Monitoring International Trendsposted August 2015

The NBA monitors international developments that may influence the management of blood and blood products in Australia. Our focus is on:

Potential new product developments and applications; Global regulatory and blood practice trends; Events that may have an impact on global supply, demand and pricing, such as changes

in company structure, capacity, organisation and ownership; and Other emerging risks that could potentially put financial or other pressures on the

Australian sector.A selection of recent matters of interest appears below. Highlights include:

Baxalta published data suggesting that BAX 855 has the potential to provide strong bleed prevention in haemophilia A patients with twice weekly dosing. (Section 1)

Baxalta reported that 100 per cent of the von Willebrand patients treated with BAX 111 achieved success in the management of bleeding episodes. (Section 1)

CSL is recruiting patients for a Phase IIB study of its drug CSL112 for acute coronary syndrome. (Section 1)

Researchers say they are nearing approval by the FDA for a small device that allows trauma medics to monitor rate of blood loss more precisely. (Section 1)

The US Food and Drug Administration (FDA) accepted for review CSL Behring's Biologics License Application for its recombinant factor VIII single-chain drug, CSL 627, designed for molecular stability in treating haemophilia A. (Section 2)

Swissmedic accepted for review a Marketing Authorization Application for CSL Behring’s long-acting fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP) for the prophylaxis and treatment of bleeding episodes in haemophilia B. This rIX-FP allows dosing intervals up to 14 days. (Section 2)

ADMA Biologics has submitted its Biologics License Application to the FDA seeking marketing authorization for RI-002. This is a plasma-derived, polyclonal, intravenous immune globulin derived from human plasma. (Section 2)

The FDA granted Fresenius Kabi approval for a labelling change that permits blood centres to use the Fenwal Amicus system for the storage of Amicus-derived platelets in plasma for up to seven days. (Section 2)

Remedium Technologies has FDA 510(k) clearance to market its Hemogrip patch. The patch controls bleeding occurring from access to veins or arteries during surgery. (Section 2)

Swedish Orphan Biovitrum (Sobi) decided to exercise its opt-in right to take over final development and commercialisation of Alprolix (long acting recombinant factor IX for haemophilia B) for Europe, North Africa, Russia and some Middle Eastern markets. Biogen has led development for Alprolix, has manufacturing rights, and has commercialisation rights in North America and other regions in the world excluding the Sobi territory. (Section 3)

Cerus Corporation announced that Unyts, headquartered in Buffalo, had signed a three-year purchase agreement for the INTERCEPT Blood System for platelets and plasma. `

Baxalta reported revenues for the second quarter and first half of 2015, which exceeded expectations. (Section 3)

Baxalta has a contract fractionation agreement with Sanquin Blood Supply Foundation to enhance supply and support growth in global demand for plasma-based therapies. Sanquin has submitted the production line for approval in Europe, which will provide additional manufacturing flexibility. (Section 3)

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On 4 August, Shire went public with a $US 30 billion bid for Baxalta that had already been made privately and been rejected. Baxalta said later that day that Shire's $US 45.23-per-share bid "significantly undervalues" the young company. (Section 3)

CSL announced that it had secured the necessary approvals required to proceed with the acquisition of the influenza vaccines business of Novartis. (Section 3)

Pfizer offered concessions in seeking EU regulatory approval for its $US 15 billion takeover of rival Hospira. (Section 3)

Therapure Biopharma received $C 20 million contribution from the Canadian government. Therapure has developed a proprietary technology called PlasmaCap Expanded Bed Adsorption, which it says increases protein yields from plasma, separates them faster, and costs less. (Section 4)

A biosafety level 4 laboratory in Tokyo is Japan’s first facility able to handle Ebola. (Section 4)

A Transylvanian electronic music festival offered its potential audience free or discounted tickets in exchange for blood donations to the National Institute of Blood Transfusion. (Section 4)

A Californian study showed that haemophilia accounted for the largest share of the State’s expenditure on outpatient drugs for publicly insured children with serious chronic illnesses. (Section 4)

A study found that patients who received an allogeneic blood transfusion during lumbar spine surgery were at higher risk for surgical site infection, urinary tract infection and overall postoperative infections. (Section 5)

Researchers found that the clinical benefits of minimally invasive aortic valve replacement via lower hemi-sternotomy include decreased transfusion requirements, decreased ventilation times, and shorter ICU and hospital stays. (Section 5)

A report suggested patients who experienced simultaneous bilateral anterior approach total hip arthroplasty enjoyed low rates of perioperative complications and excellent clinical outcomes. (Section 5)

Researchers found that iron bio-fortified pearl millet resolved iron deficiency in a group of school-aged children in India within four to six months (Section 5)

A randomized study confirmed that CSL Behring’s Kcentra (4-factor prothrombin complex concentrate) reversed the anticoagulation effects of vitamin K antagonists (VKA) at a faster rate than plasma in patients requiring emergency invasive procedures. (Section 5)

Scientists funded by Australia’s National Heart Foundation have been working towards a revolutionary treatment for blood clots that could be administered by paramedics without the need for specialised equipment. (Section 5)

St. Teresa Medical enrolled the first patient in its UK clinical trial of its Surgiclot wound dressing to reduce blood loss. (Section 5)

BioLife Solutions announced that manufacturing process validation has begun to support a new product, directed towards cryopreservation, including freezing of platelets for subsequent clinical use. (Section 5)

The adoption of new reporting standards may have reduced the proportion of studies reporting positive research findings among large-budget clinical trials funded by the US National Heart, Lung and Blood Institute. (Section 6)

At Stanford University’s School of Medicine, infusions of blood plasma from young people are being given to patients with mild to moderate Alzheimer’s disease. Doctors are looking for cognitive improvements. (Section 6)

Researchers have developed a system that mimics the human circulatory system. They coupled it with an optical technique that can provide quantitative in vivo information on individual red blood cells. (Section 6)

A group of downhill skiers have been trying to verify whether endurance performance can be improved by living at high altitudes while training at lower levels, (Section 6)

Scientists at the University of Pennsylvania have been investigating a new approach to vaccines, creating immunity without vaccination. (Section 7)

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European drug regulators recommended GlaxoSmithKline's Mosquirix (malaria vaccine) as safe and effective to use in at risk babies in Africa. (Section 7)

The United Nations Food and Agriculture Organization (FAO) warned in late July that timely intervention was essential to prevent the highly virulent avian flu virus H5N1 (which had already spread to five West African countries in six months) from spreading further. (Section 7)

A study found that two doses of H7N9 avian flu vaccine produced an adequate immune response in 2 per cent of adults vaccinated, but two distinct adjuvants increased that to 57 per cent and 84 per cent respectively. (Section 7)

Scientists found significantly fewer serious cardio-respiratory events possibly related to influenza in study participants 65 years of age and older who received a higher-dose split-virus inactivated influenza vaccine compared with a standard-dose split-virus inactivated influenza vaccine. (Section 7)

On 27 July, the final South Koreans suspected of possibly being infected with MERS were released from self or mandatory quarantine. (Section 7)

The Kingdom of Saudi Arabia continues to notify the World Health Organisation (WHO) of MERS cases. A surge in numbers has been observed ahead of the Hajj pilgrimage.

