We examined the costs and benefits of antiviral and vaccination strategies for an influenza A (H5N1) pandemic in a metropolitan city and defined ranges of vaccine effectiveness and population coverage necessary to avert the pandemic. An expanded adjuvanted vaccination strategy layered onto existing pharmaceutical and non-pharmaceutical HHS pandemic mitigation strategies is the most effective strategy and is cost-effective. A strategy of increasing the number of individuals receiving extended-duration antiviral prophylaxis delays the pandemic.
Higher vaccine effectiveness and greater population coverage are the two most important factors in the adjuvanted vaccination strategy's relative effectiveness and cost-effectiveness. Our assumption about effectiveness is supported by studies suggesting that adjuvanted vaccination increases human A (H5N1) antibody responses and provides cross-protection across multiple clades and subclades (36
). We found that vaccinating 60% of the population with an 80% effective vaccine (similar to a well-matched seasonal influenza vaccine in adults) averts the pandemic. The 50% effective vaccine we modeled would require 90% population coverage, a level that could be attained by supplementing the current national HHS vaccine antigen supply with 530 million doses of adjuvant. This relationship allows policymakers to define target population adjuvant and antigen stockpile goals as vaccine technology progresses and more effective vaccines are developed.
Pre-pandemic administration of the primer vaccine is feasible, as studies have shown effective antibody responses in individuals receiving booster vaccination as late as eight years following the primer (72
). However, our analysis shows that pre-pandemic primer administration would provide a modest increase in effectiveness. Pre-pandemic vaccination may also not be widely accepted in light of historical pre-pandemic vaccination efforts (93
An expanded antiviral prophylaxis strategy will delay the pandemic while prophylaxis is implemented, but the health benefits relative to the stockpiled strategy are modest, and it is less cost-effective than the expanded adjuvanted vaccine strategy. This antiviral strategy could be considered as a bridge to development and administration of a well-matched pandemic vaccine, particularly if novel vaccine production strategies (such as cell-based and DNA-based vaccines as described in HHS goals (44
) reduce the time required for vaccine development.
Our analysis has several limitations. Our deterministic modeling approach is a general population model of influenza transmission that assumes homogenous mixing; all individuals have the same frequency of contacts; there may be increased spread associated with large groups or frequent contacts, resulting in a more rapid initial spread of the epidemic, followed by slowing as it spreads to lower contact rates (96
). We assume that a fixed fraction of individuals seek inpatient care; this number may vary as healthcare resources become more limited. Recent studies have shown that simple classical compartmental models are likely to be sufficient for these types of policy decisions (97
), so these concerns are unlikely to affect our conclusions.
We did not model children or individuals older than 65 separately with regards to spread of infection. Patterns of influenza transmission among children and the elderly may not be the same as for the general population, but have been different in different pandemics: Children may have transmitted virus more efficiently than adults in the 1918 and 1957 pandemics, but had similar attack rates to adults in the 1968 pandemic (98
). Additionally, adjuvanted A (H5N1) vaccines have not yet been studied extensively in children and the elderly (99
), and zanamivir prophylaxis is not approved in children under five years (34
). Our expanded stockpiling strategies only address the stockpiling of additional adjuvant and antivirals at this time. A decision to target interventions to particular age groups will need to be made as data regarding disproportionately affected groups becomes available after the outbreak of a pandemic. In light of the possibility of more efficient transmission by children, or increased mortality in young children and the elderly, we encourage ongoing efforts to establish the safety and efficacy of A (H5N1) vaccination in children and elderly, and the safety of zanamivir prophylaxis in children under five.
An assumption of continued neuraminidase inhibitor effectiveness may not apply to a (mutated) pandemic strain. Neuraminidase inhibitors have demonstrated effectiveness across a wide range of viral mutations including the 1918 A (H1N1) (100
) and the current pandemic novel A (H1N1) (101
), but some A (H5N1) strains are resistant to oseltamivir (102
). Resistance may be less likely to occur with zanamivir; our model's 50/50 oseltamivir and zanamivir stockpile can be adjusted to include higher proportions of zanamivir without changing effectiveness or cost-effectiveness.
We accounted for lost productivity with reduced QALYs in our analysis, but we did not include all costs to uninfected individuals in the setting of a pandemic; these may be greater than costs to sick individuals (104
). We also did not include several potential net savings of adjuvanted vaccination, such as limiting displacement of hospitalized patients and disruptions to trading and payments systems from decreased investment. Some analyses suggest that such costs could exceed the direct medical costs that we included in our analysis (104
). However, including these costs and savings would only make the pandemic mitigation strategies we examined more cost-effective, or even cost-saving.
Adjuvanted vaccination is a feasible, effective, and cost-effective pandemic mitigation strategy with advantages over non-adjuvanted vaccination, including the potential to protect across different A (H5N1) clades and subclades, a crucial consideration in vaccinating against a mutated pandemic influenza strain. An extended-duration antiviral prophylactic strategy can serve to delay the pandemic as vaccination strategies are implemented. Expanded stockpiles of vaccine adjuvant and neuraminidase inhibitors could be used in pandemics caused by influenza strains other than A (H5N1), as well as in seasonal influenza epidemics. Indeed, current mitigation plans for pandemic novel influenza A (H1N1) include adjuvanted vaccination (105
), and the use of neuraminidase inhibitors (101
). Our finding that the expanded adjuvanted vaccination strategy's advantage was due to increased effectiveness and population coverage is encouraging, as it demonstrates that ongoing HHS efforts to increase stockpiles of adjuvant can substantially reduce the morbidity and mortality of a severe influenza pandemic. The recently approved U.S. Omnibus Appropriations Bill devotes $700 million in additional funding to pandemic preparedness (106
); a significant percentage of these funds should be dedicated to expanding the current HHS adjuvant stockpile.