Transmissible diseases, whether endemic to Australia, newly emerging, or potential arrivals, are of concern to the NBA due to their potential to impact on both the safety and the supply of product. The impacts may be regional or national. The NBA monitors global experience with a number of diseases.
Both dengue and chikungunya have been strongly in evidence in warmer parts of the world and have also appeared in places where they have not been recorded in recent years. In Australia, for example, the Northern Territory Health Department reported the first case of dengue fever in 70 years, Queensland faced imported and local cases of dengue in the north, including both type-two and type-four dengue, and a Perth-based doctor contracted dengue fever from a needle stick injury, the first recorded case of its kind in Australia..
Internationally, locally-acquired dengue returned to continental USA in 2010, specifically Florida, the first outbreak since the mid-1930s. Entomologists found a small colony of Aedes aegypti in the Netherlands, on and near facilities of a company that imports used tyres from the southern part of the USA. Aedes aegypti carries yellow fever as well as dengue and chikungunya. The World Health Organization (WHO) has warned that India and parts of South East Asia face the threat of yellow fever virus, carried by the mosquito that carries dengue.
During the year, good advances in understanding the diseases were made.
Daily temperature fluctuations, not just high temperatures, play a significant role in the transmission of dengue, according to research led by French, Thai and USA scientists1.
A statistical study of 1,500 individuals2 has shown that chikungunya infections were higher in Rh positive individuals compared with their Rh negative counterparts. Results also indicated more infections in adults over 30 years of age and more in males than females enrolled in this study.
The Singapore Immunology Network, an institute of the Agency of Science, Technology and Research, and Vivalis, a French biopharmaceutical company, announced the discovery of two new fully human monoclonal antibodies which could battle chikungunya, a disease that currently has no available vaccine or specific treatment3.
A successful dengue vaccine needs to protect against all four types of dengue and work continues by many scientists, research institutes and pharmaceutical companies on a variety of vaccines. Chikungunya vaccines are also under development.
Sanofi Pasteur has conducted Phase III trials of its dengue vaccine on an industrial scale with expectations that the vaccine may be launched in 2015. GlaxoSmithKline (GSK) also had a live, weakened dengue vaccine in clinical trials.
There were a number of Phase I human clinical studies underway including:
Insecticide-based strategies for dengue control may result in worse future epidemics due to increased insecticide resistance and lower herd immunity, according to research published in The Lancet on 3 May 2011. Innovative strategies not relying on insecticide are being actively pursued:
Over the summer, Victoria and South Australia saw increased incidence of Ross River virus and Barmah Forest virus.
Murray Valley encephalitis virus infection (MVEV) is a mosquito-borne illness that occurs periodically in humans in Australia and is endemic in the Northern Territory and northern Western Australia. In previous years 14 MVEV cases were notified to the National Notifiable Diseases Surveillance System (NNDSS) from WA (9), South Australia (2), the NT (2) and NSW (1). Two of the 14 notified cases died. In addition a Canadian resident with a recent travel history to the NT died as a result of MVEV. Public health authorities continue to monitor this season’s MVEV activity given the increased rainfall, mosquitoes and amplifying hosts across Australia. There were no cases of MVEV notified in 2010.
More broadly, an increased number of insect-borne viral infections causing neurological or musculoskeletal disease have been reported in horses in NSW, Victoria and South Australia since February 2011.
The West Nile Virus (WNV) continues to spread. It has been isolated in Sarawak in the form of the Kunjin virus which was reclassified as a subtype of WNV in 2000. WNV is thought to have caused encephalitis in northern Greece with transfusions and blood donations banned in the affected regions. Scientists have successfully sequenced the genetic code of the Culex mosquito that transmits WNV, aiming to elucidate how the insect carries and transfers the virus that it picks up after feeding on infected birds and then disabling the specific genes that allow transmission. Researchers from Purdue University have discovered that when a certain antibody binds to the WNV, it manages to lock up the infection mechanism and neutralise it. This could be a step towards developing a vaccine.
Work on potential vaccines and treatment for malaria continues round the world. In a promising development, scientists have identified how to stop the malaria parasite from infecting red blood cells, with carbohydrate molecules similar to heparin. A new oral treatment for malaria, containing a synthetic, modified version of heparin, could result.
The PATH Malaria Vaccine Initiative is a global program established in 1999, through a grant from the Bill and Melinda Gates Foundation, to accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world. In June 2011 the program began collaborating with Crucell and GSK to develop a second-generation vaccine bringing together two promising approaches.
