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MONITORING INTERNATIONAL TRENDS Prepared August 2011 The NBA monitors international developments that may influence the management of blood and blood products in Australia. Our focus is on: Information that may have an impact on global supply, demand and pricing, such as changes in company structure, capacity, organisation and ownership Potential new product developments and applications Global regulatory and blood practice trends and Other emerging risks that could potentially put financial or other pressures on the Australian sector. A summary of current matters of interest appears below. Highlights include: The US Food and Drug Administration (FDA) has recommended more conservative dosing of erythropoiesis – stimulating agents in patients with chronic kidney disease. CSL Behring has been granted Orphan Drug Designation by the European Commission for the development of its recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP). CSL’s capacity to produce Hizentra has more than doubled. NovoNordisk is investing in a new manufacturing facility. CSL has removed Vivaglobin from the market. Baxter’s HyQ injectable immunoglobulin has performed satisfactorily in a Phase III trial. An active pipeline in clotting factors has seen some progress. Serious doubts have been raised about whether chronic fatigue syndrome is linked to xenotropic murine leukemia virus (XMRV). Two significant studies on red blood cell storage have been reported. 1. Regulatory Matters: a. The US FDA publicised modified recommendations for more conservative dosing of erythropoiesis-stimulating agents (ESAs) in patients with chronic kidney disease (CKD). ESA labels now warn: In controlled trials with CKD patients, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered ESAs to target a hemoglobin level of greater than 11 g/dL. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. ESA labels now recommend: For patients with CKD, consider starting ESA treatment when the hemoglobin level is less than 10 g/dL. This advice does not define how far below 10 g/dL is appropriate for an individual to initiate. This advice also does not recommend that the goal is to achieve a hemoglobin of 10 g/dL or a hemoglobin above 10 g/dL. Individualize dosing and use the lowest dose of ESA sufficient to reduce the need for red blood cell transfusions. Adjust dosing as appropriate. The label previously recommended that ESAs should be dosed to achieve and maintain haemoglobin levels within the range of 10 to 12 g/dL in CKD patients. b. Baxter announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion for extension of the therapeutic indications of KIOVIG to include a new indication for multifocal motor neuropathy (MMN). With adoption by the European Commission, Baxter will receive marketing authorization for KIOVIG MMN indication in all European Union (EU) Member States. KIOVIG is marketed as GAMMAGARD LIQUID(TM) [Immune Globulin Intravenous (Human)], in the US. c. Shire announced that the Pulmonary-Allergy Drugs Advisory Committee to the FDA recommended that the efficacy and safety data provides substantial evidence to support approval of Firazyr (icatibant) for the treatment of acute attacks of hereditary angioedema (HAE) in patients 18 years and older. In addition, the Committee recommended selfadministration of the drug by patients. d. GTC Biotherapeutics, acquired by LFB Biotechnologies in 2010, has been granted a patent covering any production of therapeutic protein in the milk of transgenic animals. The patent, granted by the US Patent and Trademark Office, extends to 2027. GTC said it has also received a new US patent for its lead product, ATryn, an anticoagulant and anti-inflammatory product derived from the milk of genetically modified goats. The new patent relates to a method of treatment of patients with a particular protein deficiency or inflammation. ATryn is the only transgenically produced therapeutic protein that has been approved by both the FDA and EMA. e. CSL Behring has been granted Orphan Drug Designation by the European Commission for the development of its recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP), a novel therapy to treat hemophilia A and hemophilia B patients with inhibitors. The designation would entitle CSL Behring to exclusively market recombinant factor VIIa fused with albumin in Europe for a period of 10 years if the product at the stage of license application fulfills the orphan drug requirements. Based on the submission of data from the company's Pediatric Investigation Plan, once available, the 10-year market exclusivity may be extended to 12 years. Under these designations EMA will also provide CSL Behring with development assistance and reductions in regulatory fees. f. CSL Behring’s capacity to produce Hizentra®, its subcutaneous immunoglobulin, more than doubled following FDA approval of the company’s high tech production facility in Bern, Switzerland. Demand for Hizentra is growing rapidly in the US, and CSL Behring anticipates regulatory approvals of Hizentra in Europe. g. CSL Behring announced that the European Commission has granted marketing authorization for Hizentra for treating patients diagnosed with primary immunodeficiency (PI) as well as secondary immunodeficiencies. This is valid for all 29 European/European Economic Area member states. h. At its August meeting, the FDA’s Transmissible Spongiform Encephalopathies Advisory Committee will discuss donor deferral (for time spent in Saudi Arabia) to reduce the risk of variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products and human cells, tissues and cellular and tissue-based products. i. LFB was issued with a US Patent titled “Monoclonal Antibodies with Enhanced ADCC Function”. LFB has developed in clinical trials two monoclonal antibodies with this new technology: One is a monoclonal antibody targeting alloimmunization in expectant mothers that are Rhesus negative with a baby that is Rhesus positive. j. The FDA Blood Products Advisory Committeee at its August meeting will discuss a study on the incidence of Trypanosoma cruzi infection in blood donors and its implications for selective testing of blood donors. The Committee will also discuss measures to preserve the blood supply during a severe emergency (Trypanosoma cruzi is the parasite which causes Chagas disease). k. The FDA is convening in September a public workshop entitled: “Quarantine Release Errors in Blood Establishments.” The purpose of this public workshop is to provide a forum for discussion of quarantine release errors (QREs) and provide FDA and industry with information necessary to reduce the rates of QREs. l. A number of Medicines Australia member companies are considering delaying bringing new drugs into the country, following the Australian government's decision to defer listing of new medicines on the Pharmaceutical Benefits Scheme (PBS), a Senate Committee has been told as it investigates the new policy. m. The FDA on 21 July issued draft guidance (for comment purposes only) on mobile medical applications. This was to inform manufacturers, distributors, and other entities about how the FDA intends to apply its regulatory authorities to select software applications intended for use on mobile platforms (mobile applications or "mobile apps"). At this time, the FDA intends to apply its regulatory requirements solely to a subset of mobile apps that it is calling mobile medical applications or "mobile medical apps." 2. Products a. Immunetics received a grant to commercialize its BacTx® rapid test for detecting bacterial b. c. d. e. f. g. h i. contamination in platelets. Immunetics has concluded clinical trials for BacTx® and is submitting an application for approval to the FDA this year. Immunetics also received grants from the National Heart, Lung, and Blood Institute (NHLBI), an