Meeting the Challenge of Influenza Pandemic Preparedness in Developing Countries

One-sentence summary for table of contents: These countries should consider using inexpensive generic agents to confront the next pandemic.

M ore than a decade ago, the fi rst human cases of disease caused by avian infl uenza virus A (H5N1) appeared in Hong Kong Special Administrative Region, People's Republic of China. Six years ago, infl uenza virus A (H5N1) reemerged to cause highly lethal human disease in Southeast Asia. Health offi cials are concerned that these cases could be the harbinger of the next infl uenza pandemic. As a result, virtually all industrialized countries and many developing countries have mounted extensive pandemic preparedness efforts. However, as pointed out recently by Oshitani et al., industrialized countries face "unique and diffi cult issues, which make preparing for a pandemic more challenging" (1).

Why a Top-Down Approach to Confronting the Next Pandemic Will Not Work
If a pandemic form of infl uenza virus A (H5N1) emerges within the next few years, all countries will have to depend almost entirely on egg-derived inactivated adjuvanted infl uenza vaccines. For developing countries, this approach will not succeed. Estimates show that within the fi rst 6-9 months of a pandemic outbreak, vaccine companies will be only able to produce enough doses to vaccinate ≈700 million persons (2). This number is less than the combined populations of the 9 countries that produce almost all of the world's seasonal infl uenza vaccines. These countries will fi rst use their vaccines to ensure that their own populations are protected. Non-vaccine-producing countries, both industrialized and developing, will have to wait.
In 2005, a representative of the World Health Organization (WHO) Global Programme on Infl uenza concluded that "most developing countries will have no access to a vaccine during the fi rst wave of a pandemic and perhaps throughout its duration" (2). Since then, WHO has worked to build a stockpile of ≈150 million doses of vaccine against infl uenza virus A (H5N1) for developing countries (3), and 2 companies have pledged to provide WHO with 110 million doses. In 2007, a WHO scientifi c consultation on how to use this stockpile concluded, "If there is suffi cient early warning that an outbreak of infl uenza (H5N1) is due to a virus that is capable of sustained human-to-human transmission, then theoretically there may be a relatively limited 'window of opportunity' to stop the spread of the virus before it spreads nationally or internationally. … However, a containment effort would be feasible only in settings where the number of localized cases are [sic] still limited, where adequate logistical support is available, and where the national government is supported by international assistance" (3). The vaccine stockpile on which these efforts would depend does not yet exist.
Several industrialized countries are stockpiling vaccines against infl uenza virus A (H5N1) that might be used for prepandemic vaccination, but Oshitani et al. note that "both pandemic and prepandemic vaccines would not be available in developing countries unless an international mechanism exists to share such vaccine with them at low cost" (1). Even if limited supplies of vaccines could be produced for developing countries, no international mechanism is in place to pay for and distribute the vaccines, and WHO has yet to announce plans to set one up. Thus, when the next pandemic virus emerges, almost no vaccines will be available in developing countries to slow its spread (1,2).
Because global supplies of vaccines against pandemic viruses will be limited, government offi cials in a few industrialized countries have placed their hopes on stockpiles of antiviral agents, primarily oseltamivir, an expensive neuraminidase inhibitor. In 2005, WHO established its Southeast Asian Infl uenza Clinical Research Network to study neuraminidase inhibitor treatment of patients infected with viruses that possess pandemic potential (4). However, infl uenza virus A (H1N1) has developed resistance to oseltamivir, and similar antiviral resistance could develop in a future pandemic virus. Five million treatment courses (10 doses per patient) of oseltamivir have been donated to a WHO stockpile, but WHO has no plans to dramatically increase the size of this stockpile. On their own, the governments of a few countries that do not produce infl uenza vaccines or antiviral agents have purchased supplies of oseltamivir, but their stockpiles are suffi cient to treat only 1% of their combined populations (D.S. Fedson, unpub. data). Not surprisingly, developing countries themselves "will not allocate scarce resources to stockpile signifi cant quantities of oseltamivir for an unpredictable infl uenza pandemic" (1). Clearly, the limited supplies of antiviral agents available to developing countries where these infections now occur will scarcely have any effect on a pandemic after it starts to spread.
