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EINet Alert ~ Oct 12, 2007


*****A free service of the APEC Emerging Infections Network*****
APEC EINet News Briefs offers the latest news, journal articles, and notifications for emerging infections affecting the APEC member economies. It was created to foster transparency, communication, and collaboration in emerging infectious diseases among health professionals, international business and commerce leaders, and policy makers in the Asia-Pacific region.
In this edition:
- Global: Cumulative number of human cases of avian influenza A/(H5N1)
- Indonesia (Riau, Jakarta): New avian influenza H5N1 cases reported
- Viet Nam (Tra Vinh): New avian influenza H5N1 outbreak in poultry

1. Updates
- Avian/Pandemic influenza updates

2. Articles
- CDC EID Journal, Volume 13, Number 10--Oct 2007
- H5N1 mutation that could help spark pandemic identified
- Fresh doubts, new support for influenza shots for seniors
- Trends in influenza vaccination in Canada, 1996/1997 to 2005
- Influenza viruses and the evolution of avian influenza virus H5N1
- Development and evaluation of an influenza subtype H7N2 vaccine candidate for pandemic preparedness
- Antiviral Oseltamivir Is not Removed or Degraded in Normal Sewage Water Treatment: Implications for Development of Resistance by Influenza A Virus
- A Single Mutation in the PB1-F2 of H5N1 (HK/97) and 1918 Influenza A Viruses Contributes to Increased Virulence
- The role of oseltamivir in the treatment and prevention of influenza in children.
- Cross-Protection against H5N1 Influenza Virus Infection Is Afforded by Intranasal Inoculation with Seasonal Trivalent Inactivated Influenza Vaccine
- Progress and shortcomings in European national strategic plans for pandemic influenza


Global
Global: Cumulative number of human cases of avian influenza A/(H5N1)
Economy / Cases (Deaths)

2003
Viet Nam / 3 (3)
Total / 3 (3)

2004
Thailand / 17 (12)
Viet Nam / 29 (20)
Total / 46 (32)

2005
Cambodia / 4 (4)
China / 8 (5)
Indonesia / 17 (11)
Thailand / 5 (2)
Viet Nam / 61 (19)
Total / 95 (41)

2006
Azerbaijan / 8 (5)
Cambodia / 2 (2)
China / 13 (8)
Djibouti / 1 (0)
Egypt / 18 (10)
Indonesia / 56 (46)
Iraq / 3 (2)
Thailand / 3 (3)
Turkey / 12 (4)
Total / 116 (80)

2007
Cambodia/ 1 (1)
China / 3 (2)
Egypt / 20 (5)
Indonesia / 33 (29)
Laos / 2 (2)
Nigeria / 1 (1)
Viet Nam 7 (4)
Total / 67 (44)

Total no. of confirmed human cases of avian influenza A/(H5N1), Dec 2003 to present: 330 (202).
(WHO 10/8/07 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 10/2/07)

WHO's maps showing world's areas affected by H5N1 avian influenza (last updated 10/11/07): http://gamapserver.who.int/mapLibrary/

WHO’s timeline of important H5N1-related events (last updated 9/11/07): http://www.who.int/csr/disease/avian_influenza/ai_timeline/en/index.html.

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Asia
Indonesia (Riau, Jakarta): New avian influenza H5N1 cases reported
A 44-year-old Indonesian woman who died Oct 6, 2007 had H5N1 avian influenza, marking the country's 108th human H5N1 case and 87th death. The woman, from Pekan Baru city in Sumatra's Riau province, fell ill Sep 27 and was hospitalized Oct 2, said I Nyoman Kandun of the Indonesian Health Ministry. Kandun said it was unclear how the woman contracted the disease, but she often visited marketplaces and might have had contact with poultry there. He said the ministry was sending a team to Riau to conduct an investigation. The patient's contacts remain healthy but are being monitored. Riau has recorded 4 bird flu cases since 2005.

