Protective Efficacy and Immunogenicity of an Adenoviral Vector Vaccine Encoding the Codon-Optimized F Protein of Respiratory Syncytial Virus

Abstract

Adenoviral vectors (AdV) have received considerable attention for vaccine development because of their high immunogenicity and efficacy. In previous studies, it was shown that DNA immunization of mice with codonoptimized expression plasmids encoding the fusion protein of respiratory syncytial virus (RSV F) resulted in enhanced protection against RSV challenge compared to immunization with plasmids carrying the wild-type cDNA sequence of RSV F. In this study, we constructed AdV carrying the codon-optimized full-length RSV F gene (AdV-F) or the soluble form of the RSV F gene (AdV-Fsol). BALB/c mice were immunized twice with AdV-F or AdV-Fsol and challenged with RSV intranasally. Substantial levels of antibody to RSV F were induced by both AdV vaccines, with peak neutralizing-antibody titers of 1:900. Consistently, the viral loads in lung homogenates and bronchoalveolar lavage fluids were significantly reduced by a factor of more than 60,000. The protection against viral challenge could be measured even 8 months after the booster immunization. AdV-F and AdV-Fsol induced similar levels of immunogenicity and protective efficacy. Therefore, these results encourage further development of AdV vaccines against RSV infection in humans.Human respiratory syncytial virus (RSV) is a highly infectious member of the paramyxovirus family causing upper and lower respiratory tract infections in humans. Serious acute RSV infections, including fatal cases of bronchiolitis and pneumonia, occur particularly in premature infants, immunocompromised adults, and patients with pre-existing chronic lung diseases or underlying heart defects (11,12,14,39,46,56). In young children, RSV is the most common respiratory tract pathogen, accounting for approximately 50% of hospitalizations due to lower respiratory tract infections (21). In population-based surveillance studies for hospitalization in Europe, RSV was identified in 42 to 45% of enrolled children younger than 2 years with lower respiratory tract infections, and the rate of hospitalization due to RSV-induced respiratory illnesses was estimated at 3 to 6% among industrialized nations (45). Children with severe RSV infections suffer from oxygen deficiency with cyanosis and require intensive medical care. Furthermore, RSV infection in childhood is suspected to be a risk factor for development of asthma (36,41,43,59). The urgent need for an RSV vaccine is further demonstrated by a study showing that levels of disease burden, mortality, and morbidity caused by RSV infections in the elderly are comparable to those induced by nonpandemic influenza A infections (11). However, the immunization of children with a formalininactivated (FI) RSV vaccine in the 1960s resulted in a more severe clinical illness, with two fatal cases, than in nonvaccinated infants following RSV infection, pointing out the difficulties in developing a safe and efficacious RSV vaccine (7,29). It was shown previously that the enhanced disease severity and the development of pulmonary eosinophilia are mainly attributable to a...

Novel Vaccine Regimen Elicits Strong Airway Immune Responses and Control of Respiratory Syncytial Virus in Nonhuman Primates

“…For the immunization in the presented study, the secreted form of hRSV-F was used as a vaccine antigen since expression of a fusion active full-length hRSV-F was shown to be cytotoxic (18). Consistent with other studies (19,20), we had previously observed that immunization with DNA or adenoviral vectors (AdV) vaccines expressing the soluble hRSV-F protein, resulted in a superior immune response and protective efficacy in mice, which opened the possibility to further explore these genetic vaccines against hRSV in NHPs (21,22). Structural data further support the concept of induction of neutralizing antibodies by soluble forms of the hRSV-F (23).…”

“…The concentration of endotoxin was measured as described previously (21). Recombinant replication deficient adenoviral vector (rAdV) carrying the soluble form of the codon optimized hRSV-F gene (rAdV-Fsol) was described previously (22). The rAdV-Fsol vaccine preparation used had a particle concentration of 10 11 gene transferring units per ml.…”

“…As described previously, serum, plasma, and BAL fluid samples were analyzed for IgA and IgG hRSV and hRSV-F specific antibody levels using a conventional enzyme-linked immunosorbent assay (ELISA) methodology (5,22). For coating of ELISA plates, heat-inactivated whole virus based on RSV A2 Long strain was used (21,22).…”

Purification of HRSV F protein from a eukaryotic expression vector and establishment of a sandwich ELISA method

“…The safety, immunogenicity and efficacy of the PFP23 vaccine have been confirmed for the protection of children with cystic fibrosis against HRSV lung infection. Treatment with the humanized monoclonal antibody, palivizumab, which targets the F protein has also achieved great success in the prevention of HRSV infection in high-risk groups (6,7).…”

Anti-Respiratory Syncytial Virus Agents from Phytomedicine

“…Although traditionally regarded as a pediatric pathogen, RSV can also cause life-threatening pulmonary disease in bone marrow transplant recipients (Fouillard et al 1992) and the elderly (Dowell et al 1996;Falsey et al 1992Falsey et al , 1995Falsey et al , 2005Falsey and Walsh, 1998). Although the global prevalence of RSV infection especially among infants and young children is on the increase, vaccine development, unfortunately, has been fraught with spectacular failure and with difficult obstacles, and there are only limited therapeutic options for treatment of this disease (Collins et al, 1996;Wright et al, 2000;Kohlmann et al, 2009;Tregoning and Schwarze et al, 2010). Therefore, the search for novel anti-viral inhibitors of RSV has become more intensive.…”