EINet Alert ~ Feb 27, 2009

2009
China/ 7 (4)
Egypt/ 4 (0)
Viet Nam/ 2 (2)
Total/ 13 (6)

***For data on human cases of avian influenza prior to 2009, go to:
http://depts.washington.edu/einet/humanh5n1.html

Total no. of confirmed human cases of avian influenza A/(H5N1), Dec 2003 to present: 408 (256).
(WHO 2/27/09 http://www.who.int/csr/disease/avian_influenza/en/index.html )

Avian influenza age distribution data from WHO/WPRO:
http://www.wpro.who.int/sites/csr/data/data_Graphs.htm (WHO/WPRO 2/2/09)

WHO's maps showing world's areas affected by H5N1 avian influenza (last updated 2/23/09): http://gamapserver.who.int/mapLibrary/

WHO’s timeline of important H5N1-related events (last updated 2/23/09):
http://www.who.int/csr/disease/avian_influenza/ai_timeline/en/index.html

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Global: Researchers find antibody that fights avian influenza H5N1 and seasonal influenza strains
In a development that could create new tools to prevent and treat seasonal and pandemic influenza, researchers have identified and tested human monoclonal antibodies (mAbs) that can neutralize influenza A viruses, including lethal H5N1 avian influenza. The findings raise hopes for a universal flu vaccine and shed light on new options for preventing and treating influenza infections, researchers from Dana-Farber Cancer Center, Burnham Institute for Medical Research, and the US Centers for Disease Control and Prevention (CDC) reported in an early online edition of Nature Structural and Molecular Biology on 22 Feb 2009.

Monoclonal antibodies—highly specific infection-fighting proteins derived from the same cell lineage—are being used to treat some cancers and immunologic diseases. Physicians sometimes used a basic form of the therapy during the "Spanish flu" pandemic of 1918-19, by administering blood products from recovering patients to sick patients. Antibody treatment, also called passive immunotherapy, has been used to prevent infectious diseases such as hepatitis A and B and respiratory syncytial virus infections.

Billions of antibodies scanned
A team from Dana-Farber Cancer Institute, an affiliate of Harvard Medical School, scanned billions of mAbs produced in bacteriophages and found 10 that were active against the four major H5N1 virus subtypes. Collaborating with a researcher from the CDC's influenza division, they found that three of the mAbs had broad neutralizing effects when tested in cell cultures and mice against other known influenza A viruses, including H1 seasonal strains and the one that caused the 1918 pandemic.

At the same time, the Dana-Farber group worked with researchers at Burnham to visualize the x-ray crystal structure of an mAb that was bound to the H5N1 hemagglutinin. The image shows one arm of the mAb inserted into a genetically stable pocket in the neck of the hemagglutanin protein, which blocks the structural change needed to allow the virus to enter host cells.

Wayne Marasco, MD, PhD, associate professor of medicine at Dana-Farber, said in the press release that humans rarely make antibodies to the highly conserved region in the neck of the hemagglutinin protein. "We believe this is because the head of the hemagglutinin protein acts as a decoy by constantly undergoing mutation and thereby attracting the immune system to producing antibodies against it, rather than against the pocket in the neck of the protein," he said.

The conserved region in the neck—rather than the constantly mutating head—of the protein could provide a useful and stable new target for vaccine developers, Marasco said, adding, "An important goal is to redirect the immune response of vaccines to this invariable region of the hemagglutinin to try to obtain durable lifelong immunity."

The new strategy would offer an advantage over current seasonal flu vaccines, which are sometimes ineffective because they don't match circulating flu strains. Though vaccines developed against the H5N1 vaccine have been promising, none have elicited a broad response in humans to different H5N1 subtypes.