Influenza has made fewer headlines than during the H1N1 influenza pandemic (‘swine flu’) in 2009. Avian influenza (H5N1) continues to infect bird flocks on a major scale, and although there are humans affected, person-to-person transmission does not appear to have increased.
Chinese researchers have shown that the H1N1 pandemic virus, which originated in pigs, is capable of going back into pigs and trading genes with other flu viruses to generate more virulent strains. Pigs are known as mixing vessels for flu viruses, because they can be infected with human, avian and swine strains.
A team from China and the USA has found evidence suggesting southern China as the origin of multiple clusters of the human H5N1 avian influenza viruses4. The group proposed that the virus spread into Southeast Asia and western and northern China and then made a final spread across Eurasia and into the Middle East and Africa. The initial spread from southern China into India was followed by transmission into Indonesia.
A team which discovered that pigs in Indonesia have been infected with the disease since 20055 said that bird flu virus may be evolving the ability to spread from mammal to mammal. The European Union (EU) is funding a scientific collaboration called FLUPIG, to study how bird flu adapts to pigs and how swine flu spreads to people.
A meeting, coordinated by WHO, agreed to a framework for sharing influenza virus samples during a pandemic. This includes binding legal regimes for WHO, national influenza laboratories and industry in both developed and developing countries. It should increase and expedite access to essential vaccines, antivirals and diagnostic kits for lower-income countries. The International Federation of Pharmaceutical Manufacturers and Associations, which represents 26 research-based drug makers, welcomed the plan and confirmed its members’ commitments.
Research on possible vaccines has focused on developing a capacity to protect against all strains of influenza:
Prion diseases and in particular variant Creutzfeldt-Jakob Disease (vCJD) remain a concern to those responsible for the safety of the blood supplies round the world.
The UK Health Protection Agency said 1 in 9,160 tonsil samples tested showed evidence of vCJD.
Research is improving the understanding of transmission of prions:
The EU’s executive arm proposed an end to the systematic killing of entire herds when a sick cow is discovered, in mid-July 2010. The Commission has also proposed to relax a 2001 ban on animal protein used in pig and poultry feed, to allow pig meal to be fed to poultry and poultry meal to be fed to pigs.
A blood test for vCJD has been developed by British scientists. The lead author of the research, Dr Graham Jackson of the Medical Research Council’s Prion Unit, said,
This test could potentially go on to allow blood services to screen the population for vCJD infection, assess how many people in the UK are silent carriers and prevent onward transmission of the disease.
But the sensitivity must be improved and the specificity confirmed in much larger studies before the test could be used to screen asymptomatic individuals, the researchers cautioned in The Lancet.7
In 2010 in the UK, USA and Canada there was alarm about the global spread of bacteria that had been made resistant to nearly all antibiotics by a new gene. The North American cases involved people who had recently received medical care in India, where the problem was regarded as widespread. A British medical journal8 revealed the risk in an article describing dozens of cases in Britain of people who had gone to India for medical procedures. To date, the gene called NDM-1 has mostly been found in bacteria that cause gut or urinary infections and is carried by bacteria that can spread hand-to-mouth.
International travel and the spread of new diseases pose an ongoing challenge to blood services to screen and actively manage donor risks. In 2010 these challenges included:
Progress in detection and management research is promising, for example:
New guidelines in Australia mean people who receive a tattoo, piercing or acupuncture can now donate blood after six months, down from the previous waiting period of 12 months.
Two issues under active debate in the past year in a number of countries have been:
The Blood Service guidelines require a 12 month ban on donation after engaging in homosexual intercourse. In 2010 the Blood Service announced an independent review of its current policies, taking into account the most recent scientific evidence. This is due to be finalised in late 2011.
Policies do differ internationally:
Research published late in 2009 had suggested a link between CFS and Xenotropic Murine Leukemia Virus-Related Virus (XMRV)9. Decisions taken on the evidence available at the time moved swiftly around the world. Several countries, including Canada, Australia, New Zealand and the UK, moved to ban donors who had current or previous CFS infection. A task force formed by the American Association of Blood Banks (AABB) said that people diagnosed with CFS should not donate blood. In December 2010, the European Medicines Agency (EMA) called on Europe’s Health Ministers to initiate an immediate Europe-wide prohibition of blood donation from people who have been diagnosed with myalgic encephalomyelitis (ME/CFS). This followed the decision by the UK government to issue a permanent, lifetime ban on all ME patients (including those who have ‘recovered’) giving blood. The American Red Cross implemented indefinite deferral for donors with a history of a medical diagnosis of CFS following consideration by the FDA Blood Products Advisory Committee (BPAC).
