Safety and immunogenicity of an intranasal Sendai virus-based human parainfluenza virus type 1 vaccine in 3- to 6-year-old children

Abstract

Human parainfluenza virus type 1 (hPIV-1) is the most common cause of laryngotracheobronchitis (croup), resulting in tens of thousands of hospitalizations each year in the United States alone. No licensed vaccine is yet available. We have developed murine PIV-1 (Sendai virus [SeV]) as a live Jennerian vaccine for hPIV-1. Here, we describe vaccine testing in healthy 3- to 6-year-old hPIV-1-seropositive children in a dose escalation study. One dose of the vaccine (5 × 10(5), 5 × 10(6), or 5 × 10(7) 50% egg infectious doses) was delivered by the intranasal route to each study participant. The vaccine was well tolerated by all the study participants. There was no sign of vaccine virus replication in the airway in any participant. Most children exhibited an increase in antibody binding and neutralizing responses toward hPIV-1 within 4 weeks from the time of vaccination. In several children, antibody responses remained above incoming levels for at least 6 months after vaccination. Data suggest that SeV may provide a benefit to 3- to 6-year-old children, even when vaccine recipients have preexisting cross-reactive antibodies due to previous exposures to hPIV-1. Results encourage the testing of SeV administration in young seronegative children to protect against the serious respiratory tract diseases caused by hPIV-1 infections.

FIG 1

Analysis of Sendai virus (SeV)-specific antibody among recipients of intranasal SeV vaccine. Serum samples obtained from ten 3- to 6-year-old participants at indicated time points prevaccination and postvaccination were examined for SeV-specific antibody binding. Results are reported as antibody titers defined by nonlinear regression calculations. Antibody binding titer was defined as the highest sample dilution that scored an OD of at least 0.1 at 405 nm on the ELISA. All study participants had SeV-specific binding antibody titers of at least 1,000 prior to vaccination. Means and standard errors are shown. *, assays were conducted prior to collection of the 6-month sample from participant S713.

FIG 2

Analysis of human parainfluenza virus type 1 (hPIV-1)-specific antibody among recipients of intranasal SeV vaccine. Serum samples obtained from ten 3- to 6-year-old participants at indicated time points prevaccination and postvaccination were examined for hPIV-1-specific antibody binding. Results are reported as antibody titers defined by nonlinear regression calculations. Antibody binding titer was defined as the highest sample dilution that scored an OD of at least 0.1 at 405 nm on the ELISA. Means and standard errors are shown. *, assays were conducted prior to collection of the 6-month sample from participant S713. Student's t tests were performed to compare hPIV-1-specific binding antibody responses before and after vaccinations. Except for one participant (S708), significant improvements in hPIV-1-specific antibody binding titers occurred on day 14 after vaccinations compared to prevaccination titers for all individuals (Student's t test [GraphPad Prism], P < 0.05).

FIG 3

Similar temporal trends for Sendai virus (SeV)-specific and human parainfluenza virus type 1 (hPIV-1)-specific binding antibody titers. SeV and hPIV-1 binding titers were plotted side by side for participants S703, S704, and S710.

FIG 4

Analysis of human parainfluenza virus type 1 (hPIV-1)-specific neutralizing antibody among recipients of intranasal SeV vaccine. Serum samples obtained from ten 3- to 6-year-old participants at indicated time points prevaccination and postvaccination were examined for hPIV-1-specific neutralizing antibody activities. Results are reported as antibody titers defined by nonlinear regression calculations. The neutralization titer was defined as the highest sample dilution for which the majority of wells in the assay scored negatively for hemagglutination (HA). *, assays were conducted prior to collection of the 6-month sample from participant S713; dotted lines, results were either too high or too low for quantification.