The immune system has evolved to repel viruses, so it is not surprising that these responses impact Ad-based vaccines.

Innate Immune Responses

Innate immune responses occur in a dose-dependent fashion in mice, nonhuman primates, and humans after intravenous injection of Ad vectors. Uptake of Ad virions by immune and non-immune cells precipitates the release of massive amounts of inflammatory cytokines including IL-6 and TNF-a within 3-24 hours of intravenous injection (reviewed in Reference 61).

These events produced by intravenous injection of large Ad doses (e.g., 1013 virus particles) can lead to lethal events in nonhuman primates (62). Innate responses to Ad also likely played a significant role in the unfortunate death of Jessie Gelsinger in the ornithine transcarbamylase deficiency gene therapy trial (63). While these events are a problem after intravenous administration, oral administration is in contrast remarkably safe, as evidenced by the safe administration of live RC-Ad to thousands of military recruits (15). These innate responses tend to be markedly weaker when Ads are applied by intranasal routes (data not shown). They can be quite strong after i.m. injection of Ads since a substantial portion of the vector will actually leak into the blood and infect the liver.

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