Absence of vaccine-enhanced RSV disease and changes in pulmonary dendritic cells with adenovirus-based RSV vaccine
© Krause et al; licensee BioMed Central Ltd. 2011
Received: 20 May 2011
Accepted: 29 July 2011
Published: 29 July 2011
The development of a vaccine against respiratory syncytial virus (RSV) has been hampered by the risk for vaccine-enhanced RSV pulmonary disease induced by immunization with formalin-inactivated RSV (FIRSV). This study focuses on the evaluation of vaccine-enhanced pulmonary disease following immunization with AdF.RGD, an integrin-targeted adenovirus vector that expresses the RSV F protein and includes an RGD (Arg-Gly-Asp) motif. Immunization of BALB/c mice with AdF.RGD, resulted in anti-RSV protective immunity and induced increased RSV-specific IFN-γ T cell responses compared to FIRSV. RSV infection 5 wk after immunization with FIRSV induced pulmonary inflammatory responses in the lung, that was not observed with AdF.RGD. Additionally, In the FIRSV-immunized mice following infection with RSV, pulmonary DC increased and Tregs decreased. This suggests that distinct responses of pulmonary DC and Tregs are a features of vaccine-enhanced RSV disease and that immunization with an RGD-modified Ad vaccine does not trigger vaccine-enhanced disease.
RSV is a leading cause of severe viral respiratory disease in infants and children . A major obstacle in the development of an RSV vaccine has been vaccine-enhanced disease triggered by immunization with inactivated virus antigen [2, 3]. This aberrant immune-mediated response is characterized by infiltration of neutrophils and eosinophils, increased complement-fixing antibody titers and lymphoproliferative responses [4–7]. The exact mechanism has not been fully elucidated. An altered pattern of CD4 lymphocyte activation with eosinophil recruitment and Th2-type-predominant cytokine production (IL-4, IL-5, IL-13 and eotaxin) suggests an aberrant immune-mediated response skewed towards Th2 responses [4, 8–10]. This is supported by data demonstrating that the disease following RSV infection can be transferred by RSV G protein-specific CD4 T cells and also occurs in the absence of CD8 T cells or IFN-γ [11–13]. RSV-specific CD8 T cells can even inhibit the disease [7, 13, 14]. Initially, the RSV G protein itself was implicated based on studies using vaccinia virus expressing the membrane-anchored part or the entire G protein for immunization [15–17]. Recently, it has been suggested that the pathway of antigen processing, rather than the antigenic content, is responsible [4, 7]. In addition, low avidity anti-RSV antibodies, which may have resulted from poor activation of toll-like receptors, have been observed in mice following immunization with FIRSV , the most commonly used model to study vaccine-enhanced RSV disease [4, 19–21].
The RSV F protein, one of the main capsid proteins that confers protective immunity against RSV, has been a major target in RSV vaccine development . Vaccination with the F protein generates helper T cell responses that are Th1 in character . Adenovirus (Ad)-based gene delivery systems are promising platforms for genetic vaccines due to their ability to act as immune system adjuvants and to induce strong cellular and humoral responses against the virus and the transgene [24, 25] and have been used as experimental vaccines against RSV [26–32]. In part, the effectiveness of Ad-based vaccines results from the ability of Ad vectors to transfer genes to antigen presenting cells in vivo, particularly dendritic cells (DC) [33–37]. The immune response can be further enhanced to a more Th1-dominant response by modification of Ad capsid proteins to infect DC more efficiently [38–40]. The primary interaction of Ad with cells in vitro is through the knob domain of fiber to the coxsackievirus and adenovirus receptor (CAR) on the target cell [41, 42]. A secondary interaction occurs between the RGD (Asp-Arg-Gly) motif in the penton base and integrins. The addition of an RGD motif (in addition to that found in the penton base) enhances infection of DC, which express low levels of CAR and high levels of surface integrins [38–40].
