Nayer Khazeni, MD, MS; David W. Hutton, MS; Alan M. Garber, MD, PhD; Douglas K. Owens, MD, MS
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality.
Acknowledgment: The authors thank the reviewers for their extremely thorough and helpful reviews; Anne Berry, JD, MBA, and Edward Sheen, MD, MBA, of Stanford University for their contributions to the early design of this project; Sara Cody, MD, of the Santa Clara County Public Health Department for her assistance with the design of our Influenza Care Center; Mark Holodniy, MD, of the Veterans Affairs Palo Alto Health Care System for his assistance with cost information; and Michael Gould, MD, MS, of Stanford University, Timothy Uyeki, MD, MPH, MPP, of the Centers for Disease Control and Prevention, and David Fedson, MD, for their thoughtful reviews of an earlier version of the manuscript. None of the listed individuals received additional compensation in association with this work.
Grant Support: By the National Institutes of Health (Stanford University T32 HL007948; Dr. Khazeni), the Agency for Healthcare Research and Quality (1 F32 HS018003-01A1; Dr. Khazeni), the Helena Anna Henzl Gabor Travel Award (Dr. Khazeni), the National Institute on Drug Abuse (2 R01 DA15612-016; Dr. Owens), a Stanford Graduate Fellowship (Mr. Hutton), and the Department of Veterans Affairs (Drs. Owens and Garber).
Potential Conflicts of Interest: None disclosed.
Reproducible Research Statement: An annotated version of the model is available in Appendix 1 so that others can test the authors' findings and conclusions.
Requests for Single Reprints: Nayer Khazeni, MD, MS, Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, 300 Pasteur Drive, H3143, Stanford, CA 94305.
Current Author Addresses: Dr. Khazeni: Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, 300 Pasteur Drive, H3143, Stanford, CA 94305.
Mr. Hutton: 496 Terman Engineering Center, Stanford University, Stanford, CA 94305.
Drs. Garber and Owens: Center for Health Policy and Center for Primary Care and Outcomes Research, Stanford University, 117 Encina Commons, Stanford, CA 94305-6019.
Author Contributions: Conception and design: N. Khazeni, D.W. Hutton, A.M. Garber, D.K. Owens.
Analysis and interpretation of the data: N. Khazeni, D.W. Hutton, A.M. Garber, D.K. Owens.
Drafting of the article: N. Khazeni, D.W. Hutton, A.M. Garber, D.K. Owens.
Critical revision of the article for important intellectual content: N. Khazeni, D.W. Hutton, A.M. Garber, D.K. Owens.
Final approval of the article: N. Khazeni, D.W. Hutton, A.M. Garber, D.K. Owens.
Provision of study materials or patients: N. Khazeni.
Statistical expertise: N. Khazeni, D.W. Hutton, A.M. Garber, D.K. Owens.
Obtaining of funding: N. Khazeni.
Administrative, technical, or logistic support: N. Khazeni, A.M. Garber.
Collection and assembly of data: N. Khazeni, D.W. Hutton.
Khazeni N, Hutton DW, Garber AM, Owens DK. Effectiveness and Cost-Effectiveness of Expanded Antiviral Prophylaxis and Adjuvanted Vaccination Strategies for an Influenza A (H5N1) Pandemic. Ann Intern Med. 2009;151:840-853. doi: 10.7326/0000605-200912150-00156
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Published: Ann Intern Med. 2009;151(12):840-853.
The pandemic potential of influenza A (H5N1) virus is a prominent public health concern of the 21st century.
To estimate the effectiveness and cost-effectiveness of alternative pandemic (H5N1) mitigation and response strategies.
Compartmental epidemic model in conjunction with a Markov model of disease progression.
Literature and expert opinion.
Residents of a U.S. metropolitan city with a population of 8.3 million.