Infl uenza virologists report that recent isolates of highly pathogenic infl uenza viruses (H5N1 and H7N1) have acquired molecular characteristics suggesting they might become more easily transmissible among humans (5,6). In Indonesia, physicians have reported that everyone infected with the clade 2 infl uenza virus A (H5N1) who did not receive antiviral treatment has died (Table 1) (7). Given extremely limited global supplies of antiviral agents, this is a terrifying observation. If a pandemic virus were to emerge with a level of virulence approaching that of infl uenza virus A (H5N1) in Indonesia, it could lead to a global population collapse. Many infl uenza virologists doubt this will ever happen and believe instead that infl uenza virus (H7N7) or reemergent infl uenza virus (H2N2) could also cause the next pandemic. Chances are they might be right. Moreover, health offi cials in national governments and international agencies estimate that expected pandemic deaths will be no more than what can be extrapolated from the 1918-1920 pandemic (8). These offi cials seldom, if ever, use the phrases "population collapse" or "population die off," and their estimates may also be right. Nonetheless, in a seminal experiment reported in 1974, Webster and Campbell showed that genetic reassortment, the process that gave rise to pandemic viruses in 1957 and 1968, could give rise to a readily transmissible virus of extraordinary virulence (Figure) (9). This experiment and human experience with infl uenza virus A (H5N1) in Indonesia suggest it would be prudent for all countries to plan for something much worse than what occurred in 1918-1920.
The current approach to pandemic planning for all countries involves small groups of health offi cials, infl uenza scientists, and company executives, most of whom come from industrialized countries. For the foreseeable future, this top-down approach will be incapable of providing developing countries with timely supplies of affordable vaccines and antiviral agents. (Most industrialized countries that do not produce infl uenza vaccines will have similar diffi culties, at least for the fi rst pandemic wave.) The Indonesian Health Minister, for one, understands this. With little prospect that people in her country will be able to obtain vaccines against pandemic viruses, she precipitated a standoff with WHO by announcing in February 2007 that unless Indonesia is able to gain access to supplies of vaccines against pandemic viruses, her country will no longer share its infl uenza viruses A (H5N1) with WHO's laboratory-based surveillance system (2). Despite unorthodox arguments (10), her position has garnered wide support from the health ministers of many developing countries (11). Recently, Indonesia agreed to share infl uenza virus A (H5N1) sequences (not the viruses themselves) with the Global Initiative on Sharing Avian Infl uenza Data, but the country no longer promptly reports deaths from infl uenza virus A (H5N1), in defi ance of new International Health Regulations. WHO has been unable to come up with a solution to this impasse. In identifying the major issues and challenges of a pandemic threat facing developing countries, Oshitani et al. have called for better preparedness planning, improved systems for medical care and public health, expanded use of nonpharmaceutical interventions, and strengthened core capacities for seasonal infl uenza surveillance and vaccination (1). They recognize that this is a challenge few developing countries will be able to meet, but go on to say, "Preparing for a pandemic by simply strengthening preparedness within a single country is not possible. A pandemic is a global issue, and pandemic preparedness should be considered from a global perspective" (1). In practical terms, what exactly does this mean? The record thus far indicates that truly international efforts to prepare for pandemic vaccination and antiviral use have been meager. In almost all instances, these efforts have been vastly outweighed by efforts that refl ect national concerns and interests.

A Bottom-Up Approach that Developing Countries Can Use to Confront the Next Pandemic
A top-down approach will not ensure that adequate and affordable supplies of vaccines against pandemic viruses and antiviral agents can be produced and distributed in time to protect populations in developing countries. Transferring technology for vaccine and antiviral agent production to a small number of developing countries will proceed slowly and will inevitably fail to meet the needs of neighboring countries not favored by these programs (12). Consequently, developing countries must consider an alternative bottom-up approach to pandemic control, an approach based on existing healthcare workers and institutions and that uses inexpensive and widely available generic agents that have intrinsic antiviral activities or that modify the host response (13,14).