Virus-specific humoral and cellular adaptive immune responses are responsible for protection and recovery from RSV infection. Lung DC, as part of the pulmonary innate immune system, recognize the infection, evoke anti-viral responses and modulate the Th1/Th2 balance [43–47]. There are two major subsets of DC in the mouse, (1) the CD11b+, CD11chigh conventional DC (cDC), and (2) the CD11blow-, CD11chigh, B220+ plasmacytoid DC (pDC) [48–52]. Resting lung cDC have been implicated in initiating a pro-allergic Th2 response in the lung and in requiring special cytokine signals to induce Th1 response, whereas pDC seem to have a primary role in producing IFN-α in response to viral infections and in promoting a Th1 response by blocking the pulmonary immune environment against a Th2 response [43, 50, 53–56]. PDC balance the T helper cell responses through cross-talk with regulatory T cells (Tregs). The number of pDC and cDC is increased in lung and draining lymph nodes following experimental RSV infection in mice [55, 57–59] as well as in nasal washings of RSV-infected infants . RSV-stimulated cDC seem to have immunostimulatory effects on both Th1 and Th2 responses . RSV-stimulated pDC have direct antiviral activity through the release of IFN-α (2). Depletion of pulmonary pDC leads to an exaggerated Th2 response to RSV [55, 56], whereas increasing the number of pDC by recombinant Flt3 ligand leads to an increased Th1 response . Increasing cDC while depleting pDC leads to enhanced Th2-type pathology . We hypothesized that the lung DC subsets stimulated in response to RSV infection in immunized animals would depend upon the T-helper cell type induced by immunization.
The present study demonstrates that immunization with the capsid-modified Ad vector AdF.RGD compared to immunization with FIRSV, at doses inducing comparable levels of anti-RSV neutralizing and protective immunity, leads to a more pronounced RSV-specific Th1 response and does not prime for vaccine-induced enhanced RSV disease. Furthermore, immunization with AdF.RGD or FIRSV results in a distinct response of pulmonary DC and Tregs that may be useful for the characterization of vaccine-enhanced pulmonary RSV disease.
Immunization with AdF.RGD Leads to Enhanced Th1-Type anti-RSV Immunity and Improved Protection against RSV
Immunization with AdF.RGD Leads to Improved Humoral anti-RSV Immunity Without Inducing Vaccine-enhanced Disease
Immunization with AdF.RGD Leads to Cellular and Protective anti-RSV Immunity
Characterization of Lung DC following Infection with RSV in AdF.RGD-Immunized Mice
Based on the exaggerated inflammatory Th2 response primed by the formalin-inactivated RSV vaccine more than 40 years ago, it has been thought that an efficient and safe vaccine against RSV should induce a Th1-dominant response. Our present study shows that, compared to FIRSV, an integrin-targeted Ad vector expressing the RSV F protein induces higher levels of serum neutralizing anti-RSV antibodies with equivalent protection against RSV, but showed a decreased Th2 response and did not induce RSV disease. Immunization with FIRSV followed by RSV infection induces an imbalance in the pulmonary cDC and pDC population, diminished anti-viral activity in pDC, and a lower frequency of regulatory T cells that was not present following immunization with AdF.RGD.
Modification of Ad Vector to Increase Th1 Responses
The effectiveness of Ad-based vaccines is thought to be based on the efficient infection of a variety of cells in vivo, subsequently the expression of a pathogen-specific protein encoded by the Ad expression cassette in these cells, as well as Ad vectors functioning as adjuvants [24, 25]. Ad vectors have the capability to infect DC and this is critical for the induction of a strong anti-Ad and anti-transgene immune response [33–37]. Generating protective immunity against viruses like RSV requires the generation of humoral and cellular immunity by the vaccine. One attractive feature of Ad for genetic vaccination is the capability to modify the Ad capsid to enhance immune responses [38–40]. Targeting Ad to antigen-presenting cells by adding the RGD integrin-binding motif to the fiber knob enhances anti-transgene cellular immune responses in mice and predominantly skews cellular immune responses towards Th1, a prerequisite to develop successful anti-viral vaccines [38–40]. AdF.RGD induced neutralizing anti-RSV titer, a strong anti-RSV Th1-dominant cellular response and protected from RSV after challenge.