agency of the National Institutes of Health (NIH). The technology underlying the test is protected by a recently issued US patent, and foreign patents with approved claims are in process of issue. Fenwal received CE Mark approval for a therapeutic plasma exchange (TPE) protocol for the company’s Amicus® system. TPE removes substances from blood that can cause or complicate disease and is used in the treatment of a wide range of haematologic, neurologic, autoimmune, and kidney disorders. The Amicus® system is used globally to collect platelets, platelets with concurrent plasma and red cells, and mononuclear cells used for therapeutic applications and clinical research. Affymax and Takeda announced the submission of a New Drug Application (NDA) to the FDA for the investigational agent peginesatide (formerly known as Hematide™) for the treatment of anemia associated with chronic renal failure in adult patients on dialysis. Peginesatide is a synthetic PEGylated peptide compound that binds to and activates the erythropoietin receptor, thus acting as an ESA. A continuous spectrophotometric haemoglobin sensor may offer a new approach for non–invasive blood haemoglobin monitoring during surgery, according to a study published in the April issue of Anesthesia & Analgesia. Ronald D. Miller, from the University of California in San Francisco, and his colleagues compared the accuracy of SpHb and point-of-care HemoCue to that of the invasive laboratory Co-Oximetry (tHb) method for monitoring blood haemoglobin during perioperative transfusions. Medgenics announced an extension of its agreement with Baxter for the joint development of the Factor VIII Biopump. Confirmatory studies will be conducted implanting Factor VIII Biopumps in mice. During the extended agreement, which will expire by 30 September 2011, Baxter has the opportunity, to exercise an exclusive option for 6 months to negotiate with Medgenics an agreement for commercialization of the Biopump Factor VIII technology. Medgenics’ Biopump is a proprietary tissue-based platform technology for the sustained production and delivery of therapeutic proteins using the patient's own skin biopsy for the treatment of a range of chronic diseases including anaemia, hepatitis C and haemophilia. Medgenics has three long-acting protein therapy products in development based on this technology. Hemodure is a sustained Factor VIII therapy for the prophylactic treatment of haemophilia. CSL Behring took its immune globulin subcutaneous (human) 6% liquid (Vivaglobin) off the market on 4 April 2011. It was on the FDA watch list. Inspiration Biopharmaceuticals reported on its clinical development program for OBI1, an intravenous (IV) recombinant porcine factor VIII product (rpFVIII), intended for the treatment of bleeding in people with hemophilia A with inhibitors and in people with acquired hemophilia. The data were presented at the 23rd Congress of the International Society on Thrombosis and Haemostasis (ISTH) in Kyoto. Nehora Photonics of Israel is developing optical technology for the non-invasive continuous monitoring of hematocrit, the proportion of the blood, by volume, that contains red blood cells. In July, Baxter presented preclinical data to the 23rd Congress of the ISTH on its investigational compound BAX 499 for potential subcutaneous haemophilia therapy and final Phase I data on recombinant von Willebrand Factor. BAX 499 is in early stage clinical development to treat blood clotting disorders haemophilia A and B by targeting a novel pathway responsible for regulating the clotting process. The studies presented at ISTH validate the pathway as a potentially viable target for the treatment of haemophilia. Data were also presented on recombinant von Willebrand Factor (rVWF), the only recombinant replacement protein currently in clinical development, to assess its safety and efficacy for the treatment of von Willebrand disease (VWD). The data indicated overall that the pharmacokinetics of rVWF and pdVWF were found to be similar. A larger Phase III trial study is required to further assess the safety and efficacy of rVWF. Baxter anticipates beginning recruitment later this year. j. Biogen Idec's CEO, speaking on 26 July, said “we shared important data today at the 23rd Congress of the International Society on Thrombosis and Haemostasis in Kyoto, Japan. Six out of our eight abstracts were platform presentations and focused on the advancements of our hemophilia programs. One presentation that I'll highlight includes a Phase I 2a study of our long-lasting fully recombinant Factor VIII Fc fusion protein, which showed that the drug demonstrated on approximately 1.7 fold increase in half-life compared with Advate, a commercially available Factor VIII product in 16 previously treated patients with severe hemophilia A. Our long-lasting recombinant Factor VIII had comparable -- in dose-dependent peak plasma concentration, comparable recovery but reduced clearance relative to Advate. Importantly, no inhibitor formation was observed. These data indicate that there would be 50 to 80 less injections per year for hemophilia A patients”. k. The FDA has approved the subcutaneous administration of Baxter’s Gammagard Liquid 10% [Immune Globulin Infusion (Human)] for patients with PI. Subcutaneous use of GAMMAGARD LIQUID allows patients to self-administer their therapy at home on a weekly basis. 3. Market structure and company news: a. NovoNordisk plans to invest €134 million in a new biologics manufacturing facility at its Kalundborg site, the largest in the group's production network. The new capacity will be used to manufacture Factor VIIa, as well other biologic medicines. The company says it needs to boost capacity for its existing products, but "also to be ready to produce future haemophilia products that are in the pipeline". Nearest to the market is Novo's recombinant factor XIII drug NN1841. The drug was filed for approval in the US in February. An improved Factor VIII called N8 is in phase III trials for haemophilia A, as is a long-acting formulation of Factor IX for haemophilia B. The packaging facility is expected to be operational in 2013, while the other facilities are expected to be up and running in 2015. A recent report in the Financial Times shows Novo Nordisk is one of the world’s ten most valuable medical companies. It occupies position 115 on the list of largest companies in the world. b. Canadian company Compass Biotechnologies announced that the first product to be sourced from its manufacturing partner (PanGen of South Korea) will be erythropoietins (EPO). c. OPK Biotech LLC has grown from eight employees to over 100 since its commencement of operations in October 2009. The Massachusetts company manufactures two oxygen therapeutics: Hemopure® [hemoglobin glutamer – 250 (bovine)], or HBOC-201, for human use and Oxyglobin® [hemoglobin glutamer – 200 (bovine)], or HBOC-301, for veterinary use. Hemopure has been approved for use the treatment of acute surgical anaemia in South Africa since 2001 and recently won approval in Russia for acute anaemia. d. ProMetic Life Sciences has received a follow-on purchase order for its Mimetic Ligand product, used for biomolecular purification manufacturing processes. The order stems from a long-term supply agreement with Halozyme Therapeutics. e. CSL Behring donated more than 1 million international units of von Willebrand factor /Factor VIII replacement medication to patients through the World Federation of Hemophilia (WFH). The donation supports WFH’s progress in improving the diagnosis and treatment of bleeding disorders in developing countries through its Global Alliance for Progress (GAP) program. It is part of the commitment CSL Behring has made to WFH to donate two million IUs of FVIII each year for three years. The July donation is commercially valued at $US 1.3 million. GAP partners include