3 scenarios: 1) vaccination and antiviral pharmacotherapy in quantities similar to those currently available in the U.S. stockpile (stockpiled strategy), 2) stockpiled strategy but with expanded distribution of antiviral agents (expanded prophylaxis strategy), and 3) stockpiled strategy but with adjuvanted vaccine (expanded vaccination strategy). All scenarios assumed standard nonpharmaceutical interventions.
Infections and deaths averted, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness.
Expanded vaccination was the most effective and cost-effective of the 3 strategies, averting 68% of infections and deaths and gaining 404Â 030 QALYs at $10Â 844 per QALY gained relative to the stockpiled strategy.
Expanded vaccination remained incrementally cost-effective over a wide range of assumptions.
The model assumed homogenous mixing of cases and contacts; heterogeneous mixing would result in faster initial spread, followed by slower spread. We did not model interventions for children or older adults; the model is not designed to target interventions to specific groups.
Expanded adjuvanted vaccination is an effective and cost-effective mitigation strategy for an influenza A (H5N1) pandemic. Expanded antiviral prophylaxis can help delay the pandemic while additional strategies are implemented.
National Institutes of Health and Agency for Healthcare Research and Quality.
Proper pandemic planning for an influenza A (H5N1) pandemic is a public health priority.
This decision model for pandemic planning suggests that stockpiling sufficient adjuvanted vaccine for immunizing 40% of the population is more effective and cost-effective than immunizing a smaller proportion of the population or providing them with antiviral drugs.
The model makes several assumptions that may not bear out in a real H5N1 pandemic. However, users can test their own assumptions with a model provided by the authors.
Expanding immunization with adjuvanted vaccine may prevent spread of pandemic influenza A (H5N1) better than the U.S. government's current pandemic prevention strategy.
The 2009 influenza A (H1N1) pandemic has highlighted the urgent need for effective mitigation strategies for an influenza pandemic. Despite the appropriate current focus, the pandemic potential of the influenza A (H5N1) virus remains one of the most important international public health concerns of the 21st century (1). Unlike the influenza A (H1N1) pandemic, which has had a low case-fatality rate to date (2), the A (H5N1) virus is not yet easily transmissible but is highly fatal. In addition, the A (H5N1) virus has raised concern by following 3 patterns historically reminiscent of pandemic viruses: 1) increasing numbers of human infections in Southeast Asia; 2) spread to Europe, Africa, and the Middle East; and 3) accelerated development of distinct genetic groups known as clades and subclades(3). Of the viruses responsible for the three 20th-century influenza pandemics, A (H5N1) genetically most closely resembles the A (H1N1) virus, which caused the 1918 pandemic (4, 5). This pandemic was one of the most devastating, killing 50 to 100 million people, with a propensity for pregnant women and young, healthy adults (6).
A virus must meet 3 conditions to have pandemic potential: high virulence, antigenic uniqueness, and sustained human-to-human transmissibility (7). Existing A (H5N1) meets 2 of these but does not have the ability to spread sustainably among humans (8, 9). It could develop this ability by genetic reassortment via an interspecies link (such as swine, whose trachea contain receptors for both human and avian influenza viruses) or a spontaneous mutation. Because it has no error-checking mechanism, influenza is particularly susceptible to such a mutation during replication. The 2009 (H1N1) pandemic has convincingly demonstrated the extraordinary rapidity of the global spread of a new influenza virus (10) The World Health Organization (WHO) and World Bank predict that an A (H5N1) pandemic could cause hundreds of millions of deaths, with a lasting and crippling impact on global economies (11).
Public health strategies for mitigating an influenza pandemic consist of nonpharmaceutical interventions, such as social distancing, use of masks and respirators, hand hygiene, and cough etiquette, and pharmaceutical interventions, such as vaccines and antiviral agents (12). Previous models have targeted antiviral distribution to close contacts of infected individuals (13–16), a strategy criticized as having limited usefulness in the 2009 (H1N1) pandemic (17). Researchers have not examined broader distribution strategies for large urban populations with high contact rates between random individuals. Vaccination against A (H5N1) has had limited success in eliciting adequate human antibody response, and designing a vaccine effective against a frequently changing virus has been challenging (18). Few studies have analyzed the cost-effectiveness of pandemic mitigation strategies.