Vaccine-induced RSV Disease
Although many vaccine approaches, including live attenuated, viral and bacterial vectored and adjuvanted subunit vaccines, have been evaluated in rodent and primate models, there is currently no approved RSV vaccine. Screening for a live attenuated RSV vaccine candidate with the right balance of attenuation and immunogenicity has been hampered by a lack of suitable in vitro and in vivo models capable of accurately predicting attenuation in naive infants . Vaccine-induced RSV disease following immunization with formalin-inactivated preparations of RSV, based on the initial clinical FIRSV vaccine, has been extensively studied in animal models responses [4–7, 19, 21]. Studies in cotton rats, vaccinated with FIRSV and then challenged with RSV showed infiltration with neutrophils, macrophages and lymphocytes and increased Th2-type cytokines like IL-4, IL-10, IL-13 and eotaxin in the lung, indicating a Th2 bias in enhanced inflammation [5, 65]. The central role of T cells in the augmented lung pathology has been elucidated using the BALB/c mouse model. It has been shown that CD4 T cells are crucial to the immunopathogenesis of vaccine-augmented RSV disease [4, 66, 67], and that RSV-specific antibodies (in the absence of CD4 and CD8 T cells) are not sufficient to cause disease enhancement [4, 66]. It has recently been reported that immunization with FIRSV induces low avidity anti-RSV antibodies due to poor activation of toll-like receptors that could consequently result in an aberrant Th2 immune response . Therefore, skewing to a Th1-type pattern of cytokine production by priming with live RSV prevented subsequent enhanced disease . Studies using recombinant vaccinia viruses expressing various RSV proteins have pointed to the G protein as a potential crucial factor in the induction of vaccine-enhanced disease . Since the challenge lies in inducing a strong and protective T cell response, while avoiding the pathological consequences of unbalanced Th1/Th2 responses, Ad vectors, which tend to induce strong Th1 responses, are a promising tool for a RSV vaccine. The addition of the RGD motif to the fiber further increased the Th1 response against the F protein and did not induce vaccine-enhance diseased.
Role of DC in Vaccine-induced RSV Disease
It has been reported that the number of cDC and pDC is increased during RSV infection and even after apparent resolution [55, 57–61]. Collectively, these data support the hypothesis that recruitment of recently attracted DCs in the lung leads to maintenance and control of the immune response in the lung, even after the actual infection and inflammation in the lung is resolved [43, 50, 54–56].
To date, there has been no description of the role of lung DC subsets in respiratory viral infections during the onset of vaccine-induced RSV disease. RSV-infected mice developed airway hyperreactivity as measured by a strong increase in airway resistance in response to methacholine. Depletion of pDCs around the time of RSV infection enhanced peribronchial and perivascular inflammatory infiltrates consisting of mononuclear cells and increased pro-inflammatory cytokines and decreased anti-viral secretion [55, 56]. Mice that were immunized with FIRSV and subsequently challenged with RSV showed similar patterns of lung DC subset imbalance, resulting in down-regulation of anti-viral secretion in pDC as well as decreased numbers of Treg cells. Although the subset populations were increased after RSV challenge, decreased Treg cells and elevated levels of IL-17 levels indicated a Th2-type milieu which may reflect an imbalance of pDC and consequently cDC function and which was not seen following immunization with AdF.RGD. The analysis of lung DCs and Tregs may thus be useful in the evaluation for vaccine-enhanced disease of new RSV vaccines.
The recombinant Ad vectors used in this study are E1a-, partial E1b- and partial E3- vectors based on the Ad5 genome. AdF contains the human cytomegalovirus (CMV) intermediate early promoter/enhancer, the sequenced F protein cDNA of the RSV A2 strain, same that was used for further challenge experiments, and the simian virus 40 (SV40) polyA stop signal as an expression cassette inserted into the E1 region. The F protein cDNA was kindly provided by P. Collins (Bethesda, MD). AdF.RGD has the high-affinity RGD sequence GCDCRGDCFCA incorporated at the COOH-terminal end of the fiber protein . The AdNull control vector contains no transgene in the expression cassette. The vectors were used on the basis of equal number of physical particle concentration and were propagated and purified as described previously .
