in infants. PATIENTS AND METHODS: Healthy, formula-fed infants, > or =34 weeks' gestation and < or =4 weeks of age, enrolled in a pediatric clinic. Infants received either formula supplemented with lactoferrin (850 mg/L) or commercial cow milk-based formula (102 mg/L) for 12 months. Growth parameters and information on gastrointestinal, respiratory, and colic illnesses were collected for the infants' first year. Antibodies to immunizations and hematologic parameters were measured at 9 and 12 months. RESULTS: The lactoferrin-enhanced formula was well tolerated. There were significantly fewer lower respiratory tract illnesses, primarily wheezing, in the 26 lactoferrin-fed (0.15 episodes/y) compared with the 26 regular formula-fed (0.5 episodes/y) infants (P < 0.05). Significantly higher hematocrit levels at 9 months (37.1% vs 35.4%; P < 0.05) occurred in the lactoferrin-supplemented group compared with the control formula group. CONCLUSIONS: Lactoferrin supplementation was associated with potentially beneficial outcomes such as significantly fewer lower respiratory tract illnesses and higher hematocrits. Larger, more focused studies in infants are warranted.

Effectiveness of school-based influenza vaccination.

BACKGROUND: Vaccination of children in school is one strategy to reduce the spread of influenza in households and communities. METHODS: We identified 11 demographically similar clusters of elementary schools in four states, consisting of one school we assigned to participate in a vaccination program (intervention school) and one or two schools that did not participate (control schools). During a predicted week of peak influenza activity in each state, all households with children in intervention and control schools were surveyed regarding demographic characteristics, influenza vaccination, and outcomes of influenza-like illness during the previous 7 days. RESULTS: In all, 47% of students in intervention schools received live attenuated influenza vaccine. As compared with control-school households, intervention-school households had significantly fewer influenza-like symptoms and outcomes during the recall week. Paradoxically, intervention-school households (both children and adults) had higher rates of hospitalization per 100 persons than did control-school households. However, there was no difference in the overall hospitalization rates for children or adults in households with vaccinated children, as compared with those with unvaccinated children, regardless of study-group assignment. Rates of school absenteeism for any cause (based on school records) were not significantly different between intervention and control schools. CONCLUSIONS: Most outcomes related to influenza-like illness were significantly lower in intervention-school households than in control-school households. (ClinicalTrials.gov number, NCT00192218.)

The interferon antagonist NS2 protein of respiratory syncytial virus is an important virulence determinant for humans.

BACKGROUND: Respiratory syncytial virus (RSV) is targeted for vaccine development, because it causes severe respiratory tract illness in the elderly, young children, and infants. A primary strategy has been to derive live attenuated viruses for use in intranasally administered vaccines that will induce a protective immune response. In the present study, the NS2 gene, whose encoded protein antagonizes the host's interferon- alpha / beta response, was deleted from RSV vaccine candidates by use of reverse genetics. METHODS: Three NS2 gene-deleted RSV vaccine candidates were studied: rA2cp Delta NS2, rA2cp248/404 Delta NS2, and rA2cp530/1009 Delta NS2. rA2cp Delta NS2, which had the fewest attenuating mutations, was evaluated in adults and RSV-seropositive children. rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2 were evaluated in adults and RSV-seropositive and RSV-seronegative children. RESULTS: At a high dose (10(7.0) pfu), rA2cp Delta NS2 was not shed by adults, and only 13% of them had an immune response. The other vaccine candidates, rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2, had greatly decreased infectivity in RSV-seronegative children, compared with that of their immediate parent strains, which possess an intact NS2 gene. CONCLUSIONS: Deletion of the NS2 gene attenuates RSV in subjects of all ages studied. This validates the strategy of developing live respiratory tract virus vaccines in which the virus's ability to inhibit the human innate immune system is blocked. rA2cp248/404 Delta NS2 should be studied in children at a higher input titer, because it was more infectious and immunogenic than was rA2cp530/1009 Delta NS2.

A pilot study of the effectiveness of a school-based influenza vaccination program.

OBJECTIVE: The objective of this study was to evaluate the feasibility of a school-based influenza immunization program. METHODS: Pupils and their families from 3 demographically similar elementary schools participated in this pilot, unblinded, controlled intervention study. Live attenuated influenza vaccine (FluMist) was made available to all eligible pupils in 1 target school during regular school hours. Two schools where vaccine was not offered served as control schools. All families from the 3 study schools were sent an anonymous questionnaire requesting 7-day recall data on fever or respiratory illness (FRI)-related medical visits, medications purchased, and days of school or paid work lost during the peak influenza week. Changes in weekly pupil absenteeism were also examined. RESULTS: One hundred eighty-five (40%) of the target school pupils received vaccine, of whom >50% were vaccinated < or =3 weeks before the influenza outbreak period. Questionnaires were returned by 43% to 51% of households. Significant (45-70%) relative reductions in FRI-related outcomes, including doctor visits by adults or children, prescription or other medicines purchased, and family schooldays or workdays missed, were observed for target school households, compared with control school households. The increases in absenteeism rates during the influenza outbreak period, compared with baseline rates earlier in the fall, were not significantly different between target and control schools. Within the target school, however, the increase in absenteeism rates was significantly smaller for the FluMist-vaccinated pupils, compared with the non-FluMist-vaccinated pupils. CONCLUSIONS: This school-based influenza immunization program was associated with significant reductions in FRI-related outcomes in households of pupils attending an intervention school. These results might have underestimated the potential impact of FluMist, because the majority of children received intraepidemic vaccination.