Recent studies (19–34) have overcome limitations of A (H5N1) vaccines by administering them with adjuvants, substances that make them more immunogenic at lower doses. We developed a model of an influenza A (H5N1) pandemic to examine the effectiveness and cost-effectiveness of a pharmaceutical intervention strategy with vaccination and extended-duration antiviral prophylaxis, an expanded antiviral prophylaxis strategy, and an expanded adjuvanted vaccination strategy.
We developed a compartmental epidemic model in conjunction with a Markov model of disease progression to elucidate the spread of A (H5N1) in a susceptible population (Appendix Figure A1 [all appendix figures and tables are in Appendix 2]). We evaluated 3 mitigation strategies, described further below. Each strategy included nonpharmacologic interventions, such as hand washing and social distancing. The first strategy, which we call the stockpiled strategy, was designed to be similar to the U.S. Department of Health and Human Services (HHS) pandemic plan, with the use of currently stockpiled vaccine and antiviral agents. We also evaluated 2 additional strategies that use expanded antiviral drugs (expanded prophylaxis strategy) or expanded adjuvanted vaccination (expanded vaccination strategy). We modeled the dynamics of disease transmission and progression of the first pandemic wave daily over a period of 1 year. Following the recommendations of the Panel on Cost-Effectiveness in Health and Medicine (35), we adopted a societal perspective for costs and benefits, discounted at 3% annually. We analyzed outcomes for the remaining lifetime of the individuals. We expressed these outcomes in infections and deaths, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. We developed the simulation model and performed analyses by using Microsoft Excel, version 2003 (Microsoft, Redmond, Washington), and we provide an annotated version of the model (Appendix 1) so that readers can test model output for different assumptions and circumstances.
For the purposes of our analysis (see Appendix Figure A1), we divided the population into susceptible, infected, and individuals who had recovered from or died of influenza.
We followed a hypothetical cohort of persons living in a large U.S. city with a sex distribution (53% women), age (0 to 100 years), and average remaining life expectancy similar to those of the population of New York City (36). We assumed that 1000 individuals were infected at the start of the pandemic, and we varied this number from 100 to 10 000 in sensitivity analysis. Lacking previous exposure to A (H5N1) (7), all individuals entering the model were susceptible to infection. In sensitivity analysis, we examined scenarios in which 10% of individuals were immune to the virus.
The size of the infected population depends on the ease of influenza transmission. We measure transmissibility by the reproductive number, R0, the average number of secondary infections caused by a single infectious individual in a susceptible population. The reproductive number of a pandemic strain of A (H5N1) virus depends on the unknown transmissibility of a novel human subtype. We assumed an R0 of 1.8, based on the 1918 Spanish flu pandemic, corresponding to a Centers for Disease Control and Prevention (CDC) severity category 5 pandemic (15). In sensitivity analysis, we varied R0 from 1.4 (less severe than the 1957 and 1968 pandemics) to 2.2 (more severe than the 1918 pandemic).
Antigenic drift occurs throughout a pandemic; estimations of reinfection with drifted influenza A viruses range from 2% to 25% (37–40). Most reinfected individuals are asymptomatic or mildly symptomatic, with a shorter duration of illness and less viral shedding. Thus, we assumed that 5% of the recovered population was once again susceptible to infection at an average of 5 months after recovery (Appendix 2).
