COMMENTARY

Influenza Literature: Commentary by Dr. John G. Bartlett -- April 2007

John G. Bartlett, MD

Disclosures

April 25, 2007

Pandemic Influenza Task Force of the Infectious Diseases Society of America. Pandemic and Seasonal Influenza: Principles for U.S. Action, January 2007

As background information, it is noteworthy that between 2005 and 2007, federal and state governments, private industry, and international stakeholders made substantial advances to prepare for pandemic influenza. In the United States, over $6 billion has been committed for pandemic flu preparedness to date. In December 2006, Congress passed the Pandemic and All Hazards Preparedness Act that authorized substantial funding to support the public health system and its ability to respond to emergencies. Included in the Act is the Biomedical Advanced Research and Development Authority (BARDA), designed to foster research, development, and purchase of countermeasures, including therapeutics, diagnostics, and vaccines. The Infectious Diseases Society of America (IDSA) Influenza Task Force applauded these developments, but also felt that there needed to be a much greater effort. The following are their recommendations, which include some that will require additional support from Congress. These are addressed by a tabulation of priorities which address both seasonal influenza and preparedness for pandemic influenza:

  1. Strengthen pandemic influenza vaccine efforts by establishing a multinational pandemic influenza master program: The United States Department of Health and Human Services (HHS) has invested over $1 billion to develop cell-based vaccines, and HHS has stockpiled about 8 million doses of vaccine against clade one H5N1 (a possibly antiquated clade recovered in Vietnam in early 2004). The IDSA expressed concern about the "lack of coordination, rapid sharing of results, and transparency." Their proposal is for a global master program funded at the "scale of the Apollo Space Project" (funded at $73 billion from 1960-73). This would be a global plan to increase vaccine research and development and increase vaccine production capacity (which is now limited to 400 million doses of influenza vaccine/year for the world). The recommended investment is $2.8 billion for fiscal year 2007 from the United States on the basis of the World Health Organization (WHO) projection of a need for $3-10 billion of over 5-10 years for a global plan.

  2. Strengthen efforts for anti-infected pharmaceutical research and development and stockpiling: HHS plans to stockpile sufficient antiviral courses to treat 25% of the US population and has allocated $782 million in 2006 to purchase neuraminidase inhibitors. The HHS plan also includes $200 million in contracts for the development of new antiviral agents. The recommendation is to accelerate the development of an adequate stockpile, perform additional research on new agents, and establish methods to ensure equity in antiviral supplies.

  3. Improve quality and availability of diagnostic tools for influenza: This is needed to quickly and accurately detect pandemic influenza strains in the laboratory as well as at the point of care. Recent developments include the Flu Chip and the Influenza A/H5 virus real-time polymerase chain reaction (RT-PCR); these need to be developed and critically analyzed along with other novel detection methods.

  4. Accelerate development of countermeasures to prevent, treat, and diagnose pandemic influenza: The goal is to increase incentives for pharmaceutical companies and streamline the regulatory processes to facilitate production of products relevant to this effort, including vaccines and antivirals.

  5. Update US plans for countermeasure distribution and prioritization of use: The request is for national guidelines on the use of antivirals and vaccines. It is noted that the HHS plan does contain plans for distribution, but there is no tracking system for distribution and use of influenza vaccine currently available.

  6. Expand vaccine uptake, stabilize vaccine manufacture, and test and evaluate vaccine distribution plans during the annual influenza seasons: The case is made for promotion of more public uptake of vaccinations for seasonal influenza and a strong case is made for mandatory annual influenza vaccine for healthcare workers.

  7. Protect the healthcare work force during a pandemic: Healthcare workers are obviously critical to the response to pandemic influenza, but this work obviously puts them at substantial risk. The recommendation is to make this group a high priority for immunization and antiviral drug treatment and to establish an injury compensation fund as well as providing liability protection where relevant.

  8. Build national, regional, and local healthcare systems capable of responding to mass-casualty events: The request is to establish a national strategy to ensure a coordinated continuum of care during pandemic influenza. There are 3 components: (1) Establish protocols for a sustained medical surge capacity; (2) Provide training and credentialing of public health personnel for this task; and (3) Develop evidence-based guidance that will include guidelines for medical triage and allocation of scarce resources, including prioritization of equipment such as masks, ventilators, etc.

  9. Develop and test community mitigation measures: This refers to community interventions for "social distancing" including school closures, business closures, border closing, quarantines, prophylactic antivirals, mathematical modeling for disease containment, etc. The concern is that the science supporting the efficacy of these maneuvers is pretty thin and the request is for additional research and collaborative input from stakeholders and technical experts.

