Monitoring International Trends
posted September 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:
 The European Commission granted CSL Behring marketing authorization in all European
Union (EU) member states for Respreeza (a purified Alpha-1 protein derived from human
plasma) to treat the hereditary condition Alpha-1 antitrypsin deficiency (AATD). (Section
2)
 ADMA Biologics, announced that the US Patent and Trademark Office (USPTO) had
issued to it United States Patent 9,107,906, titled, 'Compositions And Methods For The
Treatment of Immunodeficiency'. (Section 2)
 Roche has gained fast-track designation from the US Food and Drug Administration
(FDA) for its haemophilia drug ACE910. This is an investigational humanised bispecific
monoclonal antibody engineered to mimic the function of factor VIII. (Section 2)
 The FDA accepted Dimension Therapeutics’ investigational new drug (IND) application
and granted orphan drug designation for its lead product candidate, DTX101, for the
treatment of haemophilia B. (Section 2)
 The FDA has expanded the use of Novartis’ Promacta (eltrombopag) to include children
one year of age and older with the rare blood disorder chronic immune thrombocytopenia
(ITP) who have not responded sufficiently to immunoglobulins, corticosteroids, or
splenectomy. (Section 2)
 From 1 July, Baxter International spun off part of its operations as Baxalta. Shire then
made a private takeover bid followed by a public bid. The Baxalta Board rejected the
advance, although there were suggestions that private talks were proceeding. (Section 3)
 Gauss Surgical has raised $US 3.3 million to support its Triton System that gives a fast,
real-time assessment of blood loss during surgery. (Section 3)
 LFB USA of Framingham has opened a facility on its 383-acre Central Massachusetts
farm for genetically altered rabbits that produce milk containing Factor VIIa, a protein
used to treat haemophilia. (Section 3)
 The US Biomedical Advanced Research and Development Authority (BARDA) has
exercised a contract option for $US 15.5 million with start-up company Velico to back the
development of its dried plasma technology. (Section 3)
 Technavio's analysts forecast the global plasma therapeutics market to grow to 2019 at a
compound annual growth rate of 12.10 per cent. (Section 3)
 In the US, tick-borne babesiosis is thought to be the pathogen most often spread by blood
transfusions. (Section 4)
 Four researchers in India say that the expense of treating patients bitten by rabid dogs
and monkeys can be substantially reduced by an eight-fold reduction in the quantity of
immunoglobulin used and a five-fold reduction in the vaccine used. (Section 4)
1
 Korea’s Samsung Medical Center will overhaul its intensive care unit (ICU) system after
its experience in the recent spread of the Middle East Respiratory Syndrome (MERS)
coronavirus. (Section 4)
 Canadian researchers reported that universal administration of tranexamic acid in
patients undergoing hip or knee replacement surgery is safe and effective at reducing the
incidence of red blood cell transfusion. (Section 5)
 A recent review in the British Journal of Surgery concluded that: “The significance of
preoperative anaemia appears underappreciated, and its detection should lead to routine
investigation and treatment before elective surgery.” (Section 5)
 The US Preventive Services Task Force (USPSTF) concluded that there is insufficient
evidence to determine the balance of benefits and harms of routine screening for iron
deficiency anaemia (IDA) in pregnant women or for the use of iron supplements during
pregnancy to prevent adverse maternal health and birth outcomes. (Section 5)
 A study suggested that after 5g of idarucizumab emergency surgery could be initiated
rapidly in patients treated with Pradaxa (dabigatran etexilate mesylate). (Section 5)
 The first patient has been enrolled in the trial to evaluate the safety of Eliquis versus
warfarin or other vitamin K antagonists in patients with nonvalvular atrial fibrillation and a
recent acute coronary syndrome or undergoing percutaneous coronary intervention (a
stent). (Section 5)
 Another study found that CSL Behring’s 4-factor prothrombin complex concentrate,
Kcentra, reverses the anticoagulation effects of vitamin K antagonists at a faster rate than
plasma in patients requiring emergency invasive procedures. (Section 5)
 Visterra of Massachusetts and the Serum Institute of India have entered into a license
agreement for the development, manufacture and commercialization of VIS513 in
countries on the Indian subcontinent. This is a humanized monoclonal antibody
engineered to bind and neutralize all four serotypes of the dengue virus. (Section 8)
 Researchers found that drugs developed to treat sepsis could successfully treat dengue
fever in mice. (Section 8)
 Chinese researchers reported that while temporary poultry market closures can reduce
environmental levels of H7N9 and other avian flu viruses, contamination quickly returns to
pre closure levels, when markets re-open. (Section 8)
 Between 4 and 18 September, there were 18 new MERS cases reported in Saudi Arabia,
15 of them in Riyadh, with links to an ongoing hospital outbreak at King Abdulaziz
Medical City. 158 illnesses had been reported in Riyadh since 21 July. (Section 8)
 An experimental vaccine given six weeks before exposure to MERS-CoV fully protects
rhesus macaques from disease. (Section 8)
 Researchers (led from the Chinese Center for Disease Control and Prevention)
sequenced the genome of a MERS-CoV strain introduced to China in May after first
reaching South Korea. They concluded that the Chinese and South Korean MERS-CoV
strain resulted from recombination between MERS viruses which probably occurred in
mid to late 2014. (Section 8)
 In Saudi Arabia, the Ministry of Agriculture announced 7,700 out of 233,000 camels in the
Kingdom have been infected with the MERS coronavirus. (Section 8)
 A team from The University of Texas Medical Branch at Galveston and Profectus
BioSciences reported in Nature that it had developed a quick-acting Ebola vaccine that it
claims to be safe and effective with a single dose. (Section 8)
 Inovio Pharmaceuticals announced that the first patient has been dosed in a Phase I trial
of Pennvax-GP, the company’s DNA vaccine for HIV. (Section 8)
 The Queensland Government says it will contact the parents of children who are not
properly vaccinated to encourage them to get their vaccinations up to date. (Section 8)
 The US Centers for Disease Control and Prevention (CDC) has been encouraging more
states to publish vaccination statistics online. (Section 8)
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 By 2 September there had been eight cases of measles reported on the University of
Queensland campus at St Lucia since July. The Metro North Public Health unit set up a
five-day on-campus vaccination clinic. (Section 8)
 Europe has been reporting that refugees are bringing cutaneous diphtheria with them.