The mortality rate associated with a pandemic strain of A (H5N1) virus is uncertain; a mutated virus capable of efficient human-to-human transmission may develop other mutations, thereby affecting its virulence. We modeled a severe (consistent with CDC severity category 5) pandemic, with a 20% to 40% population illness rate and a 2.5% clinical case-fatality proportion (12). In sensitivity analysis, we modeled a more severe 60% clinical case-fatality proportion (current human case-fatality rate of A (H5N1) ) and a less severe 0.5% clinical case-fatality proportion (CDC severity category 2, based on the 1957 and 1968 pandemics) (12). We modeled age-specific mortality, with a J-shaped mortality curve in which mortality rates were greater in newborns and individuals older than 65 years. This is consistent with the 1957 and 1968 pandemics and seasonal influenza epidemics (41–43). In sensitivity analysis, we examined a W-shaped mortality curve, in which there are additional increases in mortality in young adults, as occurred in the 1918 pandemic (41, 43). On the basis of population behavior in previous pandemics (44), we assumed that healthy individuals would begin voluntary reactive social distancing as mortality rates in the city increased (Appendix 2).
Because they rely on state and local jurisdiction, HHS nonpharmaceutical interventions are not standardized (12). The main nonpharmaceutical interventions that could be undertaken include social distancing, such as school closure and workplace reduction of contacts (for example, telecommuting). In addition, a recent randomized trial suggested that hand washing, use of alcohol-based hand gels, and use of such personal protective equipment as masks could reduce transmission to household contacts by as much as 66% if they are implemented within 36 hours of an index case-patient becoming ill (45). Our model is not designed to directly evaluate the impact of social distancing strategies. Instead, we used the results of a complex network model developed by Davey and colleagues (46) at Sandia National Laboratories, Albuquerque, New Mexico, to estimate the reduction in contacts that would occur if nonpharmaceutical interventions were enacted. On the basis of this work, we assumed that implementation of nonpharmaceutical interventions would reduce contacts by 25%. We evaluated reduction in contacts from 10% to 70% in sensitivity analyses.
Two approaches to A (H5N1) vaccination are under consideration. Vaccine can be given without an adjuvant in 2 doses (nonadjuvanted), or vaccine can be combined with an adjuvant in each dose that heightens the immune response to the vaccine antigen, a strategy being tested against pandemic (H1N1) (47, 48). The potential advantages of the adjuvanted vaccine are increased effectiveness and the ability to reduce the amount of antigen in each dose, which would allow more individuals to be vaccinated (25, 29).
On the basis of the 1976 influenza vaccination campaign in New York City (49), we assumed that all individuals in the city could be vaccinated in 10 days. According to studies of 2-dose A (H5N1) vaccination (50), we also assumed that the second dose would be administered 21 days later and that immunity would be achieved 14 days later. In light of viral mutations causing a pandemic, the effectiveness of any vaccine against a novel human influenza subtype is unknown and is unlikely to be complete; we assumed that nonadjuvanted vaccine would not be well-matched to the mutated virus and would be 30% effective. On the basis of studies showing that adjuvanted vaccines help overcome humans' poor immunogenic response to novel viruses, elicit antibody responses in much higher percentages than can nonadjuvanted vaccines and can protect against different A (H5N1) clades (25, 29, 34), we assumed that the adjuvanted 2-dose vaccination sequence would be 50% effective. We assumed an effectiveness of 40% for individuals who received only 1 of 2 adjuvanted doses (51).
On the basis of adjuvanted and nonadjuvanted A (H5N1) vaccination data (29, 50), we assumed that 45% of vaccinated individuals would experience mild to moderate adverse reactions, such as pain, redness, swelling, induration, ecchymosis, low-grade fevers, arthralgias, fatigue, headaches, myalgias, shivering, or sweating for up to 7 days. According to data on seasonal influenza, A (H5N1), and the 1976 vaccination (52, 53), we assumed that 0.001% of the population experienced severe adverse reactions, such as angioedema, anaphylaxis, or the Guillain–Barré syndrome.
We evaluated the use of antiviral drugs for both treatment and prophylaxis and made the following additional assumptions: antiviral distribution would begin on target city pandemic day 10 and be completed by day 19, and full antiviral effectiveness would occur on the first day of dosing (plasma levels peaking 1 hour after administration ). On the basis of a meta-analysis of extended-duration neuraminidase inhibitor prophylaxis against influenza A (55), we assumed 74% effectiveness for zanamivir and 37% effectiveness for oseltamivir in light of developing resistance (56–58).