Female BALB/c mice were obtained from Taconic Farms (Tarrytown, NY). The animals were housed under specific pathogen-free conditions and used at 6 to 8 wk of age. The mice were immunized by intramuscular injection of AdF.RGD, AdNull (both at 1010 particle units; pu), FIRSV (105 pfu), or by intranasal administration of RSV (105 pfu). All animal studies were conducted under protocols reviewed and approved by the Weill Cornell Institutional Animal Care and Use Committee.
The RSV strain used for immunization and protection experiments was A2 (VR-1540; ATCC). FIRSV was prepared from supernatant of RSV-infected HEp-2 cells, combined with paraformaldehyde (1:1600 dilution of 37-38% stock, Sigma) to a final dilution of 1:4000, and stirred for 3 days at 37°C. The virus was then pelleted by ultracentrifugation, resuspended, and alum-precipitated [3, 9, 67].
Cellular Immune Response
To assess the RSV F-specific cellular immune response following immunization, BALB/c mice were immunized by intramuscular administration of either AdF, AdF.RGD, AdNull (all at 1010 pu), or FIRSV (105 pfu). Unimmunized mice served as additional controls. The frequency of antigen-specific T lymphocytes was determined 10 days following immunization in an IFN-γ- and IL-4-specific ELISPOT assay. MAIPS-45 plates (Millipore, Bedford, MA) were coated overnight at 4°C with 5 μg/ml of cytokine-specific capture antibodies [AN18 (IFN-γ) or 11B11 (IL-4); Mabtech, Stockholm, Sweden]. Spleen single cell suspensions served as the source for DC, CD4 and CD8 T cells. CD4 or CD8 T cells were purified by negative depletion using SpinSep T cell subset purification kits (StemCell Technologies, Vancouver, BC, Canada). Purity for CD4 and CD8 T cells was between 95-98%. Splenic DC were purified from naive animals to serve as antigen presenting cells by positive selection using CD11c MACS beads (Miltenyi Biotec, Auburn, CA) and double-purification over two consecutive MACS LS+ columns (Milentyi Biotec). The resulting DC purity was between 90-96%. DC (5 × 106/ml) were either pulsed for 3 hr with the H-2d restricted F epitope (F85-93, KYKNAVTEL, 100 μM, purity confirmed by high-performance liquid chromatography), incubated with purified recombinant RSV F protein (100 μg/ml), or UV-inactivated RSV (105 pu/ml) in complete RPMI medium supplemented with 10 mM Hepes, pH 7.5 (BioSource International, Camarillo, CA) and 10-5 M b-mercaptoethanol (Sigma-Aldrich). The recombinant RSV F protein was produced from a bacterial expression vector. A bacterial expression vector (pSmt3-RSV F) was constructed, by cloning the PCR amplified RSV F gene (forward primer: 5'-CCC CGA TCC ACA ATG GAG TTG CTA ATC CTC-3'; reverse primer: 5'-A TAA CGT AAA TCA TTG ATT TTC GAA CCC-3') into the petSUMO expression vector (Invitrogen) and the recombinant fusion protein was purified by Ni-chelating affinity chromatography according to the manufacturer's protocol (Prebound, Qiagen, Valencia, CA). Prior to addition of responder T cells, antibody-coated plates were blocked with complete RPMI medium supplemented with 10 mM HEPES, pH 7.4 (BioSource International) and 10-5 M β-mercaptoethanol (Sigma-Aldrich) for 3 h. CD4 (2 × 105) or CD8 (105) T cells were incubated with splenic DC, pulsed with either recombinant RSV F protein, F85-93 peptide, RSV, or no antigen at a T cell: DC ratio of 6:1 for 48 h. Following washing, biotinylated anti-IFN-γ or anti-IL-4 detection antibodies (both at 1 μg/ml, Mabtech) were added and the plates were incubated for 2 h at 37°C, followed by a streptavidin-alkaline phosphatase conjugate (Vectastain-ABC peroxidase kit, Vector Laboratories, Burlingame, CA) and a 3-amino-9-ethylcarbazole substrate (Sigma) for spot detection. The spots were counted by computer-assisted ELISPOT image analysis (Zellnet Consulting, New York, NY).