(Section 8)
Table of Contents
1.
Products _______________________________________________________________ 3
Haemophilia treatments _________________________________________________________ 3
Other _________________________________________________________________________ 5
2.
Regulatory _____________________________________________________________ 6
3.
Market structure and company news _______________________________________ 7
4.
Country-specific events ___________________________________________________ 9
5.
Safety and patient blood management _____________________________________ 11
Appropriate transfusion_________________________________________________________ 11
Treating iron deficiency _________________________________________________________ 11
Other. _______________________________________________________________________ 11
6.
Research _____________________________________________________________ 12
7.
Legal actions and enquiries ______________________________________________ 12
8.
Infectious diseases _____________________________________________________ 13
Mosquito-borne diseases: dengue, chikungunya and malaria ___________________________ 13
Influenza: strains, spread, prevention and treatment _________________________________ 13
MERS-CoV (Middle East Respiratory Syndrome-Coronoavirus) __________________________ 14
Other diseases: occurrence, prevention and treatment ________________________________ 15
1. Products
Here 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.
Haemophilia treatments
a) Biogen and Swedish Orphan Biovitrium announced that newly published clinical data
demonstrate that people on extended-interval prophylaxis regimens with
ELOCTATE1 for haemophilia A experienced low bleeding rates. The interim results of
the ASPIRE Phase III, open-label extension study appeared in the online edition of
Haemophilia, the journal of the World Federation of Hemophilia, the European
1
3
Antihaemophilic Factor VIII (Recombinant), Fc Fusion Protein
Association for Haemophilia and Allied Disorders, and the Hemostasis & Thrombosis
Research Society. Participants who completed the Phase III A-LONG and Kids ALONG studies were able to participate in ASPIRE. The results to date show the
majority of participants in ASPIRE maintained or extended their dosing intervals
between treatments compared with the A-LONG and Kids A-LONG studies. At the
time of the interim analysis, the median time in the ASPIRE study was 80.9 weeks for
adults and adolescents completing the A-LONG study, and 23.9 weeks for children
completing the Kids A-LONG study. Inhibitor development is the primary endpoint of
ASPIRE and no inhibitors were reported in any treatment groups. Of the adults and
adolescents who had previously been treated prophylactically and who remained in
the study through the interim analysis (n=128), 72 per cent maintained their
prophylactic dosing interval and 22 per cent lengthened and six per cent shortened
the time between infusions. There were no reports of serious allergic reactions or
vascular clots. The most common adverse events (incidence of greater than or equal
to five per cent) included nasopharyngitis (common cold), arthralgia (joint pain) and
upper respiratory infection.
b) Biogen announced that new clinical data support the long-term safety and efficacy of
ALPROLIX2 in people with severe haemophilia B treated for up to two years.
Participants in the Phase III, open-label extension study, B-YOND, maintained low
bleeding rates with one to two week prophylaxis regimens, according to data from an
interim analysis presented for the first time at the 67th Annual Meeting of the National
Hemophilia Foundation (NHF) in Dallas. B-YOND is a multi-year study for
participants with severe haemophilia B who completed the Phase III B-LONG or Kids
B-LONG studies. In this interim analysis, the median time on ALPROLIX during BYOND was 27.6 months for the 93 adults/adolescents involved, but only 47.7 weeks
for 23 children under the age of 12 who were involved. The study’s primary endpoint
is inhibitor development, and no inhibitors have been reported to-date. According to
the interim analysis, adults and adolescents treated prophylactically maintained
protection against bleeding episodes with infusions every one to two weeks. The
most common adverse events (incidence of greater than or equal to five per cent)
included headache, common cold and vomiting for adults and adolescents. For
children under age 12, falls, common cold and seasonal allergy were the most
common adverse events. From the beginning of B-LONG or Kids-B-LONG until the
B-YOND interim data analysis, the cumulative median time on ALPROLIX was 171.6
weeks for adults and adolescents, and 95.3 weeks for children under age 12.
ALPROLIX , a recombinant clotting factor therapy with prolonged circulation in the
body, is approved in the United States, Canada, Australia and Japan. The therapy
was developed using a process called Fc fusion, which is designed to prolong a
therapy’s circulation in the body using a naturally occurring pathway. While Fc fusion
has been used for more than 15 years, Biogen is the only company to apply it to the
treatment of haemophilia. Development of neutralizing antibodies (inhibitors) to
ALPROLIX may occur following administration of treatment. Common adverse
reactions (incidence of greater than or equal to 1 per cent) from the registrational BLONG study were headache and oral paresthesia (an abnormal sensation in the
mouth).
c) CSL Behring announced that the first patient had been enrolled in Malaysia in its 54patient Phase II/III clinical trial of CSL 6893, the company's recombinant fusion
protein linking coagulation factor VIIa with albumin (rVIIa-FP). The trial will test the
pharmacokinetics, efficacy, and safety for on-demand treatment in patients with
2
Coagulation Factor IX (Recombinant), Fc Fusion Protein
This Phase II/III study is part of the PROLONG-7FP clinical development program, which aims to
demonstrate the therapeutic advantages of rVIIa-FP in patients with haemophilia A or haemophilia B
who have developed inhibitors as well as in patients with congenital FVII deficiency. A Phase I
pharmacokinetic study in patients with congenital FVII deficiency is ongoing.
3
4
congenital haemophilia A or B who have developed an inhibitor to factor VIII or factor
IX replacement therapy4. Preclinical studies in healthy volunteers have confirmed
that CSL689 has favourable pharmacokinetic properties compared with the
commercially available recombinant FVIIa product currently available. In a phase I
study it demonstrated good tolerance, and a three-to four-fold increase in half-life
compared with the commercial product. The US Food and Drug Administration (FDA)
awarded Orphan Drug Designation5 to rVIIa-FP for the treatment and prophylaxis of
bleeding episodes in patients with congenital haemophilia and inhibitors to
coagulation factor VIII or IX. The European Commission granted Orphan Drug
Designations for rVIIa-FP for the treatment of patients with haemophilia A or B who
have developed an inhibitor as well as for the treatment of congenital factor VII
deficiency.
d) Barbara A. Konkle, professor of medicine at Puget Sound Blood Center and
University of Washington, and her colleagues wrote of BAX 855: “Patients with
hemophilia A who adopt a prophylactic regimen can reduce their bleeding rate, and
thus reduce the probability of developing chronic arthropathy, which leads to
disability”. A Phase II/III study showed BAX 855, a pegylated, full-length recombinant
Factor VIII, to be safe and effective for biweekly prophylactic treatment6.
