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Homeland Security

REPORT TO THE PRESIDENT ON U.S. PREPARATIONS FOR 2009-H1N1 INFLUENZA



VIII. Planning for More Effective Future Strategies Against Influenza


CHAPTER SUMMARY

The current threat from 2009-H1N1 has highlighted critical shortcomings in public response systems to the emergence of new influenza strains and more generally to outbreaks of infectious diseases.

There are important opportunities to increase national preparedness against future epidemics. These include steps to improve: the design, production, and use of vaccines; the range of antiviral drugs; the availability of rapid diagnostics; and the breadth of health surveillance systems. Some of the steps can be achieved quickly (within the next year), while some will take longer.

We propose that the National Security Council coordinate a government-wide effort to increase national preparedness in response to the lessons learned from the 2009-H1N1 outbreak and provide periodic updates to the President on national progress toward these goals.

Introduction

The current situation with 2009-H1N1 has highlighted critical shortcomings in public response systems to the emergence of new influenza strains and more generally to outbreaks of infectious diseases. Given the emergence of multiple biological threats during the past decade (including SARS, avian flu, 2009- H1N1, and at least one instance of bioterrorism), it is likely that we will face continued challenges from infectious diseases. While there has been substantial progress in preparedness over the past several years, there is much work that needs to be rapidly completed. Even while we are dealing with 2009- H1N1, the Federal Government should take specific steps to ensure our preparedness for the next event. Some of these steps will also aid our national response to seasonal influenza.


MAIN RECOMMENDATION (CHAPTER 8)

There are important opportunities to increase national preparedness against future epidemics. These include steps to improve: the production and use of vaccines; the range of antiviral drugs; the availability of rapid diagnostics; and the breadth of health surveillance systems. Some of the steps can be achieved quickly (within the next year), while some will take longer.

We propose that the National Security Council coordinate a government-wide effort to increase national preparedness specifically in response to the lessons learned from the 2009-H1N1 outbreak and provide periodic progress updates to the President on national progress toward these goals.

Accelerate Speed and Increase Yield and Effectiveness of Vaccine Production

Current methods for producing influenza vaccine are too slow, cumbersome, and inefficient given the challenge of a rapidly spreading influenza virus epidemic. The predominant design and technologies used to produce influenza vaccines have not fundamentally changed in several decades: Viruses are grown in embryonated chicken eggs, then harvested and processed to create the vaccine. The process typically takes 6 to 9 months, from initial steps to develop a “seed” vaccine virus to completed product. Moreover, when a novel virus is isolated late in an influenza season (as was the case with 2009-H1N1), it is difficult or impossible to prepare and test vaccine before the resurgence in the next influenza season (which, moreover, tends to occur early for novel viruses).

Recently, there has been progress on two new approaches for vaccine production:

  • Cell-based vaccines , in which viruses are grown in cultured cells rather than eggs. This method obviates the need for large quantities of embryonated eggs and potentially permits increased levels of production beyond those currently achievable. The method, however, does not sub­ stantially shorten the timeline between identification of the virus strains to be included in the vaccine and the vaccine’s availability. This approach is currently being used by several companies to produce candidate 2009-H1N1 vaccines, but such cell-based vaccines have not yet achieved licensure in the United States .

  • Recombinant vaccines , in which molecular biology techniques are used to clone influenza virus vaccine proteins into various expression systems. There are several such methods currently under development and evaluation, including some by industry and by the Defense Advanced Research Projects Administration (DARPA). This approach has potential to shorten the time between vaccine strain identification and final vaccine production to as little as a few months, as well as provide a large increase in vaccine production volume. However, considerable additional development and clinical work is required to firmly prove the effectiveness of these technolo­gies and to provide the necessary data for eventual licensure.

In addition to the pursuit of these approaches, greater efforts should be made to take advantage of modern understanding of influenza virus epitopes (the sites on proteins that induce immunity), three- dimensional protein structure, the mechanisms of immune recognition, and the sites on influenza viral proteins at which the most significant variation is observed. By harnessing such information to new methods for protein design and genetic engineering, it is possible to envision influenza vaccines of the future that provide longer-lasting immunity against a wider range of viral isolates. Such vaccines might be produced efficiently as proteins in a variety of expression systems or as attenuated viruses grown in cell culture systems.

