Safety, tolerability, and immunogenicity of two Zika virus DNA vaccine candidates in healthy adults: randomised, open-label, phase 1 clinical trials.

BACKGROUND: The Zika virus epidemic and associated congenital infections have prompted rapid vaccine development. We assessed two new DNA vaccines expressing premembrane and envelope Zika virus structural proteins. METHODS: We did two phase 1, randomised, open-label trials involving healthy adult volunteers. The VRC 319 trial, done in three centres, assessed plasmid VRC5288 (Zika virus and Japanese encephalitis virus chimera), and the VRC 320, done in one centre, assessed plasmid VRC5283 (wild-type Zika virus). Eligible participants were aged 18-35 years in VRC19 and 18-50 years in VRC 320. Participants were randomly assigned 1:1 by a computer-generated randomisation schedule prepared by the study statistician. All participants received intramuscular injection of 4 mg vaccine. In VRC 319 participants were assigned to receive vaccinations via needle and syringe at 0 and 8 weeks, 0 and 12 weeks, 0, 4, and 8 weeks, or 0, 4, and 20 weeks. In VRC 320 participants were assigned to receive vaccinations at 0, 4, and 8 weeks via single-dose needle and syringe injection in one deltoid or split-dose needle and syringe or needle-free injection with the Stratis device (Pharmajet, Golden, CO, USA) in each deltoid. Both trials followed up volunteers for 24 months for the primary endpoint of safety, assessed as local and systemic reactogenicity in the 7 days after each vaccination and all adverse events in the 28 days after each vaccination. The secondary endpoint in both trials was immunogenicity 4 weeks after last vaccination. These trials are registered with ClinicalTrials.gov, numbers NCT02840487 and NCT02996461. FINDINGS: VRC 319 enrolled 80 participants (20 in each group), and VRC 320 enrolled 45 participants (15 in each group). One participant in VRC 319 and two in VRC 320 withdrew after one dose of vaccine, but were included in the safety analyses. Both vaccines were safe and well tolerated. All local and systemic symptoms were mild to moderate. In both studies, pain and tenderness at the injection site was the most frequent local symptoms (37 [46%] of 80 participants in VRC 319 and 36 [80%] of 45 in VRC 320) and malaise and headache were the most frequent systemic symptoms (22 [27%] and 18 [22%], respectively, in VRC 319 and 17 [38%] and 15 [33%], respectively, in VRC 320). For VRC5283, 14 of 14 (100%) participants who received split-dose vaccinations by needle-free injection had detectable positive antibody responses, and the geometric mean titre of 304 was the highest across all groups in both trials. INTERPRETATION: VRC5283 was well tolerated and has advanced to phase 2 efficacy testing. FUNDING: Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

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.

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.

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.

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.