Many infl uenza scientists doubt this approach will work (14)(15)(16). Nonetheless, as reviewed elsewhere (13,14), several retrospective studies suggest that outpatient statins (drugs taken to lower cholesterol levels and prevent cardiovascular diseases) reduce 30-day pneumonia mortality rates by ≈50% (Table 2) (17)(18)(19)(20)(21)(22). Most investigators agree that these observational studies must be interpreted with caution and that promising results should be followed by prospective clinical trials. One such trial is already under way, and a preliminary report has shown that in 67 pneumonia patients in intensive care units, treatment with statins reduced the hospital mortality rate by 51% (p = 0.026) (23). Pulmonary investigators also believe that peroxisome proliferator-activated receptor (PPAR) α and PPARγ agonists (fi brates and glitazones, respectively) could be used to treat acute lung injury (14). An important experimental  study has shown that the fi brate gemfi brozil, a PPARα agonist used to prevent heart disease, reduced mortality rates in mice infected with infl uenza virus (H2N2) by 54% (24). Statins and PPAR agonists have antiinfl ammatory and immunomodulatory activities, and there is considerable molecular cross-talk between these agents (14). Moreover, combination treatment is safe, and in patients with cardiovascular diseases, clinical benefi ts are additive. Used either alone or together, this treatment might similarly benefi t patients during an infl uenza pandemic. Other generic agents, some with direct activity against infl uenza virus, should also be considered (14). Chloroquine, long used as an antimalarial drug, increases endosomal pH and acts as an antiviral agent by impairing virus release into the cytosol. Resveratrol, a polyphenol found in red wine, reduces infl uenza mortality rates in experimentally infected mice (25). Catechins (found in green tea) (26) and curcumin (turmeric; found in curry powder) (27) have numerous cell-signaling effects, suggesting that they too might be benefi cial. A combination of agents that act on both the host response and the virus might be required.
It is becoming increasingly diffi cult for investigators to ignore arguments for treating the host response to infl uenza. Recently, investigators showed that giving a neuraminidase inhibitor to mice infected with infl uenza virus A (H5N1) was not nearly as effective as treating the mice with an antiviral agent and 2 immunomodulatory agents, mesalazine, a PPARγ agonist, and celecoxib, a cyclooxygenase (COX)-2 inhibitor (28,29). In this model, targeting the host response to infection was essential for improving survival rates and times. More important, 2 studies in mice showed that intratracheal administration of either a fragment of the PB1-F2 protein of the 1918 infl uenza virus (30) or an inactivated infl uenza virus A (H5N1) (31) caused severe acute lung injury similar to that seen in fatal human cases of infl uenza (either from the 1918-1920 pandemic or from the current H5N1 subtype). In these experimental models, there was no virus replication. Thus, antiviral agents would have had no effect. Although we still lack direct evidence that one or more antiinfl ammatory and immunomodulatory agents alone would effectively treat human infl uenza virus A (H5N1) infections, these results and those from the study of infl uenza virus (H2N2)-infected mice treated with gemfi brozil (24) suggest these agents might be effective.
What makes these agents so important is that many of them are currently being produced as generic drugs in developing countries (13,14). These drugs are inexpensive, could be produced in abundance, and could even be stockpiled and made available for use on the fi rst day of a pandemic. No matter what is accomplished in the years ahead, adequate supplies of vaccines and specifi c antiviral agents will never be available to persons in developing countries on the fi rst pandemic day.

A Research Agenda to Establish a Generic Approach to Pandemic Treatment and Prophylaxis
What types of research on generic agents do we need before the pandemic virus appears? First, experimental studies of several candidate treatment regimens must be undertaken in mice infected with infl uenza virus A (H5N1) or 1918-like viruses ( Table 3). The agents used in these studies might have antiinfl ammatory and immunomodulatory or antiviral properties (some might have both), but all must be generic agents that are currently produced in developing countries. Admittedly, these experimental studies in mice will have limitations (32), but they should identify avenues for further research. Once a few treatment regimens have been shown to be effective in mice, they should be tested in  ferrets. Later, 2 or 3 of the most promising regimens should be tested in nonhuman primates. After demonstrating the effectiveness of 1 or more treatment regimens in animals, infl uenza virologists should then use in vitro systems to defi ne the molecular mechanisms responsible for their protective activity. However, some of these agents will have broader effects on the host response. For example, although administering a COX-2 inhibitor along with a PPARγ agonist improved survival rates and times in mice infected with infl uenza virus A (H5N1) (21), another study showed that selective COX-2 inhibition was detrimental to the resolution of acute lung injury (33). Most infl uenza scientists focus their research on the virus or on cell-signaling events associated with viral pathogenesis (34). Yet the pathophysiologic effects of severe infections involve the entire host, something well known to researchers who study sepsis (35)(36)(37). Their studies have shown that statins and PPAR agonists stabilize myocardial and microvascular function, preserve integrity of pulmonary endothelial cell tight junctions and prevent pulmonary edema, and promote resolution of acute infl ammation (13,14). Thus, other investigators with laboratory and clinical expertise in critical care, cardiopulmonary diseases, and endocrinology and metabolism must be recruited to explore in animals the molecular mechanisms underlying these broad treatment effects on the host. However, in undertaking this research, investigators must not forget that their primary goal is to fi nd effective ways to manage a pandemic in populations and not simply to explain in more precise terms the harmful effects of pandemic virus infection in individuals.
