Bg. Harvey et al., Variability of human systemic humoral immune responses to adenovirus gene transfer vectors administered to different organs, J VIROLOGY, 73(8), 1999, pp. 6729-6742
Administration of adenovirus (Ad) vectors to immunologically naive experime
ntal animals almost invariably results in the induction of systemic anti-Ad
neutralizing antibodies. To determine if the human systemic humoral host r
esponses to Ad vectors follow a similar pattern, we evaluated the systemic
(serum) anti-Ad serotype 5 (Ad5) neutralizing antibodies in humans after ad
ministration of first generation (E1(-) E3(-)) Ad5-based gene transfer vect
ors to different hosts. Ad(GV)CFTR.10 (carrying the normal human cystic fib
rosis [CF] transmembrane regulator cDNA) was sprayed (8 x 10(7) to 2 x 10(1
0) particle units [PU]) repetitively (every 3 months or every 2 weeks) to t
he airway epithelium of 15 individuals with CF. Ad(GV)CD.10 (carrying the E
scherichia coli cytosine deaminase gene) was administered (8 x 10(8) to 8 x
10(9) PU; once a week, twice) directly to liver metastasis of five individ
uals with colon cancer and by the intradermal route (8 x 107 to 8 x 10(9) P
U, single administration) to six healthy individuals. Ad(GV)VEGF121.10 (car
rying the human vascular endothelial growth factor 121 cDNA) was administer
ed (4 x 10(8) to 4 x 10(9.5) PU, single administration) directly to the myo
cardium of 11 individuals with ischemic heart disease. Ad vector administra
tion to the airways of individuals with CF evoked no or minimal serum neutr
alizing antibodies, even with repetitive administration. In contrast, intra
tumor administration of an Ad vector to individuals with metastatic colon c
ancer resulted in a robust antibody response, with anti-Ad neutralizing ant
ibody titers of 10(2) to >10(4). Healthy individuals responded to single in
tradermal Ad vector variably, from induction of no neutralizing anti-Ad ant
ibodies to titers of 5 x 10(3). Likewise, individuals with ischemic heart d
isease had a variable response to single intramyocardial vector administrat
ion, ranging from minimal neutralizing antibody levels to titers of 10(4).
Evaluation of the data from all trials showed no correlation between the pe
ak serum neutralizing anti-Ad response and the dose of Ad vector administer
ed (P > 0.1, all comparisons). In contrast, there was a striking correlatio
n between the peak anti-Ad5 neutralizing antibody levels evoked by vector a
dministration and the level of preexisting anti-Ad5 antibodies (P = 0.0001)
. Thus, unlike the case for experimental animals, administration of Ad vect
ors to humans does not invariably evoke a systemic anti-Ad neutralizing ant
ibody response. In humans, the extent of the response is dictated by preexi
sting antibody titers and modified by route of administration but is not do
se dependent. Since the extent of anti-Ad neutralizing antibodies will like
ly modify the efficacy of administration of Ad vectors, these observations
are of fundamental importance in designing human gene therapy trials and in
interpreting the efficacy of Ad vector-mediated gene transfer.