Protection of Mice from Intranasal Challenge with RSV
To evaluate the protection against RSV infection following immunization, BALB/c mice were immunized by intramuscular administration of AdF.RGD, AdNull (both at 1010 pu) or FIRSV (105 pfu), and were then challenged with RSV (106 pfu) by intranasal inoculation after 4 wk. Four days later the mice were sacrificed, the lungs were homogenized in 1 ml MEM and the homogenates centrifuged at 1200 rpm at 4°C for 10 min. Ten-fold serial dilutions of the lung homogenate supernatant were incubated in infection medium (MEM supplemented with 1% penicillin/streptomycin) on HEp2 cells for 3 h at 37°C. The medium was then replaced with 1% methylcellulose in MEM containing 5% fetal bovine serum and 1% penicillin/streptomycin). After 4 days, the cells were fixed with 4% paraformaldehyde, stained with 1% crystal violet and the plaques were counted under a microscope. The neutralization titer was calculated from the average plaques of four wells as the reciprocal of the highest dilution of serum that completely prevented RSV activity (>90%).
Neutralizing RSV Titer
To evaluate serum anti-RSV neutralizing antibody titers, BALB/c mice were immunized by intramuscular administration of AdF.RGD, AdNull (both at 1010 pu), FIRSV (105 pfu), or by intranasal administration of RSV (105 pfu). Sera was collected 4 wk post-administration and serial dilutions of the sera in infection medium were incubated with RSV (strain A2) for 1 h at 37°C. They were then incubated on HEp2 cells for 90 min at 37°C. The medium was then changed to 1% methylcellulose medium and incubated for 4 days. The cells were fixed and the titers quantified as outlined above.
Vaccine-enhanced RSV Disease
To evaluate vaccine-enhanced RSV pulmonary disease, mice were immunized by intramuscular administration of AdF.RGD, AdNull (both at 1010 pu), FIRSV (105 pfu), or by intranasal administration of RSV (105 pfu). The mice were challenged with RSV at 5 wk post-immunization and sacrificed 6 days later. Lungs were fixed in 4% paraformaldehyde at a constant pressure of 25 cm H2O for 4 hr. Histological sections were stained with hematoxylin and eosin and evaluated in a blinded study for inflammatory changes by light microscopy. A second experimental group of mice was sacrificed at 4 days following RSV infection for evaluation of cell content and IL-4, IL-10, IL-13, IL-17 and eotaxin concentrations by ELISA (R&D System, MN).
Lung DC and Tregs
BALB/c mice were immunized with AdF.RGD, AdNull (all at 1010 pu), FIRSV (105 pfu) or RSV (105 pfu) 5 wk prior to intranasal challenge with RSV (105 pu). Lungs were harvested 6 days post-challenge, digested for 20 min at 37°C with DNAseI and Collagenase (Sigma-Aldrich, MO), and passed through a cell strainer. Myeloid and lymphoid DC were characterized as CD11b+, CD11cbright cells (conventional DC, cDC), and pDC were characterized as CD11blow, CD11cbright, B220+ and confirmed as PDCA-1+ cells by flow cytometry (BD Bioscience, CA). IFN-α secretion by pDC was determined by intracellular cytokine staining. Briefly, cells were fixed and permeabilized with Cytofix/Cytoperm reagent (BD Biosciences) for 20 min at 4°C, then washed twice in Perm/Wash solution (BD Biosciences). The cells were then stained (30 min, 4°C) for intracellular cytokine using phycoerythrin (PE)-conjugated monoclonal antibody against murine cytokine IFN-α. CD4+, CD25bright, FoxP3+ Tregs from the lung were analyzed 6 days post-challenge with RSV by co-staining the lung suspensions with allophyocyanine-conjugated anti-murine CD4, phycoerythrin-conjugated anti-murine CD25 and fluorescein-conjugated anti-murine FoxP3 antibodies (BD Bioscience). Cells were then analyzed by flow cytometry using a FACSCalibur flow cytometer (Becton Dickinson, NJ).
The data are presented as mean ± standard error of the mean. Statistical analyses were performed using a non-paired two-tailed Student's t-test. Statistical significance was determined at p < 0.05.
We thank Peter Collins for providing the RSV plasmid, Kyung Hee Kim for technical assistance and Bishnu De for helpful suggestions.
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