CSL Behring, Baxter, Bayer, Biotest, the Irish Hemophilia Society, the Jan Willem Andre de la Porte Family Foundation, Pfizer, Talecris and the World Health Organization (WHO). Sixteen countries have participated in GAP: Armenia, Azerbaijan, Belarus, China, Ecuador, Egypt, Georgia, Jordan, Lebanon, Mexico, Philippines, Russia, Syria, Thailand, and Tunisia. A GAP project in Peru has just been launched. Cerus Corporation in its second quarter 2011 results reported sales grew by 19% compared with the same quarter in 2010; and that it had entered a distribution agreement with Ilex Biotech Ltd. for Israel and South Africa, an agreement with Grifols for Mexico, and an agreement with Comércio Exportação e Importação de Materiais Médicos for Brazil. g. Baxter established Baxter Ventures to invest up to $US200 million in equity in earlystage companies developing therapies complementing Baxter's existing portfolio. Baxter announced strong financial results for the second quarter of 2011, and raised its financial outlook for full-year 2011. It reported an increase of 15% in net income compared with the same period last year. Worldwide sales totaled $US3.5 billion. Excluding the impact of foreign currency, worldwide sales increased 6%. BioScience sales advanced 10% boosted by strong demand for immunoglobulin, certain specialty plasma-based therapeutics, and vaccines. h. Israeli manufacturer Kamada signed a strategic cooperation agreement granting marketing rights of its human rabies immune globulin in the US to an un-named international pharmaceuticals manufacturer that markets in 40 countries. KamRAB is administered along with the rabies vaccine to prevent infection caused by the rabies virus. The partner will supply Kamada with the necessary plasma. KamRAB sales in the US should begin in about three years. KamRAB has been sold in Israel since 2003. It is also sold in Mexico, South Korea, Thailand, India and Russia. In August 2010 Kamada entered into a collaboration with Baxter, under which Baxter received exclusive distribution rights to Glassia, an intravenously administered therapy for emphysema, in the United States, Australia and New Zealand. Baxter also supplies Kamada with the raw materials for the product. 4. Overseas events a. In the US, an infection caused by tick bites has gained a foothold in the Lower Hudson Valley and in coastal areas of the Northeast. Babesiosis is a malaria-like illness caused by Babesia microti, a parasite that lives in red blood cells and is carried by deer ticks. Though far less common than Lyme disease, babesiosis can be fatal, particularly in people with compromised immune systems. Because there is no widely used screening test for babesiosis, its spread poses a particular threat to the blood supply. Many people who are infected with the parasite have no symptoms at all, or moderate symptoms. Experts fear that undiagnosed patients may be donating blood. Babesiosis already is the most frequently reported infection transmitted through transfusion in the United States, responsible for at least 12 deaths. Between 1999 and 2007, several infants in Rhode Island developed babesiosis following blood transfusions. The Rhode Island Blood Center has become the first in the country to use an experimental new test to screen blood for the parasite. Symptoms of babesiosis can occur up to nine weeks after a transfusion. b. A French woman suffered a severe infection with cowpox virus, a relative of the smallpox virus, as a result of contact with infected pet rats1. Wild rodents, not cows, are now considered the true reservoir for cowpox virus, and in recent years, several human cowpox infections have resulted from contact with pet rats, though humans are more commonly infected through contact with cats, which are incidental hosts. The authors say the cessation of smallpox vaccination may partly explain the reemergence of cowpox in humans, as the vaccine probably induced some immunity to other orthopoxviruses. Cowpox virus is distributed widely in Europe, western parts of the former Soviet Union, and adjacent areas of Northern and Central Asia. c. In May 2011 in the US the FDA Center for Biologics Evaluation and Research (CBER) distributed a summary of transfusion fatalities reported for the fiscal year 2010 (1 October 2009 to 30 September 2010). There were 76 fatality reports, 71 transfusion recipient fatalities and 5 post-donation fatalities. CBER concluded that of the 71 transfusion recipient fatality reports: 40 were transfusion-related, 24 were cases where transfusion could not be ruled out as the cause of the fatality, and seven of the fatalities f. were unrelated to the transfusion. TRALI remains a cause of death, and there were still some fatal reactions to bacterial- contaminated platelet transfusion. e. New Zealand's PHARMAC is moving to a more "permissive" system of assessing people seeking medicines not funded on the Pharmaceutical Schedule, in a move which is expected to double the scheme's spending in the first full year. f. In Ireland the Health Information and Quality Authority (HIQA) has said a suggested vCJD intervention is “not cost-effective” and has alerted the Government to a potential bill of between €51.6 million and €55.9 million over five years, for red blood concentrate filtration for vCJD. HIQA estimated that such a measure would, over a 10-year period, potentially prevent two deaths from vCJD. The Committee said the level of undiagnosed vCJD in Ireland is likely to be low and that the corresponding risk of transfusiontransmitted infection would be extremely low. g. Tweets posted by Bayer Healthcare about two of its products have been found to have breached the UK pharmaceutical industry Code of Conduct, including Clause 2, which deals with promotional activities that bring discredit upon, or reduce confidence in, the industry. The tweets also constituted the promotion of prescription-only medicines to the public, the Prescription Medicines Code of Practice Authority (which administers the Code), has ruled, in the first-ever cases of breaches of the Code involving social media. The guidance states that social media, including twitter, could be used to provide information to the public provided the material complied with the Code. "If a company wanted to promote a medicine via twitter it would have to ensure that if the medicine was “Severe Ear Chondritis due to Cowpox Virus Transmitted by a Pet Rat”. By Antoine Elsendoorna et al., Journal of Infection online, 24 Jun 2011 1 prescription-only, the audience was restricted to health professionals and that the message, in addition to any link to further information, complied with the Code. In addition, companies would also have to ensure that recipients had agreed to receive the information," it says. h. In the UK, where NHS Blood and Transplant (NHSBT), was given permission to sell on surplus blood products and plasma2, there has been public questioning of why the identity of the buyer cannot be revealed. i. The UK government has said its plans to introduce a value-based pricing (VBP) system for medicines from 2014 will go ahead, but respondents to its consultation on the plan have called for more details on how the system would operate in practice. 