Monitoring International Trends posted January 2015

Research

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.

1. 
   A study commissioned by the British government reported recently that drug-resistant bacteria could cause 10 million deaths a year and cost world governments billions of dollars. The World Health Organization (WHO) reports there were some 450,000 cases of multi-drug-resistant TB alone in 2012. Now University of Pittsburgh researchers have designed a synthetic compound they hope will fight "superbugs." The University’s Center for Vaccine Research co-director Ron Montelaro says it will work in a completely different way from traditional antibiotics. “Antibiotics are drugs that typically poison the bacterial cell by blocking some metabolic process. These peptides work more by a physical action, by actually punching a hole in the bacterial membrane”. Some of the testing was done on a blood-borne infection in mice. While two traditional antibiotics slowed or stopped about 50 percent of the bacteria tested, the man-made drug stopped about 90 percent. The findings were published in the journal Antimicrobial Agents and Chemotherapy. The work was funded by the US National Institutes of Health (NIH).
   
2. 
   There is nothing novel about antibiotics from soil. Penicillin came from Penicillium, a fungus found in soil, and vancomycin came from a bacterium found in dirt. Most recently, researchers from Northeastern University and NovoBiotic Pharmaceuticals and others have identified a new gram-positive bacteria-targeting antibiotic in a soil sample from the state of Maine. It can kill methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis. So far they have not found any bacteria currently resistant to the antibiotic, which they call teixobactin²⁴.
   
3. 
   Opko Health, and Immuno Technologies, announced that the NIH has awarded a $US 3 million grant to develop a rapid diagnostic test for Lyme disease.
   
4. 
   Stanford University School of Medicine researchers cured haemophilia in mice models using a new genome editing method²⁵.
   
5. 
   In a paper published online in the Journal of Biological Chemistry²⁶, senior co-author Daniel Kim-Shapiro, professor of physics at Wake Forest, and others have shown that deoxygenated hemoglobin is responsible for triggering the conversion of nitrite to nitric oxide, a process that affects blood flow and clotting. Kim-Shapiro said: “We have shown that conversion of nitrite to nitric oxide by deoxygenated hemoglobin in red blood cells reduces platelet activation….. This action has implications in treatments to reduce clotting in pathological conditions including sickle cell disease and stroke.”
   

7. Legal actions and enquiries

The NBA is interested in the implications for Australia of any proceedings against companies, governments and professional practitioners in relation to blood and blood products; or of relevant public enquiries.

1. 
   Three men who contracted hepatitis C from contaminated imported blood have begun a legal case in the UK to challenge the compensation scheme. They say it discriminates against them because they have hepatitis C, rather than HIV.
   
2. 
   British MP Andrew Burt in mid-January led his colleagues in calling for a further review into the circumstances surrounding how haemophilia and other patients were infected by blood products during the 1970s and 1980s. MPs heard an estimated 1,800 deaths had been linked to the incident, with blood products continuing to be imported into the UK during that period and used on patients despite warnings. MPs were told a Scottish public inquiry (the Penrose inquiry) into the issue is expected to report back before the general election on 7 May.
   

8. 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, chikungunya and malaria

1. 
   By 20 January an outbreak of dengue fever in Cairns had spread to a third suburb. A ninth case was confirmed in Mooroobool.
   
2. 
   The first results from the Eliminate Dengue project in Townsville show a trial to infect mosquitoes with a dengue-resistant bacteria is working. Australian researchers, in Mumbai to participate in the Australia Business Week, offered this as a possible solution to Mumbai’s growing dengue problem. They discussed how infecting mosquitoes with the bacteria reduces their life-span to half, eliminating the possibility of the mosquitoes being dengue-virus carriers.
   
3. 
   Chikungunya continues to rage in South America, the Caribbean and French Polynesia.
   
4. 
   Scientists at the International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi have developed a synthetic molecule that prevents malaria and tuberculosis microbes from invading human cells. The molecule, code-named M5, targets a set of proteins in the human body that both the malaria parasite and the tuberculosis bacilli exploit to enter human blood cells²⁷.
   
5. 
   A study of the way malaria parasites behave when they live in human red blood cells has revealed that they can rapidly change the proteins on the surface of their host cells during the course of a single infection in order to hide from the immune system²⁸.
   