Indonesia also reported an additional H5N1 avian influenza case in a 12-year-old boy in the Jakarta area, raising the country's human case count to 109. The boy is from the Jakarta suburb of Tangerang and is being treated in a Jakarta hospital, said Muhammad Nadirin, a spokesman for the health ministry's avian flu center. Nadirin said it was not clear how the boy was exposed to the virus, but some chickens had reportedly died in his neighborhood. 87 of Indonesia's H5N1 cases have been fatal. Meanwhile, 5 people with suspected avian flu in Indonesia's North Sumatra province tested negative for the H5N1 virus. The 5 were among 7 people from the same village who were admitted to a hospital in Medan, the provincial capital, Oct 6, 2007.
(CIDRAP 10/8/07, 10/11/07; Promed 10/8/07)

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Viet Nam (Tra Vinh): New avian influenza H5N1 outbreak in poultry
Avian influenza H5N1 cropped up again in poultry in southern Vietnam this week after a 2-month absence. The Agriculture Ministry said ducks from a farm in the Mekong Delta's Tra Vinh province tested positive for the virus. Testing was done after 5 birds in an unvaccinated flock of 300 died. The rest of the ducks have since been destroyed by animal-health workers. Agriculture Minister Cao Duc Phat urged veterinary authorities this week to step up poultry vaccinations. He said avian flu would soon reemerge among unvaccinated birds, especially as the weather cools in northern Vietnam.
(CIDRAP 10/11/07)

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1. Updates
Avian/Pandemic influenza updates
- UN: http://www.un-influenza.org/ : latest on Indonesian avian influenza case. Also, http://www.irinnews.org/Birdflu.asp provides information on avian influenza.
- WHO: http://www.who.int/csr/disease/avian_influenza/en/index.html.
- UN FAO: http://www.fao.org/ag/againfo/subjects/en/health/diseases-cards/special_avian.html. Link to supplement to Journal of Wildlife Diseases on avian influenza.
- OIE: http://www.oie.int/eng/info_ev/en_AI_avianinfluenza.htm.
- US CDC: http://www.cdc.gov/flu/avian/index.htm.
- The US government’s web site for pandemic/avian flu: http://www.pandemicflu.gov/.
- Health Canada: information on pandemic influenza: http://www.influenza.gc.ca/index_e.html. Latest updates on Saskatchewan H7N3 outbreak.
- CIDRAP: http://www.cidrap.umn.edu/.
- PAHO: http://www.paho.org/English/AD/DPC/CD/influenza.htm. Link to National Influenza Centers in PAHO Member States.
- US Geological Survey, National Wildlife Health Center Avian Influenza Information: http://www.nwhc.usgs.gov/disease_information/avian_influenza/index.jsp. Updated 5 Oct 2007 with information on H7N3 outbreak in Canada.
(UN; WHO; FAO, OIE; CDC; Health Canada; CIDRAP; PAHO; USGS)

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2. Articles
CDC EID Journal, Volume 13, Number 10--Oct 2007
CDC Emerging Infectious Diseases Journal Oct 2007 issue is now available at: http://www.cdc.gov/ncidod/EID/index.htm. Influenza-related articles: Preparedness for Highly Pathogenic Avian Influenza Pandemic in Africa by R.F. Breiman et al.; Influenza A and B Infection in Children in Urban Slum, Bangladesh by W.A. Brooks et al.; Confronting Potential Influenza A (H5N1) Pandemic with Better Vaccines by A. Haque et al.; Personal Protective Equipment and Antiviral Drug Use during Hospitalization for Suspected Avian or Pandemic Influenza by A. Swaminathan et al.; Chlorine Inactivation of Highly Pathogenic Avian Influenza Virus (H5N1) by E.W. Rice et al.; Multifocal Avian Influenza (H5N1) Outbreak by R.D. Balicer et al.; Super-Sentinel Chickens and Detection of Low-Pathogenicity Influenza Virus by P.I. Marcus et al.

Expedited articles can be viewed at: http://www.cdc.gov/ncidod/eid/upcoming.htm. Influenza related articles: Protection and Virus Shedding of Falcons Vaccinated against Highly Pathogenic Avian Influenza A Virus (H5N1); Role of Terrestrial Wild Birds in Ecology of Influenza A Virus (H5N1); Pandemic Influenza and Hospital Resources; Medical Students and Pandemic Influenza; Bird Flu: A Virus of Our Own Hatching.