5. Safety Issues: a. Two studies posted in Science online on May 31 raised serious doubts about earlier reports that chronic fatigue syndrome (CFS) is linked to infection with XMRV. In October 2009 the journal had published the initial research linking XMRV to CFS. In an "editorial expression of concern" accompanying the two new studies, Bruce Alberts, editor in chief of the journal, declared that the earlier finding "is now seriously in question" and was probably attributable to laboratory contamination. In one of the two new studies, researchers found no trace of XMRV or related viruses in the blood of 43 patients who had previously tested positive for XMRV. In the second study, scientists reported evidence that XMRV was probably a recombination of two mouse leukemia viruses created accidentally in laboratory experiments. b. In July a Duke University Medical Center study reported a problem in red blood cells stored for long periods. Under US federal law, whole blood can be stored for up to 42 days. Some studies have found though, that patients who receive blood stored even for a couple of weeks, are more likely to suffer infections, cardiovascular problems and even organ failure, particularly those who use several units of older blood. Previous studies of older blood have mainly focused on outcomes for patients using it, rather than the specific mechanisms that lead to the problems. This study, published in the journal Critical Care Medicine, found that stored red blood cells begin to lose the ability to release a key molecule called adenosine-5’triphosphate (ATP), which helps prevent the cell from sticking to the walls of blood vessels. The researchers think the stuck cells cause a number of problems, from obstructing blood circulation in the lungs to hampering the bloodstream’s ability to deliver oxygen around the body, said Dr Timothy J. McMahon, senior author of the study. McMahon said he and other researchers are now studying methods of boosting ATP in older blood. c. Transfused blood may need to be stored in a different way to prevent the breakdown of red blood cells that can lead to complications including infection, organ failure and death, say researchers at the University of Pittsburgh School of Medicine and Wake Forest University. In July, 2011, in the early online version of Circulation, the team reported the latest findings from its ongoing exploration of the interaction between red blood cell breakdown products and nitric oxide (NO), revealing new biological mechanisms that can reduce blood flow and possibly damage vital tissues after administration of blood that has been stored for longer than 39 days. In recent years, doctors have noted that transfusion of either many units of blood or of blood stored a long time may be associated with a greater frequency of complications, such as increased infection risk, kidney, lung or multi-organ failure and death, particularly among medically vulnerable patients, explained senior investigator Mark T. Gladwin, MD, Chief, Division of Pulmonary, Allergy and Critical Care Medicine, Pitt School of Medicine, and director of Pitt's Vascular Medicine Institute. "When blood sits for a while, some of the cells break down and release their The sale of whole blood is not allowed. Neither is anything that ‘might be administered to a person’. The discard plasma is expected to be used for research purposes, or for making diagnostic reagents. 2 contents, which include molecules of hemoglobin and red blood cell microparticles" he said. "These accumulate in the stored bag of blood and are transfused into the patient with the blood. In the bloodstream, the hemoglobin and microparticles bind to and destroy NO, a very important molecule that is used by the body to keep blood vessels dilated for normal blood flow. "The scavenging of NO causes blood vessel constriction that can prevent tissues and organs from getting adequate oxygen and activate the platelets and the coagulation system, as well as cause inflammation” Dr Gladwin said. From their experiments, he and his Wake Forest collaborators found that human blood stored under standard conditions accumulated "free" haemoglobin that was no longer contained in a cell and microparticles of damaged cells. Those breakdown products reacted with NO about 1,000 times more quickly than did intact red blood cells. Also, transfusion of even very low concentrations of haemoglobin caused blood vessel constriction and hypertension in a rat model. "Avoiding the storage lesion, as it is referred to in our field, could require a new approach to how donor blood is stored prior to transfusion" said senior author Daniel B. Kim-Shapiro, professor of physics and director of the Translational Science Center at Wake Forest. "Transfusion of stored blood is one of the most common medical therapies" he said. "By understanding the mechanism of the storage lesion, we can design methods to make blood transfusion safer. For example, perhaps we can restore nitric oxide activity that is lost upon transfusion, use preservation solutions that better limit the degradation of blood cells, or develop agents that scavenge free hemoglobin". d. A structured literature review3 of treatments for reversing warfarin anticoagulation in patients with acute intercranial haemorrhage concluded that prothrombin complex concentrate is statistically significantly faster at correcting the INR4 compared with fresh frozen plasma transfusions. Recombinant factor VIIa appears to rapidly reverse warfarin's effect on INR; however, this treatment is not FDA-approved and is associated with a 5% thromboembolic event rate. 6. Research: a. HyQ, an injectable subcutaneous immunoglobulin for treating a lifelong immunodeficiency condition (made by Halozyme Therapeutics and Baxter International5) exceeded requirements for preventing infections in a phase III clinical trial. HyQ combines Halozyme's drug absorption enzyme rHuPH20 and Baxter's immune globulin product. Halozyme's enzyme boosts absorption by breaking down the gel-like substance that fills open spaces in tissue and sometimes gets in the way of drug molecules reaching their targets. That allows a single dose of HyQ to be administered by a patient at home every three or four weeks. Baxter submitted a Biological License Application to the FDA on 30 June and expects to file regulatory submissions in Europe and Canada in the coming months. It will present results from the phase III study by the end of 2011. b. Prolor Biotech of Israel plans to initiate a Phase II trial for its factor IX (F-IX-CTP), a long lasting version of the clotting factor. In preclinical models, mice treated with Prolor's longlasting treatment lost half as much blood as the BeneFIX (current marketed drug) treated mice did, and approximately one third as much as the untreated group. In second bleeding events the BeneFIX- treated mice bleeding persisted over 3 times as long compared with the Factor IX - CTP. Furthermore, the Factor IX - CTP group experienced no spontaneous rebleeding events 12 hours post-second bleeding event, compared with 3 Brett Bechtel, Timothy Nunez, Jennifer Lyon, Bryan Cotton, Tyler Barrett. International Journal of Emergency Medicine 2011, 4:40 4 International normalized ratio, a laboratory test measure of blood coagulation based on prothrombin time 5 HyQ is a subcutaneous immune globulin product, being developed by Baxter using a recombinant human hyaluronidase technology platform licensed from Halozyme Therapeutics. Baxter will pursue an extension study to evaluate HyQ administration to patients through to March 2012. c. d. e. f. g. 50% for the BeneFIX group. Prolor intends to begin roughly a 70 patient Phase II trial sometime in 2012. Symphogen announced preliminary data from a phase II clinical trial with rozrolimupab (SYM001) in adult, RhD positive, non-splenectomized patients with immune thrombocytopenia (ITP). The study showed rozrolimupab is well tolerated with no unexpected toxicities and shows preliminary signs of clinical and biological activity by decreasing haemoglobin values. Preliminary results of the anti-RhD antibody mixture rozrolimupab in ITP were presented in a poster at the 16th Congress of the European Haematology Association meeting in London. Rozrolimupab is a fully human anti-RhD monoclonal antibody (mAb) mixture, comprising 25 mAbs that bind to RhD. Rozrolimupab is produced by a single-batch manufacturing strategy, designed to capture the natural diversity of the human antibody response to RhD as a modern