Other
e) Bio Products Laboratory (BPL) announced on 1 September that the first subject had
enrolled in SCIG03, a Phase III clinical trial evaluating the safety and
pharmacokinetics of Subgam VF, 16% liquid immunoglobulin for the treatment of
primary immunodeficiency7. This is a US trial and will form the basis of a biologics
license application for marketing authorization in the US.
f) Share prices of Sangamo BioSciences rose in response to its announcement that the
US National Institute of Health's Recombinant DNA Advisory Committee had
unanimously approved the protocol of a Phase 1 study of one of the company's ZFP
Therapeutics as a potential cure for haemophilia B. The Factor IX program will be the
first clinical trial of in vivo genome editing and the first therapeutic application of
Sangamo's In Vivo Protein Replacement Platform (IVPRP)8. Sangamo expects to file
an Investigational New Drug (IND) application with the FDA by the end of 2015 and
to initiate a Phase 1 study in 2016.
4
Development of inhibitory antibodies against factor VIII or factor IX partially or completely blocks the
efficacy of factor replacement therapy. The incidence of inhibitors in individuals with haemophilia A is
estimated to be up to 33 per cent and in haemophilia B between one and 6 per cent. The most recent
World Federation of Hemophilia (WFH) survey identified more than 4,753 patients with haemophilia A
and 248 with haemophilia B who have developed an inhibitor worldwide.
5 Orphan designation gives the company benefits such as tax credits for qualified clinical testing and
exemption from certain application fees.
6 Konkle BA, et al. Blood. 2015;doi:10.1182/blood-2015-03-630897
7 The trial is titled, “A Phase III, Multicenter, Open-Label Study to Evaluate the Pharmacokinetics and
Safety of Subgam VF in Primary Immunodeficiency Diseases” (clinicaltrials.gov identifier,
NCT01884311).
8 IVPRP technology employs the albumin gene locus, a liver-specific genomic "safe harbor" site. Zinc
finger nucleases (ZFNs) can be used to edit the locus to accept and express any therapeutic gene.
The liver will continue to produce therapeutic levels of the corrected protein such as factor VIII or IX to
treat haemophilia. Since the liver produces albumin in excess of the body’s requirements, capturing a
small portion of the albumin gene's capacity is enough to produce the replacement protein at a
therapeutic level.
5
2. Regulatory
The NBA monitors overseas regulatory decisions on products, processes or procedures
which are or may be of relevance to its responsibilities.
a) The European Commission granted CSL Behring marketing authorization in all
European Union (EU) member states for Respreeza (a purified Alpha-1 protein
derived from human plasma) to treat the hereditary condition Alpha-1 antitrypsin
deficiency (AATD). The main function of the Alpha-1 antitrypsin protein is to protect
the lungs from inflammation. This particular Alpha-1 proteinase inhibitor has been
shown in a prospective double blind, placebo controlled trial (the RAPID study) to
reduce significantly the loss of lung tissue by slowing the progression of emphysema
due to AATD.
b) ADMA Biologics announced that the U.S. Patent and Trademark Office (USPTO) had
issued United States Patent 9,107,906, titled, 'Compositions And Methods For The
Treatment of Immunodeficiency'. It relates to the use of human plasma
immunoglobulin compositions containing select antibody titres specific for a plurality
of respiratory pathogens; methods of identifying human donors and donor samples
for use in the compositions; methods of manufacturing the compositions; and
methods of utilizing the compositions by prophylactic and or therapeutic treatments
(e.g. passive immunization). The patent extends to January 20359.
c) Roche has gained fast-track designation10 from the FDA for its haemophilia drug
ACE910. This is an investigational humanised bispecific monoclonal antibody
engineered to mimic the function of factor VIII. It is a new approach to treating
haemophilia, independent of whether or not patients have developed inhibitors. In the
Phase I/II study11 ACE910 was administered as a weekly subcutaneous injection to
patients with severe haemophilia A, with or without inhibitors. The drug appeared
safe and effective for prophylaxis. Further trials of the drug, including for paediatric
patients, will go into 2016. Separate Phase III trials will be conducted for patients with
and without inhibitors.
d) The FDA accepted Dimension Therapeutics’ investigational new drug (IND)
application and granted orphan drug designation12 for its lead product candidate,
DTX101, for the treatment of haemophilia B. Dimension will conduct a multi-centre
Phase I/II study to evaluate DTX101 in adult patients with moderate/severe to severe
haemophilia B. DTX101 is designed to deliver blood clotting Factor IX (FIX) gene
expression. The current standard of care involves chronic replacement of FIX protein
through intravenous infusion.
9
Adam Grossman, President and CEO of ADMA Biologics, said: "The issuance of ADMA's patent
validates the differentiated, unique and novel way ADMA approaches immune globulin products.
ADMA's goal is to ensure adherence to all FDA standards and produce an IG product with consistent
lot to lot potency of polyclonal anti pathogen antibodies…. This is a major milestone for our company
as it provides us the ability to protect our lead product candidate and at the same time supports
development of a wide range of other therapeutic IG products for patients with immunodeficiency and
related diseases. The company will continue to aggressively pursue additional proprietary rights
encompassing this technology."
10 Fast-track designation has been available in the US since 2012. It allows the FDA to hasten the
development and review of drugs where early trials suggest significant improvement over current
therapies.
11 The Phase I/II study was study conducted with Japanese and Caucasian healthy volunteers as well
as Japanese haemophilia A patients. Bleeding was completely controlled in nine out of 18 patients.