According to data on neuraminidase inhibitors (59), we assumed that 10% of the population receiving oseltamivir or zanamivir experienced mild to moderate adverse reactions, such as nausea, vomiting, diarrhea, bronchitis, fatigue, dermatitis, worsening diabetes, rash, seizures, hepatitis, and abdominal pain, for the duration of the 40-day treatment. On the basis of a meta-analysis of extended-duration neuraminidase inhibitor prophylaxis against influenza (55), we assumed that 0.001% of the population would experience severe adverse reactions, including systemic allergic reactions, arrhythmia, and psychosis.
The stockpiled strategy was designed to assess the impact of U.S. nonpharmaceutical intervention approaches along with the use of the antiviral drugs and vaccines currently stockpiled in the United States (Table 1). The HHS is stockpiling 3.6 billion μg of A (H5N1) vaccine antigen and 2.6 million 2-dose courses of vaccine adjuvant (60), a quantity of adjuvant sufficient for 1% of the U.S. population. Given studies showing efficacy of 2-dose nonaluminum adjuvanted A (H5N1) vaccines with 3.8 μg of antigen (25, 29), and on the basis of the U.S. adjuvant stockpile, we assumed that 2-dose 3.8-μg adjuvanted vaccine was administered to 1% of individuals in the target city and that the remaining nonadjuvanted antigen was used to vaccinate another 7% of the population with a 2-dose 90-μg (minimal effective nonadjuvanted dose ) vaccine.
Individual states and HHS are stockpiling 2.7 billion doses of neuraminidase inhibitors for treatment and prophylaxis (60). According to published HHS distribution plans (61), we assumed that 28% of the city's population would receive 5-day treatment courses of neuraminidase inhibitors and that 5% would receive neuraminidase inhibitor prophylaxis daily for 40 days.
In the expanded vaccination strategy, we assumed that sufficient adjuvanted vaccine had been stockpiled to vaccinate 40% of the population with the adjuvanted vaccine. We examined the range of vaccination coverage required to end the pandemic (defined as an effective R0 ≤1) in sensitivity analysis. We assumed that nonadjuvanted vaccine was not administered. The nonpharmaceutical intervention component and use of antiviral drugs were the same as those in the stockpiled strategy.
In the expanded prophylaxis strategy, we assumed that sufficient antiviral drugs had been stockpiled to provide 40% of individuals with 40 days of antiviral prophylaxis. We evaluated a 50/50 stockpile of oseltamivir and zanamivir because zanamivir has remained effective against influenza subtypes that have developed oseltamivir resistance (57) and might be less likely to develop in vivo resistance (62). The nonpharmaceutical intervention component and use of vaccination were the same as those in the stockpiled strategy.
Our analysis included the costs of interventions, based on wholesale pricing available to the U.S. government, and average hospitalization costs. Costs and sources are described in Appendix 2. All costs were expressed in 2009 U.S. dollars using the Gross Domestic Product deflator. We adjusted for quality of life (Table 2[63–93] and Appendix 2).
The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript.
With no intervention, the first pandemic wave (defined as >1% of the population infected) would last 50 days and wane as a result of voluntary social distancing. A second wave, lasting 32 days, would result from decreases in voluntary social distancing and reinfection as the virus undergoes drift changes. Of the city's 8.3 million individuals, an estimated 2.74 million would become symptomatically infected, for an attack rate of 33%, and 67 822 would die (Figure 1 and Table 3).
Expanded vaccination results in the shortest-duration pandemic wave and averts the most deaths. Expanded prophylaxis extends the time to the first pandemic wave and modestly reduces mortality compared with the stockpiled strategy. Additional waves occur in all strategies as a result of decreases in voluntary social distancing, as well as a low reinfection rate as the virus undergoes drift changes.
