Saturday, March 25, 2023
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As noted in Part I, the optimal means of control of an influenza pandemic would include the use of safe, effective, affordable, and widely available vaccines and antiviral drugs. Unfortunately, such tools are unlikely to be available in large quantities when the next pandemic arrives. Furthermore, the optimal usage of drugs and vaccines that do exist is far from clear. Nonetheless, as outlined below, there have been several promising recent developments in both drugs and vaccines directed at influenza.
Several vaccine makers are currently working on vaccines that could prevent infection by influenza strains with pandemic potential. A recently described, US Food and Drug Administration (FDA)-approved killed virus vaccine against H5N1 influenza has been the subject of clinical trials, in which it has appeared safe and immunogenic.[1]
The rarity of human H5N1 means that effectiveness of this vaccine has to be estimated indirectly, based on its ability to generate an antibody response in vaccinated individuals. Other concerns that relate to all current vaccines in development for use in an influenza pandemic include: (i) difficulties related to producing vaccine in sufficient quantities to provide rapid vaccination to large numbers of people at risk for pandemic influenza; (ii) the possibility that vaccine stockpiles may deteriorate prior to pandemic emergence, further diminishing the availability of vaccine supplies; (iii) the requirement of multiple doses of vaccine to achieve immunity, which diminishes the effective amount of vaccine available and makes rapid establishment of immunity in vaccinated individuals difficult; (iv) uncertainty related to whether the pandemic strain that ultimately emerges will be H5N1, although that certainly seems to be the most likely candidate at the time of writing; and (v) the possibility that, even if the pandemic strain is H5N1, sufficient antigenic drift will have occurred that current vaccine formulations provide little cross-protection against the actual pandemic strain.
It is assumed in most current pandemic plans that an effective vaccine will not be available in large quantities during initial pandemic waves, but that vaccine production will be scaled up over time. As such, pandemic planners must deal with the difficult question of who should be vaccinated early in an influenza pandemic to prevent extreme societal disruption, and to attenuate the impact of disease transmission. Such decisions require difficult choices: should scarce vaccine be given to healthcare workers who need to care for the sick? Should those with underlying medical conditions, who are most likely to die of influenza, be vaccinated? What about essential service workers, such as police, utility workers, and those involved with maintenance of the food supply? Children and adolescents may be the most efficient transmitters of influenza, but may be less likely to become severely ill: should the primary aim of vaccination be to reduce disease spread, or to attenuate illness in exposed individuals?
There are no clear answers to these questions, but prioritization is important. The US Department of Health and Human Services has prepared a draft document on prioritization in the face of limited quantities of vaccine, which may be obtained via the Internet at: http://www.pandemicflu.gov/vaccine/prioritization.html
Clearly, the anticipated shortfall in vaccine supply in the face of a pandemic is a major concern. Current research and preparedness are aimed at developing cell culture-based (rather than egg-based) vaccine production efforts, which will likely facilitate rapid expansion of vaccine supply, and which should prove more robust than egg-based methods in the face of pandemic-related societal disruption. Other research efforts include evaluation of lower dosing schedules, the use of immunogenic adjuvants,[2] and intradermal routes of vaccine administration: each of these could have the advantage of reducing the amount of vaccine required to generate immunity in the population, and effectively augment the available supply of vaccine. It is the stated goal of the US government that sufficient vaccine be available at the beginning of a pandemic to provide protection to approximately 10 million front-line medical and emergency support workers (ie, 20 million doses of a 2-dose vaccine), and that the country have the capacity to produce sufficient vaccine for the entire population in a 6-month period (http://www.whitehouse.gov/homeland/nspi_implementation_briefing.pdf). Given that this quantity exceeds the maximum annual output of all available US vaccine facilities, it is clear that much work remains on strengthening and expanding vaccine production capacity before the next pandemic strikes.
