Priming with an adenovirus 35-circumsporozoite protein (CS) vaccine followed by RTS,S/AS01B boosting significantly improves immunogenicity to Plasmodium falciparum CS compared to that with either malaria vaccine alone.

The RTS,S/AS02A protein-based vaccine consistently demonstrates significant protection against infection with Plasmodium falciparum malaria and also against clinical malaria and severe disease in children in areas of endemicity. Here we demonstrate with rhesus macaques that priming with a replication-defective human adenovirus serotype 35 (Ad35) vector encoding circumsporozoite protein (CS) (Ad35.CS), followed by boosting with RTS,S in an improved MPL- and QS21-based adjuvant formulation, AS01B, maintains antibody responses and dramatically increases levels of T cells producing gamma interferon and other Th1 cytokines in response to CS peptides. The increased T-cell responses induced by the combination of Ad35.CS and RTS,S/AS01B are sustained for at least 6 months postvaccination and may translate to improved and more durable protection against P. falciparum infection in humans.

Pre-clinical evaluation of new adjuvant formulations to improve the immunogenicity of the malaria vaccine RTS,S/AS02A.

BACKGROUND: RTS,S/AS02A, a pre-erythrocytic Plasmodium falciparum vaccine based upon the circumsporozoite protein, is the only vaccine demonstrated in field trials to confer partial protection against a range of malaria disease manifestations. Pre-clinical studies are on-going to identify new RTS,S formulations with improved magnitude and duration of specific immunity. METHODS: Rhesus macaques were immunized with saline or one of four "RTS,S/adjuvant" formulations at 0, 4, and 12 weeks: RTS,S/AS01B, RTS,S/AS02A-standard (current formulation), RTS,S/AS05 or RTS,S/AS06. An RTS,S/AS02A-accelerated group was immunized at 0, 1, and 4 weeks. Outcomes were safety, RTS,S-specific antibody, and IFN-gamma and IL-5 ELISpots (weeks 14 and 34). FINDINGS: All regimens were safe and, except for RTS,S/AS06, generated equivalent high titer antibody levels. For IFN-gamma ELISpots, RTS,S/AS01B had the highest geometric mean (GM) values at weeks 14 and 34, and was the only group with an overall GM mean (weeks 14+34) higher than RTS,S/AS02A-standard (p<0.015). For IFN-gamma to IL-5 ELISpot response ratios, RTS,S/AS01B had the highest values at weeks 14 and 34, and was the only group higher than RTS,S/AS02A-standard at each individual time point and overall (weeks 14+34) (p<0.015). INTERPRETATION: RTS,S/AS01B is a safe and immunogenically superior formulation for cellular responses, in comparison with the RTS,S/AS02A-standard. Phase 1, 2a, and 2b clinical trials are underway to determine if RTS,S/AS01B demonstrates improved immunogenicity and protective efficacy against experimental challenge and natural mosquito-borne malaria.

Choice of fluid influences outcome in prolonged hypotensive resuscitation after hemorrhage in awake rats.

Hypotensive resuscitation (Hypo) has been considered an alternate resuscitation strategy in clinical settings that prevent the application of standard Advanced Trauma Life Support care. However, validation of this approach when used for prolonged periods of time remains to be demonstrated. The purpose of this study was to evaluate prolonged Hypo as an alternative to standard resuscitation using various currently available resuscitative fluids. Unanesthetized, male Sprague-Dawley rats underwent computer-controlled hemorrhagic shock and resuscitation. There were six experimental groups; nonhemorrhage (NH), nonresuscitated control (C), Hypo with lactated Ringer's (HypoLR), Hypo with Hextend, 6% hydroxyethyl starch in a balanced salt solution (HEX), Hypo with PolyHeme, a polymerized hemoglobin solution (HBOC), or standard resuscitation with LR (StandLR). Animals were bled over 15 min to a mean arterial blood pressure (MAP) of 40 mmHg where the blood pressure (BP) was held for 30 min. Hypo groups were resuscitated to 60 mmHg for 4 h followed by further resuscitation to 80 mmHg. StandLR rats were resuscitated to 80 mmHg immediately after the hemorrhage period. Animals were monitored until death or they were sacrifice at 24 h. Prolonged Hypo with HEX or LR resulted in a trend toward improved 24-h survival compared with C (71%, 65%, and 48%, respectively), and performed at least as well as StandLR (58% survival). HEX required significantly less intravenous fluid (0.7x total estimated blood volume [EBV]) compared with HypoLR (1.9x EBV) and StandLR (3.2x EBV) (P < 0.05). Although HBOC required the smallest fluid volume (0.4x EBV), survival was no better than C and it resulted in the most significant acidosis. These results support the decision to use Hextend for Hypo, a strategy currently being applied on the battlefield.

Isoproterenol accelerates decompression sickness and death after saturation dives in swine.

BACKGROUND: Disabled submarine (DISSUB) survivors are expected to achieve inert gas tissue saturation that would likely cause severe decompression sickness (DCS). Rescue procedures in a DISSUB scenario cannot accommodate a staged decompression and the availability of recompression treatment chambers is limited. Alternatives to the standard recompression procedures for treating DCS are needed. Experimentally, isoproterenol has successfully addressed many underlying physiological concerns expected to result in cardiopulmonary DCS in this group. HYPOTHESIS: We hypothesized that isoproterenol would reduce the incidence of cardiopulmonary DCS in a saturation dropout model. METHODS: Yorkshire swine (21.8 +/- 1.68 kg) were fitted with an external jugular catheter and compressed to 4.33 ATA in a dry chamber for 22 h. They were infused with isoproterenol (0.002 mg x kg(-1)) while still at depth and returned to the surface without decompression stops. They received additional infusions every 10 min throughout a 2-h observation period. Signs of DCS were recorded to the nearest minute. RESULTS: Isoproterenol administration resulted in a significant increase in the incidence of severe cardiopulmonary DCS (13/34 control vs. 12/18 isoproterenol) and death from DCS (10/34 control vs. 11/18 isoproterenol). There was no difference in the incidence of severe neurological DCS. CONCLUSIONS: Administering isoproterenol as an intervention/treatment for DCS significantly increases the risk of cardiopulmonary DCS and death following saturation dropout in 20-kg swine. As an adjunctive therapy or alternative to staged decompression, isoproterenol in the dose regimen delivered here is not expected to improve outcome in a DISSUB mass casualty scenario.