Intramuscular rather than oral administration of replication-defective adenoviral vaccine vector induces specific CD8+ T cell responses in the gut

Abstract

Gut-associated lymphoid tissue (GALT) is the primary replication site for HIV-1, resulting in a pronounced CD4 + T cell loss in this tissue during primary infection. A mucosal vaccine that generates HIV-specific CD8 + T cells in the gut could prevent the establishment of founder populations and broadcasting of virus. Here, we immunized mice orally and systemically with a chimpanzee derived adenoviral vector expressing HIV gag (AdC68gag) and measured frequencies of gag-specific interferon-gamma (IFN-γ) producing CD8 + T cells in the GALT. A single oral administration was inefficient at eliciting responses in the mesenteric lymph nodes and Peyer's Patches, while a single intramuscular administration elicited strong systemic and detectable mucosal responses. The gagspecific CD8 + T cell responses were present in both acute and memory phases following intramuscular administration.

Quality of the Transgene-Specific CD8+ T Cell Response Induced by Adenoviral Vector Immunization Is Critically Influenced by Virus Dose and Route of Vaccination

“…administration is capable of inducing mucosal immune responses, as a high-dose i.m. administration might be distributed to peripheral mucosal sites or lymphoid organs draining such sites (21). Conversely, our reports of highly persistent immunological surveillance in the f.p.-injected target organ may help explain why intranasal virus administration may induce persistent T cell responses at this site only (63).…”

“…infection can mediate cytotoxicity ex vivo and in vivo and protect against a vaccinia virus challenge i.p. ; thus, even though these cells cannot easily be mobilized to a site of infection, it remains a possibility that mucosal immune responses induced by highdose vaccination will prove effective against a localized mucosal challenge (this has not yet been addressed in published studies) (21). However, it must be stressed that previous studies using adenoviral vectors in humans have found a dose ceiling of ∼10 11 particles (7).…”

“…There have been some efforts in determining requirements for induction of mucosal immunity (19)(20)(21)(22), but only one recent study has compared induction of systemic immunity by different relevant routes, yet this study did not address the role of dosage of the adenovirus used or investigate the functional capabilities of the primed cells, nor did it follow the cells over time to allow assessment of the quality of immunological memory (23).…”

What Role Does the Route of Immunization Play in the Generation of Protective Immunity against Mucosal Pathogens?

“…However, the requirement for mucosal immunization to generate protective "frontline immunity" against mucosal pathogens is highly controversial. On the one hand, numerous studies in the literature have demonstrated that immune responses are readily detectable at mucosal sites following systemic delivery of vaccines, and complete or partial protection from mucosal challenge is attainable (2,(33)(34)(35)(36)(37)(38)(39)(40). Systemic immunization is adequate for successful vaccines for some mucosal pathogens, notably the polio virus and the influenza virus, where high titers of neutralizing Abs are capable of clearing cellfree virus and preventing disease (34,41).…”

Harnessing the Potential of Adenovirus Vectored Vaccines

“…Also, regarding the ability to apply vaccines in manners that will induce local immunosurveillance at the likely site of virus entry or early replication, adenoviral vaccines have been found to be very useful. Thus, studies have suggested that local application can be used to augment mucosal CD8+ T cell memory (Belyakov et al, 2008;de Souza et al, 2007;Kaufman et al, 2010;Lemiale et al, 2007), and also that parenteral immunization can be used to induce T cell homing to mucosal sites (Haut et al, 2010;Kaufman et al, 2010;Lin et al, 2007;Tatsis et al, 2007b). The ability to induce local T cell responses is not a quality unique to adenovirus vectors and local immunity can also be obtained by mucosal application of pox-viral vectors (Corbett et al, 2008).…”