Category Archives: Swine flu

Swine flu

Journal retracts paper linking vaccine and narcolepsy

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A paper that once promised to help unravel a medical mystery — why some children developed narcolepsy after receiving an influenza vaccine — has been retracted.

Narcolepsy is a disorder that causes extreme sleepiness, sometimes inducing uncontrollable ‘sleep attacks’ that can strike at any time of day. In 2010, a puzzling cluster of sudden-onset narcolepsy cases was reported in Europe among children vaccinated with GlaxoSmithKline’s Pandemrix flu vaccine against the H1N1 ‘swine flu’ that had caused a pandemic in 2009.

On 18 December 2013, researchers reported a possible connection between the vaccine and narcolepsy. In a paper published in Science Translational Medicine, they showed that people with narcolepsy produce immune cells called T cells that recognize hypocretin, a neurotransmitter that regulates wakefulness. People with narcolepsy tend to have low levels of hypocretin in neurons that control wakefulness, and the results supported the notion that autoimmune responses could be destroying the neurotransmitter.

The authors, led by immunologist Elizabeth Mellins and narcolepsy researcher Emmanuel Mignot of the Stanford School of Medicine in Palo Alto, California, went on to demonstrate that pieces of a flu protein often used in vaccines stimulated immune cells that recognize hypocretin. This suggested a mechanism by which the vaccine could contribute to narcolepsy in some people.

But on 31 July, the authors announced that they have been unable to repeat a key finding: that immune cells from people with narcolepsy respond to hypocretin more so than immune cells from people who do not have narcolepsy. “Because the validity of the conclusions reported in the study cannot be confirmed, we are retracting the article,” the team wrote.

The retraction is a setback for a field struggling to find an answer. “We continue to believe that the original scientific hypothesis remains a valid one that needs to be further explored,” said GlaxoSmithKline, a London-based pharmaceutical firm, in a statement. The company says that it is supporting research, including in its own labs, to explore the possible link between its vaccine and narcolepsy, and particularly to learn more about interactions between the vaccine and other risk factors in the people who developed the condition.

Those risk factors were a mystery even before the retraction. And although the paper suggested a possible link between flu vaccines and narcolepsy, it did not clarify why Pandemrix, in particular, would be problematic. The original study was also conducted in a relatively small number of people.

Given such small numbers, the retraction comes as little surprise, says immunologist Outi Vaarala of the Finland National Institute for Health and Welfare in Helsinki. Vaarala, who praises the authors for openly addressing the problems with their paper, also notes that the methods use to assay immune responses are difficult to reproduce, and says reviewers should demand that researchers repeat their experiments using multiple methods. “If you can show differences in T-cell reactivity between patients and controls when different read-outs are used,” she says, “the findings are likely to be reliable.”

China’s stealthy bird flu spreads

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Chinese health authorities are urging calm as the circle of people infected with an elusive influenza virus widens.

Over the past two days, Zhejiang province reported its first three cases — a 67-year-old retiree from Hangzhou, a 64-year-old man from Huzhou and a 38-year-old chef. The 38-year-old chef worked in neighboring Jiangsu province, where four cases had already been reported, and died on 27 March. As of 4 April, ten people, all in the Shanghai region, have been infected. Three have died, and the rest are listed in critical condition.

Health authorities are working under the assumption that poultry is to blame, and the government has warned people not to slaughter chickens. The warning is timely: some families in southern China sacrifice chickens as part of a ritual during tomb-sweeping holidays, which start today.

But the source of the virus is still a mystery. A few of those infected had direct contact with poultry, but others did not. According to official state media, tests have failed to find the virus in poultry or pigs. Shanghai tested 34 of the some 16,000 carcasses recently found floating nearby in the Huangpu River following concern that they could have carried the disease. So far, no infections in animals have been confirmed.

If it is birds that are carrying the virus, they do not seem to suffer symptoms. This makes it difficult to implement what has been the most effective tool against H5N1 and other avian flu viruses — culling of sick birds.

Although the virus clearly can be pathogenic in humans, it does not seem to be passing easily from human to human. Among hundreds of people who have been in contact with those who fell sick, none have been found to be infected.

At present, there is no vaccine.  ‘Candidate’ vaccines against other H7 viruses are available, but none target the various strains of H7N9.

