DISCUSSION
RSV infection, upper respiratory tract, nasal F-specific IgA Ab, RSV-specific nasal IgA, infection, human disease
INFECTION, VIRUS, RSV INFECTION
This clinical study of the PIV5-vectored RSV vaccine candidate BLB201 was the first in-human study for this vaccine and for the replicating PIV5 vector. The study showed that BLB201 administered as a single intranasal dose had an acceptable safety profile. Solicited local and systemic AEs were generally mild and only reported by approximately half of the vaccine recipients. No SAE related to vaccination was reported. This result is consistent with the long history of PIV5 vector’s use in dogs. The vector has been used in dogs for 50 years, and yet no human disease has ever been reported from human exposure to PIV5-immunized animals. In this phase 1 study, approximately half of the enrolled participants were PIV5 seropositive based on nAb titer >1:10 at baseline, suggesting that asymptomatic exposures occur in a high percentage of the U.S. population. The safety profile of BLB201 is comparable to other intranasal live virus–based vaccines including live-attenuated RSV vaccines, MEDI-534, and PanAd3-RSV in adults (Although RSV preF protein–based vaccines have been approved for reducing symptoms in lower respiratory tract of RSV-infected elderly, an RSV vaccine that prevents symptomatic infection in lower respiratory tract and even symptomatic infection in upper respiratory tract is highly desirable. While it is thought that serum Ab, nasal IgA, and CMI all contribute to protection against symptomatic RSV infection, RSV-specific nasal IgA is thought to be the most critical in preventing RSV infection (There are several intranasal RSV vaccines advanced to human clinical trials. Most are live-attenuated RSV vaccines. Because of the existing anti-RSV antibodies, these live-attenuated RSV vaccines did not generate detectable immune responses in RSV-seropositive people (The induction of cytotoxic CD8The rate of the induction of nasal F-specific IgA Ab response was higher in the younger age group than the elderly group, indicating that, similar to many other vaccines, there was an age-dependent difference in magnitude for responses to BLB201 in nasal IgA Ab. This may be attributed to age-related immunosenescence (In this study, approximately 50% (group 1) and 40% (group 2) of participants were seropositive at baseline for PIV5 nAbs. Seropositivity to PIV5 in this study was a little higher than previously reported at about 30% (The shedding of vaccine virus in nasal swabs after vaccination was transient, lasting less than 4 weeks, suggesting that BLB201 has the capacity to replicate in the nasal cavities of RSV-experienced adults. This self-limiting infection in the respiratory mucosa by BLB201 may help in the development of RSV-specific immunity. Although vaccine virus shedding was only identified in five participants, it is plausible that it had occurred in other participants but at earlier time points than were sampled here, i.e., within 1 week after vaccination. The result that over 93% participants had robust anti-RSV F cellular immune responses is consistent with replication of BLB201 in humans: BLB201 likely entered human cells and expressed RSV F that was presented by major histocompatibility complex I in infected cells.The genetic stability of the viral vaccine vector is important for its use in humans. MEDI-534 was not stable in infants, resulting in the termination of its clinical development (In conclusion, BLB201 is a PIV5-based intranasal RSV candidate vaccine that demonstrated safety and immunogenicity in this phase 1 study. The ability of BLB201 to boost pre-existing cellular, humoral, and mucosal responses in adults supports further clinical evaluation of this approach in infants and adult populations.