Controversy continued in 2011 on whether XMRV is in fact linked to CFS and on how to test for XMRV. Some researchers reported they were unable to find any evidence of XMRV in various groups, including those diagnosed with CFS. A number of studies indicated that previous research that associated the XMRV virus with CFS and prostate cancer may have involved contaminated samples and chemicals.
On 2 June 2011 the NIH issued a news bulletin concerning recent research on XMRV. It concluded that:
Delineation of the origin of the retrovirus known as XMRV from the genomes of laboratory mice indicates that the virus is unlikely to be responsible for either prostate cancer or chronic fatigue syndrome (CFS) in humans, as has been widely published. The virus arose because of genetic recombination of two mouse viruses. Subsequent infection of lab experiments with XMRV formed the basis of the original association.
Editors of the journal Science asked the co-authors of the 2009 paper that linked CFS with the retrovirus XMRV to retract the paper voluntarily. The letter said two additional papers that ‘cast further doubt’ on the 2009 paper’s findings would be published on 2 June in Science and Science would be publishing an editorial expression of concern. In a written response, study coauthor Judy A. Mikovits of the Whittemore Peterson Institute for Neuro-Immune Disease said ‘it is premature to retract our paper.’
The issue of donor vigilance—or the careful monitoring and management of the impact on the health of donors arising from their donations—gained prominence in 2010–11, especially through the Dublin Consensus Statement10 (referred to on page 68). Inter alia, the Statement declared that:
While blood services have for a long time understood the potential risk of iron depletion to their donors, and have implemented a range of strategies to address these concerns, two other issues relating to donor vigilance have attracted debate during the year in Australia and overseas.
The first relates to the additional intervention that mid-term saline replacement procedures may have on plasmapheresis donors. There is increasing interest in ensuring that the adverse events of this form of donation are fully understood and managed with appropriate attention to the health of the donor. Interestingly, the effect of the saline infusion on the second stage plasma collection is uncertain and there is not yet robust data internationally to determine the impact of the concentration of immunoglobulins of this form of donation.
The second issue has implications for product recipients as well as regular apheresis donors. During 2010–11, concern has been expressed that Di(2-ethylhexyl)phthalate (DEHP) could be harmful11. DEHP is commonly contained in plastic blood bags and tubing sets. The EU has said that DEHP poses no general risk to human health12. However, an EU Scientific Review examining whether there may be any risk from the use of DEHP in certain medical applications (children and neonates undergoing long-term blood transfusion and adults undergoing long-term haemodialysis) suggested that alternatives were available and relative toxicities could be explored13.
Jordi Segura, head of a Barcelona laboratory accredited by the World Anti-Doping Agency (WADA), was among 12 researchers to publish a joint study which found the concentration of residue from DEHP ‘significantly’ differs in a person’s urine after a transfusion. Segura said he is leading research to validate a test for the compound, which could be used to pursue doping violations in cyclist samples dating back eight years, under WADA rules.
During the year, the Caridian BCT Mirasol Pathogen Reduction Technology (PRT) System was chosen by the Poland government for FFP, and the Belgian Red Cross-Flanders for platelets.
The Cerus INTERCEPT Blood System was approved for the use of plasma components by Swiss regulators and the FDA granted Cerus Corporation orphan drug status for plasma prepared for treatment of thrombotic thrombocytopenic purpura (TTP).
Cerus was also awarded a further grant from the USA Department of Defense (DoD) to support advanced development of the company’s pathogen inactivation technology for red blood cells, and received USA government funds to support the development of the Intercept Blood System for platelets.
ProMetic’s P-Capt filter incorporates the prion-specific affinity resin that was developed by Pathogen Removal and Diagnostic Technologies Inc. and is supplied by ProMetic to MacoPharma. The P-Capt filter is a single-use sterile device which has been CE-marked14 since 2006 for the removal of prion infectivity from red blood cell concentrate prior to transfusion.
The UK’s Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) recommended that the Department of Health adopt the P-Capt filter subject to the completion of the PRISM (prion-filtered versus standard red cells in surgical and multi-transfused patients) study. In Ireland, P-Capt has been used routinely in one pilot hospital and is currently undergoing a health technology assessment in relation to national policy and adoption. Macau has a blood transfusion service that has started to use P-Capt to remove vCJD from red blood cell concentrates donated by Caucasians thought to be at risk of carrying the prion.
