Evaluation of a Live-Attenuated Human Parainfluenza Type 1 Vaccine in Adults and Children.

We conducted a phase I clinical trial (clinicaltrials.gov identifier, NCT00641017) of the experimental live-attenuated human parainfluenza virus type 1 (HPIV-1) vaccine rHPIV-1/84/del 170/942A sequentially in 3 groups: adults, HPIV-1-seropositive children, and HPIV-1-seronegative children, the target population for vaccination. rHPIV-1/84/del 170/942A was appropriately restricted in replication in adults and HPIV-1-seropositive children but was overattenuated (ie, insufficiently infectious and immunogenic) for HPIV-1-seronegative children.

Human PIV-2 recombinant Sendai virus (rSeV) elicits durable immunity and combines with two additional rSeVs to protect against hPIV-1, hPIV-2, hPIV-3, and RSV.

The human parainfluenza viruses (hPIVs) and respiratory syncytial viruses (RSVs) are the leading causes of hospitalizations due to respiratory viral disease in infants and young children, but no vaccines are yet available. Here we describe the use of recombinant Sendai viruses (rSeVs) as candidate vaccine vectors for these respiratory viruses in a cotton rat model. Two new Sendai virus (SeV)-based hPIV-2 vaccine constructs were generated by inserting the fusion (F) gene or the hemagglutinin-neuraminidase (HN) gene from hPIV-2 into the rSeV genome. The inoculation of either vaccine into cotton rats elicited neutralizing antibodies toward both homologous and heterologous hPIV-2 virus isolates. The vaccines elicited robust and durable antibodies toward hPIV-2, and cotton rats immunized with individual or mixed vaccines were fully protected against hPIV-2 infections of the lower respiratory tract. The immune responses toward a single inoculation with rSeV vaccines were long-lasting and cotton rats were protected against viral challenge for as long as 11 months after vaccination. One inoculation with a mixture of the hPIV-2-HN-expressing construct and two additional rSeVs (expressing the F protein of RSV and the HN protein of hPIV-3) resulted in protection against challenge viruses hPIV-1, hPIV-2, hPIV-3, and RSV. Results identify SeV vectors as promising vaccine candidates for four different paramyxoviruses, each responsible for serious respiratory infections in children.

Medical burden of respiratory syncytial virus and parainfluenza virus type 3 infection among US children. Implications for design of vaccine trials.

Respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) are two leading causes of lower respiratory illness (LRI) in infants. Many efforts have been directed to develop vaccines against these two viruses. Licensure of new vaccines includes three phases of clinical trials to evaluate safety, immunogenicity, and efficacy. To design an efficacy trial, age-specific incidence rates of suitable clinical endpoints need to be available. In this review, historical data are summarized to estimate the age-specific rates of acute respiratory illness (ARI), LRI, and hospitalization caused by RSV and PIV3 among US children <5 years of age. Nation-wide data are available for hospitalization but not ARI and LRI. Age-specific rates of RSV and PIV3-related ARI or LRI can vary 9-fold or 5-fold, respectively, in different studies conducted in different populations using different clinical and laboratory definitions. The annual medical burden for RSV and PIV3 in children <5 was estimated respectively to be about 4.19 and 3.24 million cases of medically-attended ARI, 2.1 and 1.08 million cases of LRI, and 113 and 29 thousand cases of hospitalization, respectively. The impact of three important variables including age at vaccination, clinical endpoints, and laboratory diagnosis in designing efficacy trials is discussed. A RSV vaccine which is safe and effective in the first six months of life is optimal to reduce the severe disease burden of LRI and hospitalization, however, interference of maternal antibody may reduce vaccine efficacy in this age group. LRI occurs more frequently than hospitalization and may be the most feasible clinical endpoint for designing efficacy trials. Since age-specific rates of RSV and PIV3-related LRI can vary significantly in different populations, collecting age-specific LRI rates in phase 1 and 2 trials to further understand this variability appears warranted.

Safety and immunogenicity of intranasal murine parainfluenza virus type 1 (Sendai virus) in healthy human adults.

Human parainfluenza virus-type 1 (hPIV-1) is the most common cause of pediatric laryngotracheobronchitis (croup) and results in close to 30,000 US hospitalizations each year. No effective vaccine is available. We examined murine PIV-1 (Sendai virus, SeV) as a live, xenotropic vaccine for the closely related human PIV-1 in a phase I, dose escalation study in healthy adults. Intranasal Sendai virus was uniformly well-tolerated and showed evidence of immunogenicity in three of nine vaccinees despite pre-existing, cross-reactive immunity presumably induced by previous exposure to human PIV-1. Results encourage future trials to evaluate the efficacy of Sendai virus in preventing human PIV-1 infection in infants and children.

Construction of a live-attenuated bivalent vaccine virus against human parainfluenza virus (PIV) types 1 and 2 using a recombinant PIV3 backbone.

PIV1 and PIV2 are important agents of pediatric respiratory tract disease. We are developing live-attenuated vaccines against these viruses. We earlier constructed a PIV3/PIV1 antigenic chimeric virus, designated rPIV3-1, in which the hemagglutinin-neuraminidase (HN) and fusion (F) proteins of wild type rPIV3 were replaced by their PIV1 counterparts. In the present study, rPIV3-1 was used as a vector to express the HN protein of PIV2 to generate a single virus capable of inducing immunity to both PIV1 and PIV2. The PIV2 HN open reading frame was expressed from an extra gene cassette, under the control of PIV3 cis-acting transcription signals, inserted between the F and HN genes of rPIV3-1. The recombinant derivative, designated rPIV3-1.2HN, was readily recovered and exhibited a level of temperature sensitivity and in vitro growth similar to that of its parental virus. The rPIV3-1.2HN virus was restricted in replication in both the upper and lower respiratory tracts of hamsters compared with rPIV3-1, identifying an attenuating effect of the PIV2 HN insert in hamsters. rPIV3-1.2HN elicited serum antibodies to both PIV1 and PIV2 and induced resistance against challenge with wild type PIV1 or PIV2. Thus, rPIV3-1.2HN, a virus attenuated solely by the insertion of the PIV2 HN gene, functioned as a live attenuated bivalent vaccine candidate against both PIV1 and PIV2.

Half-life of human parainfluenza virus type 3 (hPIV3) maternal antibody and cumulative proportion of hPIV3 infection in young infants.

During a phase 2 trial of parainfluenza virus type 3 (PIV3) vaccine, sequential serum samples were obtained from infants at 2, 6, 7, 12-15, and 13-16 months of age. Paired serum samples obtained at 2 and 6 months of age were used to estimate the biologic half-life of human PIV3 (hPIV3) maternal antibody in young infants. On the basis of the assumption that hPIV3 maternal antibody decays exponentially and constantly, the biologic half-life was estimated without adjusting for body weight increases. Cumulative proportions of hPIV3 infection in young infants were further estimated after adjusting for maternal antibody decline. A hemagglutination inhibition assay was used to quantify hPIV3 antibody. The mean (95% confidence interval) biologic half-life was estimated to be 51 (42-60) days, on the basis of which cumulative proportions of hPIV3 infection were estimated to be 11% at 6 months of age, 47% at 12-15 months of age, and 50% at 13-16 months of age.