Supplementing antivirals?
Antiviral medications have been the gold standard for H5N1 treatment, but they are mainly effective when given within 24 to 48 hours of symptom onset, and health officials have voiced concerns about antiviral-resistant strains of H5N1 and seasonal influenza that have surfaced in recent years. The human mAbs are ready for advanced preclinical testing, and the next step will be to test the antibodies in ferrets, which have sialic acid receptors in their respiratory tracts resembling those in humans, Marasco said. Then researchers will develop a clinical version of one of the mAbs for use in human trials. He said that if mAbs are safe and effective in humans, a licensed product could still be several years away.

For seasonal influenza, treatments using mAbs could be used for those who have immune-system impairments, the NIAID said. In a pandemic setting, this group and others at risk, such as first responders, healthcare workers, and those exposed to the virus, could also benefit from mAb prophylaxis or treatment. Therapeutic mAbs are more costly to produce than other influenza drugs, but they can be readily manufactured and stockpiled, according to Dana-Farber. In a pandemic, mAbs treatment could be used with antivirals until a vaccine specific to the circulating strain becomes available.

The antibodies could be frozen and have a fairly long shelf life, Anthony Fauci, director of the NIAID, said. He added that mAb therapy typically provides potent protection for the first few weeks but wanes over the next few months.

Implications for vaccine development
William Schaffner, chairman of the Department of Preventive Medicine at the Vanderbilt University School of Medicine in Nashville, said that the findings might change the way healthcare officials approach seasonal and pandemic flu, but he cautioned that the research is still in the early stages. Schaffner said he sees two implications of the study, one focusing on vaccine development and the other on the development of new antibody treatments. However, he said he's a little more excited about what the findings mean for the future of vaccines.

"The holy grail of vaccine research is finding some part of the flu virus code that is conserved among different strains," he said, adding that if the protein the researchers found is successful in future trials, the method could be used to provide long-lasting immunity against a host of strains. As a result, scientists wouldn't need to develop a new vaccine every year, and people might need only periodic boosters, as in tetanus immunization, Schaffner said, adding that the prospect of saving money and having a healthier population is very exciting.
(CIDRAP 2/23/09)

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Global: Pandemic vaccine–making capacity rising, but still inadequate
The world's capacity to produce vaccines for an influenza pandemic has risen sharply in the past two years, but it would still take an estimated four years to meet the global demand if a pandemic emerged now, according to a report from an international strategy consulting firm. The report was prepared by the New York City–based firm Oliver Wyman in collaboration with the World Health Organization (WHO) and the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA).

"Pandemic vaccine production capacity has increased by 300 percent over the last two years, largely driven by improvements in production yields and dosage-sparing technologies," Oliver Wyman and the IFPMA stated. The company did not release the full report. If a pandemic emerged this year, the most likely case is that manufacturers could produce 2.5 billion doses in the first 12 months after they received the production strain, the firm said. It would take four years to produce enough to meet total global demand, meaning two doses for each of the world's 6.7 billion people. In the best case, the industry could produce 7.7 billion doses in the first 12 months of a pandemic and could meet global demand in 1½ years, the firm said.

The company predicts that annual pandemic vaccine production capacity will rise to somewhere between five billion and 14.5 billion doses over the next five years. That means the time needed to meet global demand could drop to 2½ years in the most likely case or one year in the best case.

The firm also expects that surplus vaccine production capacity—above and beyond the demand for seasonal flu vaccine and prepandemic vaccine stockpiling—will increase over the next 5 years, to between 2.6 billion and 5.4 billion annual doses. How much the capacity actually rises is likely to depend on the demand for both seasonal and prepandemic vaccines, officials said.

"I think this is a mixed story," Adam Sabow, the Wyman partner who led the preparation of the report, said. "This is good if there's new seasonal [flu vaccine] demand or if there's demand for H5N1 vaccine during the interpandemic period for efforts such as stockpiling. "However, if there isn't demand, there's a possibility that some of that capacity could be rationalized. By that we mean that capacity may either be shut down or may be redeployed for other purposes," which would reduce the ability to respond quickly to a pandemic.