Scientists in Switzerland have found an antibody that neutralises multiple strains of Mers-CoV. They found in mice that the antibody could be used both prophylactically and therapeutically. (Section 7)

After a delay awaiting approval, plasma donated by Ebola survivors was administered to Ebola patients in West Africa. (Section 7)

The US Department of Health and Human Services (HHS) has issued a two-year $US 19.7 million task order to Emergent BioSolutions’ Baltimore Bayview Center for Innovation in Advanced Development and Manufacturing (CIADM) to produce a novel therapeutic drug to treat Ebola virus disease. (Section 7)

The FDA awarded OraSure Technologies' rapid Ebola test special status, allowing marketing of the test for use in areas where the virus is still circulating while the company works toward final approval. (Section 7)

A vaccine against Ebola was reported to be 100 per cent successful in trials in Guinea. The vaccine is made by Merck. (Section 7)

Research has found that urine from black flying foxes poses biggest Hendra virus risk to horses, following a confirmed Hendra case in far north Queensland. (Section 7)

Contents1. Products.........................................................................................................................................4

Clotting factors..............................................................................................................................4

Other.............................................................................................................................................5

2. Regulatory.....................................................................................................................................5

Plasma and recombinant products................................................................................................5

Other.............................................................................................................................................6

3. Market structure and company news............................................................................................7

4. Country-specific events.................................................................................................................9

5. Safety and patient blood management.......................................................................................10

Appropriate transfusion..............................................................................................................10

Treating iron deficiency...............................................................................................................11

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Other...........................................................................................................................................11

6. Research......................................................................................................................................13

7. Infectious diseases.......................................................................................................................14

Mosquito-borne diseases: dengue, malaria and West Nile virus.................................................14

Influenza: strains, spread, prevention and treatment.................................................................15

Middle East Respiratory Syndrome Coronavirus (MERS-CoV).....................................................17

Ebola Virus Disease......................................................................................................................17

Hendra virus................................................................................................................................18

1. ProductsHere the NBA follows the progress in research and clinical trials that may within a reasonable timeframe make new products available, or may lead to new uses or changes in use for existing products.

Clotting factorsa) Pivotal data for Baxalta’s BAX 855 was published in the journal Blood. The company

says the drug has the potential to provide strong bleed prevention in haemophilia A patients with twice weekly dosing. The drug is based on Advate and when approved by the FDA will be marketed in the US as Adynovate. The trial showed a mean half-life extension of 1.4 to 1.5 fold compared with Advate. Baxalta expects to file for marketing authorization with the European Medicines Agency in 2016. A regulatory application was filed in Japan earlier this year.

b) Baxalta announced the publication1 of pivotal phase III data for BAX 111, a highly purified recombinant von Willebrand factor (rVWF) candidate. The data showed that 100 per cent of the patients treated with BAX 111 achieved success in the management of bleeding episodes2. BAX 111 is currently under review by the US Food and Drug Administration (FDA). If approved, BAX 111 would become the first recombinant replacement treatment for managing bleeding episodes for von Willebrand patients. BAX 111 was developed using a plasma- and albumin-free manufacturing method. Both the FDA and the European Medicines Agency granted orphan drug designation in November 2010, which is reserved for products that meet medical needs for a disease that is classified as rare.

Othera) CSL is recruiting 1200 patients for a Phase IIB study of its drug CSL112 for acute

coronary syndrome, designed to prevent a second heart attack after a patient has already suffered the first.

1 in Blood, the journal of the American Society of Hematology2 The phase III multicentre, open-label clinical trial assessed the safety, efficacy and pharmacokinetics of BAX 111 in the on-demand treatment of patients with severe von Willebrand disease. There were 37 participants across trial sites in the US, Australia, Japan, Europe, Russia and India. The primary endpoint was the number of patients experiencing successful treatment for bleeding episodes. Secondary endpoints included other efficacy measures, pharmacokinetics, the number of infusions and the number of units administered per bleeding episode. One patient experienced chest discomfort and increased heart rate during infusion.

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b) A study conducted at the Royal Free Hospital in Kuala Lumpur suggested that patients with gastrointestinal symptoms related to systemic sclerosis may benefit from treatment with intravenous immunoglobulin3

c) Researchers from Pohang University of Science and Technology reported “a new light-activated, mussel protein-based bio adhesive (LAMBA) inspired by mussel adhesion and insect dityrosine crosslinking chemistry. LAMBA exhibited substantially stronger bulk wet tissue adhesion than commercially available fibrin glue and good biocompatibility in both in vitro and in vivo studies”4. The researchers praised the potential of their product as surgical glue for sutureless wound closures, both internal and external.

d) Israeli startup LifeBond has developed a firm but elastic hydrogel matrix using a combination of gelatin and microbial transglutaminase (mTG) enzyme. Investors have now made $US 27 million available to fund a US trial of this LifeSeal Surgical Sealant in minimizing postoperative complications such as staple-line leakage in gastro-intestinal and bariatric surgeries. The product has previously undergone a multinational, randomized controlled pilot in Europe and is expected to be granted a CE mark.

e) Vic Convertino (senior scientist for the US Army Combat Casualty Care Research program at Joint Base San Antonio in Texas) and his fellow researchers say they are nearing approval by the FDA for a small device5 that allows trauma medics to monitor precisely the rate at which a bleeding patient will reach “decompensation,” the point when the body can no longer offset blood loss, shock sets in and death soon follows. Such a device could be of use on the battlefield, where a blood pressure monitor may not indicate much change even when a soldier is losing a significant amount of blood.

2. RegulatoryThe NBA monitors overseas regulatory decisions on products, processes or procedures which are or may be of relevance to its responsibilities.

Plasma and recombinant productsa) Baxalta announced that the Committee for Medicinal Products for Human Use

(CHMP) of the European Medicines Agency expressed a positive opinion for the marketing authorization of Obizur [Antihaemophilic Factor (Recombinant), Porcine Sequence]. Baxalta requested authorization for the treatment of bleeding episodes in adult patients with acquired haemophilia6 caused by antibodies to Factor VIII (FVIII).The European Commission has yet to announce its decision on the recommendation7. John Orloff, head of Research & Development and chief scientific officer, Baxalta, said: “The marketing authorization anticipated later this year for Obizur will be an important milestone, offering patients with acquired haemophilia A in Europe a treatment option that transforms their care by allowing physicians to monitor treatment response”. The CHMP positive opinion follows a global,

3 Raja J et al, Paper #FRI0470, European League Against Rheumatism Annual European Congress of Rheumatology; June 10-13, 2015; Rome.4 Eun Young Jeon, Byeong Hee Hwang, Yun Jung Yang, Bum Jin Kim, Bong-Hyuk Choi, Gyu Yong Jung, Hyung Joon Cha, ”Rapidly light-activated surgical protein glue inspired by mussel adhesion and insect structural crosslinking”, Biomaterials, Volume 67, October 2015, Pages 11–19, doi:10.1016/j.biomaterials.2015.07.014 5 the Compensatory Reserve Index device, which is clamped to the end of a finger and measures heartbeat.6 Acquired haemophilia is a rare but potentially life-threatening condition. Obizur is not indicated for the treatment of congenital haemophilia A or von Willebrand disease. 7 Obizur already has orphan-drug designation from the European Commission based on the potential for the treatment to address an important unmet medical need in a rare disease

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prospective, controlled, multi-centre Phase II/III open-label clinical trial testing the efficacy of Obizur in treating serious bleeding episodes in adults with acquired haemophilia A. All 28 patients treated with Obizur had their bleeding stopped or decreased. Adverse reactions were development of inhibitors to porcine FVIII. Obizur is already approved in the US and is being reviewed by regulators in Australia, Canada, Switzerland, and Colombia.

