Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

Choi, Jin Huk; Dekker, Joe; Schafer, Stephen C.; John, J Cush; Whitfill, Craig E.; Petty, Christopher S; Haddad, Eid E.; Croyle, Maria A.

doi:10.1128/cvi.05319-11

Cited by 6 publications

(7 citation statements)

References 58 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During a secondary antigenic exposure, memory B-cells and pre-existing Ag-specific antibodies are already present, and immune complexes may be formed with the exposed antigen, which may lead to higher antibody titers than caused by the antigen on its own [ 40 , 41 ]. An increase in harvest time for IgG antibodies resulted in less complex carbohydrate structures, possibly due to the enzymatic activity being put under strenuous pressure, resulting in incomplete carbohydrate structures [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

A pilot study showing differences in glycosylation patterns of IgG subclasses induced by pneumococcal, meningococcal, and two types of influenza vaccines

Vestrheim

Moen

Egge-Jacobsen

et al. 2014

Immunity, Inflammation and Disease

View full text Add to dashboard Cite

The presence of a carbohydrate moiety on asparagine 297 in the Fc part of an IgG molecule is essential for its effector functions and thus influences its vaccine protective effect. Detailed structural carbohydrate analysis of vaccine induced IgGs is therefore of interest as this knowledge can prove valuable in vaccine research and design and when optimizing vaccine schedules. In order to better understand and exploit the protective potential of IgG antibodies, we carried out a pilot study; collecting serum or plasma from volunteers receiving different vaccines and determining the IgG subclass glycosylation patterns against specific vaccine antigens at different time points using LC-ESI-MS analysis. The four vaccines included a pneumococcal capsule polysaccharide vaccine, a meningococcal outer membrane vesicle vaccine, a seasonal influenza vaccine, and a pandemic influenza vaccine. The number of volunteers was limited, but the results following immunization indicated that the IgG subclass which dominated the response showed increased galactose and the level of sialic acid increased with time for most vaccinees. Fucose levels increased for some vaccinees but in general stayed relatively unaltered. The total background IgG glycosylation analyzed in parallel varied little with time and hence the changes seen were likely to be caused by vaccination. The presence of an adjuvant in the pandemic influenza vaccine seemed to produce simpler and less varied glycoforms compared to the adjuvant-free seasonal influenza vaccine. This pilot study demonstrates that detailed IgG glycosylation pattern analysis might be a necessary step in addition to biological testing for optimizing vaccine development and strategies.

show abstract

Section: Discussionmentioning

confidence: 99%

A pilot study showing differences in glycosylation patterns of IgG subclasses induced by pneumococcal, meningococcal, and two types of influenza vaccines

Vestrheim

Moen

Egge-Jacobsen

et al. 2014

Immunity, Inflammation and Disease

View full text Add to dashboard Cite

show abstract

“…Cells were incubated additional 24 hours and β-galactosidase expression visualized by histochemical staining. For each sample, the serum dilution that corresponded to a 50% reduction in transgene expression was obtained by the method of Reed and Muench as described previously 39 . The absence of neutralization in samples containing medium only (negative control) and FBS (serum control) and an average titer of 1:1,280 ± 210 read from an internally generated positive control stock serum were criteria for qualification of each assay.…”

Section: Methodsmentioning

confidence: 99%

Modeling Pre-Existing Immunity to Adenovirus in Rodents: Immunological Requirements for Successful Development of a Recombinant Adenovirus Serotype 5-Based Ebola Vaccine