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H5N1 mutation that could help spark pandemic identified
An international research team led by the University of Wisconsin at Madison (UW-Madison) has identified a key mutation that would arm the H5N1 avian influenza virus with one of the tools it needs to more easily infect and spread among humans. The mutation consists of a single amino acid change that improves the virus' ability to infect cells in the upper respiratory tract of mammals. The research group, headed by virologist Yoshihiro Kawaoka, published its findings in the online journal Public Library of Science Pathogens (PLoS Pathogens). The change promotes better viral replication at the lower temperatures found in the upper airways of mammals. Once the H5N1 virus is established in the upper respiratory tract, infected patients can more easily spread the disease to others through coughing and sneezing, making the infection more contagious.

The authors write that the hemagglutinin protein's specificity for avian- or human-type receptors on airway cells is thought to be a major factor governing the efficient transmission of H5N1 viruses. Yet the disease still doesn't spread easily among humans, though scientists have isolated from humans some H5N1 viruses that had specificity for human receptors. To determine what other amino acid substitutions are needed to make the virus more transmissible among humans, they explored the role of the amino acid at position 627 of the PB2 viral protein, one of the key proteins involved in viral replication. The scientists used two H5N1 viruses—one from the lungs and one from the upper airway—that were isolated from a single patient in Vietnam. They found that the virus from the patient's upper airway exhibited a single amino acid change at position 627 of PB2: from glutamic acid (Glu) to lysine (Lys).

The researchers then compared the growth of the two viral strains in mice and in different cell types. They found that viruses with Lys at position 627 replicated more efficiently in mammalian respiratory tracts, at temperatures as low as 33°C [91.4°F], and in a wider range of cells than those with Glu at the same amino acid position. Kawaoka said that the H5N1 viruses circulating now are more "mammalian-like" than the ones that circulated in 1997, when the first human infections were identified. "The viruses that are circulating in Africa and Europe are the ones closest to becoming a human virus," he said. However, the researchers say in their report that additional genetic changes are probably needed to equip the H5N1 virus with full pandemic potential. "Indeed, multiple amino acid changes have been identified in the so-called Spanish influenza virus, which is thought to be derived from an avian antecedent," they write. Kawaoka and his team believe it's only a matter of time before the H5N1 virus evolves into a strain that's capable of launching a pandemic. "I don't like to scare the public, because they cannot do very much," Kawaoka was quoted. "But at the same time it is important to the scientific community to understand what is happening."

Hatta M, Hatta Y, Kim J, et al. Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice. PLoS Pathogens 2007 Oct 4;3(10):e133
(CIDRAP 10/5/07)

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Fresh doubts, new support for influenza shots for seniors
In quick succession, the view that influenza shots yield life-saving benefits for elderly people has come under serious attack and received fresh support in recent weeks. One group of experts, writing in the October issue of Lancet Infectious Diseases, argued that the mortality benefits of flu shots for the elderly have been greatly exaggerated because of a subtle bias and other methodologic problems in many of the relevant studies. "The remaining evidence base is currently insufficient to indicate the magnitude of the mortality benefit, if any, that elderly people derive from the vaccination programme," says the analysis by Lone Simonsen and colleagues. But in the Oct 4 New England Journal of Medicine (NEJM), another team of experts presented a study showing that in the course of up to 10 flu seasons, flu shots reduced the risk of hospitalization for pneumonia and flu by 27% and shrank the risk of death by 48% for elderly members of three health maintenance organizations (HMOs). The study addresses several of the methodologic problems raised by the Lancet authors. "Vaccine delivery to this high-priority group should be improved," states the report by Kristin Nichol and coauthors. The controversy has major policy implications, since CDC and other medical groups heavily promote flu shots for elderly people. This policy is reinforced by Medicare coverage of flu shots for this age-group.