Chinese central and local governments seem to be acting relatively quickly to track new cases and prepare health centres to deal with them. The health ministry distributed reagents for detecting H7N9 to the country’s 31 administrative districts. Jiangsu province, which accounts for four of the nine cases, has implemented emergency measures including strengthening of networks to report unexplained cases of pneumonia and communication with agriculture departments to expand epidemiological studies.

But health authorities have still come under criticism for delays in reporting cases and apprising families of the extent of the problem. The uncle of one victim said he thought that his son had died from pneumonia until he saw the news about H7N9 on television. He says that the hospital failed to recognize the seriousness of his nephew’s condition.

 

Potential treatment for severe influenza found in Omega-3 fatty acids

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shutterstock_129688976Omega-3 fatty acids, which have an important role in promoting healthy growth and development, have made headlines in recent years for, among other things, their possible cardiovascular benefits. Found in high levels in fish oil, these fatty acids are the most consumed non-vitamin or non-mineral supplement in the US. Now, researchers have discovered another potential use for these fat building blocks: using them as a treatment for flu.

In a study published today in Cell, a modified omega-3 fatty acid known as protectin D1 was found to markedly increase the chances of survival in mice with infected with various strains of influenza, including the H1N1 strain behind the 2009 ‘swine flu’ epidemic.

“The authors show for the first time that [protectin D1] actually disrupts replication of influenza,” says Charles Serhan, an anesthesiologist at Brigham and Women’s Hospital in Boston. “It provides a natural template for new therapeutic development.”

When given microgram doses of protectin D1 intravenously 12 hours before and immediately after infection with a strain of influenza A, three out of eight treated animals survived past a two-week end point; by comparison, all seven control counterparts died within eight days. Mice infected with the 2009 strain of H1N1 swine flu fared even better when treated in this manner—all six survived, compared with only two out of six in the group that received only a saline solution.

Protectin D1 given two days post-infection appeared nearly as effective in preventing death in mice as Peramivir, an intravenous anti-viral drug marketed by BioCryst Pharmaceuticals of Durham, North Carolina. Approved in Japan and Korea for treating severe flu, Peramivir did not move past phase III clinical trials in the US for efficacy, but was subject to an emergency FDA authorization in 2009 as a treatment for H1N1 swine flu.

Remarkably, while less than half of treated animals survived past two weeks on either therapeutic alone after infection with influenza A, none died after receiving protectin D1 and Peramivir in conjunction.

In a petri dish model using human lung cells, protectin D1 appeared to reduce the virulence of influenza by blocking the export of viral mRNA from a cell’s nucleus, according to the new study. This is reflected in a massive decrease in the infection rate of cells.

Derived from omega-3 fatty acids, protectin D1 is one of a family of similar fat molecules with apparent antiinflammatory and antibiotic properties. Naturally produced, these compounds are thought to play a protective effect in the lung, brain and other organs. This study is the first to demonstrate anti-viral qualities for these molecules, with protectin D1 showing the greatest efficacy.

“I see this as opening a whole new avenue of research,” says Serhan, who was the first to characterize protectin D1 in 2007. He notes that this could represent a new class of antivirals that work by both reducing excessive inflammation and by disarming replication of the virus. The risk for side effects could be low as well since “it’s a natural mechanism,” says Serhan.

Many questions remain as to protecin D1’s therapeutic potential in humans, as well as if these omega-3 fatty acid-derived molecules could treat other types of viral infections. Future clinical trials and research are needed to prove efficacy and safety, says Serhan. For now, he recommends not over-doing it with fish oil supplements, until scientists know more about the underlying mechanisms. “You don’t want to be deficient in [omega-3], but I wouldn’t go the other direction. There could be unwanted side effects.”

Image: Shutterstock

England too finds narcolepsy link with pandemic flu vaccine

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The case for a link between a vaccine used during the 2009 H1NI ‘swine flu’ pandemic and a serious sleeping disorder known as narcolepsy was bolstered by a study published yesterday.

Studies in several other countries have found an association between administration of GlaxoSmithKline’s Pandemrix and narcolepsy, a disorder causing excessive daytime sleepiness, which in turn is often accompanied by cataplexy — sudden muscle weakness. Now, in a small study published in the British Medical Journal, researchers have found further evidence of the link in some patients with narcolepsy in the United Kingdom.

The team reviewed case notes for 245 people, aged from 4 to 18 years old, from sleep and neurology centres in England. Seventy-five of the people had developed narcolepsy since the beginning of 2008 and 11 had been vaccinated with Pandemrix. From this, the researchers concluded that the vaccine caused a 14-to-16-fold increase in risk of narcolepsy, which they estimate would correspond to 1 in 52,000–57,500 vaccinations being associated with narcolepsy.

