Limitations of the current annual influenza vaccine have led to ongoing efforts to develop a “universal” influenza vaccine, i.e., one that targets a ubiquitous portion of the influenza virus so that the coverage of a single vaccination can persist for multiple years.
To estimate the economic value of a “universal” influenza vaccine compared to the standard annual influenza vaccine, starting vaccination in the pediatric population (2–18 year olds), over the course of their lifetime.
Monte Carlo decision analytic computer simulation model
Universal vaccine dominates (i.e., less costly and more effective) the annual vaccine when the universal vaccine cost ≤$100/dose and efficacy ≥75% for both the 5 and 10 year duration. The universal vaccine is also dominant when efficacy is ≥50% and protects for 10 years. A $200 universal vaccine was only costeffective when ≥75% efficacious for a 5 year duration when annual compliance was 25% and for a 10 year duration for all annual compliance rates. A universal vaccine is not costeffective when it cost $200 and when its efficacy is ≤50%. The costeffectiveness of the universal vaccine increases with the duration of protection.
Although development of a universal vaccine requires surmounting scientific hurdles, our results delineate the circumstances under which such a vaccine would be a costeffective alternative to the annual influenza vaccine.
The following limitations of the current annual influenza vaccine have led to ongoing efforts to develop a “universal” influenza vaccine, i.e., one that targets a ubiquitous portion of the influenza virus so that the coverage of a single vaccination can persist for multiple years:
Annual vaccine administration: Administering influenza vaccine to the same patients each year incurs substantial costs and efforts. Persons must miss work. Maintaining influenza vaccination clinics and sites requires personnel time.
Annual vaccine manufacturing: Every year influenza vaccine manufacturers must allocate significant resources to produce influenza vaccines. Due to varying viral strains every season and the limited production period, the timing and preparation of vaccine development might cause unnecessary delays.
Patient compliance: Even when a person is recommended to be vaccinated, he or she may miss getting immunized certain years. According to the National Health Interview Survey and National Immunization Survey of United States for seasons 2005–2006, 2006–2007, and 2007–2008 and National Immunization Survey, influenza vaccination coverage levels ranged 31.8%–32.2% for ages 6–23 months, 26.4%–40.3% for ages 2–4 years, and 12.4%–21.1% for ages 5–17 years.[
Changing influenza strains: Each year, different influenza strains emerge as the dominant circulating strains. Although each year, scientists attempt to predict these strains, their predictions are not always accurate.[
Emergence of novel influenza strain: As the 2009 influenza pandemic demonstrated, the annual vaccine may not cover new emergent strains.
Better understanding of the potential economic value of a “universal” vaccine can help guide investment and development for policy makers, manufacturers, insurance companies, investors, scientists, and other decision makers. Forecasting the impact of a vaccine early in its development when changes can still be made can increase the chances of a vaccine's success.[
We developed a computational model to estimate the potential economic value of a “universal” influenza vaccine compared to the standard annual influenza vaccine in the pediatric population (ages 2 to 18 years), one of the Advisory Committee on Immunization Practices (ACIP) recommended high risk groups.[
The time horizon for the model is the child's lifetime. The model has a cycle length of 1 year. The Markov states are mutually exclusive; an individual can only be in one state in a given year. Each year, an individual had a probability of becoming infected with influenza. Vaccination attenuates this probability by the vaccinerelated efficacy. Each time an individual is vaccinated, he or she has a probability of developing vaccine side effects.[
Each simulation run sends 1,000 individuals 1,000 times through the model for a total of 1,000,000 trials of an individual's lifetime. For each simulation, the following equation calculates the incremental costeffectiveness ratio (ICER) of the “universal” vaccine versus the annual vaccine:
We also calculated the potential economic value of a universal influenza vaccine from the societal perspective for the U.S. pediatric population. The U.S. Census bureau estimate in July 2009 was used to provide the age stratified population: 21.3 million (under 5 years), 20.6 million (5–9 years), 20.0 million (10–14 years), and 21.5 million (15–19 years).[
Sensitivity analyses systematically varied the cost of the universal vaccine ($100, $200), universal vaccine efficacy (range: 50%–75%), probability of influenza infection being symptomatic (50% or 67%), initial age of the individual (range: 2–18 years), compliance with annual vaccine (range: 25%, 50%, 75%, and 100%), and the duration of universal vaccine protection (5 or 10 years).[
Switching from the annual vaccine to the universal vaccine can yield cost savings from the societal perspective. A $100/dose universal vaccine with a vaccine efficacy ≥75% will provide cost savings per pediatric patient vaccinated: $1–$104 (ages below 5 years), $5–$102 (5–9 years), $6–$96 (10–14 years), and $168–$266 (15–18 years). Therefore, switching the entire pediatric population to universal vaccination could generate cost savings of $15 million  $2.2 billion for those below 5 years, $101 million  $2.1 billion for 5–9 years, $121 million  $1.9 billion for 10–14 years, and $3.6 billion  $5.7 billion for 15–18 years over their lifetimes. Increasing the proportion of developing symptomatic influenza from 50% to 67% will provide more cost savings.