The alternative strategies have varying effects on the course of the influenza epidemic (Figure 1 and Table 3). The stockpiled strategy results in a 19% clinical attack rate. The expanded prophylaxis strategy is more effective than the stockpiled strategy, decreasing the clinical attack rate to 17%. This strategy's main effect is to delay the pandemic during the 40 days in which it is implemented. After prophylaxis, individuals who have not had sufficient contact with the virus to develop protective antibodies are once again fully susceptible, with consequent infections and deaths.
Given our assumption of 50% effectiveness for the adjuvanted vaccine, expanded vaccination is the most effective strategy, with an 11% clinical attack rate. It remains the most effective strategy across a range of influenza infectivity (R0, 1.4 to 2.2) and case-fatality proportions (from 0.5% to 60%) (Figure 2). Administering the first dose of the vaccination sequence before the pandemic is more effective than administering both doses at the onset of the pandemic, with a 6.9% decrease in infections (61 708 fewer) and deaths (1584 fewer) relative to postpandemic administration. If both vaccine doses could be administered before the onset of the pandemic, infections would decrease by 7.6% (68 036 fewer) and 1747 deaths would be averted relative to postpandemic administration.
Daily deaths are shown for varying values of R0 (the average number of secondary infections caused by a single infectious individual in a susceptible population) and case-fatality proportions. As the case-fatality proportion rises, deaths increase and subsequent waves become more apparent. However, because of reactive social distancing in response to mortality, the peaks in the waves are not proportional to the increase in case fatality. As mortality increases, the population reacts by reducing social interactions, which reduces the spread of infection. Because reactive social distancing occurs in response to mortality rather than infections, the effects of reactive social distancing are more apparent with high case-fatality proportions. Waves in the pandemic occur because social distancing is in response to average mortality over the past 30 days. As reactive social distancing decreases mortality, the population begins to return to higher, more normal levels of social interaction, causing another upswing in mortality (further described in Appendix 2).
Greater vaccine effectiveness and broader population coverage are the principal reasons that the adjuvanted vaccination strategy is more effective that the stockpiled strategy. We identified vaccine effectiveness and adjuvant doses required to avert the pandemic (defined as R0 ≤1) within the target population (Figure 3). The pandemic would be averted with a vaccine that was 70% effective if 70% of the population were vaccinated, which would require about 5.7 million 2-dose courses of vaccine adjuvant. For vaccines less than 70% effective, a greater proportion of the population would require vaccination. Every 10% increase in vaccine effectiveness requires approximately 10% less population coverage to avert the pandemic.
Areas to the right of the curves represent combinations of vaccine effectiveness and population coverage or adjuvant doses under which the pandemic is averted under different R0s (the average number of secondary infections caused by a single infectious individual in a susceptible population).
The stockpiled strategy increases costs by $2.30 billion, with an incremental cost-effectiveness ratio of $8907 per QALY gained relative to no intervention (Table 3 and Figure 4). Expanded prophylaxis increases cost and effectiveness but is a less efficient use of resources than expanded vaccination. Expanded vaccination yields the highest costs and effectiveness, with a cost-effectiveness ratio of $10 844 compared with the stockpiled strategy.
Expanded vaccination dominates expanded prophylaxis through extended dominance and is cost-effective compared with the stockpiled strategy. Costs are in 2009 U.S. dollars. QALY = quality-adjusted life-year.
The effectiveness of this strategy is a crucial determinant of cost-effectiveness. If vaccine effectiveness were only 10%, expanded prophylaxis would be preferred.Appendix Table A1 and Appendix Figure A2 depict changes in cost-effectiveness, with variations in efficacy of adjuvanted vaccination compared with effectiveness of nonadjuvanted vaccine.