He noted that there is some demand for H5N1 prepandemic vaccines, as some countries are stockpiling them, while the WHO is working on designing a global H5N1 vaccine stockpile. He said his firm is working with the WHO on that project.

Agreement on numbers
Sabow said that to estimate vaccine production capacity, his firm included 44 existing and planned vaccine production facilities, representing "the vast majority" of such facilities. He said the report marks a first: "This study is the first time that all the major actors have come together to agree on the capacity numbers for pandemic influenza. There's historically been a debate about the numbers that has taken away from the policy discussion. We're excited about this because the global health community has come together and agreed on the numbers and now can move on to the policy implications."

The report estimates that once a pandemic is recognized, it will take four months to develop, produce, and begin distributing a specific vaccine for it. Sabow said the estimate assumes the use of conventional egg-based production.

Egg-based and cell-based production
Although cell culture technology has been described as a faster and more flexible method for making flu vaccine, Sabow said the time needed to start making a pandemic vaccine would probably be about the same with cell culture production. While most flu vaccine production remains egg-based, the amount of cell-based production capacity is expected to increase considerably in the next 5 years, Sabow noted.

One of the uncertainties is what will happen to egg-base production capacity as cell-based capacity comes on line, particularly if demand for seasonal and prepandemic vaccines is lacking. "If there isn't demand, some of that egg-based capacity may be rationalized," he said.

Possible constraints
Sabow said the Wyman analysis did not consider potential economic constraints on vaccine production and distribution or the possible effects of supply-chain disruptions, which many experts regard as likely during a pandemic.

He also said the projections related to production of prepandemic vaccine stockpiling refer to H5N1 vaccines, but the estimates of production of actual pandemic vaccines do not assume that the next pandemic virus will be an H5N1 strain. "This is based on the history of producing a range of different influenza vaccine strains," he said.
(CIDRAP 2/24/009)

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Though it appears none of the 36 or 37 people who were exposed to the contaminated product became infected, the incident is being described as "a serious error" on the part of Baxter, which is on the brink of securing a European license for an H5N1 vaccine. That vaccine is made at a different facility, in the Czech Republic. Dr. Angus Nicoll of the ECDC said officials still aren't 100 percent sure the mixture contained live H5N1 viruses. But given that ferrets exposed to the mixture died, it likely did.
(ProMED 2/26/09)

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UK: Low pathogenic avian influenza detected on two poultry farms
Birds on two poultry farms in Suffolk and Norfolk have tested positive for a strain of avian flu. Veterinarians from Defra carried out the tests at Bernard Matthews breeder sites at Arran farm near Yaxham, Norfolk and Laurel farm, in Ubbeston, Suffolk. The birds tested positive for avian influenza but not the highly pathogenic H5 or H7 types. Defra has not advised a cull of the birds but has placed a movement restriction on them. A second series of tests is taking place to identify the strain of influenza.
(ProMED 2/26/09)

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A focal H5N1 outbreak in poultry was reported from Manipur, a north eastern state of India, in 2007. The aim of the study was to genetically characterize the Manipur virus isolate to understand the relationship with other H5N1 isolates and to trace the possible source of introduction of the virus into the country.

Characterization of the complete genome revealed that the virus belonged to clade 2.2. It was distinctly different from viruses of the 3 EMA sub-lineages of clade 2.2 but related to isolates from wild migratory waterfowl from Russia, China, and Mongolia. A stop codon at position 29 in the PB1-F2 protein could have implications on the replication efficiency. The acquisition of polymorphisms as seen in recent isolates of 2005-07 from distinct geographical regions suggests the possibility of transportation of H5N1 viruses through migratory birds.