As with vaccines against pandemic influenza strains, a survey of current options with respect to antiviral drugs for mitigation
of pandemic severity provides a mix of challenges and encouraging developments. Antiviral drugs may play several different
roles in a pandemic situation: these drugs diminish the severity of seasonal influenza, and might be used to provide treatment
to critically ill individuals; however, antiviral drugs can also be used for postexposure prophylaxis, and have been used
for control of influenza outbreaks in healthcare institutions and long-term care facilities. As such, it is possible that
antiviral prophylaxis might be used to contain small influenza outbreaks that follow initial importation of a pandemic strain
into North America, but the utility of postexposure prophylaxis during a full-fledged influenza pandemic may be
limited.[3]
A description of novel antiviral agents for the treatment of influenza is the subject of an excellent recent review.[4] Novel drug classes, including drugs that target viral polymerases and hemagglutinin receptors, may be part of a future armamentarium of anti-influenza drugs, and the drug ribavirin has activity against influenza, although toxicity and cost may limit its wide application. However, at the time of writing, only 2 classes of antiviral drugs, adamantanes (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir), are available for the prevention and treatment of influenza infection. Furthermore, the adamantanes, notwithstanding a proven track-record in reducing viral shedding, and preventing secondary cases in outbreak situations,[5] are unlikely to be useful in a future pandemic situation, due to the rapid emergence of antiviral resistance when these drugs are used. Indeed, most seasonal H3N2 viral strains now circulating in the United States are resistant to adamantanes, and resistance to both H3N2 and H1N1 strains is common in Asia. The H5N1 influenza strain, the current subject of concern due to pandemic potential is, unfortunately, also resistant to adamantanes.[3] The situation with neuraminidase inhibitors is more hopeful. These drugs act by preventing viral neuraminidase from cleaving newly formed virions from infected cells. To date, resistance to these agents in H5N1 strains, and other circulating viral strains, has been uncommon, though emergence of resistance following antiviral exposure has been described.[6] Like adamantanes, these drugs appear to be effective both in prophylaxis of influenza in exposed individuals, and in decreasing the severity of influenza caused by seasonal influenza strains.[5] A recent systematic review and meta-analysis estimated that treatment with neuraminidase inhibitors reduces the risk of severe complications of influenza by approximately 60%.[5] Although these drugs have not been particularly helpful in reducing the extremely high case-fatality rate associated with H5N1 influenza in humans, it has been suggested that this lack of success might relate at least in part to late application of these drugs, due to the occurrence of human H5N1 cases in largely poor, rural areas[3] (the drugs appear most effective if given within 48 hours of illness onset). At the time of writing, only oseltamivir can be administered systemically, while zanamivir is administered intranasally, but a parenteral formulation of zanamivir is currently being developed.
Assuming that the pandemic strain that ultimately emerges is sensitive to neuraminidase inhibitors, and that antiviral resistance does not emerge rapidly once widespread use occurs for pandemic control, the neuraminidase inhibitors would be important tools for the mitigation of a future pandemic. However, as is the case with vaccine stocks, adequate availability of antivirals in a pandemic situation depends on stockpiling during the pre-pandemic period, and consideration of how these limited stocks will be distributed in the early days, weeks, and months of a pandemic. Also analogous to vaccine stockpiling is the necessity of continuously refreshing antiviral drug stockpiles, such that old, inactive drug is constantly replaced with new product. The United States is currently building a large stockpile of neuraminidase inhibitor doses; the projected allocation scheme for these drugs in the event of a pandemic is available at http://www.pandemicflu.gov/plan/states/antivirals.html. Because these drugs are costly, it might be asked whether maintenance of stockpiles of antiviral drugs is economically feasible.
This question was the subject of a recent health economic analysis, based on the projected impact of an influenza pandemic in Singapore.[7] These authors, using a model-based approach, projected that having adequate antiviral stockpiles to treat 40% of Singapore's population of 4.2 million would prevent several hundred deaths, and also save over 400 million Singapore dollars (approximately 275 million US dollars). Under more pessimistic assumptions related to pandemic severity, larger stockpiles, and the use of antiviral prophylaxis to prevent infection became economically attractive. Of course, the "up front" cost of maintenance of such a stockpile, (and replenishing drug stocks every 4 years) was large as well (estimated at around 50 million Singapore dollars annually in the base case). As such, the economics of stockpile maintenance depend in large part upon the presumption that a pandemic will indeed occur in the next 1-2 decades.
In summary, at the beginning of the 21st century, an influenza pandemic appears inevitable rather than likely. The nature of this pandemic cannot be predicted with certainty, but the virulence of the current leading candidate strain (H5N1) is extremely concerning. Meeting this threat requires planning, resources, and innovation before the pandemic strikes. As Albert Camus wrote in his novel The Plague, "There have been as many plagues as wars in history, yet always plagues and wars take people by surprise"; it is important that the next pandemic not have the element of surprise on its side.
That said, never before have such efforts been devoted to pandemic preparedness, either in the United States or internationally. Innovations in drug and vaccine development, cooperation between human and animal health authorities, efforts at truly global surveillance, and the successful "dress rehearsal" seen with severe acute respiratory syndrome containment, all provide hopeful notes in an otherwise stark scenario. Should we be fortunate enough to avoid an H5N1 pandemic, these efforts will not have been wasted, because the strengthening of surveillance and public health and hospital infrastructure will pay dividends in confronting the multitude of emerging infectious disease threats that currently face both developed and developing countries.
This activity is supported by an independent educational grant from GlaxoSmithKline