6. 
   University of Massachusetts Amherst microbiologist Stephen Rich and his team report in the Proceedings of the National Academy of Sciences on a new malaria intervention. The new treatment is based on a use of the whole plant Artemisia annua, from which the current drug artemisinin is extracted. The team tested a special cultivar developed by Pamela Weathers, professor of biology and biotechnology at Worcester Polytechnic Institute. They found that the whole plant treatment withstands the evolution of resistance and remains effective for up to three times longer than the pure drug.
   

Ebola Virus Disease

1. 
   On 20 January, WHO reported there had probably been around 21,689 cases of Ebola, with 8626 deaths as of 18 January.
   
2. 
   Ebola has been described as currently the single greatest threat to the survival of gorillas and chimpanzees, having wiped out one-third of their populations since the 1990s. Mortality rates are up to 95 per cent for gorillas and 77 per cent for chimpanzees.
   
3. 
   WHO said the two most advanced Ebola vaccines would soon be tested in healthy volunteers in West Africa. It reported that the vaccines (one made by GlaxoSmithKline and the other licensed by Merck and NewLink²⁹) have been shown to have "an acceptable safety profile."
   
4. 
   Johnson and Johnson announced the formation of consortia with leading global research institutions and non-government organizations to work in conjunction with Janssen Pharmaceutical to accelerate the development of its Ebola vaccine regimen. The Innovative Medicines Initiative (IMI)³⁰ plans to award these consortia grants totalling over €100 million to support the development, manufacturing and patient education for the vaccine regimen.
   
5. 
   BioCryst Pharmaceuticals said its experimental broad-spectrum antiviral drug showed promise against Ebola when tested in monkeys at the United States Army Medical Research Institute of Infectious Diseases. Ten out of 12 monkeys treated with the drug survived, including all six given the higher of two doses³¹. None of the animals given the placebo survived. The drug is also being tested in an early-stage trial in healthy volunteers. The US National Institutes of Health (NIH) is funding the development of the intramuscular formulation of the drug, BCX4430.
   
6. 
   Canada’s Tekmira announced it would supply one of its experimental Ebola treatments for clinical studies to be conducted in West Africa in 2015.
   
7. 
   Kymab of Cambridge in the UK has received a grant from the Wellcome Trust to develop treatments against Ebola using its human antibody discovery platform, Kymouse. The grant is for Kymab to lead a consortium which includes the Wellcome Trust, Sanger Institute, the University of Westminster and Public Health England, tasked with discovering and developing antibodies against evolving strains of the Ebola virus.
   

Influenza: strains, spread, prevention and treatment

1. 
   H7N9, a subtype of influenza found in birds was first identified in humans in China in 2013³². Human cases continue to be reported there eg by 21 January Zhejiang Province had reported 14 human cases this winter, and Guangdon province reported three cases in the first week of January. The strain can cause severe pneumonia and death³³ but is not thought to spread easily from person to person. In its October 2014 assessment of the risk posed by H7N9, WHO found 453 laboratory-confirmed cases of the strain and 175 deaths.
   

2. 
   At the end of January the Public health Agency of Canada confirmed North America’s first human case of H7N9. Two British Columbia residents returned home from China on 12 January carrying the infection.
   
3. 
   China’s Guangdong province and Hong Kong in the first week of January culled thousands of chickens after Guangdong’s poultry exports to Hong Kong were found to be infected with H7N9. Hong Kong temporarily banned live poultry imports from China.
   
4. 
   In a report released mid-January, WHO said preliminary studies suggested no major genetic changes in the H5N1 virus in Egypt to explain that country’s busiest month ever for human cases. Eighteen laboratory-confirmed cases were recorded between 4 December and 6 January.
   
5. 
   A second case of H5N6 avian flu was reported from China’s Guangdong province in December.
   
6. 
   H5N8, H5N2 and H5N3 outbreaks were found in birds in Europe, North America and Asia. H5N8 is thought to have the potential to cause human disease but none has yet been reported. In mid-January Hong Kong banned Taiwanese eggs, after discovery of a new H5N2 avian influenza strain and the H5N8 flu virus at goose and duck farms in southern Taiwan. The US Department of Agriculture found the H5N8 virus in wild birds in the west, while there was an H5N2 outbreak in birds in Washington State. Scientists writing in the Proceedings of the National Academy of Sciences (PNAS) on 6 January said they found a close association between H5N1 outbreaks and wild bird migrations in Asia. H5N1 was confirmed in flocks of birds in India.
   