The authors concluded that considering that all eight genes of the earlier Indian isolates belonged to the EMA3 sub-lineage and similar strains have not been reported from neighboring countries of the sub-continent, it appears that the virus may have been introduced independently.
(ProMED 2/26/09)

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Indonesia: Two Tangerang residents test negative for avian influenza H5N1
Tangerang health agency said on 26 Feb 2009, two residents of Kampung Geruduk, Tangerang, who were suspected of having contracted the avian influenza virus had tested negative for the disease. "Both tests came back negative," health agency official Yully Soenar said.

A 15-year-old boy and a 2-year-old child were being treated in the bird flu isolation unit at Tangerang General Hospital for almost a week. The pair was admitted to the unit when the hospital found they had high fever and difficulty breathing, and local authorities reported that there was dead poultry near their places of residence. Yully said the symptoms found were indicative of acute respiratory infection disease and bronchitis.
(ProMED 2/26/09)

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Indonesia (Bali): Officials detect second avian influenza H5N1 flare-up in 10 days
Avian influenza has struck a second district in Bali despite efforts to contain the spread of the disease on the island, the district's animal husbandry, marine, and fisheries agency said on 20 Feb 2009. I Gusti Ngurah Sandjaja, the head of the agency in Jembrana district in western Bali, said the outbreak was discovered after 52 chickens in the village of Banyubiru died over the course of four days.

"We immediately conducted a rapid test and found that the chickens were infected with the H5N1 virus," Sandjada said. Following the discovery, Sandjaja said the agency banned the transportation of poultry in and out of the village and had been culling the bird population and disinfecting cages since 19 Feb 2009. He said the agency was still concerned because a number of birds from Banyubiru had been sold to neighboring villages.

To head off further spread of the virus, the agency also conducted disinfecting drives in the nearby Gilimanuk market and chicken slaughterhouses. Dozens of chickens had died recently in the Arum Gilimanuk area.

Bird flu first emerged on the island in Jembrana district in 2007-08, causing the deaths of hundreds of chickens and infecting some local residents. One person died from the virus.

Sandjaja said the local government was concerned because the latest outbreak was the second to strike in less than 10 days. Earlier in February 2009, a bird flu outbreak emerged in Badung district, causing 133 chickens to be destroyed. One person suffered bird-flu-like symptoms after contact with sick poultry but later recovered. The Ministry of Health only releases information about suspected cases a few times a year, and test results from that particular case have not yet been released.
(ProMED 2/26/09)

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Nepal: New avian influenza H5N1 scare in eastern region
Less than two weeks after Nepal's government announced that the bird flu situation was under control in eastern Nepal, fresh fears of another outbreak rose with another village in the same area close to the Indian border reporting poultry deaths. The first outbreak was reported in January 2009.

"Bird flu has been detected in Sharanmati village in Jhapa district," said Hari Dahal, spokesman at Nepal's Agriculture and Cooperatives Ministry. The village lies close to Nepal's border with India's West Bengal state, about 40 km southwest of the border town of Kakarbhitta, where the first outbreak was reported in mid-January 2009.

From 20-22 Feb 2009, 150 chickens died in Sharanmati, Dahal said, causing the government to bring samples to Kathmandu for examination. After the tests confirmed the presence of the H5N1 virus, the samples were sent to London's Weybridge Laboratory for further tests. "They have just informed us that all the seven samples tested positive," Dahal said.

The government is sending a rapid action team to the village and setting up a control room. It is going to sound a high alert and declare emergency operations in and around the village. The culling of poultry will start fresh in the bird flu-hit tea district and surveillance on the border entries with India tightened.

Dahal expressed fears that the ailing birds could have been smuggled from India for sale in Nepal. "India has bird flu outbreak in West Bengal, Sikkim and Assam states," he said. "The birds are likely to have been brought from there. They were hidden in a backyard." Dahal said that Kakarbhitta, where the first outbreak was reported, leading to the destruction of nearly 25 000 chickens and poultry products, had not reported fresh signs of the disease. The disease has not been reported in humans in Nepal.
(ProMED 2/21/09)

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Singapore: Announces plan to buy 2.6m doses of avian influenza H5N1 vaccine
Singapore is stepping up its defenses against a possible bird flu pandemic with the purchase of enough vaccines for 1.3 million people. Vaccines give the best protection against the flu, but the one for H5N1 or bird flu just became available in 2007.