The Lancet Infectious Diseases authors offer several reasons for questioning the notion that flu immunization saves lives in the elderly:
• Vaccination coverage among the elderly has increased from 15% to 65% since 1980, but instead of declining, overall mortality due to pneumonia and influenza in elderly people has increased in that period.
• Few randomized, placebo-controlled trials have examined flu vaccine effectiveness in elderly people. The largest and best study, done in the Netherlands, showed a 50% reduction in confirmed flu cases among all the volunteers, but the reduction for those older than 70 was only 23%. There was no significant reduction in influenza-like illness.
• A number of investigators have reported finding evidence of flu vaccination benefits in the elderly by analyzing the records of large healthcare organizations. But these studies typically are flawed in that investigators looked for an effect on all-cause mortality, a nonspecific outcome, rather than on lab-confirmed flu. Further, many such studies may be marred by selection bias, wherein relatively healthy older people were more likely to be vaccinated than frail seniors were, thereby making vaccination look more beneficial than it really was. A further problem is that cohort studies typically have defined the flu season arbitrarily as December through March, rather than on the basis of flu surveillance.

Simonsen and colleagues also write that since 1968, flu has accounted for an average of about 5% of all winter deaths in older people. Yet the results of cohort studies have prompted claims that flu vaccination reduces the risk of winter death from any cause by about 50% for community-dwelling people older than 65. "That influenza vaccination can prevent ten times as many deaths as the disease itself causes is not plausible," say Simonsen et al. They argue that in view of the "slim" evidence that flu immunization prolongs elderly people's lives, it may be time to consider doing more randomized, placebo-controlled trials—even though using a placebo would be "ethically unappealing." In addition, they suggest, other options for protecting the elderly should be pursued, such as developing vaccines that are more immunogenic, using larger vaccine doses, and employing antiviral drugs more aggressively. The researchers say elderly people should continue to be vaccinated, because "even a partly effective vaccine would be better than no vaccine at all."

The review by Simonsen et al. drew praise in an editorial in The Lancet, written by 2 other vaccine experts who have reviewed the case for flu immunization in the elderly. Tom Jefferson and Carlo Di Pietrantonj of the Cochrane Vaccine Fields in Italy, write that Smonsen et al "prove that statistical methods for adjustment for residual bias used in the observational studies of influenza vaccines did not work, largely because of the difficulty of adjusting for frailty with data available in electronic records." Jefferson and Di Pietrantonj endorse the idea of doing new randomized, placebo-controlled trials of flu vaccination in older people, arguing that such studies are "the only ethical and scientific way" to settle conclusively whether the vaccines are protective. The trials must cover more than 1 flu season and be large enough to detect rare outcomes, such as deaths due to flu, the pair assert.

In an interview, a flu expert with the CDC asserted that the evidence of effectiveness remains strong enough to justify the US policy of promoting flu shots for the elderly. David K. Shay, a medical officer in the CDC's influenza division, agreed that better vaccines are needed, but he rejected the idea of doing placebo-controlled trials in the elderly as unethical. Shay said the randomized, controlled trial from the Netherlands that showed a 50% reduction in confirmed flu cases among the elderly provided "gold standard evidence" for a protective effect. The risk was reduced 57% in 60- to 69-year-olds versus 23% in those 70 and older, but because of wide confidence intervals, the difference between the two groups was not significant, he said. The Dutch findings and the high risk of flu-related hospitalization and death in the elderly provide the major underpinnings of the US policy of promoting flu vaccination in the elderly, Shay said, adding, "We're left with the fact that this study [by Simonsen et al] isn't going to change policy in the US for the use of these vaccines."

As for the suggestion that unmeasured confounding variables have inflated the effectiveness of flu vaccines in observational studies, Shay said, "We also think that's possible. The CDC is interested in working with HMOs to get a better handle on how to do vaccine effectiveness studies and mortality outcome studies." But given the existing evidence that flu shots do help protect seniors, he rejected the suggestion of doing placebo-controlled trials. On the other hand, Shay commented, "Everybody would agree that we need a vaccine with greater effectiveness and greater immunogenicity in the elderly. Manufacturers are working on adjuvanted vaccines that hopefully will be more effective."