7. 
   In the US, the seasonal flu vaccine this winter has proved less effective than expected, as around two-thirds of the H3N2 viruses tested by the US Centers for Disease Control and Prevention (CDC) have proved to be antigenically or genetically different from the H3N2 vaccine virus. The CDC has recommended doctors step up the use of antivirals against the flu.
   
8. 
   The FDA approved BioCryst Pharmaceuticals’ Rapivab (peramivir) to treat influenza infection in adults. Rapivab inhibits influenza virus neuraminidase, an enzyme that releases viral particles from infected cells. Rapivab is the first neuraminidase inhibitor approved for intravenous use³⁴. It is administered as a single dose, in adult patients who have acute uncomplicated influenza and have shown flu symptoms for no more than 48 hours.
   

MERS-CoV³⁵

1. 
   As at January 20, 2015, WHO has reported 955 human cases, including 351 deaths. New cases of MERS continue to occur, eg in Saudi Arabia³⁶ and Oman.
   
2. 
   Researchers from King Faisal University (Saudi Arabia) and the University of Hong Kong said of their small study of interaction between camels and humans ““Our findings do not imply that dromedaries are not a source of infection for humans, but are consistent with observations that human disease is not directly proportional to potential exposure to a virus that seems to be common in dromedary camels”.³⁷
   
3. 
   Greek researchers have concluded that inadequate infection control has contributed to the widespread transmission of MERS³⁸.
   
4. 
   The Saudi Health Ministry announced on 21 January 2015 the appointment of US experts to halt the spread of infectious diseases, including MERS-CoV. There had by then been 837 MERS infections and 361 fatalities in the country since September 2012. The experts are from the CDC. The decision includes training and support for Saudi professionals under the Field Epidemiology Training Program (FETP).
   
5. 
   The Saudi Ministry was reported by Arab News to have suspended 38 contracts worth a total SR1 billion ($266 million). The contracts were all related to MERS. The ministry said some of the companies contracted had not performed the work they were signed to do.
   
6. 
   MERS has been transmitted from one person to another in the US; a University of Iowa scientist has reportedly been sanctioned for working on the virus without appropriate approval and in an inappropriate laboratory setting.
   

Other diseases: occurrence, prevention and treatment

1. 
   NHS England and Public Health England are spending £11.5 million in an attempt to eliminate tuberculosis from England by 2020. The UK has the second-highest rate of TB in western Europe, five times higher than in the US. Without intervention, England alone would have more TB cases than the whole of the US within two years.  
   
2. 
   US researchers say they have developed a vaccine that counters Chronic Wasting Disease of deer and elk and therefore holds promise of doing the same for Creutzfeldt Jakob disease of humans, Bovine Spongiform Encephalopathy of cattle and scrapie in sheep. Senior study investigator and neurologist Thomas Wisniewski, a professor at New York University, Langone, said: “Now that we have found that preventing prion infection is possible in animals, it’s likely feasible in humans as well.” The team says that if further vaccine experiments prove successful, a relatively small number of animals (as few as 10 per cent) could be inoculated to induce herd immunity for elk and deer in the wild. They are thought at present to be likely to spread CWD prions to cattle. A report on a vaccine developed by researchers at Colorado State University which has proved to be partially successful in combating chronic wasting disease in deer can be found in the journal Vaccine..
   
3. 
   European researchers say they have linking the infectious agent behind scrapie in sheep with sporadic CJD (sCJD), a fatal human disease³⁹. They say they have no proof that consuming lamb infected with scrapie can lead to sCJD in humans, but tests on humanised laboratory mice show that potentially scrapie is capable of infecting humans. The way the infection spreads in the brain is identical to that seen in cases of sCJD. The scientists, led by Dr Olivier Andreoletti, from the National Veterinary School of Toulouse, wrote in the journal Nature Communications: "Our data on their own do not unequivocally establish a causative link between natural exposure to sheep scrapie and the subsequent appearance of sCJD in humans. However, our studies clearly point out the need to consider this possibility."
   
4. 
   Novira Therapeutics’ Hepatitis B antiviral, NVR 3-778 is a small molecule drug that inhibits the Hepatitis B core or capsid protein. The company released Phase Ib trial results, which showed the drug was well-tolerated in the 40 subjects.
   