The original defense against a bird flu pandemic was to give the more than 50,000 'essential' people, such as doctors and policemen, six weeks' supply of Tamiflu, an antiviral drug that reduces the effects of the illness by preventing the bug from multiplying. But there has been growing resistance to the drug recently, which could mean it might be less effective in the event of a bird flu pandemic. This past winter, the northern hemisphere has thrown up a 15 percent resistance to the medicine in another flu strain - the H1N1 - up from 1 percent the previous winter.

The vaccine Singapore will be spending tens of millions of dollars to buy is targeted at the H5N1 or bird flu virus. It is not effective against other strains of flu. So if the next pandemic is not the H5N1, the vaccines would be useless.

This is why Singapore is also increasing its stockpile of Tamiflu, an antiviral drug that works for all flu strains. By the end of this year, Singapore will have 1.7 million courses, up from the original 1.05 million courses. Each course consists of 10 capsules which are taken over five days. It also has 50,000 courses of Relenza, another antiviral.

The United States has stockpiled about 26 million doses of the H5N1 vaccine. Countries like Switzerland and Ireland have enough for their entire population. Singapore expects to get its 2.6 million doses within six months.

For the vaccine to be effective, people need to get two doses three weeks apart. The plan is to start vaccinating the moment the World Health Organisation declares an increase in human-to-human transmission. For the moment, these transmissions remain rare.
(Straits Times 2/27/09)

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Viet Nam: Previously reported avian influenza H5N1 case dies
Viet Nam confirmed that the 23-year-old woman from northern Quang Ninh province who was confirmed of being infected with the H5N1 virus has died. The patient had been taken to a local hospital with bird flu symptoms of high temperature and difficulty in breathing in late January 2009 after eating sick fowl. The patient was then taken to the provincial hospital Quang Ninh of Viet Nam because her health condition worsened, with severe respiratory illness and deteriorated internal organs, said the provincial staff of doctors from Quang Ninh hospital. The woman died after 18 days of treatment with advanced respiratory tube.

So far in 2009, nine provinces of Viet Nam nationwide have been hit by avian flu, including four provinces in the Mekong Delta, namely Ca Mau, Soc Trang, Hau Giang, and Bac Lieu, two northern provinces of Bac Ninh and Quang Ninh, two central provinces of Nghe An and Quang Tri, and the newly confirmed southern Khanh Hoa, said the Department of Animal Health of the Vietnamese Ministry of Agriculture and Rural Development.

Viet Nam has reported three human cases of bird flu so far in 2009. An eight-year-old girl from northern Thanh Hoa province in early January 2009 has recovered, a newly-confirmed man who is still being treated, and the first and recently deceased 23-year-old woman from northern Quang Ninh province.

In 2008, bird flu killed 5 people in Viet Nam.
(ProMED 2/22/09)

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Bacterial coinfections were confirmed in six of the nine children; four involved Staphylococcus aureus, two of which were methicillin resistant. All of the children who had coinfections were age 5 or older. Meanwhile, other states reported more new pediatric flu deaths, which will likely be included in upcoming CDC weekly influenza updates.

Colorado's Department of Public Health and Environment (CDPHE) announced on 19 Feb 2009 that four Colorado children have died from influenza-related complications in 2009. The first occurred in mid-January, and the last was reported on 18 Feb 2009. The CDPHE said the state's number of pediatric flu deaths has already topped the past four flu seasons, which averaged two fatalities per year.

Three of the children were toddlers, and one was an infant. Two of the children had received partial vaccines (one of two recommended doses), and the other two were unvaccinated. At least two of the children had serious underlying medical conditions, the CDPHE said.

