A 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.
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.
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.
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.
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.
Uli Herrmann31and 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.
Infectious diseases
The 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 virus
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.
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 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.
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 treatment
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.
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.
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 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.
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."
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.
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."
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)
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 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.
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.
Data from a hospital outbreak of MERS cases in Saudi Arabia in 2014 indicated continuous healthcare-associated transmission for several months46.
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.
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 Disease
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.
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.
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.
A vaccine against Ebola was reported to be 100 per cent successful in trials in Guinea. The vaccine is made by Merck.
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
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.
1 in Blood, the journal of the American Society of Hematology
2 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.
3 Raja J et al, Paper #FRI0470, European League Against Rheumatism Annual European Congress of Rheumatology; June 10-13, 2015; Rome.
4Eun 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
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
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.
12 On 10 July
13 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".
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.