b) The FDA accepted for review CSL Behring's Biologics License Application (BLA) for its recombinant factor VIII single-chain (rVIII SingleChain or CSL 627), designed for molecular stability in treating haemophilia A. The product met all primary endpoints in the pivotal trial. The BLA relies on the AFFINITY clinical development program, including a phase I/III open-label, multi-centre trial examining safety and efficacy. Pharmacokinetics were compared with a current standard of care, recombinant human anti-haemophilic factor VIII (octocog alfa). CSL627 has a strong affinity for von Willebrand factor, leading to greater stability and integrity of FVIII in circulation.

c) Swissmedic accepted for review a Marketing Authorization Application for CSL Behring’s long-acting fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP) for the prophylaxis and treatment of bleeding episodes in haemophilia B. This rIX-FP allows dosing intervals up to 14 days.

d) Baxalta announced in the US that the Centers for Medicare and Medicaid Services (CMS) have expanded coverage to include in-home use of Hyqvia [Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase], a treatment for adults with primary immunodeficiency (PI). After the FDA approved Hyqvia in 2014, CMS covered both provider facility and in-office treatment with Hyqvia. This new decision expands its provisions to include durable medical equipment coverage of the infusion pump required to administer Hyqvia, facilitating the self-administration (at home) option for patients. In the clinical trial for Hyqvia, the majority of PI patients expressed a desire for the ability to administer infusions at home.

e) ADMA Biologics has submitted its Biologics License Application to the FDA seeking marketing authorization for RI-002. This is a plasma-derived, polyclonal, intravenous immune globulin derived from human plasma containing naturally occurring polyclonal antibodies (Streptococcus pneumoniae, H. influenza type B, cytomegalovirus (CMV), measles, tetanus, etc.) as well as standardized, high levels of antibodies to respiratory syncytial virus (RSV)8. In a Phase III study in patients with primary immunodeficiency, RI-002 met its primary endpoint of no serious bacterial infections (SBI). The requirement specified by FDA guidance is ≤ 1 SBI per patient-year.

Othera) FDA officials have met with Google to “begin a discussion on how we might

collaborate with Google on identifying adverse event data, using Google’s technologies and data.”9

b) The FDA granted Fresenius Kabi approval for a labelling change that permits blood centres to use the Fenwal Amicus system for the storage of Amicus-derived platelets in plasma for up to seven days. Where blood centres do store apheresis-derived platelets for seven days they must label each product with a statement that the product must be tested with a bacterial detection device cleared by FDA and labelled as a “safety measure”. Fresenius Kabi is the sole distributor of the Verax Platelet

8 On June 30, 2015, ADMA announced that it had received a notice of allowance for a US patent relating to RI-002 entitled "Compositions and Methods for the Treatment of Immunodeficiency."9 Google specialist in data mining Evgeniy Gabrilovich, who formerly worked for Yahoo, was co-author of a 2013 paper which used Yahoo search data 176 million queries in 2010) to identify suspected drug reactions that had “so far eluded discovery by the existing mechanisms". Elad Yom-Tov, Evgeniy Gabrilovich, “Postmarket Drug Surveillance Without Trial Costs: Discovery of Adverse Drug Reactions Through Large-Scale Analysis of Web Search Queries”, J Med Internet Res 2013;15(6):e124). doi:10.2196/jmir.2614

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PGD test, a rapid test approved by the FDA as a “safety measure” for leuko reduced apheresis platelets within 24 hours prior to transfusion.

c) Hospira received approval from the FDA to launch bivalirudin for injection, a generic version of The Medicines Company's Angiomax. Bivalirudin is a direct thrombin inhibitor indicated amongst other things for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty.

d) The FDA, the US Department of Homeland Security’s Industrial Control Systems Cyber Emergency Response Team, and Hospira announced that Hospira’s Symbiq Infusion System could be accessed remotely through a hospital’s network. An unauthorized user could control the device and change the dosage the pump delivers. While neither the FDA nor Hospira are aware of any unauthorized access of a Symbiq Infusion System in a US health care setting, the FDA urged health care facilities to discontinue use of these pumps.

e) Remedium Technologies has FDA 510(k) clearance to market its Hemogrip patch. The patch controls bleeding occurring from access to veins or arteries during surgery. The product is based on chitosan, from the exoskeleton of crustaceans. Based at the University of Maryland, Remedium10 has a number of other bleeding control products in development, including a clear transparent film, haemostatic gauze and a foam spray.

3. Market structure and company newsThe NBA’s business intelligence follows company profitability, business forecasts, capital raisings or returns, mergers and takeovers, arrangements for joint research and/or development, contracts for supply of manufacturing inputs, and marketing agreements. Companies considered include suppliers, potential suppliers and developers of products which may be of interest.

a) Swedish Orphan Biovitrum (Sobi) announced the company has decided to exercise its opt-in right to take over final development and commercialisation of Alprolix (rFIXFc for haemophilia B) for Europe, North Africa, Russia and some Middle Eastern markets. Sobi will pay Biogen $US 10 million to be held in escrow awaiting the regulatory approval of Alprolix in Europe11. Biogen has led development for Alprolix, has manufacturing rights, and has commercialisation rights in North America and other regions in the world excluding the Sobi territory.

b) Cerus Corporation announced that Unyts had signed a three-year purchase agreement for the INTERCEPT Blood System for platelets and plasma. Unyts, headquartered in Buffalo, services eight counties in Western New York with 5,000 platelet and 11,000 plasma units annually. Cerus had already signed a three-year purchase agreement for the INTERCEPT Blood System for platelets and plasma with Bonfils Blood Center. Bonfils supplies blood and blood products to over 100 facilities in Colorado and further afield, providing 20,000 platelet and 25,000 plasma units annually. Bonfils is an affiliate of Blood Systems Inc., a major blood product supplier in the US.

c) Baxalta reported revenues for the second quarter and first half of 2015, which exceeded expectations. Haematology revenues (excluding the impact of foreign currency) grew 6 per cent in the second quarter driven by demand for Advate, and double-digit growth of FEIBA. Also contributing to growth were new products Rixubis (for haemophilia B) and Obizur (for acquired hemophilia A). Immunology sales (excluding the impact of foreign currency) grew 10 per cent driven by demand for

10 The company has received funding from the US Army Research Lab, the National Science Foundation, Maryland Industrial Partnerships, the Maryland Biotechnology Center and Tedco. 11 Alprolix [Coagulation Factor IX (Recombinant), Fc Fusion Protein] has regulatory approval for treating haemophilia B in the US, Canada, Australia, and Japan.

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immunoglobulin therapies and continued success of Hyqvia (10% concentration), the once-monthly subcutaneous treatment available for adults with primary immunodeficiency. Baxalta has submitted a European Marketing Authorization Application for approval of its investigational 20% concentration subcutaneous immune globulin treatment for primary immunodeficiencies. This higher potency treatment would offer faster infusions with less volume. Baxalta expects to file for US approval before the end of 2015.

d) Baxalta has established UK headquarters for 100 employees in Staines-upon-Thames.

e) The Board of Directors of Baxalta declared its first quarterly cash dividend of $US0.07 per share of common stock. It will be paid on October 1, 2015, to stockholders of record at close of business on September 4. The Board also approved a share repurchase authorization for up to $US 1 billion of its common stock in the open market at times and amounts determined by the company.

f) Baxalta has a contract fractionation agreement with Stichting Sanquin Bloedvoorziening (Sanquin Blood Supply Foundation) to enhance supply and support growth in global demand for plasma-based therapies. Sanquin has submitted the production line for approval in Europe, which will provide additional manufacturing flexibility.