12
The FDA Office of Orphan Products Development grants orphan designation to drugs and biologics
expected to be used for treatment of diseases or conditions that affect fewer than 200,000 people in
the US. The designation provides certain benefits such as tax credits for qualified clinical trials costs,
and exemption from FDA user fees. If approved, the drug quality for seven years of market
exclusivity.
6
e) The FDA approved AstraZeneca’s Brilinta tablets at a 60 mg dose that would be
taken along with aspirin beyond a year after a heart attack. The drug had originally
been approved at a higher dose for use during the year following a heart attack.
European cardiologists recently endorsed the longer use of Brilinta and other blood
clot preventers, with large clinical studies having found decreased heart risk from use
of dual blood thinners for more than the first year after an attack.
f) La Jolla Pharmaceutical Company announced that the European Medicines Agency
(EMA) Committee for Orphan Medicinal Products (COMP) issued a positive opinion
recommending LJPC-401, La Jolla’s novel formulation of hepcidin, for designation as
an orphan medicinal product13 for the treatment of chronic iron overload14 requiring
chelation therapy15. The final opinion, which is subject to review and approval by the
European Commission (EC), may include all or a subset of these conditions.
g) The FDA has expanded the use of Novartis’ Promacta (eltrombopag) to include
children 1 year of age and older with the rare blood disorder chronic immune
thrombocytopenia (ITP) who have not responded sufficiently to immunoglobulins,
corticosteroids, or splenectomy. The updated label also includes a new oral
suspension formulation for younger children who may not be able to swallow tablets.
Promacta was approved by the FDA as a tablet formulation in June 2015 for children
6 years of age and older and in 2008 for use in adult patients with the same
condition.
3. Market structure and company news
The 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) From 1 July, Baxter International spun off part of its operations as Baxalta. It retained
a stake, which it is planning to dispose of in a tax-free manner over 18 months.
b) Baxalta R&D chief John Orloff told the Boston Business Journal that his company's
new hub in Cambridge, Massachusetts, will be far from a traditional research
campus. Baxalta plans to have 350 R&D workers at the site by 2016, but the
company isn't building lab space there, keeping its in-house discovery unit in Europe.
The Cambridge facility will be Baxalta's deal making hub looking for partnerships to
widen the company's pipeline. Orloff told the Journal: "Our whole approach is one
based on external innovation."
c) Soon after Baxalta was spun off by Baxter International, Shire made a private
takeover bid followed by a public bid. The Baxalta Board rejected the advance,
although there were suggestions that talks were proceeding in private. Meanwhile,
Baxalta was reported to be interested in acquiring Ariad Pharmaceuticals16, which
already has Iclusig (an FDA approved cancer drug) on the market, with another
13
To achieve orphan status in the European Union (EU), a drug must be for the treatment of a lifethreatening or chronically debilitating condition that affects no more than five in 10,000 people in the
EU and for which no satisfactory treatments exist or, ir they do exist, the new drug will be of significant
benefit to those affected by that condition.
14 Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease and
hereditary haemochromatosis (HH). Beta thalassemia and sickle cell disease often require frequent
and life-long blood transfusions, which can cause excessive iron accumulation in the body, which is
toxic to vital organs. HH is a disease caused by a genetic deficiency in hepcidin production, resulting
in excessive iron accumulation.
15 Iron chelators bind to and help clear excessive iron from the body. They can, however, cause
toxicity, including kidney failure, liver failure or gastrointestinal haemorrhage.
16 At a reported offer price of $US 2 billion.
7
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therapy in trials. Ariad’s share price rose dramatically on news of the offer, but
Baxalta was soon reported to have abandoned takeover talks.
Shire CEO Flemming Ornskov was reported to have said that he would cut costs by
£1 billion if his new £19 billion bid to acquire Baxalta is successful. As much as half
the cuts were expected to result from overlapping research and development
operations.
Shire was said to have back-up plans for acquisitions if its bid for Baxter failed, but its
own falling share price presented problems.
In 2014, Shire bought Cinryze, a drug for hereditary angioedema (HAE)17, from
ViroPharma. The drug, derived from human plasma, is a C1 esterase inhibitor and
has been supplied by Sanquin. Shire has renegotiated its terms with Sanquin so it
can use other contractors to increase its supply. Cinryze generated $US 503 million
in revenue for Shire last year, compared with $US 364 million from its other HAE
drug, Firazyr.
Shire has returned rights to Sangamo’s experimental gene editing programs for
haemophilia A and B to the California company, and kept the rights to a prospective
treatment for Huntington’s disease and another unspecified program. Rights to other
targets that were part of the original 2012 deal have also been handed back to
Sangamo. Shire still has a right of first negotiation to re-acquire the haemophilia
programs in the future. Sangamo claims that the new arrangements will enable it to
“accelerate the development” of its haemophilia A and B programs, and that it will.
file papers by the end of the year to begin the first trial for its haemophilia B
treatment18.
Gauss Surgical has raised $US 3.3 million to support its Triton System that gives a
fast, real-time assessment of blood loss during surgery and can reduce the perceived
need for transfusion. The system is already in use at a number of US hospitals19.
South Korean biopharmaceuticals company Green Cross has opened its eighth US
blood centre, this time in San Antonio, Texas.
Novo Nordisk is investing DKK 500 million in a new raw material warehouse in
Denmark.
Sweden Orphan Biovitrium (Sobi) has opened a new European and Benelux office in
Brussels. Europe accounts for sixty per cent of Sobi’s annual product sales.
NovoNordisk and the Langer Laboratory at the Massachusetts Institute of
Technology are collaborating on the next generation of drug delivery devices for the
administration of peptides.
LFB USA of Framingham has opened a facility on its 383-acre Central
Massachusetts for genetically altered rabbits that produce milk containing Factor
VIIa, a protein used to treat haemophilia. LFB’s French parent company, LFB SA, is
already in the final stages of testing its Factor VIIa in humans, using material made in
Hereditary Angioedema is an inherited blood disorder characterised by episodic attacks of swelling
that affect the face, extremities, genitals, gastrointestinal tract and upper airways.