For short-term budgetary considerations, federal costs for expanded vaccination for a city of 8.3 million individuals, compared with the stockpiled strategy, would be $231 million in additional adjuvant and stockpiling costs; city costs would be $102 million to administer the vaccines; and city and individual costs would be $56 million in vaccine recipient time and $10 million for treating short-term severe side effects. Savings to the city and individuals would be $139 million in pandemic treatment costs relative to the stockpiled strategy (Table 3).
Allocating 5-day treatment courses of neuraminidase inhibitors to 28% of the population is adequate to cover symptomatic patients seeking treatment under all scenarios; additional neuraminidase inhibitors allocated to 40-day prophylaxis do not affect the availability of neuraminidase inhibitors for treatment.
Although variations in R0 and case-fatality rates change the number of infections and deaths (Figure 2), they do not change the strategies that would be selected by cost-effectiveness criterion (Appendix Table A1).
In the base case, we assumed that all individuals were susceptible to the virus. If 10% of the population had preexisting immunity to A (H5N1), 49% fewer infections and deaths would occur under the stockpiled strategy and 76% fewer infections and deaths would occur under expanded vaccination. The strategies that would be selected according to cost-effectiveness criterion do not change (Appendix Table A1).
We performed additional analyses on the basis of a study showing decreased effectiveness with a 1.9-μg (as compared with a 3.8-μg) antigen dose (25). At this dose, with lower vaccine efficacy (Appendix 2), twice as many individuals could be vaccinated. Vaccination would avert 1.2 million infections and 29 435 deaths, with a symptomatic attack rate of 4% in the population at a cost of $11 080 per QALY relative to the stockpiled strategy. However, this intervention would be limited by the need for twice as many doses of vaccine adjuvant.
Studies examining human adverse events of adjuvanted A (H5N1) vaccination (19–32) have reported no severe events from vaccination in 6095 participants. Based on these data, the highest incidence of serious adverse events in which no cases would still fall within the 95% CI would be 49 per 100 000 individuals (49 times more frequently than a nonadjuvanted vaccine).
In the base case, we assumed that the probability of severe side effects from an adjuvanted vaccine was the same as that from a nonadjuvanted vaccine. In this case, about 6000 lives are saved for each death from severe adverse effects. If an adjuvanted vaccine were to increase the incidence of severe side effects 49-fold, 102 lives would be saved for each death from vaccine reactions, and the incremental cost-effectiveness ratio of expanded adjuvanted compared with expanded nonadjuvanted vaccination would be $21 423 per QALY. If an adjuvanted vaccine were to increase severe side effects 150-fold, 33 lives would be saved for each death from vaccine reactions, and the incremental cost-effectiveness ratio of expanded adjuvanted compared with expanded nonadjuvanted vaccination would be $49 570 per QALY. If side effects occurred 650 times more frequently than with a nonadjuvanted vaccine, 8 lives would be saved for each death from vaccine reactions. In this case, a nonadjuvanted vaccine would provide more benefits at a lower cost than the adjuvanted vaccine.
In the base case, we assumed a 25% reduction in contacts due to nonpharmaceutical interventions. If contacts were reduced by only 10%, 44% of infections and deaths would be averted compared with no intervention, with little change in the incremental cost-effectiveness ratio. If contacts decreased by 70%, 99% of infections and deaths would be averted with expanded adjuvanted vaccination versus no intervention. However, vaccination would then provide less additional benefit, at a cost of $101 682 per QALY (Appendix Table A1).
In the base-case analysis, we had examined increased deaths in newborns and individuals aged 65 years or older (J-shaped mortality). We also performed sensitivity analyses to determine the effect of W-shaped mortality (increased deaths in adults aged 20 to 50 years, newborns, and individuals older than 65 years), such as that seen in the 1918 pandemic (Appendix Figure A6) (44). With W-shaped mortality, the increase in deaths among young adults means that significantly more QALYs are lost per death (22.1 vs. 8.2). Averting these deaths and QALY losses makes our strategies more cost-effective, with expanded vaccination costing $8674 per QALY gained relative to the stockpiled strategy.