The FDA has approved the first rapid hepatitis C virus test for patients 15 years and older. The OraQuick HCV Rapid Antibody Test is claimed to read oral and blood samples for hepatitis C in 20–40 minutes with 99 per cent accuracy.
Standard tests for HIV cannot identify people very recently infected with the virus, but a more sensitive test has now been developed. By testing for HIV’s genetic material in addition to antibodies against the virus in more than 3,000 people, Dr Sheldon R. Morris of the University of California San Diego and colleagues identified 15 HIV-infected patients whom the standard test would have missed15.
The cobas TaqScreen MPX Test test is a qualitative in vitro test for the direct detection of Human Immunodeficiency Virus Type 1 (HIV-1) Group M RNA, HIV-1 Group O RNA, Human Immunodeficiency Virus Type 2 (HIV-2) RNA, Hepatitis C Virus (HCV) RNA and Hepatitis B Virus (HBV) DNA in human plasma. Roche announced that the cobas TaqScreen MPX Test, version 2.0 for use on the cobas s 201 system is now commercially available in Europe. This test is intended for use to screen samples of donations of human whole blood and blood components including source plasma.
In the USA, the only recorded case of HIV transmission from a blood transfusion in eight years has been linked to a Missouri blood donor, according to the USA Centers for Disease Control and Prevention (CDC). The man’s HIV positive status was not confirmed until after he donated blood a second time.
A boy with a peanut allergy had a severe anaphylactic reaction after receiving a platelet transfusion that may have contained undigested peanut protein, according to a report in the 18 May issue of the New England Journal of Medicine.
The boy was given adrenalin and recovered. Three of the five platelet donors admitted eating several handfuls of peanuts less than 24 hours before donating blood. However the report’s authors say it is premature to encourage blood donors not to eat peanuts before giving blood or for questions about diet to become part of the screening process.
Interest in the extent to which the age of product influences its efficacy and its risk to patients, if at all, is strong and there are many large and small studies becoming available:
A study by the Hovon cooperative group21, Clinical effectiveness of leucoreduced, pooled donor platelet concentrates, stored in plasma or additive solution with and without pathogen reduction, concluded that despite the potential advantages of pathogen (and leucocyte) inactivation of amotosalen–HCl/UVA–treated platelet products, their clinical efficacy is inferior to platelets stored in plasma, warranting a critical reappraisal of employing this technique for clinical use.
Entegrion is working on Stasix, derived from blood platelets and developed to stop internal bleeding. It is freeze-dried, extending shelf-life, but could be quickly rehydrated.
A study22 published in the November 2010 issue of Transfusion explored whether the use of platelet additive solution for platelet storage would enable more efficient bacterial screening. The authors examined the effect of selected bacterial species on measurable platelet quality variables over time as well as on biofilm-forming ability. Their study showed that platelet additive solution-based platelet storage allows for faster detection of Serratia liquefaciens, and potentially other species such as the closely related Serratia marcescens.
The Blood Service is working with the Australian Defence Force to freeze blood for troops in remote locations. New research on the cryopreservation of blood is expected to provide Australian troops in Afghanistan with home-sourced blood within two years, rather than relying on American and Dutch supplies..
Core Dynamics received a grant from the USA Army Foundation for the Advancement of Military Medicine, Telemedicine & Advanced Technology Research Center, for development of freeze-dried blood. It is expected that the result will be individual freeze-dried blood units that can be carried into the battle field and, upon rehydration with sterile water, transfused.
At the annual Advanced Technology Applications for Combat Casualty Care Conference, in the USA haemorrhage was a major topic. Two products showcased at the conference, namely freeze-dried plasma (which is already in human trials) and spray-dried plasma, may be approved for use within three to five years.
Army doctors are also encouraging the interosseous catheter technique for administering intravenous fluids directly into bone marrow, which can be done in low-lighting or combat conditions. Dried plasma can be given this way.
Entegrion is one of several companies developing a dried plasma product and received two grants from the DoD. Entegrion’s Resusix (dehydrated human plasma) is a shelf-stable alternative to FFP and does not need to be thawed in emergency situations.
Interest in artificial blood arises from concern about the availability of donors, possible infection from donations and, for military purposes, the need for access to significant supplies in battlefield locations. Trials have continued, for example on perfluorocarbon-based and haemoglobin-based blood substitutes.
Governments are starting to commit funding to manufacture synthetic products although production costs are high. However, some associated risks have been identified and it is unclear when any products will be able to be marketed.