counterpart to the plasma-derived anti-RhD immunoglobulins currently used in the treatment of ITP. The beneficial effect of this agent in patients with ITP is also being evaluated at doses beyond 200µg/kg. Biogen Idec was given a positive opinion by European healthcare regulators on a planned paediatric trial of its new haemophilia B treatment. In association with partner Swedish Orphan Biovitrum, the company is planning to initiate a global investigational plan of their new long-lasting, fully-recombinant Factor IX Fc fusion protein among previously treated patients aged below 12 years of age. Having received approval from the EMA’s Paediatric Committee, the companies will seek to begin the study when sufficient data has been collated from a trial involving adult patients. Dr Glenn Pierce, senior vice-president for haemophilia at Biogen Idec, said: "With this opinion and the ongoing phase III trials of our long-lasting Factor IX and Factor VIII programmes, we continue to make progress toward our goal of improving the way haemophilia is treated worldwide." Biogen Idec in April entered a partnership with Amunix to develop recombinant blood factors with improved therapeutic properties. Amunix has expertise in protein pharmaceuticals and focuses on the discovery and development of novel therapeutics with improved dosing frequency and administration. The company's patented platform technology, XTEN, extends the half-life of protein. In July it was confirmed that the first of Baxter's two phase III IVIg for Alzheimer's trials has completed enrollment. 390 patients have been randomized to either (a) 400mg of IVIG/kg of bodyweight every 2 weeks; (b) 200mg of IVIg/kg; or (c) placebo. Patients will be dosed and followed for 18 months with the last patient now expected to reach followup in January 2013. Given time for data gathering and analysis, this might mean headline data by mid-2013. A number of papers/posters at a global Alzheimer’s disease conference continued to feed an expectation that the outcome of the Baxter trial will be positive. They also fed a continuing concern that plasma collection and fractionation, at least in the short term, would struggle to meet demand arising from a positive outcome, and that price will be a rationing mechanism. Some research is being directed to identifying the mechanism by which IVIg may have a favourable effect on Alzheimer’s, and synthesizing a compound which can replicate it. Amgen announced that interim results from an international, single-arm study evaluating the safety and efficacy of Nplate® (romiplostim) in adults with primary ITP demonstrated that Nplate induced a rapid platelet response with a good safety profile in adult ITP patients with low platelet counts and bleeding symptoms. With 400 patients to be enrolled this will be the largest study so far in adult ITP. The interim results covered the first 235 patients enrolled. The US Defense Advanced Research Projects Agency (DARPA) recently announced its budget estimates for fiscal year 2012 . They included $US 17 million for Tactical Biomedical Technologies, including preventing battlefield fatalities due to uncontrolled blood loss by creating technologies that enable unskilled personnel to locate and stop deep bleeders. $US4.295 million was provided for Blood Pharming to produce a large quantity of safe, transfusable blood to satisfy battlefield demand and reduce logistics of sourcing donated blood. The goal is to produce 100 units of O-negative red blood cells per week using renewable stem cells. Arteriocyte and Johns Hopkins University have developed the NANEX Stem Cell Expansion technology, which allows for quick reproduction of universal donor red blood units from umbilical cord blood – and more research is needed. Arteriocyte signed a research and development deal with the Army to investigate new therapies for orthopedic trauma and battlefield injuries. Arteriocyte is already working with the US Army Institute of Surgical Research (USAISR) to develop stem cellbased, point-of-care therapies for amputation prevention, burn debridement and postsurgical wound infection prevention. Under terms of the new three-year deal, Arteriocyte would work with USAISR to explore broader use of its technologies to treat orthopaedic trauma, such as limb injuries that affect battlefield-wounded soldiers. The work will involve two Arteriocyte technologies: Magellan and NANEX. Magellan involves a bedside device that harvests and quickly concentrates stem cells and blood platelets during surgeries. The concentrated cells can then be fed back to patients to boost the body’s ability to repair itself. NANEX technology is described above. “These technologies have significant potential to improve outcomes for our injured personnel and assist in their healthy recovery to active duty” said Joseph Wenke, manager of USAISR’s orthopaedic extremity trauma research program. Earlier this year, Arteriocyte received FDA approval to begin a phase 1 clinical trial that uses the Magellan technology for the treatment of critical limb ischemia. 7. On the horizon a. Scientists have for the first time isolated single stem cells that give rise to many different types of blood cell, from the white cells of the immune system and the platelets that help to clot blood, to the red cells that carry oxygen around the body. The breakthrough holds out the promise that it may be possible one day to use stem cells to regenerate the entire blood system, or to isolate stem cells from individual patients in order to grow their own personal supplies of blood cells or clotting factors. John Dick of the University Health Network in Toronto led the study. The study, published in the journal Science6, was carried out using genetically modified mice that did not have their own immune systems. This allowed the scientists to grow human bone marrow cells within the animals in order to target those that are the stem cells of the blood system. The team discovered that the single cell type has the CD49f protein on its surface, which marks it out from the rest. When they transplanted bone marrow and blood samples minus the CD49f-marked cells, the blood system failed to regenerate. The CD49f "biomarker" is vital for further research, because it will enable the genuine hematopoietic stem cells (HSCs) to be extracted from all other blood stem cells, some of which will be at more advanced stages of maturity, and so not capable of turning into all blood types. Dick says doctors might be able to safely regenerate a patient's entire blood system from scratch, using just a small population of the CD49f-marked cell, offering new ways to treat people with leukaemia. At present, such patients would receive new bone marrow from tissue-matched donors, if available – only a third of patients find a donor. But now it might be possible to reconstitute marrow from HSCs extracted before chemotherapy starts. Checks could be done to make sure the HSCs chosen for regeneration are not cancerous. Researchers can now also experiment with the HSCs to work out the different stages and steps by which they develop into all types of blood cells, potentially allowing them to make specific blood cells by design. "This specific HSC marker, CD49f, could not only help to identify which cells are capable of long-term engraftment in patients, but also as a tool to help us generate these cells in the lab from pluripotent 6 Science, DOI: 10.1126/science.1206360 b. c. d. e. 7 stem cell sources" says Robert Lanza, chief scientist at Advanced Cell Technology in Worcester, Massachusetts. In 2008, the company developed red blood cells from human embryonic stem cells, and hopes soon to begin testing them in patients. Scientists at the Salk Institute for Biological Studies have developed an improved technique for generating large numbers of blood cells from a patient's own cells. The new