18
There are seven groups known to be hoping to use either gene therapy, or, in Sangamo’s case,
gene editing, for treating haemophilia. Sangamo’s treatment would make use of zinc finger proteins
which are thought, theoretically at least, to be able to deliver a permanent fix by making genetic
corrections that would be passed on to other cells. The other six are: Baxalta, Biogen, Dimension
Therapeutics/Bayer, Spark Therapeutics/Pfizer, UniQure, and BioMarin Pharmaceutical. Some are
using different types of adeno-associated virus and lentivirus vectors, which may call forth varying
immune responses, and each have their purported strengths and weaknesses. Others are delivering
different types of genes with these vectors. Baxalta and Spark, for instance, are using mutant
therapeutic genes meant to clot blood much faster than normal—which might produce unpredictable
results. A possible problem with gene therapies using adeno-associated virus is that they may have to
be repeated at regular intervals.
19 An iPad camera photographs the surgical canister or surgical sponges used. Images are analysed
via algorithms to assess the haemoglobin content and to assess blood loss regardless of the
presence of saline or irrigation fluid, lighting variations and the rupture of red cells.
8
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rabbits in France. The company also has a herd of more than 1,000 genetically
engineered (transgenic) goats, capable of producing the human clot-busting protein
antithrombin III in their milk. The protein is sold under the name ATryn by another
LFB subsidiary, rEVO Biologics, to prevent clotting problems before surgery or
childbirth in patients who lack antithrombin. rEVO is hoping to expand its use by
testing the protein as a treatment for the pregnancy ailment pre-eclampsia. rEvo had
had an initial public offering of $US 50 million planned, but withdrew it on 9
September citing market conditions. It had planned to list on the Nasdaq as RBIO.
The US Biomedical Advanced Research and Development Authority (BARDA) has
exercised a contract option for $US 15.5 million with start-up Velico to back the
development of its dried plasma technology. BARDA is building on a 2012
commitment it made to Velico for $US 8.9 million.
Cerus Corporation reported a $US 16 million second quarter loss. On 2 September,
the Chief Scientific Officer of Cerus Corporation, Laurence Corash, was reported to
have purchased shares of the company $US 96,330. Over the month up to and
including that date he had reported four purchases of the company shares for a total
of $US 901,400.
Novo Nordisk announced that the company is investing 500 million Danish kroner in
a new 19,000 m2 warehouse in Hillerød, Denmark. The warehouse will handle all
inbound raw materials for Novo Nordisk's production in Denmark and will have a
capacity of around 17,000 pallets. The warehouse is expected to be fully operational
by the end of 2017.
Technavio's analysts forecast the global plasma therapeutics market to grow at a
compound annual growth rate of 12.10 per cent over the period to 201920.
4. Country-specific events
The 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 the US, tick-borne babesiosis is thought to be the pathogen most often spread by
blood transfusions21, but there is no large-scale, FDA-approved way to test for
Babesia in the 5 million transfusions annually. The prescription drugs azithromycin
and atovaquone usually fight off a babesiosis infection quite quickly. However, in highrisk groups (the elderly, people without a spleen, the immune-compromised including
cancer patients on immunosuppressive drugs) the mortality rate can be as high as 20
per cent. The risk to the blood supply comes from donors who are asymptomatic,
which is one quarter of infected adults and half of infected children, whose infections
can last months or years. The Centres for Disease Control (CDC) recorded 3,862
cases of babesiosis in the US from 2011-2013. About three-quarters were in the
elderly. Babesiosis cases always spike during the summer. Five states (Rhode Island,
Massachusetts, Connecticut, New York, and New Jersey) together account for more
than 85 per cent of cases. Infections also appear across the Northeast and the
Midwest. In 1994, it was found that about one in 601 tested blood transfusions in
Connecticut resulted in a babesiosis infection. Since then the FDA believes there
have been “expanding areas of transmission and infections”. While examining blood
under a microscope can allow an expert to identify parasites present, this is not a
feasible method on a large scale. Two US companies (IGeneX and Imugen) are each
developing two types of tests to detect babesiosis, looking either for Babesia
microbes directly by detecting their DNA in a person’s blood, or for antibodies that a
20
Global Plasma Therapeutics Market 2015-2019
Edouard Vannier and Peter J. Krause, “Human Babesiosis” N Engl J Med 2012; 366:2397-2407
(June 21, 2012) DOI: 10.1056/NEJMra1202018
21
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person generates to fight Babesia. Before approving a test the FDA will need to know
it works and is reliable, without too many false positive or negative results. The
expected plan, if tests are approved, will be mandatory antibody screening in donors
across fifty States, with additional DNA testing in high-risk States.
In the US, the Centers for Medicare and Medicaid Services (CMS) extended for a third
year the new technology add-on payment (NTAP)22 for Kcentra (CSL Behring’s
Prothrombin Complex Concentrate [Human]). The NTAP will now be available to the end
of September 2016 for eligible Medicare beneficiaries treated as hospital inpatients.
Kcentra is the only non-activated 4-factor prothrombin complex concentrate (4F-PCC)
approved by the FDA for the urgent reversal of acquired coagulation factor deficiency
induced by Vitamin K antagonist (e.g. warfarin) therapy in adult patients with acute major
bleeding or in need of an urgent surgery or invasive procedure. Unlike fresh frozen
plasma (FFP), the most widely used agent in the US for warfarin reversal, Kcentra does
not require thawing or blood-type matching and can be administered more quickly and
with lower volume than FFP. Kcentra was first approved for use in the US in April 2013,
and received its NTAP designation on 1 October the following year.
In the US, the Governor of Georgia opened the Georgia BioScience Training Center
at Stanton Springs. The $US 14-million state-owned biotech training centre arose
from the negotiations to encourage Baxter International, now Baxalta, to the state.
The centre, operated by Georgia Quick Start, will provide customized training to meet
Baxalta’s start-up training needs. Although Baxalta will be given preferential use for
several years other companies coming to or expanding in Georgia will also be able to
use the centre to train employees on technical equipment.
Four researchers in India say that the expense of treating patients bitten by rabid
dogs and monkeys can be substantially reduced by an eight-fold reduction in the
quantity of immunoglobulin used and a five-fold reduction in the vaccine used23. They
found the key was injecting directly into the wound.