g) On 4 August, Shire went public with a $30 billion bid for Baxalta that had already been made privately12 and been rejected. Baxalta said later that day that Shire's $US 45.23-per-share bid "significantly undervalues" the young company13. Baxalta’s CEO had already questioned the logic behind a merger, writing: “we do not think the combination would generate substantial operational or revenue synergies, which would be critical to any potential value creation". However, by 10 August there were reports that Baxter directors were proposed to negotiate with Shire for a significantly increased bid.

h) CSL announced that it had secured the necessary approvals required to proceed with the acquisition of the influenza vaccines business of Novartis, and that it was working with Novartis to bring forward the close date for the transaction. The new CSL subsidiary resulting from the acquisition will be called Seqirus. CSL’s Chief Financial Officer, Gordon Naylor, will lead the new business, and the corporate office will be located in Maidenhead, outside London.

i) CSL is recruiting 1200 patients for a Phase IIB study of its drug CSL112 for acute coronary syndrome, designed to prevent a second heart attack after a patient has already suffered the first.

j) Pfizer has offered concessions in seeking EU regulatory approval for its $US 15 billion takeover of rival Hospira. The EU competition authority could approve the deal or begin a full-scale investigation.

k) Abeona Therapeutics, formerly PlasmaTech Biopharmaceuticals, is focussed on developing and delivering gene therapy and plasma-based products for severe and rare diseases, including Fanconi anaemia and other rare blood diseases. The company offers two platforms: Salt Diafiltration (SDF) Process and Polymer Hydrogel Technology (PHT). It recently raised $US 8.5 million in equity financing from its current institutional investors and directors, with its SDF Alpha (alpha-1 protease inhibitor) for inherited chronic obstructive pulmonary diseases cited as the major recipient of funding.

12 On 10 July13 Baxalta CEO Ludwig Hantson wrote to Shire chief Flemming Ornskov: "As a new, publicly-traded entity only since July 1, we are just in the initial stages of implementing our growth strategy as a standalone company and our stock has not yet achieved a price level that appropriately reflects the company's value and prospects.” Baxalta Chairman Wayne Hockmeyer in a statement: "Diving into a merger just a month after spinning off from parent company Baxter International would be severely disruptive".

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l) Tekmira Pharmaceuticals Corporation announced in British Columbia and Pennsylvania its plans to change its corporate name without delay to Arbutus Biopharma Corporation, a therapeutic solutions company dedicated to developing a cure for chronic hepatitis B virus infection (HBV).

m) Eisai Co of Tokyo announced that its US subsidiary Eisai Inc. will transfer ownership of its manufacturing facility in Research Triangle Park, North Carolina, to Biogen, whose US headquarters is in Massachusetts. Biogen will manufacture some products for Eisai.

n) Ra Pharmaceuticals, of Cambridge, Massachusetts, secured $US58.5 million in Series B financing to support development of its lead molecule, RA101495, for treating paroxysmal nocturnal haemoglobinuria (PNH)14. Doug Treco, founder and CEO of Ra Pharma said: “…..preclinical data demonstrate a near complete inhibition of hemolysis, the hallmark of PNH, in non-human primates”.

4. Country-specific eventsThe NBA is interested in relevant safety issues which arise in particular countries, and also instances of good practice. We monitor health issues in countries from which Australia’s visitors and immigrants come.

a) In Canada, Therapure Biopharma of Mississauga received $C 20 million contribution from the Federal Economic Development Agency for Southern Ontario’s Advanced Manufacturing Fund. Therapure has developed a proprietary technology called PlasmaCap Expanded Bed Adsorption15, which it says increases protein yields from plasma, separates them faster, and costs less. Nick Green, president and CEO of Therapure, said: “This investment, for which we thank the Government of Canada, will help us expand our scope and accelerate our growth in the plasma proteins industry. This expansion was a natural progression for Therapure after having established ourselves as a successful contract manufacturer of complicated biologics with additional expertise in plasma-derived proteins. We believe that our PlasmaCap EBA™ technology delivers the highest yields in the industry and will allow us to produce safe, quality, life-changing products for patients".

b) A biosafety level 4 lab in Musahimurayama, Tokyo, will be Japan’s first facility able to handle Ebola, joining around 40 labs worldwide. The upgrade of the National Institute of Infectious Diseases lab, built over 30 years ago, followed talks between the health minister and the local mayor to overcome local opposition.

c) Transylvania electronic music festival Untold in 2015 offered its potential audience free or discounted tickets in exchange for blood donations. In partnership with the National Institute of Blood Transfusion, donation centres were established in 41 Romanian cities during a ten day window in July.

d) In India, which experiences around 20,000 deaths annually from rabies, there is a shortage of human rabies immunoglobulin.

e) The Haemovigilance Programme of India (HvPI), launched in December 2012 by National Institute of Biologicals (NIB), reported 2303 adverse transfusion reaction reports during its first two and a half years of operation. Dr Surinder Singh, director, NIB says the Programme is confidential, independent, offers expert analysis through a Haemovigilance Advisory Committee, is systems oriented and is responsive. It aims to improve transfusion safety by identifying trends in adverse events, targeting areas for improved practice, and increasing awareness of transfusion hazards.

14 This disorder develops over time. A defect in the formation of surface proteins on red blood cells causes the patient’s immune system to attack and destroy the cells.15 PlasmaCap EBA uses proprietary affinity adsorbents in expanded bed adsorption (EBA) chromatography to capture plasma proteins directly from plasma or fractionated plasma materials.

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f) In Australia, a partnership between the Royal Flying Doctor Service, New South Wales Ambulance Service, The Western Local Health District and Pathology West- Dubbo will allow blood to be carried in RFDS aircraft for use in trauma cases.

g) A Californian study16 showed that haemophilia accounted for the largest share of the State’s expenditure on outpatient drugs for publicly insured children with serious chronic illnesses. A group led by Sonja Swenson of Stanford University wrote that their study "underscores the potential effect of new, expensive but [effective] pharmaceuticals on public insurance programs for children with chronic illness.” The study tracked 2010-2012 data from more than 34,300 patients under the age of 21. Antihaemophilic factor accounted for 41 per cent of pharmacy expenditure on children although children treated with antihaemophilic factor made up only 0.4 per cent of all the children in the study. Over the period of the study, the average per-child cost for antihaemophilic factor was about $US 1.3 million.

h) Two of Florida’s independent, nonprofit blood centers, OneBlood Inc. and The Blood Alliance Inc., merged and will carry the OneBlood brand. They said the merger will result in operational efficiencies, enhance donor outreach initiatives and further stabilize the blood supply, especially in times of natural disasters. The merged organisation will employ 2,400 people and serve over 210 hospitals in Florida, Georgia, Alabama and South Carolina.

5. Safety and patient blood managementWe follow current issues in patient safety and achieving favourable patient outcomes.