technique will be immediately useful in further stem cell studies, and when perfected, could be used in stem cell therapies for a wide variety of conditions including cancers and immune ailments. "There are further improvements that we need to make, but this takes us a significant step closer to the ultimate goal, which is to be able to take ordinary cells from a patient, induce them to become stem cells, and then use those stem cells to rebuild lost or diseased tissues, for example the patient's bone marrow" says Inder M. Verma, Irwin and Joan Jacobs Chair in Exemplary Life Science and American Cancer Society Professor of Molecular Biology at the Salk Institute Laboratory of Genetics. Verma is senior author (July edition of Stem Cells). In a report in Nature, a team led by Katherine High at the Children's Hospital of Philadelphia describes how genome editing reversed haemophilia B in mice, restoring blood clotting times to near-normal without any apparent side-effects. San Diego’s Sangart announced in June that it has launched a second Phase II clinical trial of an experimental drug for boosting the delivery of oxygen in trauma patients who have suffered large losses of blood. The study of MP4OX will be conducted on about 360 patients recruited from 50 trial sites in 15 countries. All participants will receive standard treatments such as red blood cell transfusions, fluids, kidney dialysis, surgery and mechanical ventilation, a company spokeswoman said. Additionally, one group will receive MP4OX while the other will receive saline. An earlier Phase II trial of the drug on 51 trauma patients showed that it quickly lowered levels of lactic acid, which builds up in oxygen-depleted tissue and can be an indicator of damage. More patients who received the drug also left hospitals alive within 28 days. MP4OX helps to open capillaries and carry oxygen deeper into tissue. The liquid therapy is given alongside blood transfusions and doesn't replace blood. Karim Brohi, a professor of trauma sciences at the Royal London Hospital, is the trial's principal investigator. iBio of Delaware announced successful production of human plasma proteins. Human alpha 1-antitrypsin7 and human C1 esterase inhibitor8 were successfully produced at high yield in green plants via the Company's proprietary iBioLaunch technology9. "… iBio's technology offers traditional plasma protein producers the opportunity to move away from reliance on the human blood supply and introduce recombinant alternatives free of any animal or human cell or tissue components" said Robert Kay, iBio's Chairman and Chief Executive Officer. Plasma-derived alpha 1-antitrypsin is supplied by several companies for treatment of emphysema due to deficiency of this protein, and several preclinical and clinical research programs suggest it also may be useful in additional applications such as the treatment of diabetes and certain types of asthma. 8 Plasma-derived C1esterase inhibitor is an Orphan Drug approved by the FDA to treat or prevent the symptoms of hereditary angioedema (HAE). In addition, this protein has been used in Europe for more than thirty-five years to treat acute symptoms of HAE, and is the subject of multiple research programs investigating its potential use in the treatment of other inflammatory diseases. 9 The iBioLaunch platform is a proprietary technology for development and production of biologics using transient gene expression in unmodified green plants. The company says advantages over other systems include: success with proteins difficult or impossible to produce with other methods; broadly applicable to biologics, including monoclonal antibodies, other therapeutic proteins and vaccines; enables rapid development and validation of modular, scalable, and optionally robotic, multi-product manufacturing facilities; production time measured in weeks instead of months or more. The company claims additional benefits include a practically unlimited surge capacity for remedial action against bioterrorism and pandemic disease; product entry that is unconstrained by traditional process patents, and significantly lower capital and operating costs for comparable production. f. People at risk for Alzheimer's are twice as likely to fall as healthy people, and the disease may also be visible in scans of the eye, researchers reported at the Alzheimer's Association International Conference in Paris in July. The studies are part of a widespread search for ways to detect Alzheimer's before memory problems begin, when drugs and treatments have a better chance of making a difference. Shaun Frost, of CSIRO, looked to see whether changes in the retina at the back of the eye -- which is closely related to the brain -- could be used to detect early Alzheimer's disease. Frost's team found the width of certain blood vessels were significantly different in people with early signs of Alzheimer's disease compared with healthy people. People in the small study who had abnormal blood vessels in their eye also had plaque deposits of an Alzheimer's-related protein known as beta amyloid on positron emission tomography, or PET brain scans. g. Scientists have launched a clinical trial of an anti-HIV biotech medicine produced using genetically modified tobacco. Molecular farming may offer a cheaper way of making complex biotech drugs and vaccines than traditional factory systems. Project coordinator is Julian Ma, Professor of Molecular Immunology at St George's, University of London. 8. Legal actions and enquiries a. An Ontario Supreme Court justice found that victims of Canada’s worst public health scandal to date were never formally informed that they were entitled to compensation. The thousands of haemophiliacs and transfusion recipients who received diseased blood transfusions in the late 1980s and early 1990s were not given notice about a $500,000 sum for victims who contracted blood-borne illnesses other than HIV, hepatitis C and Creutzfeldt-Jakob disease (CJD). Justice D.M. Brown granted a one-year extension on the Other Transfusion Claims Trust, after only two individuals made claims in the last 10 years. 20,000 people contracted hepatitis C, and 2,000 people contracted HIV/AIDS in the tainted blood scandal. 9. Infectious diseases: a. Mosquito- borne diseases Technology developed by Arbovax creates virus host-range mutations that will reproduce in insect cells while being severely restricted in their ability to reproduce in mammalian cells. Pre-clinical animal experiments have shown that this approach can be used to create immunity to insect-borne viral diseases such as dengue fever. Modifications to the virus are hidden from the immune system and so produce strong immunity in the absence of disease. The virus can also be grown in a very cost-effective manner in an insect cell reactor. Arbovax expects to initiate human clinical trials of its dengue vaccine by the end of 2012.10 On 9 July, the Sydney Morning Herald reported that increasing numbers of Australians have been returning home with dengue; travellers appear unaware of the dangers of becoming infected overseas, particularly in south-east Asia. In Australia, the number who tested positive to dengue in the three months to March more than doubled from the same period last year, figures from the World Health Organisation (WHO) show. There had been 354 cases of dengue fever so far this year, compared with 156 last year. Almost half of them were reported in Western Australia (166 in the first quarter of this year, 85 published in the June edition of Virology Journal, ‘Structural mutants of Dengue Virus 2 transmembrane domains exhibit host-range phenotype.’ http://www.virologyj.com/content/8/1/289 10 last year). The WA Department of Health says no recent infections were contracted in the state. Nearly all were acquired in south-east Asia, predominantly in Bali. A specialist in infectious diseases at the James Cook University clinical school at Cairns Base Hospital, Professor John McBride, says the jump in dengue cases in north Queensland corresponds with an increase in the spread of dengue fever worldwide over the past decade11. Professor Michael Good from Griffith University says research has shown that a small number of malaria parasites "hide" in white blood cells and escape treatments targeting red cells and the liver. He says researchers at the Queensland Institute of Glycomics on the Gold Coast are developing a vaccine to eradicate the disease. "A different class of immune cell is induced by our vaccine compared to other types of immunity that are being developed and that type we believe will target inside the white blood cell as well as inside the red blood cell" he said. "It will prevent the infection within a patient and eradicate it as well. We believe this acts like a Trojan Horse where the parasite can actually hide inside the white blood cell while all the immune response is going on around it and while perhaps drugs are having an effect outside the white blood cell it is hiding inside there and then later on the parasite comes out of the white blood cell and gets into the red cells". (July 2011) The University of Glasgow has received a grant from the Bill & Melinda Gates Foundation to help in the diagnosis of malaria. The $100,000 award goes towards developing a device which uses mobile-phone derived technology to detect and separate red blood cells infected with malaria parasites. The researchers hope, if successful, devices based on the technology could be produced for the masses for rapid and accurate malaria diagnosis. The study will exploit surface acoustic wave devices which are electronic components commonly found in televisions, mobile phones and other electronic display devices. The team proposes to use surface acoustic wave devices to exert selective forces on malaria infected red blood cells to separate them from uninfected red cells. Different cells respond to surface acoustic waves in different ways, depending on their physical properties, including their elasticity and their shape. Since malaria parasites cause red cells to alter their elasticity and their shape, they should respond differently to surface acoustic waves at particular frequencies. The team hopes to produce a hand-held device that can identify infected cells quickly. Mosquitoes die soon after a blood meal if certain protein components are experimentally disrupted, a team of biochemists at the University of Arizona has discovered (reported July). When the researchers blocked a cellular process known as vesicle transport, on which the mosquitoes rely to release digestive enzymes into the gut among other functions, it caused the affected animals to die within two days of blood feeding. b. Influenza/Avian Influenza The Department of Health and Ageing reported on 24 June that flu activity in Australia was increasing, with the biggest spikes in South Australia, Queensland, and New South Wales. The 2009 H1N1 virus was the most frequently detected strain, circulating alongside influenza B. Circulating flu strains are a close match with the ones included in the seasonal flu vaccine. Queensland Health was reported on 9 July to have estimated a sixfold increase in flu cases in Brisbane compared with the same time period last year. Nationally, the number of diagnosed cases by mid-July was some four times the “usual rate”. Preliminary studies in cell culture and mice conducted by researchers at Scripps Research Institute and the Dutch company Crucell have identified an antibody effective against a broad array of group 2 influenza A strains, including H3 and H7, both of which 11 Last year, more than 80,000 cases of dengue were reported in Indonesia, compared with 33,443 a decade earlier. In south-east Asia as a whole, dengue cases numbered more than 210,000 last year, compared with 63,668 in 2000. Brazil confirmed almost 500,000 cases last year. have been transmitted to humans. The group said in a press release on 7 July that the findings, coupled with their 2009 identification of a similar antibody effective against group 1 influenza A strains, may offer a combination therapy effective against a wide range of strains. Group 1 strains include H1N1, which caused pandemics in 1918 and 2009, as well as H5, including H5N1 avian flu. The newly identified antibody, CR8020, interferes with a binding site, or epitope, on the stalk of the flu virus's mushroom-shaped hemagglutinin protein, a portion of the virus that varies little among strains (as opposed to the head, which varies widely and is the target of current vaccines). Canadian company Medicago reported positive final results from a Phase II human clinical trial with its H5N1 avian Influenza vaccine candidate. The vaccine induced a solid immune response and was found to be safe and well tolerated. Medicago's H5N1 vaccine as formulated to protect against the Indonesian influenza virus. It is manufactured in Nicotiana benthamiana, a relative of the tobacco plant, using the Company's proprietary VLP (virus-like particles) technology. VLPs may have several advantages over traditional flu vaccines. They are made to look like a virus, allowing them to be recognized readily by the body's immune system, however, they lack the core genetic material, so they are non-infectious and unable to replicate. Medicago's technology requires only the genetic sequence of a viral strain and not the live influenza virus. This allows vaccines to be manufactured within four weeks of obtaining the genetic sequence of a pandemic strain. Current manufacturing technologies which rely on strain adaptation can deliver a vaccine only six to nine months after a pandemic is declared. Medicago expects to produce vaccines commercially in North Carolina shortly. It will be trialing a seasonal flu vaccine candidate in the US later this year. In late June, Australian company Biota released preliminary data from a flu Phase III prophylaxis study that showed the protective efficacies of a single, inhaled dose of CS8958 of 20 milligrams and 40 milligrams as measured by the Risk Reduction Rate (RRR) were 43.7% and 43.2%, but were lower than the preset RRR endpoint of 70%. The trial evaluated the prevention and safety of laninamivir octanoate in families of influenza A and B sufferers. The study measured transmission to other household members. Biota said it will conduct additional trials. Australian scientist Barry Marshall is planning a drinkable flu vaccine to begin trials next year. He and J. Robin Warren won the 2005 Nobel Prize in Medicine for their discovery of the Helicobacter pylori bacterium and its role in gastritis and peptic-ulcer disease. Marshall founded Ondek, which plans to modify the bacterium, which colonizes the stomach and can lead to cancer. Researchers will replace cancer-causing genes with influenza genes to stimulate an immune response. Marshall envisions a freeze-dried powder or a capsule, which would avoid cold-chain requirements and injection side effects. A trial of at least 30 people in the US is planned for next year, with results expected by mid-2013. The chief of the US National Institutes of Health predicts a universal flu vaccine that protects against all strains may be within reach in the next five years, replacing annual shots developed for specifics flu viruses. Researchers from the University of Hong Kong said an osteoporosis drug called pamidronate was able to increase a class of human immune cells called gamma-delta Tcells in mice. The cells were effective in fighting various flu viruses, including the H5N1 bird flu virus, according to the findings reported in the Journal of Experimental Medicine. The drug is set to be tested for this indication in human trials. Inovio Pharmaceuticals announced that significant T cell and