The association between Pandemrix and narcolepsy has become well established since the first reports in Sweden and Finland in 2011. Two Europe-wide reviews providing further analysis of the link between Pandemrix and narcolepsy (summary) were published last September by the Vaccine Adverse Events Surveillance and Communication consortium, funded by the European Centre for Disease Control and Prevention (see here  and here for the full reports).

The association found will require further investigation into the safety of the ASO3 adjuvant formula used in Pandemrix. Such additives are used in some vaccines to boost the immune response so that each vaccine dose can be smaller, allowing global vaccine capacity to be stretched to cover several times as many people. Without that multiplier effect, there would in a pandemic be only enough vaccine to cover a fraction of the world’s population (for some of Nature‘s stories on this issue during the 2009 H1N1 pandemic, see ‘Regulators face tough flu-jab choices‘, ‘US ramps up swine flu protection‘, ‘US puts flu vaccines on trial‘ and ‘Vaccine decisions loom for new flu strain‘).

But ultimately the situation remains the same as Nature reported in 2011:

Side effects of vaccines are part of any public health response risk equation. No amount of clinical trials can detect rare side-effects in advance, as statistically one would need impractically large population-size experimental cohorts to pick up very low incidence rates. Instead, regulators use pharmacovigilance once vaccines have been deployed to spot early on any problems. With some 30.8 million Europeans, including this author, already vaccinated with Pandemrix since autumn 2009, no serious safety concern has been detected.

Although anti-vaccine groups will no doubt leap on the preliminary reports from Scandinavia to scream “side-effects,” the sober reality is that not using modern and safe vaccines causes many more people to become ill or die than any rare side-effect.

EDITORIAL: A long pause

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A version of this editorial appears in the February 2013 issue of Nature Medicine.

Last January, scientists voluntarily imposed a pause on research that could lead to the generation of highly pathogenic avian influenza viruses with increased transmissibility to mammals. Now, new restrictions currently under debate further risk stalling progress in avian flu research.

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In late 2011, a firestorm erupted around two papers under peer review on highly pathogenic avian influenza (HPAI) H5N1 viruses. Both identified mutations that would permit airborne transmission of the viruses to ferrets. Although the viruses were not highly pathogenic in the ferrets, the papers sparked concerns that the mutant H5N1 viruses might have pandemic potential.

The concerns are not unwarranted given the history of H5N1 infections. The case fatality rate due to H5N1 in humans exceeds 50%, yet only 610 infections have been recorded since 2003, in part because of its low capacity for human-to-human transmission. However, there is fear that avian influenza could acquire the mutations necessary to rapidly transmit among humans, similar to seasonal influenza. Therefore, a better understanding of the mutations necessary to facilitate transmission of H5N1 in mammals and their effects on the fitness of the virus is considered by many to be crucial in developing countermeasures in the event of an avian flu pandemic.

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A universal problem: One virologist’s 20-year effort to challenge an imperfect flu test

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{credit}Bindu Marathe{/credit}

Recent headlines have promised that a ‘universal flu vaccine’ may be within reach, pointing to antibodies that offer broad protection in animal studies. But the scientists behind this effort had to first overcome great skepticism from their peers—as well as an imperfect laboratory test. Hannah Hoag reports on one virologist’s 20-year effort to challenge the tenets of the field.

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Influenza is the Lady Gaga of viruses: it reinvents itself each year, often in unexpected ways. But the flu virus is far more dangerous than an infectious tune. Although the flu usually manifests as a mild illness, the virus kills as many as 500,000 people worldwide each year, and it continues to provide a challenge from a vaccination standpoint. Whereas most vaccines for illnesses such as measles or polio offer years or decades of protection, influenza vaccines tend to work for only one season. The relentless refashioning means new influenza vaccines must be routinely reformulated, all at a cost to consumers and global health systems of more than $4 billion each year.

A new type of vaccine could be on the way. In the past few years, a flurry of papers has provided firm evidence of antibodies capable of neutralizing multiple subtypes of the influenza virus. Immunologists say that isolating such antibodies is the first step toward the creation of a universal influenza vaccine that protects against seasonal flu year after year—and possibly prevents hundreds of millions of deaths when the next influenza pandemic sweeps across the globe. Several such universal flu vaccines are already in early human clinical testing. But convincing the biology community of the existence and potential of such antibodies was an uphill battle, and one complicated by a ‘gold standard’ test that masked the key findings.

