Mucosal Immunization of Rhesus Monkeys against Respiratory Syncytial Virus Subgroups A and B and Human Parainfluenza Virus Type 3 by Using a Live cDNA-Derived Vaccine Based on a Host Range-Attenuated Bovine Parainfluenza Virus Type 3 Vector Backbone

Abstract

Respiratory syncytial virus (RSV) is the most common cause of acute viral lower respiratory disease in infants and young children, followed by human parainfluenza virus type 3 (HPIV3) as the second most important viral respiratory pathogen. In the United States, RSV and HPIV3 are responsible for approximately one-third of all pediatric respiratory tract disease leading to hospitalization (13,20,45), and RSV alone is estimated to account for between 73,000 and 126,000 annual hospitalizations of infants younger than 1 year of age (51). Worldwide, acute lower respiratory tract disease is the leading cause of mortality due to infectious diseases (63), and in infants and young children RSV is the most commonly isolated viral pathogen in this disease entity (59). To reduce the burden of disease caused by RSV and HPIV3, vaccines that are safe and immunogenic are clearly needed.The first RSV vaccine candidate, a formalin-inactivated vaccine developed in the 1960s, failed to provide protection against RSV infection and resulted in immune-mediated enhanced disease upon subsequent infection by wild-type RSV (40). Enhancement of RSV disease does not occur after natural RSV infection and has not been seen following immunization with an intranasally administered, live attenuated RSV vaccine candidate (65). This is an important factor in favor of a topically administered live attenuated RSV vaccine. To date, several live attenuated RSV vaccine candidates have been evaluated in clinical trials (33,39,64,65), but a licensed RSV vaccine is still not available. The most challenging aspect of developing a live attenuated RSV vaccine is to achieve an appropriate balance between attenuation and immunogenicity in the young infant, in whom immune responses are reduced due to immunologic immaturity and the immunosuppressive effects of maternally derived virus-specific serum immunoglobulin G (65). Mucosal immunization provides a partial escape from immunosuppression by serum antibodies (44), and therefore topically administered live attenuated vaccines seem ideal for immunization of young infants. However, all live attenuated RSV vaccine candidates tested to date have been either overattenuated and insufficiently immunogenic (34, 64) or underattenuated (36, 65) in this age group.Protection against reinfection with RSV and HPIV3 is mainly conferred by serum and mucosal antibodies directed against their viral surface glycoproteins (16). The RSV G and

New Generation Live Vaccines against Human Respiratory Syncytial Virus Designed by Reverse Genetics

“…The magnitude of expression of the vectored RSV genes in vitro was greater than that of RSV, especially for the single-gene inserts. The resulting viruses were suitably attenuated and highly immunogenic against both viruses when evaluated in rhesus monkeys (46). The inserted genes were surprisingly stable and suitable for vaccine manufacture.…”

Treatment of Respiratory Syncytial Virus Infection: Past, Present and Future

“…Recently, results of a phase I trial studying viral take, serum antibody response and safety were encouraging 205 and at the moment, the vaccine is undergoing phase II clinical evaluation in 2-24 month children (van Bleeck et al, 2011). A big advantage of such chimeric vaccine candidates is that they can be developed as a bivalent RSV/PIV vaccine for the pediatric population (Schmidt et al, 2001(Schmidt et al, , 2002Tang et al, 2003).…”

Bovine parainfluenza virus type 3 (PIV3) expressing the respiratory syncytial virus (RSV) attachment and fusion proteins protects hamsters from challenge with human PIV3 and RSV

“…The recombinant bovine/human PIV3 harboured the RSV genes at the 39 end of the viral genome, while bPIV3/RSV(I) contained the RSV G and F genes in the centre of the genome, between the HN and L genes of bPIV3. Schmidt et al (2001Schmidt et al ( , 2002) employed a chimeric bovine/human PIV3 as a vector backbone to enhance PIV3 antigenicity. However, the humanization of the bPIV3 surface glycoproteins may result in the loss of the critical attenuation phenotype observed in humans.…”

“…Recently, Schmidt et al (2001Schmidt et al ( , 2002) generated recombinant chimeric bovine/human PIV3 expressing RSV G and/or F proteins. Hamsters immunized with these recombinant viruses were protected in challenge studies from RSV as well as hPIV3.…”