In addition to improving vaccine design and technology for vaccine production, efforts need to be undertaken to assess and license adjuvants that are compatible with influenza vaccines. Adjuvants can greatly increase the potency of vaccines and thereby extend the number of people who can be vac­ cinated with a given supply. None is currently approved for use with influenza vaccines in the United States , although adjuvants have been approved and are being used with influenza vaccines in Europe .

The use of adjuvants thus currently requires Emergency Use Authorization (EUA), a step that regulators may be reluctant to take. Although clinical trials of 2009-H1N1 vaccines with adjuvants are planned for the coming months, it will not be feasible to obtain standard FDA approval in time for use this fall. Nonetheless, it would be desirable to achieve licensure of the currently available adjuvants for use in the near future. Beyond existing adjuvants, recent advances in immunology point the way to powerful new types of adjuvants, the pursuit of which may ultimately enhance the efficacy and lower the costs of influenza vaccines.

Even while these new products are being developed and tested, it is important that the Federal Government ensure that capacity is maintained for influenza production by traditional approaches for the foreseeable future. Capacity was increased in preparation for a potential avian influenza (H5N1) pandemic and is thus available for response to the current 2009-H1N1 pandemic. However, if such high capacity levels are not needed over the coming years, companies may reduce production capacity to bring it more in line with the lower anticipated demand for seasonal influenza vaccine. The prospect of such reduced capacity, which would limit the ability to respond to novel influenza pandemics, provides further incentive for developing more efficient means of production.


RECOMMENDATION 8-1: VACCINES

We recommend that the Federal Government work to:

    A. ensure that influenza virus vaccines produced in cell culture, as well as vaccines formulated with the currently available adjuvants, proceed expeditiously through the FDA regulatory process for licensure;

    B. fully support and encourage development of recombinant influenza vaccines and provide a clear regulatory path for licensure;

    C. encourage and support the development of new adjuvants; and

    D. ensure that adequate manufacturing capacity is maintained for production of influenza vaccine using currently approved methods.

 

Facilitate Development of Additional Antiviral Drugs

There is an urgent need to expand the available range of antiviral drugs that can be used for prophy­ laxis or treatment of influenza. Currently, there is only a handful of antiviral drugs and only two that are licensed and expected to be effective against 2009-H1N1: the oral drug oseltamivir (Tamiflu) and the inhaled drug zanamivir (Relenza). There currently are no antiviral drugs approved for intravenous use to treat seriously ill patients—although one new drug (peramivir) and the two existing drugs are also being tested in intravenous formulations.

Moreover, these options may narrow further as influenza viruses develop resistance to these drugs. Most seasonal influenza has already developed resistance to oseltamivir, and a handful of cases of oseltamivir­ resistance have been reported among 2009-H1N1 isolates (nine as of the end of July), indicating that this virus can also develop resistance.

It will be important to develop new classes of drugs to expand the armamentarium. A particularly promising new approach is to develop drugs that block the virus by acting on a human cellular function (‘host target’), rather than a viral protein (‘pathogen target’), because such drugs should be less likely to encounter acquired resistance.

RECOMMENDATION 8-2: ANTIVIRALS

We recommend that the Federal Government work to:

    A. expedite the licensure of intravenous formulations of antivirals, and

    B. stimulate the development of new influenza drugs that have novel mechanisms of action in order to reduce the potential for antiviral resistance.

Facilitate Development of Rapid Point-of-Care Diagnostics

Influenza can be difficult to diagnose because similar symptoms can be caused by agents other than the influenza virus, including adenovirus, respiratory syncytial virus, rhinovirus, parainfluenza viruses, mycoplasma, and other agents. Moreover, it is important to be able to distinguish among different influenza strains, such as seasonal influenza and 2009-H1N1 influenza, because resistance patterns and drug-of-choice may vary. Definitive diagnosis can be important to guide medical decisions for individual patients and to permit accurate epidemiological surveillance.

