BackgroundMicrovesicles (MV) have been implicated in the development of thrombotic disease, such as acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF). Trauma patients are at increased risk of late thrombotic events, particularly those who receive a major transfusion. The aims of this study were: (a) to determine whether there were increased numbers of pro-coagulant MV following injury; (b) to determine their cellular origin; and (c) to explore the effects of MV with clinical outcomes; in particular red cell transfusion requirements and death.MethodsTrauma patients were recruited at a Level 1 trauma centre. The presence of MV procoagulant phospholipid (PPL) was assessed using 2 activity assays (PPL and thrombin generation). Enumeration and MV cellular origin was assessed using 2 colour flow cytometry.ResultsFifty consecutive patients were recruited; median age 38 (IQR: 24–55), median ISS 18 (IQR: 9–27). Circulating procoagulant MV, rich in phospholipid, were significantly elevated following traumatic injury relative to controls and remained elevated at 72 h post-injury. Red cell/AnnV+ and platelet/AnnV+ MV numbers were 6-fold and 2-fold higher than controls, respectively. Patients who died (n=9, 18%) had significantly fewer CD41/AnnV+ MV and lower endogenous thrombin potential relative to patients who survived.ConclusionsMV are elevated following traumatic injury and may be implicated in the increased risk of trauma patients to pro-thrombotic states such as MOF and ARDS. Lower levels of procoagulant MV are associated with mortality and further investigation of this association is warranted.

The development of a vaccine is essential for the elimination of malaria. However, despite many years of effort, a successful vaccine has not been achieved. Most subunit vaccine candidates tested in clinical trials have provided limited efficacy, and thus attenuated whole-parasite vaccines are now receiving close scrutiny. Here, we test chemically attenuated Plasmodium yoelii 17X and demonstrate significant protection following homologous and heterologous blood-stage challenge. Protection against blood-stage infection persisted for at least 9 months. Activation of both CD4+ and CD8+ T cells was shown after vaccination; however, in vivo studies demonstrated a pivotal role for both CD4+ T cells and B cells since the absence of either cell type led to loss of vaccine-induced protection. In spite of significant activation of circulating CD8+ T cells, liver-stage immunity was not evident. Neither did vaccine-induced CD8+ T cells contribute to blood-stage protection; rather, these cells contributed to pathogenesis, since all vaccinated mice depleted of both CD4+ and CD8+ T cells survived a challenge infection. This study provides critical insight into whole-parasite vaccine-induced immunity and strong support for testing whole-parasite vaccines in humans.

Malaria vaccine development has been dominated by the subunit approach; however, many subunit vaccine candidates have had limited efficacy in settings of malaria endemicity. As our search for an efficacious malaria vaccine continues, the development of a whole-organism vaccine is now receiving much scrutiny. One strategy currently being explored in the development of a whole-organism vaccine involves chemical attenuation of the malaria parasite. In vivo and in vitro chemical attenuation of both liver-stage and blood-stage Plasmodium parasites has been investigated. Here, we discuss both approaches of chemical attenuation in the development of a whole-organism vaccine against malaria.KEYWORDS chemical attenuation, malaria, whole-organism vaccine C urrent methods in malaria control, such as the use of indoor residual spraying, insecticide-treated nets, and drug therapies, have led to reductions in malaria cases and malaria-related deaths (1). However, malaria still remains a leading cause of morbidity and mortality, with 3.3 billion people at risk of becoming infected with Plasmodium parasites (1). In 2015 alone, there were 212 million clinical cases and approximately 429,000 deaths due to malaria (2); therefore, the need for an efficacious malaria vaccine remains prominent. However, despite concerted efforts over many years, an effective malaria vaccine remains elusive. There have been continued concerns with the efficacy of the subunit vaccine approach (3-6), leading to a renewed interest in the use of the whole-organism vaccine approach for malaria.Whole-organism vaccines have been used successfully to protect individuals and populations from infectious diseases (reviewed in reference 7). This approach maximizes the number of antigens presented to the immune system and thus may limit the impact of antigenic diversity on vaccine efficacy. There are different types of wholeorganism vaccines, including killed and live attenuated vaccines, that can be produced using heat, genetic manipulation, radiation, or chemicals. Some of the earliest vaccines utilized formalin to chemically treat the infectious organism (reviewed in reference 8). These vaccines are often referred to as "inactivated" vaccines and include vaccines against polio, hepatitis A, and cholera (9-11). More recently, chemicals have been used as attenuating agents in the development of a malaria vaccine, with promising results. CHEMICAL ATTENUATION OF MALARIA PARASITES IN VIVOSome of the earliest evidence that protection could be induced by infection and drug cure in malaria was provided by antimalaria drug evaluation studies in monkeys (12) and studies using malaria therapy in patients with neurosyphilis (13,14). Although not the primary aim of these studies, they demonstrated that drug cure given after a patent primary infection induced protection against a subsequent secondary infection, (12)(13)(14). Since these initial studies were conducted, numerous studies (in animals and humans) have focused on the protection and immunity induced by a ...