Comparative Evaluation of the Vaccine Efficacies of Three Adenovirus-Based Vector Types in the Friend Retrovirus Infection Model

Abstract

Adenovirus (AdV)-based vectors are popular experimental vaccine vectors, but despite their ability to induce strong immune responses, their application is impeded by widespread preexisting immunity against many AdV types that can impair or even abrogate the induction of transgene-specific immune responses. Therefore, the development of vectors based on AdV types with a low seroprevalence is important for effective AdV-based immunization in humans. We investigated the immunization efficacy of vectors based on AdV type 48 (Ad48) and Ad50 in the ovalbumin (ova) model as well as the Friend retrovirus (FV) model, which allows testing of the protective effect of vaccine-induced immunity. Using ova-encoding vectors, we found a significantly lower induction of ova-specific CD8+ T cells and antibody responses by Ad48- and Ad50-based vectors than by Ad5-based vectors. Similarly, we found a reduced induction of FV-specific CD8+ T cell responses in Ad48- and Ad50.Leader-Gag-immunized mice compared with that in Ad5-immunized mice; however, some of those mice were able to control the FV infection, and protection correlated with the level of neutralizing antibodies 10 days after FV challenge. Analyses of the AdV-specific antibodies and CD8+ T cells induced by the individual AdV types revealed a high level of cross-reactivity, and the efficacy of Ad48-based immunization was impaired in Ad5-preimmune mice. Our results show that the immunity induced by Ad48- and Ad50-based vectors is reduced compared to that induced by Ad5 and is sufficient to control FV infection in only some of the immunized mice. A high level of cross-reactivity suggests that AdV preimmunity must be considered even when applying rare AdV-based vectors. IMPORTANCE AdV-based vectors are important tools for the development of vaccines against a wide range of pathogens. While AdV vectors are generally considered safe and highly effective, their application can be severely impaired by preexisting immunity due to the widespread seroprevalence of some AdV types. The characterization of different AdV types with regard to immunogenicity and efficacy in challenge models is of great importance for the development of improved AdV-based vectors that allow for efficient immunization despite anti-AdV immunity. We show that the immunity induced by an Ad48-based vector is inferior to that induced by an Ad5-based vector but can still mediate the control of an FV infection in highly FV-susceptible mice. However, the efficacy of Ad48-based immunization was impaired in Ad5-preimmune mice. Importantly, we found cross-reactivity of both the humoral and cellular immune responses raised by the individual AdV types, suggesting that switching to a different AdV type may not be sufficient to circumvent preexisting anti-AdV immunity.

Seroprevalence of Binding and Neutralizing Antibodies against 39 Human Adenovirus Types in Patients with Neuromuscular Disorders

“…While a strong immunogenicity is a desirable feature of vaccine vectors, the opposite is true for gene therapy vectors. In this regard, some HAdV types such as HAdV-D48 have already been pursued as vaccine vectors and were found to be rather poorly immunogenic [ 58 , 59 ], which might make them preferred gene therapy vector candidates.…”

Analysis of the Prevalence of Binding and Neutralizing Antibodies against 39 Human Adenovirus Types in Student Cohorts Reveals Low-Prevalence Types and a Decline in Binding Antibody Levels during the SARS-CoV-2 Pandemic

“…The vectors Ad16.GLN, Ad65.GLN, and Ad69.GLN encode enhanced green fluorescent protein (eGFP) and luciferase and were constructed as described previously ( 42 ). The eGFP-encoding vector Ad48.GFP and the luciferase-encoding vector Ad50.Luc were constructed using the pAdApt system as described previously ( 43 ).…”

Comparative analysis of the impact of 40 adenovirus types on dendritic cell activation and CD8+ T cell proliferation capacity for the identification of favorable immunization vector candidates

“…We observed in the past that vectors based on different HAdV types encoding the same transgene had strikingly different potential to induce transgene-specific CD8 + T cells in vivo and to stimulate the proliferation of transgene-specific CD8 + T cells in an in vitro proliferation assay ( 19 ). To inform future selection of HAdV types for the development of new HAdV-based vectors, we decided to screen a wide range of HAdV types in an in vitro proliferation assay and to characterize their influence on antigen-presenting cells.…”

“…The model that we developed for the prediction of favorable vector candidates attributes the highest importance to the division index of CD8 + T cells in the in vitro proliferation assay and the expression levels of the DC surface markers MHC-II, CD83, CD86 and CD252, as well as the secretion levels of some cytokines. Data from in vivo studies where different HAdV-based vectors were compared side-by-side demonstrated widely varying potency, and limited induction of cellular immunity was observed for the HAdV types HAdV-B11, -B14, -B34, -B35, -B50, -D24 and -D48 [ (15)(16)(17)(18)(19)(20)(22)(23)(24)(25); Table 1]. Interestingly, not all of them showed a strong impact on the CD8 + T cell proliferation capacity in our in vitro assay, highlighting the complex immune mechanisms underlying the induction of effective immune responses and the value of analyzing a wide range of immune parameters for the prediction of favorable HAdV types for vector development.…”