Appropriate transfusiona) A retrospective study 17of 3,721 patients from a tertiary care spine referral centre

found that patients who received an allogeneic blood transfusion during lumbar spine surgery were at higher risk for surgical site infection, urinary tract infection and overall postoperative infections. No dose-response relationship was observed between any of the postoperative infection types and the number of units of blood transfused.

b) Researchers have found18 that the clinical benefits of minimally invasive aortic valve replacement via lower hemi-sternotomy19 include decreased transfusion requirements, decreased ventilation times, and shorter ICU and hospital stays, without compromising short and long term survival compared with conventional full sternotomy20.

c) A recent report21 suggested patients who experienced simultaneous bilateral anterior approach total hip arthroplasty enjoyed low rates of perioperative complications and excellent clinical outcomes. The retrospective review for 75 patients found mean

16 Sonja M. Swenson; Lisa J. Chamberlain, Lee M. Sanders; Vandana Sundaram, Paul H. Wise, “Outpatient Pharmacy Expenditures for Children With Serious Chronic Illness in California, 2010-2012”, published in the Journal of the American Medical Association, 28 July. JAMA. 2015;314(4):405-407. doi:10.1001/jama.2015.7169. 17 Stein J. Janssen, Yvonne Braun, Kirkham B. Wood, Thomas D. Cha, Joseph H. Schwab, “Allogeneic blood transfusions and postoperative infections after lumbar spine surgery”, The Spine Journal, Vol. 15, Issue 5, p901–909. DOI: http://dx.doi.org/10.1016/j.spinee.2015.02.01018 Neely RC, Boskovski MT, Gosev I, Kaneko T, McGurk S, Leacche M, Cohn LH., “Minimally invasive aortic valve replacement versus aortic valve replacement through full sternotomy: the Brigham and Women's Hospital experience.” Ann Cardiothoracic Surg. 2015 Jan;4(1):38-48. doi: 10.3978/j.issn.2225-319X.2014.08.13.19 A sternotomy is an incision in the centre of the chest that separates the sternum) to allow access to the heart.20 Minimally invasive aortic valve replacement is an alternative to conventional full sternotomy for patients with isolated pathology of the aortic valve and ascending aorta without coronary artery disease.

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blood loss was 565 mls, with 13 patients not being transfused. In the first 25 patients, the average volume transfused was 2.6 units, while in the remaining 50 patients the average volume transfused was 1.6 units.

Treating iron deficiencyd) Medgenics began patient enrolment in Phase II clinical trial in the US of MDGN-201

(TARG-TEPO), a gene therapy designed to treat anaemia in end stage renal disease) in patients who are undergoing peritoneal dialysis.

e) The first cohort of patients treated by Xenetic Biosciences in a Phase II trial for ErepoXen (a treatment for anaemia in patients with chronic kidney disease) saw their haemoglobin levels rise but not into the therapeutic range. Now in a second cohort 91 per cent of the enrolled patients increased haemoglobin levels, while three-quarters of them had their haemoglobin levels rise into the therapeutic range. Haemoglobin levels stayed within the therapeutic range for the rest of the 17-week study. In both cohorts, ErepoXen appeared well tolerated without any significant treatment related adverse events. A third cohort will be given higher doses in an attempt to identify the optimal therapeutic dose. Principal investigator is Professor Simon Roger at Gosford Hospital.

f) A Cornell-led study22 found that iron bio fortified pearl millet23 resolved iron deficiency in a group of school-aged children in India within four to six months, compared with a control group fed unfortified pearl millet for the same time period.

Other.h) A randomized study24 of 168 patients confirmed that CSL Behring’s Kcentra (4-factor

prothrombin complex concentrate) reversed the anticoagulation effects of vitamin K antagonists (VKA) at a faster rate than plasma in patients requiring emergency invasive procedures. The results are consistent with previous studies, including another randomized trial of only 20 patients25.

i) Verax Biomedical renewed its exclusive worldwide commercialization agreement with Fresenius Kabi USA to market Verax's PanGenera Detection (PGD) test. This rapid in vitro test is used to detect bacterial contaminants in donated platelets26. It is the only rapid test approved by the FDA for all commonly available US platelet types.

j) Scientists funded by Australia’s National Heart Foundation have been working towards a revolutionary treatment for blood clots that could be administered by paramedics without the need for specialised equipment as is currently the case27.

21 Joseph S. Gondusky, Kevin A. Pinkos, Leera Choi, Jay J. Patel, Steven Barnett, Robert S. Gorab, “Simultaneous Bilateral Anterior Approach Total Hip Arthroplasty”,Orthopedics, July 2015-Volume 38 Issue 7: e611-e615. DOI: 10.3928/01477447-20150701-6022 Julia L Finkelstein, Saurabh Mehta, Shobha A Udipi, Padmini S Ghugre, Sarah V Luna, Michael J Wenger, Laura E Murray-Kolb, Eric M Przybyszewski, and Jere D Haas, “A Randomized Trial of Iron-Biofortified Pearl Millet in School Children in India”, J. Nutr. July 1, 2015 vol. 145 no. 7 1576-1581. doi: 10.3945/jn.114.208009 23 The fortified grain was developed by the HarvestPlus program, in partnership with the International Crops Research Institute for the Semi-Arid Tropics (ICRISAT) in India.24 Joshua N Goldstein, Majed A Refaai, Truman J Milling Jr, Brandon Lewis, Robert Goldberg-Alberts, Bruce A Hug, and others, “Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial”, The Lancet, Volume 385, No. 9982, p2077–2087, 23 May 2015. DOI: http://dx.doi.org/10.1016/S0140-6736(14)61685-825 Vox Sang 2010;99:251-260),26 Globally, over 6 million platelet doses are transfused annually. Estimates suggest 1 in 2,000 doses exhibit bacterial contamination which can cause sepsis and death. 27 Sylvia T. Gunawan, Kristian Kempe, Thomas Bonnard, Jiwei Cui, Karen Alt, Lok S. Law, Xiaowei Wang, Erik Westein, Georgina K. Such, Karlheinz Peter, Christoph E. Hagemeyer, and Frank Caruso, “Multifunctional Thrombin-Activatable Polymer Capsules for Specific Targeting to Activated Platelets”, Advanced Materials, first published online: 3 August 2015. DOI: 10.1002/adma.201502243

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Professor Christoph Hagemeyer, Head of the Vascular Biotechnology Laboratory at Baker IDI Heart and Diabetes Institute, said: “We’ve created a nanocapsule that contains a clot-busting drug. The drug-loaded nanocapsule is coated with an antibody that specifically targets activated platelets, the cells that form blood clots……..Once located at the site of the blood clot, thrombin (a molecule at the centre of the clotting process) breaks open the outer layer of the nanocapsule, releasing the clot-busting drug. We are effectively hijacking the blood clotting system to initiate the removal of the blockage in the blood vessel”. Joint leader of the project, Professor Frank Caruso, an ARC Australian Laureate Fellow in the Department of Chemical and Biomolecular Engineering at the University of Melbourne said the targeted drug and novel delivery can potentially offer a safer alternative with fewer side effects. He said: “Up to 55,000 Australians experience a heart attack or suffer a stroke every year…….About half of the people who need a clot-busting drug can’t use the current treatments because the risk of serious bleeding is too high”.

k) St. Teresa Medical of St Paul, Minnesota, has enrolled the first patient in its UK clinical trial of its Surgiclot wound dressing to reduce blood loss. The 40 patient trial will support the company’s application for CE Mark certification. The company says Surgiclot dissolves in seconds to minutes, leaving behind a clot which can achieve haemostasis in under three minutes.

l) BioLife Solutions of Washington State announced that manufacturing process validation has begun to support a new product, BloodStor 27 NaCl, directed towards cryopreservation, including freezing of platelets for subsequent clinical use. Mike Rice, the company’s CEO, said: "We have been monitoring clinical use of frozen platelets for hemodynamically unstable patients and have been in discussions with leading international clinical centers about the need for a stable supply of GMP manufactured, clinical grade freeze media for freezing therapeutic platelets. Additionally, there is clearly strong interest to improve battlefield trauma care for wounded warriors28. We believe that we can add incremental revenue by expanding our product portfolio with this new GMP grade bio preservation media." BioLife expects inventory of BloodStor 27 NaCl to be available to fill orders early in the fourth quarter of 201529. 