In the NEJM study, Nichol and associates sought specifically to address the kinds of methodologic problems cited by Simonsen et al. They retrospectively gathered data on flu vaccination, hospitalization for pneumonia and flu, and death from any cause among community-dwelling elderly members of three HMOs. The study covered the flu seasons from 1990-91 through 1999-2000 for one HMO and those from 1996-97 through 1999-2000 for the other two. The HMOs were in Minnesota and Wisconsin, Washington state, and the New York City area. The study included 713,872 person-seasons of observation. Vaccinated subjects were slightly older and had slightly higher rates of most of the underlying medical conditions that were recorded. There were 4,599 hospitalizations for pneumonia or flu and 8,796 deaths. The per-season hospitalization rates for unvaccinated and vaccinated people were 0.7% and 0.6%, and the corresponding death rates were 1.6% and 1.0%. The figures translated into a 27% reduction in hospitalization rate for pneumonia and flu among the vaccinated (adjusted odds ratio, 0.73; 95% confidence interval [CI], 0.68 to 0.77) and a 48% reduction in mortality (adjusted odds ratio, 0.52; 95% CI, 0.50 to 0.55).

The vaccine was somewhat less effective in preventing death—a 37% compared with 48% reduction—in the two seasons when the vaccine was a poor match for the circulating viral strains. For the seasons in which there was a good match, the vaccine yielded a 52% reduction in mortality risk. In an effort to detect any "healthy-vaccinee bias" (better underlying health among the vaccinated than the unvaccinated), the authors compared the risk of hospitalization among vaccinated and unvaccinated subjects during the summers (noninfluenza seasons) of 1999 and 2000. They found that the risks were similar for the two groups.

The researchers went a step further by hypothesizing that an unmeasured confounding variable was influencing their findings and then estimating what that influence would be under various assumptions. They picked functional status as the unmeasured variable most likely to affect their subjects' risk of hospitalization or death. On the basis of studies of functional status, the authors estimated that subjects with poor functional status would be half as likely to get a flu shot and two to three times as likely to be hospitalized or die, compared with those with better functional status. When they plugged these estimates into their data, along with estimates of the prevalence of the confounding variable, they found that the effectiveness of vaccination was reduced but still significant.

The researchers write that their study "showed multiple benefits across multiple subgroups, a result suggesting that vaccination benefits probably extend to a broad spectrum of elderly persons." However, they acknowledge that elderly HMO members may differ from elderly nonmembers, and the study did not include the frailest elderly, such as those living in nursing homes, who are likely to have weaker immune responses.

In an accompanying NEJM editorial, John D. Treanor writes that the study by Nichol et al addresses many of the concerns raised about other observational studies "and increases our confidence in the benefits of influenza vaccination in older adults." Because the evidence of vaccine effectiveness held up well through 10 seasons, the findings "convincingly dispel concerns that the previous studies were artifacts of a specific influenza season or a specific population," states Treanor. He also comments favorably on the authors' efforts to address the concerns about unmeasured confounding variables, including the examination of summer hospitalization rates and the estimate of the effect of a hypothetical difference in functional status. "Overall, this study provides additional support for the current strategy to vaccinate elderly adults," Treanor asserts. The methodologic issues are important, and the precise magnitude of the benefits of vaccination is not yet clear, but it is clear that vaccination is beneficial and should be used widely, he adds.

However, he agrees with Shay that the development of more immunogenic and effective vaccines for the elderly is an important goal. Shay said CDC is contemplating a special initiative to help resolve the controversy over the value of flu immunization for seniors. "Sometime in 2008 the CDC hopes to get together a panel of consultants to bring about ways to move forward and find ways to resolve this controversy," he said. By assembling experts from the different camps, the agency hopes to come up with recommendations to guide the next series of studies, he said.