The University of Bristol and NHS Blood and Transplant are partners in a new £3M
Blood and Transplant Research Unit. It will assist the development of new red blood
cell products to support the transfusion needs of patients with rare blood groups and
those with complex and life-limiting conditions like sickle cell disease and
thalassemia. The Unit’s research will include a clinical trial of small volumes of
artificial blood in human volunteers. The Unit is one of four new Blood and Transplant
Research Units [BTRU] for which the National Institute for Health Research [NIHR]
has committed £15.1 million of funding through a competitive process. The units are
all partnerships between universities and NHS Blood and Transplant [NHSBT], and
focus on rapid translation of research findings into routine practice.
Korea’s Samsung Medical Center will overhaul its intensive care unit (ICU) system
after its experience in the recent spread of the Middle East Respiratory Syndrome
(MERS) coronavirus.
CMS implemented its NTAP policy in 2001 to encourage timely access to innovative therapies for
Medicare beneficiaries as hospital inpatients, where this is not adequately covered under the
Medicare Severity Diagnosis-Related Groups (MS-DRGs). To qualify for an NTAP, the drug must be
new and inadequately paid for under existing MS-DRGs and provide a significant clinical improvement
over existing therapies. CMS will continue to reimburse hospitals an additional amount, up to $US
1,587.50, for cases involving Kcentra that exceed the MS-DRG payment amount.
23 OK Bharti et al., “Local infiltration of rabies immunoglobulins without systemic intramuscular
administration: An alternative cost effective approach for passive immunization against rabies”,
Human Vaccines and Immunotherapeutics, online ahead of print, 28 August. PMID:26317441
(PubMed)
10
5. Safety and patient blood management
We follow current issues in patient safety and achieving favourable patient outcomes.
Appropriate transfusion
a) Canadian researchers reported24 that universal administration of tranexamic acid in
patients undergoing hip or knee replacement surgery is safe and effective at reducing
the incidence of red blood cell transfusion. One of the researchers, Dr Gregory Hare
of St Michael’s Hospital, said of future work: “We plan to continue following our
patients over time and have now accumulated data on about 2000 patients. We
continue to observe reduced rates of red blood cell transfusion and no increase in
adverse events. As part of our ongoing quality assurance program, we have
developed a computer based real-time database to continue collecting data on
patients who receive TXA peri-operatively; to ensure that transfusion rates remain low
and that no increase in adverse events are observed over time.”
b) Researchers examining transfusion practice queried New York State’s Statewide
Planning and Research Cooperative System for elective oesophagectomy,
gastrectomy, and pancreatectomy for malignancy from 2001 to 2013. They concluded
that: “Significant variation in perioperative blood transfusion utilization is present at
both the surgeon and hospital level. These findings are unexplained by patient-level
factors and other known hospital characteristics, suggesting that variation is due to
provider preferences and/or lack of standardized transfusion protocols. Implementing
institutional transfusion guidelines is necessary to limit unwarranted variation and
reduce infectious complication rates.”25
Treating iron deficiency
c) A recent review in the British Journal of Surgery concluded that: “The significance of
preoperative anaemia appears underappreciated, and its detection should lead to
routine investigation and treatment before elective surgery. The risks of unnecessary
blood transfusion are increasingly being recognized. Strategic adoption of patient
blood management in surgical practice is recommended, and will reduce costs and
improve outcomes in surgery”26.
d) The US Preventive Services Task Force (USPSTF) concluded that there is insufficient
evidence to determine the balance of benefits and harms of routine screening for iron
deficiency anaemia (IDA) in pregnant women or for the use of iron supplements
during pregnancy to prevent adverse maternal health and birth outcomes27. The task
force also considered evidence on the benefits and harms of screening for IDA in
young children ages 6 to 24 months. It found there is not enough evidence to
determine whether there was on balance benefit.
Other.
e) The European Society of Cardiology Congress in London was told that results from an
interim analysis of the Phase III RE-VERSE AD study showed that after 5g of
idarucizumab emergency surgery could be initiated rapidly in patients treated with
Pradaxa (dabigatran etexilate mesylate). Patients could be urgently brought to
surgical procedures, with a median time of 1.7 hours between administration of
James E. Baker et al., “Universal tranexamic acid therapy to minimize transfusion for major joint
arthroplasty: a retrospective analysis of protocol implementation”, Canadian Journal of
Anesthesia/Journal canadien d’anesthésie, 2015; DOI: 10.1007/s12630-015-0460-6
25 Christopher T Aquina, et al., “Significant Variation in Blood Transfusion Practice Persists following
Upper GI Cancer Resection” Journal of Gastrointestinal Surgery online: 12 August 2015
26 Clevenger, B, Mallett, S V, Klein, A A. and Richards, T (2015), “Patient blood management to
reduce surgical risk”. Br J Surg. doi: 10.1002/bjs.9898
27 www.uspreventiveservicestaskforce.org
24
11
idarucizumab and start of procedure. No bleeding complications were reported in the
24 hours after surgery. Jerrold Levy, RE-VERSE AD investigator28, said: "Dabigatran
already has a short half-life of around 12 hours, allowing for normal surgery to be
performed in a reasonable time after stopping the drug in many patients. But in case
of an emergency situation, we need to go to the operating room sooner. The data now
presented show that immediately reversing dabigatran with idarucizumab would allow
for rapid normalization of clotting and faster initiation of surgery in case it is needed."
f) Bristol-Myers Squibb and Pfizer announced that the first patient has been enrolled
into the Phase IV clinical trial, AUGUSTUS. This will evaluate the safety of Eliquis
versus warfarin or other vitamin K antagonists in patients with nonvalvular atrial
fibrillation (NVAF) and a recent acute coronary syndrome or undergoing percutaneous
coronary intervention (a stent).
g) A randomized study of 168 patients found that CSL Behring’s 4-factor prothrombin
complex concentrate (4F-PCC), Kcentra, reverses the anticoagulation effects of
vitamin K antagonists (VKA) at a faster rate than plasma in patients requiring
emergency invasive procedures29. This reinforces the findings of an earlier but smaller
randomized trial with 20 patients30.