6. ResearchA wide range of scientific research has some potential to affect the use of blood and blood products. However, research projects have time horizons which vary from “useful tomorrow” to “at least ten years away”. Likelihood of success of particular projects varies, and even research which achieves its desired scientific outcomes may not lead to scaled-up production, clinical trials, regulatory approval and market development.

28 Continuing military research on the use of platelets which have been frozen then thawed includes a US Army Medical Research and Materiel Command clinical trial, Phase 1 Safety Study of Dimethyl Sulfoxide Cryopreserved Platelets (CPP1-05), to "evaluate the safety of intravenous (IV) infusion of dimethyl sulfoxide (DMSO) cryopreserved platelets (CPP) in participants with World Health Organization (WHO) Grade 2 bleed in spite of receiving a transfusion of liquid stored platelets (LSP) in the past 48 hours by collecting adverse events (AEs) and by evaluating coagulation-related parameters to assess the evidence of any thrombotic events after CPP or LSP transfusion." 29 A Master File for BloodStor 27 NaCl will be submitted to the US Food and Drug Administration (FDA) for customers to cross reference in regulatory filings. BloodStor 27 NaCl is labelled For Research Use, For Human Cell and Tissue Preservation. Customers who incorporate the product into their frozen storage protocol for cells and tissues intended for human clinical uses are responsible for validation and fulfilling any required regulatory requirements related to the use of the product.

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a) A US study30 has concluded that the adoption of new reporting standards phased in around the year 2000 may have reduced the proportion of studies reporting positive research findings among large-budget clinical trials funded by the National Heart, Lung and Blood Institute. In summary, 57 per cent of large-budget clinical trials of drugs or dietary supplements for the treatment or prevention of cardiovascular disease published from 1970 to 1999 reported positive outcomes, while only 8 percent of trials published between 2000 and 2012 reported positive outcomes. Researchers using human subjects are required to identify the outcomes they will focus on and register their trials on the website, ClinicalTrials.gov, before they begin to collect data. Previously a researcher might have reported only an aspect of a study that was successful, even if the study overall did not produce the expected results.

b) At Stanford School of Medicine, infusions of blood plasma from young people are being given to 18 patients aged 50 to 90 with mild to moderate Alzheimer’s disease. Each participant receives a unit of young human plasma or saline weekly for four weeks. They have a break of six weeks, then another four weeks of infusions. Those who had plasma in the first round receive saline second time round, and the reverse is also true. The process is blinded, so neither the patients, nor carers, nor doctors know who is receiving what. Doctors are looking for cognitive improvements. The results are expected at the end of this year.

c) Researchers from the Rowland Institute at Harvard University, Harvard Medical School, and Massachusetts General Hospital have developed a system that mimics the human circulatory system. They coupled it with an optical technique that can provide quantitative in vivo information of individual red blood cells. They can measure cell volume, haemoglobin mass, and oxygen saturation in individual.

d) For a month, a group of Norwegian downhill skiers have been spending most of their time near Chamonix, altitude 2,200 metres. They have descended into the valley each morning for inline skating, running, weight training, cycling and swimming. They spend the afternoon and evening at an altitude where oxygen levels are 20 percent lower than at sea level. On their return to Lillehammer, their athletic performances will be measured, along with the volume of red cells in their blood, maximal oxygen intake and other criteria. A control group of nine athletes has resided and trained in the valley. The objective of the experiment is to verify whether "endurance performance is increased" after living at high altitudes while training at lower levels, says researcher Paul Robach.

e) Uli Herrmann31 and his research colleagues32 have designed new polythiophenes with optimal ability to immobilize prions in mice and hamsters33. The animals treated with the compound showed fewer prion clusters and less severe damage in the brain, the researchers said, suggesting that it stabilized small clusters of prions and locked them in place, preventing self-replication.

30 published in the journal PLOS ONE. Researchers came from Oregon State University and the federal Agency for Healthcare Research and Quality. Previously Veronica Irvin and Robert M Kaplan worked together in the National Institutes of Health's Office of Behavior and Social Science Research. Now Irvin is an assistant professor in Oregon State University's College of Public Health and Human Sciences, while Kaplan is with the Agency for Healthcare Research and Quality31 affiliated with the Institute for Neurology at the University of Zurich in Switzerland.32 Including Anja Boeckmann, from the Institute for Biology and Chemical Proteins at the University of Lyon in France33 Uli S. Herrmann, Anne K. Schütz, Hamid Shirani, Danzhi Huang,, Dino Saban, Mario Nuvolone, Bei Li, Boris Ballmer, Andreas K. O. Åslund, Jeffrey J. Mason, Elisabeth Rushing, Herbert Budka, Sofie Nyström, Per Hammarström, Anja Böckmann, Amedeo Caflisch, Beat H. Meier, K. Peter R. Nilsson, Simone Hornemann, and Adriano Aguzzi, “Structure-based drug design identifies polythiophenes as antiprion compounds”, Science Translational Medicine 05 Aug 2015: Vol. 7, Issue 299, pp. 299ra123DOI: 10.1126/scitranslmed.aab1923

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7. Infectious diseasesThe NBA takes an interest in infectious diseases because: the presence of disease in individual donors (e.g. influenza), or potential disease resulting from travel (e.g. malaria) means a donor must be deferred; temporary disease burden within a community (e.g. dengue in North Queensland) may limit blood collection in the community for a time; and some people may not be permitted to donate at all (e.g. people who lived in the UK for a period critical in the history of vCJD). Blood donations are tested for a number of diseases (e.g. HIV and Hepatitis B), but there are also emerging infectious diseases for which it may become necessary to test in the future (e.g. Chagas disease, and the tick-borne babesiosis and Lyme disease).

Mosquito-borne diseases: dengue, malaria and West Nile virusa) The unmet challenge in developing a dengue vaccine has been to produce balanced

protection against all four dengue viral strains, or serotypes. People infected with one serotype develop immunity against only that serotype, but this immunity perversely renders them vulnerable for severe disease if future infections are caused by a different serotype. Now scientists at the Perelman School of Medicine at the University of Pennsylvania have been investigating a new approach to vaccines, creating immunity without vaccination34. They demonstrated that mice injected with synthetic DNA engineered to encode a specific neutralizing antibody against dengue could produce the exact protective antibodies necessary, without any need for standard antigen-based vaccination. This approach (known as DMAb35) protected animals within a week. Senior author David B. Weiner, a professor of Pathology and Laboratory Medicine and chair of the Gene Therapy and Vaccine Program, said: "Engineering novel methods of delivering monoclonal antibodies could be an important approach in the fight against infection and in unique treatment situations. We can produce a synthetic immune response by encoding an antibody and delivering it as a non-live, non-viral, non-permanent antibody." Lead author, doctoral candidate Seleeke Flingai, said the rapidity of protection, along with the ability to tailor the exact features of a protective antibody-including those that cannot be created by a traditional vaccination response-give the DMAb platform great versatility36.

b) European drug regulators recommended GlaxoSmithKline's Mosquirix (malaria vaccine) as safe and effective to use in at risk babies in Africa. The vaccine was developed by GSK in partnership with the PATH Malaria Vaccine Initiative, and part-funded by the Bill & Melinda Gates Foundation. It will now be assessed by the World Health Organisation (WHO). The vaccine includes an adjuvant, or booster, made by US company Agenus. Trial data released in 2011 and 2012 showed Mosquirix reduced episodes of malaria in babies aged 6-12 weeks by only 27 percent, and by around 46 percent in children aged 5-17 months, but the European Medicines Agency nevertheless recommended it be licensed for use in babies in the full age range covered in the trials-from 6 weeks to 17 months. More than 80 per cent of

34 Seleeke Flingai, Emily M.Plummer, Ami Patel, Sujan Shresta, Janess M.Mendoza,Kate E.Broderick, Niranjan Y.Sardesai, Kar Muthumani, David B Weiner, “Protection against dengue disease by synthetic nucleic acid antibody prophylaxis/immunotherapy”, Scientific Reports 5, Article number 12616 (2015) doi:10.1038/srep1261635 Monoclonal antibodies (mAbs) are manufactured in a large-scale cell culture laboratory. Since antibodies break down over time, mAbs in the clinic require frequent repeat administrations. DMAbs are produced in the body and have the potential to reduce cost barriers.36 Additional authors were Emily M. Plummer, Ami Patel, Sujan Shresta, Kar Muthumani, all from Penn, and Janess M. Mendoza, Kate E. Broderick, and NiranjanY. Sardesai, from Inovio Pharmaceuticals, Blue Bell, Pennsylvania. The work was funded by the National Institute of Allergy and Infectious Diseases, the Defense Advanced Research Projects Agency, and Inovio Pharmaceuticals. 