- Simonsen L, Taylor RJ, Viboud C, et al. Mortality benefits of influenza vaccination in elderly people: an ongoing controversy. Lancet Infect Dis 2007 Oct;7:658-66
- Jefferson T, Di Pietrantonj C. Inactivated influenza vaccines in the elderly—are you sure? (Editorial) Lancet 2007 Oct 6;370(9594):1199-1200
- Nichol KL, Nordin JD, Nelson DB, et al. Effectiveness of influenza vaccine in the community-dwelling elderly. N Engl J Med 2007 Oct 4;357(14):1373-81
- Treanor JD. Influenza—the goal of control. (Editorial) N Engl J Med 2007 Oct 4;357(14):1439-41
(CIDRAP 10/9/07)

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Trends in influenza vaccination in Canada, 1996/1997 to 2005
Jeff C. Kwong et al. From Health Rep, published online Oct 2. http://www.statcan.ca/english/freepub/82-003-XIE/2006010/articles/vaccination/flu-en.pdf
Abstract Objectives This article reports recent trends in influenza vaccination rates in Canada, provides data on predictors of vaccination in Canada for 2005, and examines longer term effects of Ontario's universal influenza immunization program on vaccine uptake. Data sources Data are from the 1996/1997 National Population Health Survey (NPHS) and the 2000/2001, 2003, and 2005 Canadian Community Health Survey (CCHS). Analytical techniques NPHS and CCHS data were used to estimate influenza vaccination rates of the population aged 12 or older. The Z test was used to assess differences between surveys, and the chi-squared test for trend was used to examine trends over time. Logistic regression was used to identify predictors of vaccination and to compare the odds of being vaccinated in Ontario versus other provinces. Main results Nationally, influenza vaccination rates rose from 15% in 1996/1997 to 27% in 2000/2001, stabilized between 2000/2001 and 2003, and increased further to 34% by 2005. Vaccination rates for most high-risk groups still fall short of national targets. Ontarians continue to be more likely to be vaccinated than are residents of any other province, while residents of two of the territories—Nunavut and the Northwest Territories—are even more likely to be vaccinated than are Ontarians.

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Influenza viruses and the evolution of avian influenza virus H5N1
Nedaa Skeik , Fadi I. Jabr. International Journal of Infectious Diseases- 4 October 2007 (DOI: 10.1016/j.ijid.2007.07.002) http://www.ijidonline.com/article/PIIS1201971207001531/abstract
Summary: Although small in size and simple in structure, influenza viruses are sophisticated organisms with highly mutagenic genomes and wide antigenic diversity. They are species-specific organisms. Mutation and reassortment have resulted in newer viruses such as H5N1, with new resistance against anti-viral medications, and this might lead to the emergence of a fully transmissible strain, as occurred in the 1957 and 1968 pandemics. Influenza viruses are no longer just a cause of self-limited upper respiratory tract infections; the H5N1 avian influenza virus can cause severe human infection with a mortality rate exceeding 50%. The case death rate of H5N1 avian influenza infection is 20 times higher than that of the 1918 infection (50% versus 2.5%), which killed 675000 people in the USA and almost 40 million people worldwide. While the clock is still ticking towards what seems to be inevitable pandemic influenza, on April 17, 2007 the U.S. Food and Drug Administration (FDA) approved the first vaccine against the avian influenza virus H5N1 for humans at high risk. However, more research is needed to develop a more effective and affordable vaccine that can be given at lower doses.

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Development and evaluation of an influenza subtype H7N2 vaccine candidate for pandemic preparedness
Claudia Pappas et al. Clin Vaccine Immunol. 2007 Oct 3; [Epub ahead of print] http://cvi.asm.org/cgi/content/abstract/CVI.00174-07v1
Abstract: Influenza virus of the H7N2 subtype has been introduced into non-commercial poultry in the United States and probably resulted in incidents of transmission of H7N2 virus to humans, documented in 2002 and 2003. This virus could be considered a potential threat to public health if it acquired person-to-person transmissibility. A favored approach for global pandemic preparedness includes development of pre-pandemic vaccines for any potential pandemic virus. To this end, we created a high growth reassortant virus (H7N2-PR8) containing the genes for the hemagglutinin (HA) and the neuraminidase (NA) from a low pathogenic (H7N2) virus strain and the remaining six genes from a human vaccine strain (H1N1). The reassortant strain was evaluated to assess its antigenicity, safety and protective efficacy using a mouse model. Antigenicity studies using ferret antibodies raised against H7N2-PR8 indicated that this virus confers broad cross-reactivity with divergent H7 viruses of different years and lineages. Mice and chickens inoculated with high doses of H7N2-PR8 supported virus replication but survived, indicating that this virus is comparable to other avian viruses of low pathogenicity. To assess the protective efficacy of H7N2-PR8, mice were immunized with two doses of formalin-inactivated A/H7N2-PR8, alone or with alum. Vaccinated mice subsequently challenged with highly pathogenic viruses from homologous and heterologous lineages, A/Canada/444/04 (H7N3) and A/Netherlands/219/03 (H7N7), revealed pronounced reduction of wild type virus replication. These studies indicate that, A/H7N2-PR8 is immunogenic, safe and protective in animal models; these are the essential attributes to qualify for Phase I human clinical trials as a pre-pandemic vaccine.

