Advances in vaccine technology are occurring in the molecular techniques used to develop vaccines and in the assessment of vaccine efficacy, allowing more complete characterization of vaccine-induced immunity correlating to protection. FIV vaccine development has closely mirrored and occasionally surpassed the development of HIV-1 vaccine, leading to first licensed technology. This review will discuss technological advances in vaccine designs, challenge infection assessment, and characterization of vaccine immunity in the context of the protection detected with prototype and commercial dual-subtype FIV vaccines and in relation to HIV-1.

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A HIV-1 tier system has been developed to categorize the various subtype viruses based on their sensitivity to vaccine-induced neutralizing antibodies (NAbs): tier 1 with greatest sensitivity, tier 2 being moderately sensitive, and tier 3 being the least sensitive to NAbs (Mascola et al., J Virol 2005; 79:10103-7). Here, we define an FIV tier system using two related FIV dual-subtype (A+D) vaccines: the commercially available inactivated infected-cell vaccine (Fel-O-Vax® FIV) and its prototype vaccine solely composed of inactivated whole viruses. Both vaccines afforded combined protection rates of 100% against subtype-A tier-1 FIVPet, 89% against subtype-B tier-3 FIVFC1, 61% against recombinant subtype-A/B tier-2 FIVBang, 62% against recombinant subtype-F′/C tier-3 FIVNZ1, and 40% against subtype-A tier-2 FIVUK8 in short-duration (37–41 weeks) studies. In long-duration (76–80 weeks) studies, the commercial vaccine afforded a combined protection rate of at least 46% against the tier-2 and tier-3 viruses. Notably, protection rates observed here are far better than recently reported HIV-1 vaccine trials (Sanou et al., The Open AIDS 2012; 6:246-60). Prototype vaccine protection against two tier-3 and one tier-2 viruses was more effective than commercial vaccine. Such protection did not correlate with the presence of vaccine-induced NAbs to challenge viruses. This is the first large-scale (228 laboratory cats) study characterizing short- and long-duration efficacies of dual-subtype FIV vaccines against heterologous subtype and recombinant viruses, as well as FIV tiers based on in vitro NAb analysis and in vivo passive-transfer studies. These studies demonstrate that not all vaccine protection is mediated by vaccine-induced NAbs.

BackgroundUrinary bladder and renal dysfunction are secondary events associated with spinal cord injury (SCI) in humans. These secondary events not only compromise quality of life but also delay overall recovery from SCI pathophysiology. Furthermore, in experimental models the effects of SCI therapy on bladder and renal functions are generally not evaluated. In this study, we tested whether simvastatin improves bladder and renal functions in a rat model of experimental SCI.MethodsSCI was induced by controlled contusion of T9-T10 in adult female rats. Simvastatin (5 mg/Kg body weight) was administered at two hours after SCI and repeated every 24 hours until the end point. Simvastatin-treated SCI animals (simvastatin group) were compared with vehicle-treated SCI animals (vehicle group) in terms of the Basso Beattie Bresnahan score, tissue morphology, cell death, and bladder/renal functions.ResultsThe urinary bladder of vehicle animals showed a 4.3-fold increase in size and a 9-fold increase in wet weight compared to sham animals. Following SCI, the urine to plasma osmolality ratio increased initially but decreased 1 week after SCI. Hematoxylin and eosin staining of bladder tissue showed transitional epithelial hyperplasia, degeneration of lamina propria, and enlargement of tunica adventia in addition to detrusor muscle hypertrophy. Rats treated with simvastatin for 14 days displayed remarkable recovery by showing decreased bladder size and maintenance of a normal urine/plasma osmolality ratio, in addition to improved locomotion. The muscularis layer of the bladder also regained its compact nature in simvastatin animals. Moreover, SCI-induced renal caspase-3 activity was significantly decreased in the simvastatin group indicating the ability of simvastatin to reduce the renal tubular apoptosis.ConclusionPost-injury administration of simvastatin ameliorates bladder and renal dysfunction associated with SCI in rats.

Lumbar spinal stenosis (LSS) is the leading cause of morbidity and mortality worldwide. LSS pathology is associated with secondary injury caused by inflammation, oxidative damage and cell death. Apart from laminectomy, pharmacological therapy targeting secondary injury is limited. Statins are FDA-approved cholesterol-lowering drug. They also show pleiotropic anti-inflammatory, antioxidant and neuroprotective effects. To investigate the therapeutic efficacy of simvastatin in restoring normal locomotor function after cauda equina compression (CEC) in a rat model of LSS, CEC injury was induced in rats by implanting silicone gels into the epidural spaces of L4 and L6. Experimental group was treated with simvastatin (5 mg/kg body weight), while the injured (vehicle) and sham operated (sham) groups received vehicle solution. Locomotor function in terms of latency on rotarod was measured for 49 days and the threshold of pain was determined for 14 days. Rats were sacrificed on day 3 and 14 and the spinal cord and cauda equina fibers were extracted and studied by histology, immunofluorescence, electron microscopy (EM) and TUNEL assay. Simvastatin aided locomotor functional recovery and enhanced the threshold of pain after the CEC. Cellular Infiltration and demyelination decreased in the spinal cord from the simvastatin group. EM revealed enhanced myelination of cauda equina in the simvastatin group. TUNEL assay showed significantly decreased number of apoptotic neurons in spinal cord from the simvastatin group compared to the vehicle group. Simvastatin hastens the locomotor functional recovery and reduces pain after CEC. These outcomes are mediated through the neuroprotective and anti-inflammatory properties of simvastatin. The data indicate that simvastatin may be a promising drug candidate for LSS treatment in humans.

These results suggest the importance of including lentiviral p24 as vaccine immunogen for human AIDS vaccine. Moreover, these results suggest the potential importance of evolutionarily conserved, cross-protective epitopes in vaccine protection.

Lumbar spinal stenosis (LSS) causes ischemia, inflammation, demyelination and results in dysfunction of the cauda equina (CE), leading to pain and locomotor functional deficits. We investigated whether exogenous administration of S-nitrosoglutathione (GSNO), an endogenous redox modulating anti-neuroinflammatory agent, hastens functional recovery in a CE compression (CEC) rat model. CEC was induced in adult female rats by the surgical implantation of two silicone blocks within the epidural spaces of L4-L6 vertebrae. GSNO (50 μg/kg body weight) was administered by gavage 1 h after the injury, and the treatment was continued daily thereafter. GSNO induced change in the pain threshold was evaluated for four days after the compression. Tissue analyses and locomotor function evaluation were carried out at two weeks and four weeks after the CEC respectively. GSNO significantly improved motor function in CEC rats as evidenced by an increased latency on rotarod compared with vehicle-treated CEC rats. CEC induced hyperalgesia was decreased by GSNO. GSNO also increased the expression of VEGF, reduced cellular infiltration (H&E staining) and apoptotic cell death (TUNEL assay), and hampered demyelination (LFB staining and g-ratio). These data demonstrate that administration of GSNO after CEC decreased inflammation, hyperalgesia and cell death leading to improved locomotor function of CEC rats. The therapeutic potential of GSNO observed in the present study with CEC rats suggests that GSNO is a candidate drug to test in LSS patients.

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