antibody responses were generated in its Phase I clinical study of VGX-3400X, a SynCon DNA vaccine for the prevention of avian H5N1 influenza delivered using intramuscular electroporation. The WHO says the world is better prepared for the next influenza pandemic than it was in the past. WHO Assistant Director-General on Innovation, Information, Evidence and Research Marie-Paule Kieny says there have been a number of successes. They include new developments in production methods, new rules governing vaccine delivery and progress toward, what she calls the holy grail of influenza vaccination, the development of a universal vaccine. She notes pandemic vaccine production has increased markedly from 350 million doses in 2006 to more than 800 million doses now. She says a Global Action Plan is helping manufacturers in 11 developing countries produce or increase production of influenza vaccines through financial and technology transfers. New production of pandemic vaccines has been established in Brazil, Korea, India and Romania; and the establishment of new manufacturing capacity for influenza vaccine is ongoing in Egypt, Indonesia, Iran, Mexico, Serbia, Thailand, and Vietnam. A preliminary study suggests a breath test measuring the immune response to the H1N1 flu virus could help doctors avoid unnecessary vaccinations for people already infected with the virus, and prioritize those most in need of them. The study was conducted by the Cleveland Clinic in Ohio and New Zealand-based Syft Technologies, and published in the Journal of Breath Research. In an effort to overcome the difficult problem of predicting which influenza B strain will circulate in any given season, MedImmune has filed for US approval of a quadrivalent (four-strain) flu vaccine containing two influenza B strains. 10 regions of South Sulawesi in Indonesia are dealing with an unusually large die off of poultry, even by Indonesian standards. More than 100,000 birds died in two weeks amid reports of vaccine and disinfectant shortages. c. vCJD The European Parliament decided in early July to support the EU Commission’s proposals to relax the rules that control the use of animal protein in animal feed. This will permit pig and poultry protein to be used in animal feed, while maintaining the ban on cattle and sheep protein thus hoping to prevent another outbreak of bovine spongiform encephalopathy (BSE) – or “Mad Cow Disease”. Meat and bone meal can be fed from one species to another – pigs to poultry, and vice versa. The EU is only 40% self- sufficient in protein animal feed and commodity prices remain very high, so the move will reduce Europe’s spending and reliance on imported soy bean meal. The European Parliament decided that the ban would be gradually lifted as further safeguards are put in place. d. Other An immunodeficient woman receiving regular IVIg treatment became paralyzed and died 12 years after her child received the oral polio vaccine. "This patient had the first nonimported case of paralytic poliomyelitis and the second case of [vaccine-derived poliovirus] infection reported in the United States since the discontinuation in 2000 of oral poliovirus vaccinations" wrote Aaron S. DeVries, MD, of the Minnesota Department of Health in St. Paul, and colleagues. The case offers a caution for patients with primary Bcell deficiency, who may remain at risk for viral shedding and paralytic disease if they were exposed to someone who had received the oral vaccine before 2000, the investigators warned in the 16 June issue of the New England Journal of Medicine12. Poliovirus is known to evolve at a rate of approximately 1% each year, and the investigators were therefore able to date the patient's exposure to 11.9 years earlier which was shortly after her child received the oral vaccine. As to why the patient was not protected by the administration of immune globulin -- which is required to contain at least minimal titres of antibodies against poliovirus -- the investigators noted that the titre needed to be protective in immunodeficient patients is unknown. They also noted that she had received a different immunoglobulin preparation 60 days before she became ill and speculated that the lot may have contained lower titres of antibody against type 2 12 DeVries A, et al "Vaccine-derived poliomyelitis 12 years after infection in Minnesota" N Engl J Med 2011; 364: 2316-2323. poliovirus. They concluded that the case underscores the importance of ongoing surveillance, particularly among patients with B-cell immunodeficiency who could become a persistent disease reservoir hindering public health efforts to eradicate polio. A study in Mekeo in Papua New Guinea has found over 70% of people either have, or have had, the mosquito borne disease Japanese encephalitis (JE). The disease was mistaken for malaria or dengue fever by the sufferers, said the study by Dr Takatua Taufa. JE is caused by a flavivirus that affects the membranes around the brain. Researchers have discovered a new strain of gonorrhoea that is resistant to all currently available antibiotics. Details of the discovery were presented at the International Society for Sexually Transmitted Disease Research conference in Quebec. This new strain, called H041, was discovered in Japan and "is likely to transform a common and once easily treatable infection into a global threat to public health", the researchers claim. Two African studies report that taking one or two HIV pills daily can cut down on the transmission of the disease by almost three quarters. One study found those who took either the antiretroviral medication tenofovir or tenofovir in combination with emtricitabine experienced significantly fewer HIV infections than those who received a placebo. Vical of San Diego signed a licensing deal with Japan's Astellas Pharma to develop and sell its TransVax vaccine. TransVax prevents the activation of cytomegalovirus, a common herpesvirus that is dormant in most people but can cause illness and even death in those with compromised immune systems. Vical has tested the vaccine mainly in people who have undergone bone marrow transplants. In June 2011, China had 9,773 reported cases of scarlet fever. The year-to-date total was 30,999. By 13 July, Hong Kong had 874 reported cases year to date, with more than 200 of these in the previous two weeks. Horses have died in Queensland and New South Wales from Hendra virus. Human contacts are being monitored. Of 7 people known to have contracted Hendra virus in the past, four have died of the disease. Flying foxes are considered the most likely source of infection. A dog was euthanized after it was thought to have tested positive. A crossborder taskforce including the chief vets of New South Wales and Queensland, scientists, health officers and the CSIRO is co-ordinating the response. In July, South Australian health authorities issued a public alert after a man returned to Adelaide from overseas infected with measles. The WHO set 28 July 2011 as the first World Hepatitis Day, to raise awareness of the current epidemic. The outbreak of E. coli infections that began in Germany sickened more than 4,000 people in 16 countries and caused an unusually high number of cases of haemolyticuremic syndrome, which destroys red blood cells and damages the kidney. An international team hoping to understand the genetic makeup of the bacteria responsible has compared its genome to the genomes of 11 related strains of E. coli from around the world. Their analyses show that the deadly strain likely emerged when a less pathogenic E. coli picked up a critical set of virulence genes that made it more lethal in humans. This horizontal gene transfer is common among bacteria. The team, led by Howard Hughes Medical Institute investigator Matthew Waldor, published its findings in an online article in the New England Journal of Medicine on July 27, 2011.