Ken Gershman, chief of the CDPHE's communicable disease program, said that child flu deaths are tragic, because the disease is often preventable. Last year the CDC expanded its flu vaccination recommendation to include all children from ages 5 through 18. It had already recommended flu immunizations for younger children between the ages of 6 and 59 months.

Over the past few days other states have reported more pediatric flu deaths, including:
- Massachusetts, where a 12-year-old boy died on 16 Feb 2009, according to the Boston Public Health Commission
- Arizona, where a teenager from Coconino County died last week, according to the Arizona Department of Health Services
- Texas, where a 12-year-old boy from Amarillo died on Feb 18, according to a report from the Amarillo Globe-News

Nationally, the number of states reporting widespread flu activity rose to 24, eight more than the previous surveillance week that ended on 7 Feb 2009, the CDC reported. Most of the hardest-hit states are in the eastern part of the country, except for Texas, Colorado, and Nevada. Thirteen additional states reported regional influenza activity.

Nearly all (98.5%) influenza A/H1N1 samples that have been tested showed resistance to oseltamivir (Tamiflu). Of viruses that have been antigenically characterized, all influenza A/H1N1 and influenza A/H3N2 viruses matched the vaccine components. However, only about a third of the influenza B viruses match the Yamagata lineage that is included in this year's vaccine—the rest were from the Victoria lineage.
(CIDRAP 2/20/09)

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A human case of swine influenza A (H1N1) in a 50-year-old woman from a village near Teruel (Aragón, in the north-east of Spain), with a population of about 200 inhabitants, has been reported in November 2008.

On 8 November 2008, a 50-year old woman developed fever, cough, extreme tiredness, myalgia, irritation of the nasal/oral mucosae and shivers of sudden onset. During a medical visit on 12 November 2008, the general practitioner (GP) who treated the case and is a member of the sentinel influenza surveillance system, took a throat swab sample and sent it to the Microbiology Laboratory of the Miguel Servet University Hospital in Zaragoza, Aragón in the context of the Spanish Influenza Surveillance System. The patient, with no history of recent travel, did not need specific treatment or hospitalisation and recovered fully.

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Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses
Sui J et al. Nature Struct Mol Biol. 22 February 2009 (early online publication). Available at http://www.nature.com/nsmb/journal/vaop/ncurrent/abs/nsmb.1566.html.

Influenza virus remains a serious health threat, owing to its ability to evade immune surveillance through rapid genetic drift and reassortment. Here we used a human non-immune antibody phage-display library and the H5 hemagglutinin ectodomain to select ten neutralizing antibodies (nAbs) that were effective against all group 1 influenza viruses tested, including H5N1 'bird flu' and the H1N1 'Spanish flu'. The crystal structure of one such nAb bound to H5 shows that it blocks infection by inserting its heavy chain into a conserved pocket in the stem region, thus preventing membrane fusion. Nine of the nAbs employ the germline gene VH1-69, and all seem to use the same neutralizing mechanism. Our data further suggest that this region is recalcitrant to neutralization escape and that nAb-based immunotherapy is a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.

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Characterization of Avian Influenza Viruses A (H5N1) from Wild Birds, Hong Kong, 2004–2008
Smith GJD et al. Emerg Infect Dis. March 2009; 15(3). Available at http://www.cdc.gov/eid/content/15/3/402.htm.

Abstract
From January 2004 through June 2008, surveillance of dead wild birds in Hong Kong, People's Republic of China, periodically detected highly pathogenic avian influenza (HPAI) viruses (H5N1) in individual birds from different species. During this period, no viruses of subtype H5N1 were detected in poultry on farms and in markets in Hong Kong despite intensive surveillance. Thus, these findings in wild birds demonstrate the potential for wild birds to disseminate HPAI viruses (H5N1) to areas otherwise free from the viruses. Genetic and antigenic characterization of 47 HPAI (H5N1) viruses isolated from dead wild birds in Hong Kong showed that these isolates belonged to 2 antigenically distinct virus groups: clades 2.3.4 and 2.3.2. Although research has shown that clade 2.3.4 viruses are established in poultry in Asia, the emergence of clade 2.3.2 viruses in nonpasserine birds from Hong Kong, Japan, and Russia raises the possibility that this virus lineage may have become established in wild birds.