Yoshinobu Okuno, who has chased the dream of a universal antibody against flu since 1989, knows these challenges well. Okuno, a virologist at Osaka University in Japan, is now viewed by many experts in the field as an important and early champion of the idea. Yet his discovery two decades ago of a broad-acting antibody called C179 didn’t make waves at the time. “People didn’t pay attention to it,” says Ian Wilson, a structural biologist at the Scripps Research Institute in La Jolla, California. “In those days, most people weren’t thinking about broadly neutralizing antibodies that you could develop for flu.”

The very test that prompted Okuno to look for these special antibodies—a tool known as the hemagglutination inhibition assay—tripped up the efforts of others in the field. In hindsight, the fault in the assay provides a cautionary tale of how the shortcomings of a test can mean that biomedical researchers miss what they are not looking for.

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FDA approves its first egg-free seasonal flu vaccine

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{credit}George M. Groutas via Flickr{/credit}

After years of struggle, the production of seasonal flu vaccine in the United States has entered the modern era. On 20 November, the Food and Drug Administration (FDA) approved its first seasonal flu vaccine made in cell culture, rather than in fertilized chicken eggs.

The vaccine, Flucelvax, is made by the Swiss pharmaceutical company Novartis and was approved by the European Union in 2007 under the name Optaflu. The United States is the largest single market for seasonal flu vaccines, accounting for 40% of sales across in major markets in 2009.

Decades of experience have established the safety and efficacy of the chicken-egg approach. But eggs are slow and their supply is limited, making it difficult to respond to emergencies, such as the H1N1 ‘swine flu’ pandemic of 2009 (see ‘The virus grower’ and ‘Flu decisions loom for new flu strain‘). With each flu emergency comes renewed calls — and government subsidies — for alternative methods of flu vaccine production. Still, the FDA and its advisers previously balked at cell-culture grown vaccines, citing the need for additional safety data.

Flucelvax is made in Madin-Darby canine kidney epithelial cells, a well-known cell line harvested from a female Cocker Spaniel in 1958 and grown in the lab ever since. Flucelvax cells will be grown in a $1 billion manufacturing plant in Holly Spring, North Carolina paid for in part by the US Department of Health and Human Services.

US swine flu outbreak spikes

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Today the US Centers for Disease Control and Prevention (CDC) announced that the number of reported cases in an ongoing outbreak of a strain of the H3N2 animal influenza virus (H3N2v) that transmits between pigs and humans has jumped to 145 in the past week.

{credit}CDC{/credit}

On 3 August, CDC officials reported 16 total cases of H3N2v infection. In all cases, patients interacted with pigs either in their occupation or at local agricultural fairs, suggesting that the virus has not yet evolved the ability to efficiently transmit between humans. CDC first reported the variant in a 12-case outbreak from July to December 2011, with two instances of suspected weak human-to-human transmission. This week’s surge may be partially due to a change in protocol: states can now confirm positive test results before further CDC testing. But, CDC influenza division chief Joseph Bresee warned in a press teleconference today, “We’re seeing a big increase, and we think it’s a real increase.”

The outbreak covers four states, with one case in Hawaii, one in Illinois, 30 in Ohio and 113 in Indiana. Indiana’s count rose to 120 today, according to the state’s health department, and Bresee expects a continued increase in the coming weeks. The symptoms are mild and similar to those of seasonal flu, and so far the outbreak has resulted in only two hospitalizations. More than 90% of the cases have been in children — probably because many adults may have antibodies that can handle the strain.

Virologists suspect that the H3N2v strain arose from swine flu strains exchanging genetic material in a process called reassortment. What raises eyebrows is that the H3N2 virus carries a gene found in the H1N1 strain that caused a swine flu pandemic in 2009. This matrix, or M, gene may influence transmissibility. If so, the current strain offers an opportunity to study how transmission evolves over the course of an outbreak. “This is still unfolding, and we have a lot to do to understand both the biology in the natural host, pigs, and the sporadic human infections,” says Ruben Donis, a virologist with the CDC’s influenza division.

According to Bresee, the seasonal flu vaccine probably won’t be affective against the strain, but it could be a reason that adults are less susceptible. A vaccine candidate for H3N2v is slated for clinical trials this year.

Image credit: CDC

United States launches three biodefence centres

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Texas A&M University moves to the forefront of the US biodefense effort.