6. 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.
a) Researchers from New York University Polytechnic School of Engineering received a
grant of $US 368,000 from the US Army Research Laboratory to study over the
course of the next three years applications for hydrogels31 to treat wounds, including
the delivery of drugs. Hydrogels have been used as wound dressings in the past, and
this team is hoping to improve upon those functions by mimicking biochemical
processes found in nature.
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.
a) A jury awarded $US4 million to an Alabama couple who sued LifeSouth Community
Blood Center after the husband contracted HIV through contaminated blood
administered during open heart surgery.
28
and Professor of Anesthesiology and Co-Director of the Cardiothoracic Intensive Care Unit, Duke
University Medical Center, North Carolina.
29 Lancet 2015;385:2077-2087. The study was led by Dr Joshua Goldstein, an attending physician in
the Department of Emergency Medicine at Massachusetts General Hospital and an associate
professor of surgery at Harvard Medical School. His team came from 33 hospitals in the US, Europe
and Asia.
30 Vox Sang 2010;99:251-260
31 A hydrogel is a polymeric material which can hold large amounts of water in its 3-D structural
network. It acts as the gel equivalent of a sponge.
12
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
a) As New Delhi copes with an increasing number of dengue cases, the type 4 strain
emerged at first as the dominant strain in the city, then type 2 began to dominate.
b) Visterra of Massachusetts and the Serum Institute of India have entered into a
license agreement for the development, manufacture and commercialization of
VIS513 in countries on the Indian subcontinent. Visterra’s VIS513 is humanized
monoclonal antibody engineered using Visterra’s Hierotope technology. The antibody
was designed to bind and neutralize all four serotypes of the dengue virus. Preclinical
trials found a rapid reduction in viral titres after a single systemic administration.
c) Researchers from the University of Queensland’s School of Chemistry and Molecular
Biosciences and the Australian Infectious Disease Research Centre, led by Professor
Paul Young, found that drugs developed to treat sepsis could successfully treat
dengue fever in mice32. With safety trials already complete, human clinical trials could
soon follow.
d) Researchers from Yale University have found they can slow the development of the
malaria parasite inside blood cells by changing its gene expression33. They hope that
even drug-resistant strains can be dealt with this way.
e) The University of Oxford’s spin-out company Oxitec, which is commercialising
technology to control disease-carrying insects and pests, has been sold to synthetic
biology specialist Intrexon Corporation for US$160 million. Oxitec breeds genetically
modified insects whose progeny die before reproducing. ‘Sterile’ strains are mass
reared and released in an attempt to remove particular insect species eg mosquitos
carrying dengue. Trials in Grand Cayman, Brazil and Panama have all shown Aedes
Aegypti mosquito population reductions of more than 90 per cent, with the modified
mosquito the first GM insect approved as safe for use in Brazil. Oxitec has received
approval for open field trials in Brazil and the US to control the Mediterranean fruit fly
and the diamond back moth.
Influenza: strains, spread, prevention and treatment
f)
32
Vaxart reported that its H1N1 influenza tablet vaccine developed protective immunity
based on Haemagglutinin Inhibition Assay (HAI) with HAI titer increases comparable
with increases demonstrated by current FDA-approved influenza vaccines34. The
Naphak Modhiran, Paul R. Young et.al.,” Dengue virus NS1 protein activates cells via Toll-like
receptor 4 and disrupts endothelial cell monolayer integrity” Science Translational Medicine 9 Sep
2015: Vol. 7, Issue 304, pp. 304ra142, DOI: 10.1126/scitranslmed.aaa3863
33
Aprajita Garg, Sidney Altman et al., “Targeting protein translation, RNA splicing, and degradation by
morpholino-based conjugates in Plasmodium falciparum”, Proceedings of the National Academy of
Sciences, Published online before print September 8, 2015, doi: 10.1073/pnas.1515864112
34 David Liebowitz et al., “High titre neutralising antibodies to influenza after oral tablet immunisation:
a phase 1, randomised, placebo-controlled trial”, The Lancet Infectious Diseases, Volume 15, No. 9,
p1041–1048, September 2015. DOI: http://dx.doi.org/10.1016/S1473-3099(15)00266-2
13
company said its tablet vaccine also demonstrated a favourable safety and
tolerability profile.
g) At the end of August, the Australian Medical Association Queensland (AMAQ) said
the State was on the brink of an influenza epidemic. There had been more than
12,000 confirmed cases in 2015 until August 16. Almost half had been diagnosed
between August 1 and 16 and 92 people had been hospitalised. Official flu statistics
were thought to be the tip of the iceberg, with only about one person in 10 who gets
the flu having a swab. The main strain causing problems is said to have been the
Brisbane B strain, not in the (subsidised) Southern Hemisphere 3-strain vaccine this
year, although it will be included in 2016..
h) Chinese researchers reported that while temporary poultry market closures can
reduce environmental levels of H7N9 and other avian flu viruses, contamination
quickly returns to pre closure levels, when markets re-open35.
MERS-CoV (Middle East Respiratory Syndrome-Coronoavirus)
i)
MERS-CoV has continued to spread in Saudi Arabia, with some hospitals
contributing to the spread36. By 28 September the case total in Saudi Arabia since 2012
was 1,246 with 532 fatalities.
j) Around three million Muslims from all over the world attended Islam's holiest sites in
Mecca and Medina for the Hajj season. On 26 August, the World Health Organisation
(WHO) warned Pakistan that there are high chances of the MERS-CoV virus being
transported back to the country by returning pilgrims.
k) In preparation for the annual Hajj pilgrimage beginning on 22 September, Saudi
Arabia imposed a ban on individuals who have been in contact with MERS patients
from performing the pilgrimage. The Kingdom also reported imposed a ban on
sacrificing camels as part of the Hajj rituals this year.
l) Saudi Arabian health officials announced a plan to compensate the families of people
who die from MERS-CoV within the country37. A royal decree had been issued to pay
the compensation, which amounts to $US 133,300 per family.
m) An experimental vaccine given six weeks before exposure to MERS-CoV fully
protects rhesus macaques from disease38. The vaccine also generates potentially
protective MERS-CoV antibodies in blood drawn from vaccinated camels. The
research team was led by NIH-funded University of Pennsylvania scientists.39
Funding was also provided by Inovio Pharmaceuticals.