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Capacity of Thailand to Contain an Emerging Influenza Pandemic
Putthasri W et al. Emerg Infect Dis. March 2009; 15(3). Available at http://www.cdc.gov/eid/content/15/3/423.htm.

Abstract
Southeast Asia will likely be the epicenter of the next influenza pandemic. To determine whether health system resources in Thailand are sufficient to contain an emerging pandemic, we mapped health system resources in 76 provinces. We used 3 prepandemic scenarios of clustered cases and determined resource needs, availability, and gaps. We extended this analysis to a scenario of a modest pandemic and assumed that the same standards of clinical care would be required. We found that gaps exist in many resource categories, even under scenarios in which few cases occur. Such gaps are likely to be profound if a severe pandemic occurs. These gaps exist in infrastructure, personnel and materials, and surveillance capacity. Policy makers must determine whether such resource gaps can realistically be closed, ideally before a pandemic occurs. Alternatively, explicit assumptions must be made regarding allocation of scarce resources, standards of care, and priority setting during a pandemic.

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Introduction into Nigeria of a Distinct Genotype of Avian Influenza Virus (H5N1)
Furaro A et al. Emerg Infect Dis. March 2009; 15(3). Available at http://www.cdc.gov/eid/content/15/3/445.htm.

Abstract
Genetic characterization of highly pathogenic avian influenza viruses (H5N1) isolated in July 2008 in Nigeria indicates that a distinct genotype, never before detected in Africa, reached the continent. Phylogenetic analysis showed that the viruses are genetically closely related to European and Middle Eastern influenza A (H5N1) isolates detected in 2007.

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Stockpiling Drugs for an Avian Influenza Outbreak: Examining the Surge in Oseltamivir Prescriptions During Heightened Media Coverage of the Potential for a Worldwide Pandemic
Gasink LB et al. Infect Control Hosp Epidemiol. 23 Feb 2009. Available at http://www.journals.uchicago.edu/doi/abs/10.1086/596609.

Objective. During fall 2005, personal stockpiling of oseltamivir for use during an outbreak of H5N1 influenza virus infection was widely reported. The present study aimed to identify indications for oseltamivir prescriptions to determine whether oseltamivir that was not intended for seasonal influenza was inappropriately consumed and to compare persons who were likely to have stockpiled oseltamivir and those who did not with respect to their knowledge, understanding, concerns, and expectations regarding avian influenza.

Design. Survey to evaluate usage patterns for oseltamivir and assess views about avian influenza.

Subjects. A total of 109 outpatients who received a prescription for oseltamivir between September 1, 2005, and December 31, 2005, and 825 matched control subjects.

Results. Of 109 prescriptions, 36 (33.0%) were prescribed for patients with appropriate indications. Sixty-eight (62.4%) of 109 patients identified as having received oseltamivir and 440 (53.3%) of 825 individuals identified as not having received it responded to the questionnaire. Only 2 prescription recipients whose oseltamivir was not intended for immediate consumption reported that they had consumed the oseltamivir. Persons who probably intended to stockpile oseltamivir were older and more often white than those unlikely to stockpile it. They also reported greater worry about avian influenza and more often expected avian influenza to spread to the United States than those unlikely to stockpile, but there were no significant differences in responses to other questionnaire items.

Conclusions. A large proportion of the oseltamivir prescriptions written in fall 2005 were probably intended for personal stockpiling. Similarities in participants' responses to questionnaire items suggest that educational campaigns may not be an effective method to curtail stockpiling of antimicrobial medications during an infectious threat. Promoting appropriate prescribing practices among providers may be a better means by which to minimize personal stockpiling.