  10. Improve and coordinate influenza surveillance: The issue here is the importance of surveillance as a critical component to detect emergence of a novel influenza A virus. The request is to establish an effective surveillance system that will include the US healthcare system, public health, animal health, and global surveillance.

  11. Continue to strengthen leadership, international collaboration, and communication: There are 3 components: (1) Strengthen leadership by the federal government; (2) Foster international coordination; and (3) Improve communication to better educate public health and healthcare sectors.

  12. Allocate significant and sustainable funding for long-term planning and action: The Presidential request in 2005 was for $7.1 billion, and Congress has now allocated approximately $6 billion toward that effort. The concern is sustainability. Specifically, sustained funding is needed for the influenza vaccine development plan (the highest priority), stockpiling and distribution of vaccines and antivirals, surge capacity and planning, personnel, surveillance (US and international), and community mitigation.

Kandun IN, Wibisono H, Sedyaningsih ER, et al. Three Indonesian clusters of H5N1 virus infection in 2005. N Engl J Med. 2006;355:2186-2194. The study authors investigated 3 clusters of H5N1 cases in Indonesia:

  1. The first cluster involved 3 of 5 family members who lived together near Jakarta.

  2. The second cluster involved a 9-year-old boy who lived with the index case, his aunt, for a brief period during her illness.

  3. The third cluster involved 3 relatives living in the same village, but not in the same household.

  • Clinical features of the disease: the median time from onset of illness to hospitalization for the 8 cases was 7 days. This included cases of severe disease and 2 cases of relatively mild disease.

  • H5N1 testing: 5/5 patients with a confirmed diagnosis by RT-PCR; the same specimens tested negative with rapid antigen testing. All strains were susceptible to neuraminidase inhibitors. This was a clade 2 strain.

Conclusions: The study investigators, a total of 31 authors, concluded that their study documents clusters of clade 2 H5N1 virus and raises the question about genetic or other factors that may predispose to this virus infection or to serious disease. They also identified 3 pediatric patients with relatively mild disease in 2 clusters. They point out that the infections involving clade 2 were sensitive to amantadine as well as neuraminidase inhibitors, although the WHO does not recommend the amantadine due to high frequency of resistance. The study investigators also emphasize that their findings show a wide range of clinical features, including some patients with rather mild disease.

Tumpey TM, Maines TR, Van Hoeven N, et al. A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science. 2007;315:655-659. The authors address the issue of person-to-person transmission of avian strains of influenza A.

Methods: Receptor binding preference differs for avian and influenza strains. The hemagglutinin (HA) of avian influenza (H5) preferentially binds to alpha 2,3 sialic residues on epithelial cells, and these receptors predominate on epithelial cells in birds. By contrast, influenza strains that are common in humans (H1 and H2) preferentially bind to alpha 2,6 sialic residues that predominate in the upper airways of humans (Table 1). The preferential binding of humans vs birds is summarized in Table 1, which provides the background rationale for this study.

The authors used the reconstructed 1918 pandemic strain to determine the transmissibility of this strain in mammals when it was "avianized" by 2 amino acid mutations that switch receptor binding preference: The preferential alpha 2,6 binding of the parent (SC18) strain was changed to alpha 2,3 (AV18) or a mixture of alpha 2,3 and alpha 2,6 (NY18). Transmissibility was examined by infections in ferrets placed in cages next to healthy ferrets.

Results: The results of the experiment showed that the reconstructed initial strain (SC18) both infected ferrets and was efficiently transmitted. However, the mutated strains (AV18 and NY18) were transmitted poorly and showed that the human alpha 2,6 sialic acid binding preference was essential for transmission. These results are summarized in Table 2.

Conclusion: The authors concluded that the hemagglutinin receptor specificity plays an essential role in the transmission of influenza viruses among mammals.

Comment: This is an association which previously has been the subject of speculation. For pandemic influenza, 3 factors need to be present: (1) humans need to be susceptible due to immunologic naiveté; (2) the virus needs to cause disease in humans; and (3) there needs to be efficient person-to-person transmission. Avian influenza (H5N1) clearly has the first 2 required properties, but there has been no sustained human-to-human transmission, which now appears to be the Achilles' heel for pandemic influenza. The study noted above clearly supports this thesis. The implication is that H5N1 could become "humanized" with efficient human-to-human transmission with a few HA mutations. (In an editorial comment, influenza expert Yoshihiro Kawaoka from the University of Wisconsin suggested to news writer Martin Enersink that mutations in other genes are probably necessary as well.[1]).

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