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Review
.2014;10(10):2875-84.
doi: 10.4161/hv.29594.

Pre-existing immunity against Ad vectors: humoral, cellular, and innate response, what's important?

Affiliations
Review

Pre-existing immunity against Ad vectors: humoral, cellular, and innate response, what's important?

Hugues Fausther-Bovendo et al. Hum Vaccin Immunother.2014.

Abstract

Pre-existing immunity against human adenovirus (HAd) serotype 5 derived vector in the human population is widespread, thus hampering its clinical use. Various components of the immune system, including neutralizing antibodies (nAbs), Ad specific T cells and type I IFN activated NK cells, contribute to dampening the efficacy of Ad vectors in individuals with pre-existing Ad immunity. In order to circumvent pre-existing immunity to adenovirus, numerous strategies, such as developing alternative Ad serotypes, varying immunization routes and utilizing prime-boost regimens, are under pre-clinical or clinical phases of development. However, these strategies mainly focus on one arm of pre-existing immunity. Selection of alternative serotypes has been largely driven by the absence in the human population of nAbs against them with little attention paid to cross-reactive Ad specific T cells. Conversely, varying the route of immunization appears to mainly rely on avoiding Ad specific tissue-resident T cells. Finally, prime-boost regimens do not actually circumvent pre-existing immunity but instead generate immune responses of sufficient magnitude to confer protection despite pre-existing immunity. Combining the above strategies and thus taking into account all components regulating pre-existing Ad immunity will help further improve the development of Ad vectors for animal and human use.

Keywords: Adenovirus vectors; cellular responses; humoral responses; innate immunity; pre-existing immunity.

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Figures

Figure 1.
Figure 1.
Humoral and cellular recognition of Ad vector. (A) Cross-reactive Ad specific Ab (gray) can bind to conserved regions (depicted in gray) within various serotypes but they lack neutralizing ability. In contrast, neutralizing Ab (red, blue) against Ad vector pre-dominantly target highly variable regions (depicted in red and blue) in the hexon and to a lower extent in the fiber. These nAbs are unable to neutralize Ad from different serotypes. (B) Cross-reactive (gray) Ad specific CD8 (top) and CD4 (bottom) T cells are generated upon Ad vector immunization. CD8 T cells mediate killing of Ad transduced APC and secrete inflammatory cytokines, while Ad specific CD4 T cell secrete various cytokines and provide help to Ad specific CD8 and B cells.
Figure 2.
Figure 2.
Strong innate immunity. Strong Ad induced inflammatory responses result in higher levels of chemokines that in turn recruit APC, NK cells, and CD8 T cells, among other lymphocytes. Recruited NK cells are activated by the cytokine milieu. Activated NK cells, as well as Ad specific CD8 T cells, mediate lysis of Ad transduced APCs leading to lower and shorter transgene expression as well as lower cellular and humoral response against the transgene. Milder inflammatory responses result in lower chemokine levels and lower NK cell recruitment and activation. Concomitantly, lower numbers of Ad specific CD8 T cells are recruited. As a result, Ad transduced APCs are not killed, transgene expression is higher and persists for longer period of time, resulting in higher cellular and humoral response against the transgene.
Figure 3.
Figure 3.
Model of tissue resident T cells induction by various vaccination routes. The majority of vector and insert specific tissue resident T cells will reside close to the site of immunization, in the tissue where the antigen was first encountered. Some of these resident T cells migrate away from the injection site while remaining within the same tissue. Depending on the immunization routes, the generated tissue resident T cells will reside in different tissues. Of note, circulating T cells are not depicted.
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