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Antiviral Oseltamivir Is not Removed or Degraded in Normal Sewage Water Treatment: Implications for Development of Resistance by Influenza A Virus
Jerker Fick et al. PLoS ONE 2(10): e986 doi:10.1371/journal.pone.0000986. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0000986
Abstract: Oseltamivir is the main antiviral for treatment and prevention of pandemic influenza. The increase in oseltamivir resistance reported recently has therefore sparked a debate on how to use oseltamivir in non pandemic influenza and the risks associated with wide spread use during a pandemic. Several questions have been asked about the fate of oseltamivir in the sewage treatment plants and in the environment. We have assessed the fate of oseltamivir and discuss the implications of environmental residues of oseltamivir regarding the occurrence of resistance. A series of batch experiments that simulated normal sewage treatment with oseltamivir present was conducted and the UV-spectra of oseltamivir were recorded. Findings: Our experiments show that the active moiety of oseltamivir is not removed in normal sewage water treatments and is not degraded substantially by UV light radiation, and that the active substance is released in waste water leaving the plant. Our conclusion is that a ubiquitous use of oseltamivir may result in selection pressures in the environment that favor development of drug-resistance.

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A Single Mutation in the PB1-F2 of H5N1 (HK/97) and 1918 Influenza A Viruses Contributes to Increased Virulence
Gina M. Conenello et al. PLoS Pathogens Vol. 3, No. 10, e141 doi:10.1371/journal.ppat.0030141
Abstract: The proapoptotic PB1-F2 protein of influenza A viruses has been shown to contribute to pathogenesis in the mouse model. Expression of full-length PB1-F2 increases the pathogenesis of the influenza A virus, causing weight loss, slower viral clearance, and increased viral titers in the lungs. After comparing viruses from the Hong Kong 1997 H5N1 outbreak, one amino acid change (N66S) was found in the PB1-F2 sequence at position 66 that correlated with pathogenicity. This same amino acid change (N66S) was also found in the PB1-F2 protein of the 1918 pandemic A/Brevig Mission/18 virus. Two isogenic recombinant chimeric viruses were created with an influenza A/WSN/33 virus background containing the PB1 segment from the HK/156/97: WH and WH N66S. In mice infected with WH N66S virus there was increased pathogenicity as measured by weight loss and decreased survival, and a 100-fold increase in virus replication when compared to mice infected with the WH virus. The 1918 pandemic strain A/Brevig Mission/18 was reconstructed with a pathogenicity-reducing mutation in PB1-F2 (S66N). The resultant 1918 S66N virus was attenuated in mice having a 3-log lower 50% lethal dose and caused less morbidity and mortality in mice than the wild-type virus. Viral lung titers were also decreased in 1918 S66N–infected mice compared with wild-type 1918 virus–infected mice. In addition, both viruses with an S at position 66 (WH N66S and wt 1918) induced elevated levels of cytokines in the lungs of infected mice. Together, these data show that a single amino acid substitution in PB1-F2 can result in increased viral pathogenicity and could be one of the factors contributing to the high lethality seen with the 1918 pandemic virus.