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malaria deaths are in children under the age of five. Andrew Witty, GSK's chief executive, said that while Mosquirix "on its own is not the complete answer to malaria, its use alongside …interventions ... such as bed nets and insecticides would provide a very meaningful contribution to controlling the impact of malaria on children in those African communities that need it the most." GSK has undertaken to make no profit from Mosquirix, pricing it at manufacturing cost plus 5 per cent, this margin to be reinvested in research on malaria and other neglected tropical diseases. A price of around $US 5 per dose is expected, making the cost of a recommended four-dose immunisation $US 20.

c) West Nile Virus (WNV) is known to have the highest mortality in people aged 60 or more. A new study37 suggests this could be because of impairments in the early immune response to the virus. Michael Diamond, of Washington University in St. Louis, and his research team found that many important components of the early immune response to WNV were impaired in elderly mice. "In the elderly, the virus crosses the blood-brain barrier at increased frequency and infects neurons of the brain and spinal cord; this is associated with a 5-10% case-fatality rate," note Diamond and colleagues. The US National Institutes of Health has announced a trial of an experimental human vaccine for WNV.

Influenza: strains, spread, prevention and treatmentd) The United Nations Food and Agriculture Organization (FAO) warned in late July that

timely intervention was essential to prevent the highly virulent avian flu virus H5N1, which has already spread to five West African countries in six months, from spreading further. Outbreaks of the virus have been reported in poultry farms, markets and family holdings in Nigeria, Burkina Faso, Niger, Côte d’Ivoire and Ghana. Juan Lubroth, chief of FAO’s Animal Health Service Division said in a press release: “Urgent action is needed to strengthen veterinary investigation and reporting systems in the region and tackle the disease at the root, before there is a spillover to humans.” FAO said the countries across West Africa are home to 330 million people, some dealing with the aftermath of Ebola. FAO is appealing for $US 20 million to improve weak veterinary systems, improve the capabilities of local laboratories and fund field specialists.

e) A study38 found that two doses of H7N9 avian flu vaccine produced an adequate immune response in 2 per cent of adults vaccinated, but two distinct adjuvants increased that to 57 per cent39 and 84 per cent40 respectively.

f) An intranasal flu vaccine that includes 4 of the 16 types of haemagglutinin protein found in flu viruses protected mice against a broad range of the viruses, including some not targeted by the vaccine41. National Institute of Allergy and Infectious Diseases (NIAID) scientists are trying to develop a vaccine to protect against all influenza A viruses. The test vaccine cocktail includes non-infectious virus-like particles (VLPs), a technology already used in approved hepatitis B and human papillomavirus vaccines. The flu test vaccine includes H1 and H3, two human

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38 See the Journal of the American Medical Association (JAMA). Lisa A.Jackson, James D.Campbell, Sharon E.Frey, Kathryn M.Edwards, Wendy A.Keitel, Karen L.Kotloff, Andrea A.Berry, Irene Graham, Robert LAtmar, C. Buddy Creech, Isaac P. Thomsen, Shital M.Patel, Andres F.Gutierrez, Edwin L.Anderson, Hana M.El Sahly, Heather Hill, Diana L.Noah, Abbie R.Bellamy, “Effect of Varying Doses of a Monovalent H7N9 Influenza Vaccine With and Without AS03 and MF59 Adjuvants on Immune Response:A Randomized Clinical Trial”, doi:10.1001/jama.2015.7916. 39 With Novartis's MF5940 With GSK’s AS0341 Louis M. Schwartzman, Andrea L. Cathcart, Lindsey M. Pujanauski, Li Qi, John C. Kash, Jeffery K. Taubenberger, “An Intranasal Virus-Like Particle Vaccine Broadly Protects Mice from Multiple Sub-types of Influenza A Virus”, 21 July 2015 mBio vol. 6 no. 4 e01044-15. doi: 10.1128/mBio.01044-15

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haemagglutinin subtypes found in seasonal flu vaccines, and H5 and H7, two avian subtypes. Mice were significantly protected against viruses containing the 1918 pandemic H1, 1957 H2, and avian H5, H6, H7, H10, and H11 hemagglutinin subtypes. The overall survival rate for the mice was 94 per cent. The vaccine will now be tested in ferrets, followed by human trials.

g) Sanofi Pasteur announced the publication42 of positive results from a new analysis of data from a large-scale, multi-centre efficacy trial where scientists found significantly fewer serious cardio-respiratory events possibly related to influenza in study participants 65 years of age and older who received a higher-dose split-virus inactivated influenza vaccine (IIV-HD) compared with a standard-dose split-virus inactivated influenza vaccine (IIV-SD)43. David P. Greenberg, Vice President, Scientific & Medical Affairs, and Chief Medical Officer, Sanofi Pasteur US, said: "Influenza and pneumonia combined is the seventh leading cause of death in older adults in this country….. The results of this analysis focused on serious cardio-respiratory events and hospitalizations, and support the previously reported findings of the large efficacy study, in which lower rates of laboratory-confirmed influenza were observed following use of the higher-dose vaccine compared to the standard-dose vaccine among the seniors who participated."

h) Taiwan reported two new outbreaks of H5N2 in poultry, the latest in a string of such events. The first outbreak began 2 July, on a farm in Yunlin County. Of 7,700 ducks, 1,533 died from the disease and the rest were culled. The second outbreak began 8 July, and involved an abattoir in Pingtung County. Of 1,376 native chickens, seven died and the rest were culled.

i) The US Secretary of Agriculture Tom Vilsack said that a vaccine against H5N2 avian flu has been developed that is 100 per cent effective in chickens and testing has begun in turkeys44. A request has been made to the Office of Management and Budget for funds to stockpile the vaccine. Earlier, the chief veterinarian for the Animal and Plant Health Inspection Service, Dr John Clifford, advised that some trading partners would ban US poultry if a vaccine was used unless such use were known to be short-term. Dustin Vande Hoef, with the Iowa Department of Agriculture and Land Stewardship, said: "There are significant trade impacts if we do proceed with the vaccine. The vaccine keeps the virus in a dormant state, but it could still be present. Other countries may be concerned if the birds are still infected but are not showing symptoms of sickness."

j) So far in 2015 the US has had three known human cases of A (H3N2) variant virus45. The third was reported from Minnesota and the person had had close contact with swine in the week before the illness began.