et al. 2013

Self Cite

View full text Add to dashboard Cite

Pre-existing immunity (PEI) to human adenovirus serotype 5 (Ad5) worldwide is the primary limitation to routine clinical use of Ad5-based vectors in immunization platforms. Using systemic and mucosal PEI induction models in rodents (mice and guinea pigs), we assessed the influence of PEI on the type of adaptive immune response elicited by an Ad5-based vaccine for Ebola with respect to immunization route. Splenocytes isolated from vaccinated animals revealed that immunization by the same route in which PEI was induced significantly compromised Ebola Zaire glycoprotein (ZGP)-specific IFN-γ+ CD8+ T cells and ZGP-specific multifunctional CD8+ T cell populations. ZGP-specific IgG1 antibody levels were also significantly reduced and a sharp increase in serum anti-Ad5 neutralizing antibody (NAB) titers noted following immunization. These immune parameters correlated with poor survival after lethal challenge with rodent-adapted Ebola Zaire virus (ZEBOV). Although the number of IFN-γ+ CD8+ T cells was reduced in animals given the vaccine by a different route from that used for PEI induction, the multifunctional CD8+ T cell response was not compromised. Survival rates in these groups were higher than when PEI was induced by the same route as immunization. These results suggest that antigen-specific multi-functional CD8+ T cell and Th2 type antibody responses compromised by PEI to Ad5 are required for protection from Ebola. They also illustrate that methods for induction of PEI used in pre-clinical studies must be carefully evaluated for successful development of novel Ad5-based vaccines.

show abstract

“…In order to generate data that was clinically relevant, the virus was incubated with five different solutions containing a series of neutralizing antibody concentrations spanning those found in the general population. 28 , 41 Cells infected with the virus were quantitated by flow cytometry 48 h after infection. While 8.58% of the monolayer infected with unformulated virus expressed the transgene, the F16 formulation increased transduction efficiency to 38.8% (Figure 6 C).…”

Section: Resultsmentioning

confidence: 99%

“…(C) Quantitative assessment of transduction efficiency of formulated AdGFP over a range of neutralizing antibody concentrations. In this experiment, 1 × 10 8 infectious particles of AdGFP were incubated in solution containing concentrations of anti-adenovirus antibody reflective of that found in the global population , as described in panel A. Twenty-four hours after infection, infected cells, positive for GFP, were counted by flow cytometery. (D) Histological evaluation of transgene expression in the lung 4 days after intranasal administration of formulated virus.…”

Section: Resultsmentioning

confidence: 99%

Bolstering Components of the Immune Response Compromised by Prior Exposure to Adenovirus: Guided Formulation Development for a Nasal Ebola Vaccine

et al. 2015

Self Cite

View full text Add to dashboard Cite

The severity and longevity of the current Ebola outbreak highlight the need for a fast-acting yet long-lasting vaccine for at-risk populations (medical personnel and rural villagers) where repeated prime-boost regimens are not feasible. While recombinant adenovirus (rAd)-based vaccines have conferred full protection against multiple strains of Ebola after a single immunization, their efficacy is impaired by pre-existing immunity (PEI) to adenovirus. To address this important issue, a panel of formulations was evaluated by an in vitro assay for their ability to protect rAd from neutralization. An amphiphilic polymer (F16, FW ∼39,000) significantly improved transgene expression in the presence of anti-Ad neutralizing antibodies (NAB) at concentrations of 5 times the 50% neutralizing dose (ND50). In vivo performance of rAd in F16 was compared with unformulated virus, virus modified with poly(ethylene) glycol (PEG), and virus incorporated into poly(lactic-co-glycolic) acid (PLGA) polymeric beads. Histochemical analysis of lung tissue revealed that F16 promoted strong levels of transgene expression in naive mice and those that were exposed to adenovirus in the nasal cavity 28 days prior to immunization. Multiparameter flow cytometry revealed that F16 induced significantly more polyfunctional antigen-specific CD8+ T cells simultaneously producing IFN-γ, IL-2, and TNF-α than other test formulations. These effects were not compromised by PEI. Data from formulations that provided partial protection from challenge consistently identified specific immunological requirements necessary for protection. This approach may be useful for development of formulations for other vaccine platforms that also employ ubiquitous pathogens as carriers like the influenza virus.

show abstract

Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

Cited by 6 publications

References 58 publications

A pilot study showing differences in glycosylation patterns of IgG subclasses induced by pneumococcal, meningococcal, and two types of influenza vaccines

A pilot study showing differences in glycosylation patterns of IgG subclasses induced by pneumococcal, meningococcal, and two types of influenza vaccines

Modeling Pre-Existing Immunity to Adenovirus in Rodents: Immunological Requirements for Successful Development of a Recombinant Adenovirus Serotype 5-Based Ebola Vaccine

Bolstering Components of the Immune Response Compromised by Prior Exposure to Adenovirus: Guided Formulation Development for a Nasal Ebola Vaccine

Contact Info

Product

Resources

About