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Adjuvanted H5N1 vaccine induces early CD4+ T cell response that predicts long-term persistence of protective antibody levels
Galli G et al. PNAS. 23 Feb 2009. Available at http://www.pnas.org/content/early/2009/02/20/0813390106.abstract.

Abstract
Immune responses to vaccination are tested in clinical trials. This process usually requires years especially when immune memory and persistence are analyzed. Markers able to quickly predict the immune response would be very useful, particularly when dealing with emerging diseases that require a rapid response, such as avian influenza. To address this question we vaccinated healthy adults at days 1, 22, and 202 with plain or MF59-adjuvanted H5N1 subunit vaccines and tested both cell-mediated and antibody responses up to day 382. Only the MF59-H5N1 vaccine induced high titers of neutralizing antibodies, a large pool of memory H5N1-specific B lymphocytes, and H5-CD4+ T cells broadly reactive with drifted H5. The CD4+ response was dominated by IL-2+ IFN-γ− IL-13− T cells. Remarkably, a 3-fold increase in the frequency of virus-specific total CD4+ T cells, measurable after 1 dose, accurately predicted the rise of neutralizing antibodies after booster immunization and their maintenance 6 months later. We suggest that CD4+ T cell priming might be used as an early predictor of the immunogenicity of prepandemic vaccines.

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Association Between Serum 25-Hydroxyvitamin D Level and Upper Respiratory Tract Infection in the Third National Health and Nutrition Examination Survey
Gine AA et al. Arch Intern Med. 2009; 169(4): 384-390. Available at http://archinte.ama-assn.org/cgi/content/abstract/169/4/384.

Background. Recent studies suggest a role for vitamin D in innate immunity, including the prevention of respiratory tract infections (RTIs). We hypothesize that serum 25-hydroxyvitamin D (25[OH]D) levels are inversely associated with self-reported recent upper RTI (URTI).

Methods. We performed a secondary analysis of the Third National Health and Nutrition Examination Survey, a probability survey of the US population conducted between 1988 and 1994. We examined the association between 25(OH)D level and recent URTI in 18 883 participants 12 years and older. The analysis adjusted for demographics and clinical factors (season, body mass index, smoking history, asthma, and chronic obstructive pulmonary disease).

Results. The median serum 25(OH)D level was 29 ng/mL (to convert to nanomoles per liter, multiply by 2.496) (interquartile range, 21-37 ng/mL), and 19% (95% confidence interval [CI], 18%-20%) of participants reported a recent URTI. Recent URTI was reported by 24% of participants with 25(OH)D levels less than 10 ng/mL, by 20% with levels of 10 to less than 30 ng/mL, and by 17% with levels of 30 ng/mL or more (P < .001). Even after adjusting for demographic and clinical characteristics, lower 25(OH)D levels were independently associated with recent URTI (compared with 25[OH]D levels of 30 ng/mL: odds ratio [OR], 1.36; 95% CI, 1.01-1.84 for <10 ng/mL and 1.24; 1.07-1.43 for 10 to <30 ng/mL). The association between 25(OH)D level and URTI seemed to be stronger in individuals with asthma and chronic obstructive pulmonary disease (OR, 5.67 and 2.26, respectively).

Conclusions. Serum 25(OH)D levels are inversely associated with recent URTI. This association may be stronger in those with respiratory tract diseases. Randomized controlled trials are warranted to explore the effects of vitamin D supplementation on RTI.

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Weekly Epidemiological Bulletin available online
WHO. 27 Feb 2009; 84(9): 65-76. Available at http://www.who.int/wer.

Contents of this issue
65 Recommended composition of influenza virus vaccines for use in the 2009-2010 influenza season (northern hemisphere winter)
72 Antigenic and genetic characteristics of H5N1 viruses and candidate vaccine viruses developed for potential use in human vaccines, February 2009

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