In 88% of Monte Carlo probabilistic sensitivity analysis simulations (Appendix Figure A4), expanded vaccination has an estimated incremental cost less than $50 000 per QALY saved. In 92% of simulations, it has an estimated incremental cost less than $100 000 per QALY saved. In 5% of simulations, another strategy dominates expanded vaccination.
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 nonpharmaceutical HHS pandemic mitigation strategies is the most effective strategy and is also cost-effective, given our assumptions about vaccine efficacy. 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 most important factors in the relative effectiveness and cost-effectiveness of the adjuvanted vaccination strategy. Although 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 (25, 29, 34), further viral mutations could reduce vaccine effectiveness. 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 goals for adjuvant and antigen stockpiles as vaccine technology progresses and more effective vaccines are developed.
Prepandemic administration of the primer vaccine is feasible—studies have shown effective antibody responses in individuals receiving booster vaccination as late as 8 years after the primer (51, 78). However, our analysis shows that prepandemic primer administration would provide a modest increase in effectiveness. Prepandemic vaccination may also not be widely accepted in light of historical prepandemic vaccination efforts (94).
An expanded antiviral prophylaxis strategy will delay the pandemic while prophylaxis is implemented; however, the health benefits relative to the stockpiled strategy are modest, and it is less cost-effective than the expanded vaccination strategy. This antiviral strategy could be considered 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 ) (26, 95, 96) 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; and there may be increased spread associated with large groups or frequent contacts, resulting in a faster initial spread of the epidemic, followed by slowing as it spreads to groups with decreased contact rates (97). We assume that a fixed fraction of individuals seeks inpatient care; this number may vary as health care resources become more limited. Recent studies have shown that simple classic compartmental models are likely to be sufficient for these types of policy decisions (98), so these concerns are unlikely to affect our conclusions.
We did not separately model children or individuals older than age 65 years with regard 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 attack rates similar to those of adults in the 1968 pandemic (99). In addition, adjuvanted A (H5N1) vaccines have not yet been studied extensively in children and the elderly (100), and zanamivir prophylaxis is not approved in children younger than 5 years of age (79). Our expanded stockpiling strategies only address the stockpiling of additional adjuvant and antiviral agents at this time. A decision to target interventions to particular age groups will need to be made as data on disproportionately affected groups become 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 the elderly and the safety of zanamivir prophylaxis in children younger than 5 years.
An assumption of continued effectiveness of neuraminidase inhibitors 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) (101) and the pandemic (H1N1) 2009 virus (102), but some A (H5N1) strains are resistant to oseltamivir (103, 104). Resistance may be less likely 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 (105). We also did not include several potential net savings of adjuvanted vaccination, such as limiting displacement of hospitalized patients and disruptions to trading and payment systems from decreased investment. Some analyses suggest that such costs could exceed the direct medical costs that we included in our analysis (105). However, including these costs and savings would only make the pandemic mitigation strategies we examined more cost-effective, or even cost-saving.
On the basis of our assumption of 50% vaccine effectiveness, adjuvanted vaccination is a feasible, effective, and cost-effective pandemic mitigation strategy with advantages over nonadjuvanted vaccination, including the potential to protect across different A (H5N1) clades and subclades. The latter is a crucial consideration in vaccinating against a mutated pandemic influenza strain. Although existing trials report higher effectiveness as measured by antibody titers (25, 29), pandemic mutations in the virus may reduce vaccine effectiveness. An extended-duration antiviral prophylactic strategy can 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 (H1N1) 2009 include adjuvanted vaccination (106) and the use of neuraminidase inhibitors (102). Our finding that the advantage of the expanded vaccination strategy was due to increased effectiveness and population coverage is encouraging because 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 (107); a significant percentage of these funds should be dedicated to expanding the current HHS adjuvant stockpile.
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Infectious Disease, High Value Care, Vaccines/Immunization, Prevention/Screening.
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