While these studies are under way, an analysis should be undertaken for each candidate agent to determine which companies produce them, where each is manufactured, annual levels of production (and surge capacity), patterns of distribution to other developing countries, and costs for public markets (Table 3). Special attention must be given to companies that follow Good Manufacturing Practices to minimize the risk that some of these agents might be counterfeit. When animal studies have defi ned 1 or more promising regimens, an international process must be set up to develop logistics for fi nancing, producing, and distributing each agent.
Where feasible, clinical trials of promising treatment regimens might be undertaken in patients with severe seasonal infl uenza. In a few instances, clinicians might choose to treat patients infected with infl uenza virus A (H5N1) on a compassionate basis (12). However, none of these limited studies will guarantee that promising treatments in the prepandemic period will be effective against a true pandemic virus. Thus, careful plans must be made during the prepandemic period that will enable investigators to conduct randomized controlled trials of promising generic regimens during the early weeks of a new pandemic. If the case-fatality rate is similar to that of infl uenza virus A (H5N1) (≈60%), trials will not need to be large (Table 4). Within a few days, investigators should be able to recruit suffi cient numbers of patients to satisfy statistical requirements.
Planning for clinical trials during the prepandemic period must start with identifying clinical investigators who will conduct these trials and institutions that will sponsor their work. Supplies of the agents to be tested must be set aside, study protocols written, and ethical approval obtained. A mechanism for rapid regulatory approval must be developed to enable trials to be conducted wherever the pandemic virus fi rst emerges. A fi nancing mechanism must be established that enables immediate access to funds necessary to support the trials. Finally, an internet-based communication strategy must be devised that ensures prompt dissemination of study results to physicians and health offi cials worldwide.
None of this research on generic agents will be possible without international coordination. Thus far, the topdown approach that has characterized vaccine and antiviral research and development has lacked an international system for coordination and management to ensure rapid progress (2). Likewise, nothing has been done to ensure worldwide production and distribution of the vaccines and antiviral agents being developed. A similar approach must not be allowed to govern the research agenda for generic agents.
Experience with the severe acute respiratory syndrome (SARS) in 2003 shows us how we could do much better. When SARS fi rst came to international attention, WHO quickly established 3 virtual networks of experienced virologists, clinicians, and epidemiologists (38). By sharing experiences and fi ndings on secure websites and in daily teleconferences, investigators soon identifi ed and sequenced the SARS coronavirus, defi ned the clinical fea- Table 3. Research agenda to establish whether generic agents could be used for treatment and prophylaxis of a pandemic caused by a subtype H5N1-like influenza virus 1. Test candidate treatment regimens in mice, ferrets, and nonhuman primates to identify specific generic agents that might be effective in managing a pandemic 2. Study promising generic treatments in cell culture and animals to define the molecular mechanisms that explain their beneficial effects against influenza virus A (H5N1) and 1918like influenza viruses 3. Conduct a global analysis to identify developing countries where these generic agents are produced and determine quantities produced, surge capacities, patterns of distribution, and costs to public programs 4. Establish an international process to coordinate or manage the stockpiling of generic agents and/or their distribution once a pandemic virus has emerged 5. Plan to conduct randomized controlled trials of promising generic treatments immediately after the emergence of a new pandemic virus tures of the disease, and established practical measures for clinical management and epidemiologic control. Surprisingly, WHO has not set up a similar system to coordinate research and development of vaccines against pandemic viruses and antiviral agents, despite the far greater threat to global health inherent in an infl uenza (H5N1) pandemic (2). Given escalating pressure from developing countries, WHO can ill afford to adopt the same slow approach to establishing the scientifi c basis for using inexpensive and widely available generic agents for pandemic control.

Conclusions
Oshitani et al. correctly emphasize that preparing for the next pandemic requires a global perspective, but this does not necessarily mean that the measures used to confront the pandemic in developing countries must be supplied through an internationally organized top-down process. An international process will surely be required for distributing vaccines and antiviral agents, but experience indicates that the process will be slow and cumbersome and supplies of these agents will remain scarce (2). Nonetheless, developing countries will need abundant supplies of effective agents, and abundance will be guaranteed only if these agents are generic, inexpensive, and produced in developing countries themselves.
It is too soon to know whether generic agents could be used to confront the next infl uenza pandemic, yet developing countries lack realistic alternatives. For this reason, their leaders must convince scientists and international organizations, including WHO, of the urgent need for research to determine whether these inexpensive agents could mitigate the effects of a pandemic. Otherwise, developing and industrialized countries alike could be faced with an unprecedented global health crisis.