The US Department of Health and Human Services (HHS) today awarded contracts for the creation of three new centres tasked with responding to the threat of future pandemics and biological attacks. To be based in Maryland, North Carolina and Texas, the three centres are comprised of academic and industry consortia whose role it will be to hasten the development and manufacturing of vaccines and medications in the event of an emerging biological threat.

“Establishing these centers represents a dramatic step forward in ensuring that the United States can produce life-saving countermeasures quickly and nimbly,” said HHS Secretary Kathleen Sebelius in a statement on 18 June. “They will improve our ability to protect Americans’ health in an emergency and help fill gaps in preparedness so that our nation can respond to known or unknown threats.”

The three Centers for Innovation in Advanced Development and Manufacturing are the first tangible result of a review concluded by HHS in 2010, which highlighted major improvements needed to effectively fight disease outbreaks — like those of H1N1 in 2009 or severe acute respiratory syndrome (SARS) in 2003 — or a bioterrorism attack, such as the anthrax attacks of 2001.

The contracts, amounting to roughly US$400 million, represent a range of academic and private partnerships as well as partnerships between large pharmaceutical companies and small biotechnology firms. “We noted that many small companies with great ideas don’t see their products make it because they need a lot of technical help,” says Nicole Lurie, HHS assistant secretary for preparedness and response.

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Canada confines mutant flu to maximum-security facilities

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Canada this month announced that any research on mammalian-transmissible strains of the H5N1 avian flu virus in the country’s labs would need to be done at the strictest level of biocontainment, biosafety level 4 (BSL-4). It’s the first country to issue a biosafety rating following the creation of such H5N1 strains in two recent controversial studies (see Nature News Special: Mutant Flu).

The question of which biosafety rating is appropriate for research on the new strains was highlighted as crucial by an expert meeting convened in Geneva last week by the World Health Organization (WHO). The new, modified H5N1 strains are held at Erasmus Medical Center in Rotterdam, the Netherlands, and at the University of Wisconsin-Madison, in two BSL-3-enhanced facilities (the second highest biocontainment level), and the WHO described these as “well-established research facilities with high security and high safety“. But it also recommended that regulators “urgently” review the biosafety and biosecurity conditions under which further research on such strains is conducted, and that until that’s done, the strains should stay where they are and not be shared with other labs.

In biosafety assessment, pathogens are classified in terms of their ‘risk group’ (RG) on a scale of 1–4, where 4 is the highest, on the basis of an assessment of the relative threat they pose to people. They are also classified in terms of the biological containment levels needed, again on a scale of 1–4. What can be a bit confusing is that although required biocontainment levels for various research on a pathogen largely mirror the risk-group rating, they don’t necessarily equate with it. Some types of research may be permitted at a lower biocontainment level than their risk group, if it’s assessed that the research can be done safely with less-restrictive precautions. As the WHO explains, biocontainment level designations are “based on a composite of the design features, construction, containment facilities, equipment, practices and operational procedures required for working with agents from the various risk groups”.

Barry Bloom, a researcher and former dean at the Harvard School of Public Health in Boston, Massachusetts, also emphasizes the importance of training. “Security in handling dangerous pathogens is, in my view, less a function of the physical containment facilities than the training, experience and competence of the scientists working with them,” he says.

Some flu researchers are concerned that work on mammalian-transmissible H5N1 viruses will be severely hampered if it is restricted to BSL-4 laboratories, because BSL-4 conditions are much more constraining than BSL-3 labs, and because there are only a few dozen BSL-4 labs worldwide. Other experts feel that such high containment is essential, given the risk that any escape of the viruses could cause a H5N1 pandemic (see Fears grow over lab-bred flu.)

Whatever biocontainment levels are eventually decided as appropriate by the relevant authorities, many researchers are concerned about the proliferation of such mammalian-transmissible avian flu strains: as more labs work on them, the risk of release — accidental or intentional — goes up. Bloom says that he hopes that the number of labs allowed to work on them “would be limited, transparently identified, and monitored for safety under the aegis of an international body such as WHO”.

Declan Butler asked Sandra Fry, director-general of the Public Health Agency of Canada’s Pathogen Regulation Directorate, and Marianne Heisz, head of the directorate’s Office of Biosafety Programs and Planning, how the agency reached its decision to classify work on the new lab strains as requiring BSL-4 (note that Canada uses the term ‘CL’ in place of BSL) facilities.

Read the Q&A under the fold.
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