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The role of oseltamivir in the treatment and prevention of influenza in children.
Whitley RJ. Expert Opin Drug Metab Toxicol. 2007 Oct;3(5):755-767.
The burden of seasonal influenza in children is poorly recognized, in spite of the potential for severe and even life-threatening illness and common secondary complications. Children are a primary reservoir for the spread of influenza to both family members and the community, which imposes a sizeable social and economic strain. Although vaccination is the primary intervention against childhood influenza, the antiviral neuraminidase inhibitors, oseltamivir and zanamivir, provide treatment options. Oseltamivir is administered orally to children aged > 1 year and has been shown to cost-effectively reduce the influenza disease burden and duration of viral shedding. Additionally, oseltamivir postexposure prophylaxis provides protective efficacy for children and families. Oseltamivir has shown excellent tolerability and a low potential for viral resistance in pediatric studies. In the event of an influenza pandemic, oseltamivir is expected to be at the forefront of containment strategies. This article reviews the pharmacology, efficacy and tolerability of oseltamivir as treatment and prophylaxis in children.

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Cross-Protection against H5N1 Influenza Virus Infection Is Afforded by Intranasal Inoculation with Seasonal Trivalent Inactivated Influenza Vaccine
Takeshi Ichinohe et al. The Journal of Infectious Diseases 2007;196:1313-1320.
Abstract: Background. Avian H5N1 influenza A virus is an emerging pathogen with the potential to cause substantial human morbidity and mortality. We evaluated the ability of currently licensed seasonal influenza vaccine to confer cross-protection against highly pathogenic H5N1 influenza virus in mice. Methods. BALB/c mice were inoculated 3 times, either intranasally or subcutaneously, with the trivalent inactivated influenza vaccine licensed in Japan for the 2005–2006 season. The vaccine included A/NewCaledonia/20/99 (H1N1), A/NewYork/55/2004 (H3N2), and B/Shanghai/361/2002 viral strains and was administered together with poly(I):poly(C12U) (Ampligen) as an adjuvant. At 14 days after the final inoculation, the inoculated mice were challenged with either the A/HongKong/483/97, the A/Vietnam/1194/04, or the A/Indonesia/6/05 strain of H5N1 influenza virus. Results. Compared with noninoculated mice, those inoculated intranasally manifested cross-reactivity of mucosal IgA and serum IgG with H5N1 virus, as well as both a reduced H5N1 virus titer in nasal-wash samples and increased survival, after challenge with H5N1 virus. Subcutaneous inoculation did not induce a cross-reactive IgA response and did not afford protection against H5N1 viral infection. Conclusions. Intranasal inoculation with annual influenza vaccine plus the Toll-like receptor–3 agonist, poly(I):poly(C12U), may overcome the problem of a limited supply of H5N1 virus vaccine by providing cross-protective mucosal immunity against H5N1 viruses with pandemic potential.

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Progress and shortcomings in European national strategic plans for pandemic influenza
Sandra Mounier-Jack et al. Bulletin of the World Health Organization 2007; published online ahead of print. http://www.who.int/bulletin/volumes/85/06-039834.pdf
Abstract: Objective To repeat and update our previous evaluation (2005) of Europe’s national pandemic influenza preparedness plans and assess what progress has been made. Methods We assessed published national pandemic influenza preparedness plans from the European Union countries, from the two acceding countries (Bulgaria and Romania) and from Norway, Switzerland and Turkey. Plans were eligible for inclusion if formally published before 30 September 2006. We referred to WHO guidelines and used a systematically applied data extraction form. We considered plans in relation to border control measures, antiviral drugs and vaccines. Findings 29 countries had plans that were included in the analysis, compared with 21 countries in 2005. Substantial differences existed in countries’ plans for border control measures, and many plans diverged from WHO guidelines. Likewise, countries’ plans on antiviral drugs and vaccines vary and operational planning remained weak. Conclusion Although progress has been made in the completeness of plans, problems remain to be resolved regarding national plans' divergence from international recommendations, persisting strategic incoherence and operational limitations in relation to potentially scarce resources. Border control plans also show gaps and inconsistencies, and these are likely to be politically volatile during a pandemic.

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