Middle East Respiratory Syndrome Coronavirus (MERS-CoV)g) On 27 July, the final group of South Koreans suspected of possibly being infected

with MERS were released from self or mandatory quarantine. WHO suggests that the

42 Carlos A. DiazGranados, Corwin A. Robertson, H. Keipp Talbot, Victoria Landolfi, Andrew J. Dunning, David P. Greenberg, "Prevention of serious events in adults 65 years of age or older: a comparison between high-dose and standard-dose inactivated influenza vaccines", Vaccine, Volume 33, Issue 32 (2015). DOI: http://dx.doi.org/10.1016/j.vaccine.2015.07.00643 In the trial, 31,989 adults 65 years plus were randomly assigned to receive either Fluzone High-Dose vaccine or Fluzone vaccine. They were then monitored for six to eight months post-vaccination for the occurrence of influenza and serious events. (events leading to death or hospitalization, life-threatening or medically important events, or events resulting in disability). For the supplementary analysis now reported, cardio-respiratory events were grouped into seven categories: pneumonia, asthma, chronic obstructive pulmonary disease or bronchial events, influenza (laboratory-confirmed influenza), other respiratory events, coronary artery events, congestive heart failure, and cerebrovascular events.44

45 H3N2v, a virus normally circulating in swine but on this occasion in a human, hence variant

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MERS end should not be declared until four weeks after the last infectee resoundingly tests negative for the virus, which on present indications would mean the end of August.

h) The Kingdom of Saudi Arabia notified WHO of six additional cases or MERS between 1 July and 14 July. Four had known histories of close contact with camels and three drank their raw milk.

i) Data from a hospital outbreak of MERS cases in Saudi Arabia in 2014 indicated continuous healthcare-associated transmission for several months46.

j) Scientists at the Institute for Research in Biomedicine, Università della Svizzera Italiana, in Switzerland, have found an antibody that neutralises multiple strains of Mers-CoV. They found in mice that the antibody could be used both preventatively and following exposure47.

k) Researchers from the US National Institute of Allergy and Infectious Diseases and elsewhere have identified a promising strategy for approaching MERS-CoV vaccine development48.

Ebola Virus Diseaseg) After a delay awaiting approval, plasma donated by Ebola survivors is being

administered to Ebola patients at the 34 Military Hospital in Freetown. The use of convalescent plasma is also being studied in Guinea and Liberia.

h) The US Department of Health and Human Services (HHS) has issued a two-year $US 19.7 million task order to Emergent BioSolutions’ Baltimore Bayview Center for Innovation in Advanced Development and Manufacturing (CIADM)49 to produce a novel therapeutic drug to treat Ebola virus disease. “Preventing, detecting and treating Ebola infections remain critical not only for the current epidemic in West Africa but also to minimize the impacts of future outbreaks,” Said Robin Robinson, director of HHS’ Biomedical Advanced Research and Development Authority50 (BARDA). Emergent will transfer manufacturing processes and materials across from the early-stage development work of other companies, will produce the investigational drug for use in nonclinical and clinical studies, and if these studies are successful will undertake the necessary work to scale up production to commercial volumes or for the national stockpile. The new drug combines the same three monoclonal antibodies51 as ZMapp52, but for reasons of speed and volume will be produced using special mammalian cells rather than tobacco.

46 Shamsudeen F. Fagbo, Leila Skakni, Daniel K.W. Chu, Musa A. Garbati, Mercy Joseph, Malik Peiris and Ahmed M. Hakawi, “Molecular Epidemiology of Hospital Outbreak of Middle East Respiratory Syndrome, Riyadh, Saudi Arabia, 2014”, Emerg Infect Dis, 2015 Volume 21, Number 11 2015 http://dx.doi.org/10.3201/eid2111.15094447 Davide Corti, Jincun Zhao, Mattia Pedotti, Luca Simonelli, Sudhakar Agnihothram, Craig Fett, Blanca Fernandez-Rodriguez, Mathilde Foglierini, Gloria Agatic, Fabrizia Vanzetta, Robin Gopal, Christopher J. Langrish, Nicholas A Barrett, Federica Sallusto, Ralph S. Baric, Luca Varani, Maria Zambon, Stanley Perlman, and Antonio Lanzavecchia, “Prophylactic and post exposure efficacy of a potent human monoclonal antibody against MERS coronavirus”, Proceedings of the National Academy of Sciences, Published online before print July 27, 2015, doi: 10.1073/pnas.151019911248 Lingshu Wang, Wei Shi, M. Gordon Joyce, Kayvon Modjarrad, Yi Zhang, Kwanyee Leung, Christopher R. Lees, Tongqing Zhou, Hadi M. Yassine, Masaru Kanekiyo, Zhi-yong Yang, Xuejun Chen, Michelle M. Becker, Megan Freeman, Leatrice Vogel, Joshua C. Johnson, Gene Olinger, John P. Todd, Ulas Bagci, Jeffrey Solomon et al. “Evaluation of candidate vaccine approaches for MERS-CoV”,Nature Communications 6, article no. 7712. doi:10.1038/ncomms871249 Three CIADM were established as public-private partnerships with BARDA in 2012 to respond rapidly to national needs for medical countermeasures.50 BARDA is part of HHS’ Office of the Assistant Secretary for Preparedness and Response51 Monoclonal antibodies can neutralize a virus by binding to key viral proteins. This decreases the amount of the virus patients’ immune systems need to conquer.52 Made by Mapp Pharmaceuticals of San Diego)

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i) The FDA awarded OraSure Technologies' rapid Ebola test special status, allowing marketing of the test for use in areas where the virus is still circulating while the company works toward final approval. The FDA has granted emergency use authorization to nine other Ebola tests, but OraSure's is the first that does not require refrigeration at temperatures of less than 104 degrees Fahrenheit.

j) A vaccine against Ebola was reported to be 100 per cent successful in trials in Guinea. The vaccine is made by Merck.

k) At the 2015 American Association for Clinical Chemistry (AACC) Annual Meeting in Atlanta, Matt Boisen, of the Viral Hemorrhagic Fever Consortium53, expanded upon study results on the efficacy of a new point-of-care rapid response Ebola diagnostic, known as the ReEBOV Antigen Rapid Test Kit54. It requires a few drops of blood to identify the Ebola virus in 15 minutes. In February 2015 WHO granted Corgenix a listing for emergency use, and the company received an emergency use authorization from the FDA. ReEBOV’s capabilities were also evaluated in a field validates study reported in The Lancet55, which identified the advantage of not having to rely “on transport of venepuncture blood to field bio containment laboratories for testing by real-time RT-PCR, resulting in delays that complicate patient care and infection control efforts.”

Hendra virus j) Research has found that urine from black flying foxes poses biggest Hendra virus

risk to horses, following a confirmed Hendra case in far north Queensland.

53 Boisen serves as the consortium’s development director of in vitro diagnostics. He is program director of infectious diseases and emerging technologies at Corgenix, a medical diagnostics company based in Denver, Colorado.54 The presentation was entitled “Clinical Outcome-Focused Patient Care.”55 Mara Jana Broadhurst, John Daniel Kelly, Ann Miller, Amanda Semper, Daniel Bailey, Elisabetta Groppelli, Andrew Simpson, Tim Brooks, Susan Hula, Wilfred Nyoni, Alhaji B Sankoh, Santigi Kanu, Alhaji Jalloh, Quy Ton, Nicholas Sarchet, Peter George, Mark D Perkins, Betsy Wonderly, Prof Megan Murray, Dr Nira R Pollock, “ReEBOV Antigen Rapid Test kit for point-of-care and laboratory-based testing for Ebola virus disease: a field validation study”, The Lancet, Published Online: 25 June 2015. DOI: http://dx.doi.org/10.1016/S0140-6736(15)61042-X

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