Yuan J et al. “Effect of live poultry market closure on avian influenza A(H7N9) virus activity in
Guangzhou, China, 2014”. Emerg Infect Dis. October 2015. http://dx.doi.org/10.3201/eid2110.150623
36
As at noon on 30 August, there had been in Saudi Arabia since June 2012 a total of: 1178
laboratory confirmed cases of MERS-CoV, including 507 deaths, 609 recoveries, and 62 currently
active cases (including 9 on home isolation). In the previous 48 hours there had been 5 newly
confirmed cases of MERS-CoV infection reported and 5 new fatalities. Since the beginning of August
2015, there had been a total of 121 cases of MERS-CoV infection confirmed by Saudi Arabia, of
which all but 7 were reported in Riyadh (114 total). It had become clear that cases and deaths were
clustered aound Riyadh’s King Fahd Hospital in the King Abdul Aziz Medical City. The emergency
ward at the hospital was temporarily closed. By 13 September, there was speculation about a Medina
hospital cluster. Between 4 and 18 September, there were 18 new MERS cases reported in Saudi
Arabia, 15 of them in Riyadh, with links to the ongoing hospital outbreak at King Abdulaziz Medical
City. By then 158 illnesses had been reported in Riyadh since 21 July.
37 This includes families of people from other countries who fall ill with MERS-CoV in Saudi Arabia
and die, including foreign healthcare workers.
38 K. Muthumani et al. “A synthetic consensus anti-Spike protein DNA vaccine induces protective
immunity against Middle East Respiratory Syndrome Coronavirus in non-human primates”. Science
Translational Medicine DOI: 10.1126/scitranslmed.aac7462 (2015)
39 Collaborators included researchers from NIH’s National Institute of Allergy and Infectious Diseases;
Public Health Agency of Canada; Inovio Pharmaceuticals; the University of Washington; and the
University of South Florida.
35
14
n) Novavax has also said it is developing a MERS vaccine, based on the company’s
protein nanoparticle vaccine technology.
o) Researchers led from the Chinese Center for Disease Control and Prevention
sequenced the genome of a MERS-CoV strain introduced to China in May after first
reaching South Korea. They concluded that the Chinese and South Korean MERSCoV strain resulted from recombination between MERS viruses which probably
occurred in mid to late 201440. Columbia University's virologist Ian Lipkin said in his
commentary that coronaviruses such as MERS-CoV are known for their
recombination capabilities and that it "would not be surprising … if recombination
were to occur in MERS-CoV and to result in enhanced transmission or virulence."
p) In Saudi Arabia, the Ministry of Agriculture announced 7,700 out of 233,000 camels
in the Kingdom have been infected with the MERS coronavirus. Forty survey
teams and 200 veterinarians had examined 32,000 samples from 8,000 camels,
with results suggesting that 81.5 per cent of camels are immune to the virus,
while 3.3 per cent carry or spread it.
Other diseases: occurrence, prevention and treatment
t)
u)
v)
w)
x)
y)
z)
Sierra Leone began vaccinating 200 people against Ebola, after a woman died five
days into what the country hoped was its 42 day countdown to being Ebola free. By 8
September three further cases had emerged.
A team from The University of Texas Medical Branch at Galveston and Profectus
BioSciences reported in Nature that it had developed a quick-acting Ebola vaccine
that it claims to be safe and effective with a single dose.
Inovio Pharmaceuticals announced that the first patient has been dosed in a Phase I
trial to evaluate safety and tolerability41 of Pennvax-GP, the company’s DNA vaccine
for HIV. The trial will measure immune responses in four groups of healthy subjects
receiving the vaccine with or without an immune activator (IL-12) and administered
into muscle or skin using Inovio’s Cellectra delivery technology.
The Queensland Government says it will contact the parents of children who are not
properly vaccinated to encourage them to get their vaccinations up to date. The
Health Minister wants to raise the vaccination rate for children to 95 per cent. The
Commonwealth Child Care Benefit will from 1 January require children to be
immunised.
The US Centers for Disease Control and Prevention (CDC) has been encouraging
more states to publish vaccination statistics online. Dr. Anne Schuchat of the CDC
said parents could weigh their child's risk of vaccine-preventable illnesses at specific
schools or school districts, and the data could help health officials identify pockets of
unvaccinated children. At present, only 21 states publish vaccination rates for
individual schools, school districts, counties or areas of the state42.
Biopharmaceutical company CureVac, and the not-for-profit International AIDS
Vaccine Initiative (IAVI) will together develop AIDS vaccines, to be delivered via
CureVac's messenger RNA technology.
Duke University has received $US 20 million in grants from the National Institutes of
Health to develop an HIV vaccine.
Wang Y et al., 8 September 2015. “Origin and possible genetic recombination of the Middle East
respiratory syndrome coronavirus from the first imported case in China: phylogenetics and
coalescence analysis”. mBio 6(5):e01280-15. doi:10.1128/mBio.01280-15.
41 The trial is conducted by the HIV Vaccine Trials Network and funded by the US National Institute of
Allergy and Infectious Diseases (NIAID).
42
All states require children to be vaccinated against diseases such as measles and polio before
going to kindergarten, but permit exemptions on medical grounds. Many allow exemptions for
religious or philosophical reasons iIn Idaho 6.5 per cent of kindergartners have exemptions).
Following a measles outbreak this year, California dropped religious and philosophical exemptions for
school children.
40
15
aa) The Champaign-Urbana campus of the University of Illinois has had over 100 cases
of mumps. Since two doses of the MMR vaccine offer only 85 per cent protection, the
CDC and the Illinois Department of Public Health recommended everyone in the
community get a third shot to increase their immunity level to 95 per cent.
bb) By 2 September there had been eight cases of measles reported on the University of
Queensland campus at St Lucia since July. The Metro North Public Health unit set up
a five-day on-campus vaccination clinic.
cc) Europe has been reporting that refugees from Syria are bringing cutaneous
diphtheria with them.
16