Accurate diagnostic tests for distinguishing different influenza strains are available, but they (i) require several hours to days to provide results, (ii) are not readily deployed in physicians’ offices or even hospital settings, (iii) have limited sensitivity, and (iv) are available in only limited capacity that will be overwhelmed in a serious pandemic. The Nation needs the capability to perform rapid, simple, point­ of-care diagnostics. The competence and capability to develop such diagnostics exists in many places, including CDC, NIH, DARPA and DHS, and the importance of this issue warrants strong, mission-driven coordination of efforts across these agencies.


RECOMMENDATION 8-3: DIAGNOSTICS

We recommend that the Federal Government ensure the creation of a national capability to develop, on a rapid basis, accurate point-of-care diagnostics for any novel influenza virus. Such an effort might be led by DHHS, in coordination with DOD and DHS.

Improve Medical Surveillance

As described in detail in Chapter 4, there are substantial gaps in the Nation’s medical surveillance systems that limit our ability to obtain accurate, real-time information about epidemics. Some of these gaps can be closed quickly, but a more systematic, long-term effort to eliminate them would substantially improve national preparedness.

Surveillance preparedness to date has emphasized early detection of an outbreak (e.g. early knowledge of an anthrax attack), while underplaying the role of ongoing surveillance once an outbreak of infectious disease is underway. In the case of influenza, while the United States has systems to provide epidemio­ logical and virological data on influenza, we are still not able to make confident estimates each week of the number of people who are infected, seek medical care, are hospitalized, or die of influenza. Notably, the UK measures and publicizes many of these statistics weekly.

Such “situational awareness” is essential for an evaluation of the characteristics of the pandemic, effec­ tive allocation of resources to places of greatest need, and appropriate changes in mitigation and other response strategies over the course of a pandemic. Moreover, the ability to make such estimates would improve diagnosis and treatment of respiratory infections in general and of influenza specifically, both in normal and pandemic years, and would provide a basis for greater cost-effectiveness. The estimates could be obtained with a nationally representative electronic reporting system for primary care and emergency visits, hospitalizations, ICU admissions, and deaths for defined respiratory infections, com­ bined with viral testing of a representative subset of these individuals. This would permit public health departments to assess the contribution of various viruses to the disease burden at each level.

A second key shortcoming in our preparedness is the lack of a rapid system for assembling detailed clinical data on severe cases that can provide a statistically adequate and continuously updated picture of risk groups and clinical course. Current systems rely on non-standardized reports from local health departments and on peer-reviewed case series, which are slow to become public.

As the current pandemic continues to unfold, other key gaps in our situational awareness will likely emerge. These revelations should be a basis for improving public health information systems.


RECOMMENDATION 8-4: MEDICAL SURVEILLANCE

We recommend that CDC take steps to improve surveillance systems for use in epidemics. This could include:

    A. working with state and local authorities to establish a dense, geographically diverse, nation-wide, real-time surveillance network that can estimate population rates of primary care and emergency visits, hospitalizations, ICU admissions, deaths from defined respiratory syndromes, and (in a random sample of cases) presence of specific viruses.

    B. working with a set of large hospitals, at least one in each of the top 30 metropolitan areas together with the respective local authorities, to establish a system for standardized local and national reporting of demographic, laboratory, and clinical characteristics of hospitalized and more severe cases of defined syndromes, including but not limited to influenza.

We also recommend that after the current pandemic DHHS undertake a comprehensive review of unmet needs for data, possible solutions to the problems of providing such data under emergency conditions, and the costs of building the necessary surveillance systems.

Enhance Animal Surveillance Measures

Birds and pigs serve as critical intermediate hosts in the evolution of influenza viruses, including the current 2009-H1N1 virus. Methods for monitoring influenza viruses in swine and turkeys are powerful tools for following the appearance, spread, and evolution of viruses, and such surveillance would be valuable for both human public health and agriculture. Currently the United States lacks a reliable system for doing this, but a NIH-funded surveillance program of apparently healthy pigs at a slaughterhouse in Hong Kong has established the benefits of such a system.


RECOMMENDATION 8-5: USDA AND CDC COLLABORATION

We recommend that USDA and CDC collaborate to develop a cooperative program of human and animal public health that includes:

    A. prospective virological and serological surveillance of swine and turkeys, and the workers exposed to them, at permanent sites, to serve as an early warning system of potentially pandemic influenza viruses of humans, swine, and turkeys.

    B. expanded sharing of influenza viruses, viral sequence information, and reagents.



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