This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A series of three studies were conducted in African green monkeys (AGM) to test a proprietary compound, TMC 353121, formulated by Tibotec Pharmaceuticals against RSV in nonhuman primates. In previous studies, the compound, an RSV fusion inhibitor was shown to have efficacy against RSV in vivo in smaller animals. These studies were performed in collaboration with Bioqual, Inc. with animals and veterinary personnel at their facility. My laboratory was to provide not only virus challenge stock but performed all virological testing of samples taken from the animals during each of the three studies. We performed serological testing of 48 AGMs to prescreen and identify 36 RSV seronegative animals to be used for the studies. The first study, NC282, was an infection study and utilized 6 AGM. We prepared 37, 1ml vials of RSV strain at each of two concentrations of 1x10e3pfu/ml and 1x10e4pfu/ml and cryopreserved them for the entire study. The animals were divided into two groups with each group receiving either 10e3pfu/ml (Gp.1) by intranasal and intratrachael administration and the other receiving 10e4pfu/ml (Gp.2) by similar administration. Animals were monitored for clinical signs of RSV infection with nose and throat samples taken daily and bronchoalveolar lavage samples taken every two days and tested for virus loads by plaque assay. Peak viral loads were reached in both groups by day 6 in the throat with 3.7e2 pfu/ml and 1.4 e3pfu/ml and in the BAL with 2e2 pfu/ml and 3.7e2 pfu/ml and for Gps1 and 2 respectively. These results confirmed the model and the decision to utilize the 10e4pfu/ml inoculation dose for the two subsequent efficacy studies was made. Two efficacy studies with the continuous intravenous infusion of the compound were performed. Study 2 had 15 animals divided into three groups with Gps. 1 and 2, therapeutic and prophylactic arms with TMC 353121 was administered at a plasma level of 50ng/ml and Gp 3 the vehicle control arms;and Study 3 had 12 animals divided into three groups with Gps 1 and 2 therapeutic arms only with TMC 353121 administered at plasma levels of either 5ng/ml or 500ng/ml and Gp 3 a vehical control group. Animals were preconditioned to wear the jacket and tethering system, underwent surgery for implanting the catheter, and infusions begun. The animal studies have recently been completed, however, we are still conducting plaque and antibody assays and compiling data.
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