5. 
   The Northern Territory recorded its first death for the year from melioidosis. The bacteria, which lives in soils and muddy water in the NT, the Kimberley region of Western Australia and northern Queensland and South-East Asia, comes to the surface after drenching rains. The Territory usually has 35 to 45 cases per wet season, though sometimes the figure is as high as 100. Last wet season there were 66 cases.
   
6. 
   Researchers at the University of Rochester Medical Center have been testing a new oral vaccine to prevent HIV. The pill is based on a live virus, adenovirus, which is a common cause of respiratory and gastroenteritis infections. It contains a protein that triggers the body to launch an immune response against HIV.
   
7. 
   Researchers have found that a combination of antibodies from llamas can destroy-or neutralize-a wide range of circulating HIV viruses⁴⁰.
   
8. 
   Deep fried ice cream from a Chinese restaurant was blamed for a salmonella outbreak in Queensland. Eggs used in the batter were considered to be the source.
   
9. 
   The CDC and the Kansas Department of Health and Environment are investigating a new virus linked to the death of a Kansas resident during the summer of 2014. The so-called Bourbon virus is thought to be transmitted through the bites of ticks or other insects. Symptoms in the Kansas resident resembled other tick-borne diseases, including fever and fatigue.
   
10. 
    GSK announced that a Phase III trial to assess the efficacy of HZ/su, an investigational vaccine for the prevention of shingles, had met its primary endpoint. The most common adverse events were local reactions (pain, redness, swelling at the injection site) and systemic symptoms (muscle pain, fatigue and headache). 
    
11. 
    A three year old Victorian child has died and other children have become very ill after consuming unpasteurized milk.
    

1^ PERSEPT 1 is an open-label, multicenter study designed to evaluate the efficacy, safety and pharmacokinetics of LR769 in 25 adolescent and adult patients with hemophilia A and B with inhibitors. The study will evaluate two different doses and dosing regimens for the treatment of bleeding episodes. All patients enrolled into the trial will be treated and evaluated for at least 6 months. More details can be found at https://clinicaltrials.gov/ct2/show/NCT02020369.

2^ Reasons for adherence included positive effects of ICT on health, support from caregivers and clinicians, and an established routine. Reasons for nonadherence included the taste or texture of the therapy, gastrointestinal symptoms, and mealtime restrictions. Adherence by children tended to improve as they grew older. See Bal V, Cote I, Lasch K, Huang V., “Patient and caregivers perspectives of factors associated with adherence to and satisfaction with iron chelation therapy”. Blood. 2014;124(21):poster 2166.

3^ Beverung LM, Strouse JJ, Hulbert ML, et al.,“Health-related quality of life in children with sicklecell disease: impact of blood transfusion therapy”.Blood. 2014;124(21):poster 2167.

4^ Abstract #4053 by Jane Little and colleagues from University Hospitals (UH) Case Medical Center and Case Western Reserve University School of Medicine

5^ E Du, Monica Diez-Silva, Gregory J. Kato, Ming Dao, Subra Suresh,” Kinetics of sickle cell biorheology and implications for painful vaso-occlusive crisis”, Proceedings of the National Academy of Sciences, 2014.

6^ Soliris is a terminal complement inhibitor indicated for the treatment of the very rare blood disorder PNH. It is approved in nearly 40 countries to treat the very rare genetic disease aHUS. At the end of 2014 it received the backing of the UK’s National Institute for Health and Care Excellence (NICE) Highly Specialized Technologies Evaluation Committee (EC) as treatment for aHUS for patients in England. The drugt was recently granted orphan status in Japan for the treatment of neurological disorder neuromyelitis optica.

7^ Alexion included findings from its OPTIMA trial, which investigated high sensitivity flow cytometry in the detection of PNH cells in various patient populations.

8^ "Global Erythropoietin (EPO) Drugs Market (Type, Application and Geography) - Size, Share, Global Trends, Company Profiles, Demand, Insights, Analysis, Research, Report, Opportunities, Segmentation and Forecast, 2013-2020"

9^ Amgen’s Epogen (erythropoietin alfa), experienced patent expiry in 2014. Biosimilars have been launched by Biocon, Ranbaxy, and Emcure Pharmaceuticals. Amgen currently owns the patent Aranesp for darbepoetin alfa; this will expire by 2016. Other companies in the EPO drug market are Johnson & Johnson, Roche, LG Life Sciences Ltd., Intas Pharmaceuticals, Teva Pharmaceutical Industries Ltd., and Celltrion, Inc.