Increasing the duration of universal protection to 10 years further augments the potential cost savings to society. A $100/dose universal vaccine with ≥75% efficacy can provide cost savings of $295 – $398 per pediatric patients (ages below 5 years), $284 – $388 (5–9 years), $274 – $377 (10–14 years), and $261–$364 (15–18 years) vaccinated. Therefore, switching the entire pediatric population to universal vaccination could generate cost savings of $6.2 billion  $8.5 billion for those below 5 years, $5.9 billion  $8.0 billion for 5–9 years, $5.5 billion  $7.5billion for 10–14 years, and $5.6 billion  $7.8 billion for 15–18 years over their lifetimes. As before, increasing the probability of being symptomatic will provide even more cost savings.
Our results suggest that a universal vaccine could provide substantial economic value by overcoming the annual vaccine's current drawbacks. This favors investment in universal vaccine development, helps establish efficacy and duration of protection targets for developers, and prepares policy makers for reimbursement questions. Addressing these issues early in a vaccine's development when changes are easier to make could help avoid considerable problems in the future.[
In many ways, our study underestimates the potential value of a universal vaccine. Not only is compliance with the annual vaccine far less than 100%, many children do not get vaccinated until later into the influenza season, i.e., after October or even November. As previous studies have demonstrated the value of annual influenza vaccine drops the later in the season the vaccine is administered, because the longer the patient remains unvaccinated, the more susceptible they are to being infected.[
The 2009 influenza pandemic identifies another possible benefit of the universal vaccine. A universal vaccine that provides protection against novel strains may circumvent the need to develop a specific vaccine against an emerging pandemic strain. As computer simulation studies have suggested, timely and effective vaccination of the population may be the most important mitigation intervention.[
Bringing a universal vaccine to market requires surmounting numerous hurdles. First, the vaccine must contain an appropriate antigen common to all possible circulating influenza viruses. Second, the antigen should be stable and not prone to mutation. Third, the antigen must not occur in other common human tissues. Fourth, the antigen needs to generate an adequate immune response. Fifth, the vaccine must remain effective and not wane for the duration of vaccine coverage.
Du and colleagues describe the possible approaches in developing a universal influenza vaccine which focus on the conserved sequences of M2e, HA (HA1, HA2), NP, and epitopes from different influenza viral proteins.[
A recently published article reports significant human B cell responses towards the 2009 pandemic H1N1 influenza.[
Another study provides evidence that a universal vaccine which covers all influenza strains is achievable. This novel influenza vaccine is able to reactivate and induce Tcell responses (CD8+ and CD4+) towards NP and M1 proteins of the virus that is common in all influenza type A strains.[
In addition to the limitations identified earlier, all models are simplifications of real life. A model cannot represent all possible influenza outcomes and the heterogeneity that exist among the patient population. Rather than make decisions, a model provides information for decision makers such as public health officials, scientists, insurance companies, investors, manufacturers, and clinicians. Models are designed to elucidate relationships, raise questions, and approximate orders of magnitude instead of providing exact answers. Although our model does not explicitly represent natural immunity from infection, which may persist for several years, especially when occurring in children, the various outcome probabilities (e.g., risk of influenza) did draw from studies where natural immunity was present.
Limitations of the current annual influenza vaccine have led to ongoing efforts to develop a “universal“ influenza vaccine, i.e., one that targets a conserved portion of the influenza virus so that the coverage of a single vaccination can persist for multiple years. Our results suggest that a universal vaccine could provide substantial economic value by overcoming the annual vaccine's current drawbacks. This favors investment in universal vaccine development, helps establish efficacy and duration of protection targets for developers, and prepares policy makers for reimbursement questions. Addressing these issues early in a vaccine's development when changes are easier to make could help avoid considerable problems in the future. Although development of a universal vaccine requires surmounting scientific hurdles, our results delineated the circumstances under which such a vaccine would be a costeffective alternative to the annual influenza vaccine.
This work was supported by the National Institute of General Medical Sciences Models of Infectious Disease Agent Study (MIDAS) [1U54GM0884910109], the National Library of Medicine [5R01LM00913202], and the Centers for Disease Control and Prevention (CDC) University of Pittsburgh Center for Advanced Study of Informatics [1P01HK00008601]. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. B.Y.L. has served as an advisor for Novartis and Glaxosmithkline. R.K.Z. has received grants for clinical research from and served as an advisor for MedImmune and Merck & Co. This manuscript has been presented in the following conferences: 1) CDC's 2010 Conference “Modeling for Public Health Action: From Epidemiology to Operations,“ in the Behavioral and Economic Modeling track, December 8–9, 2010, Atlanta, GA, 2) 45th National Immunization Conference, March 28–31, 2011, Washington, D.C., Abstract no. 25588.
Model Structure State Diagram
Acceptability Curves a) varying the efficacy of universal vaccine, b) varying the cost of universal vaccine, c) varying the duration of universal vaccine protection, d) varying annual vaccine compliance
Data inputs
Description (units)  Distribution  Mean  Standard Deviation or Range  Source 

 
 
Annual vaccine  Point Estimate  20    [ 
 
 
Pediatric Outpatient Visit  Point Estimate  74.90  [  
Adult Outpatient Visit  Triangular  104.77  69.14 – 140.39  [ 
Elderly Outpatient visit  Triangular  155.92  118.39 – 193.44  [ 
 
Age 1 to 4  Gamma  5992  515  [ 
Age 5 to 9  Gamma  5761  561  [ 
Age 10 to 14  Gamma  8735  1231  [ 
Age 15 to 17  Gamma  6559  816  [ 
Age 18 to 44  Gamma  6506  461  [ 
Age 45 to 64  Gamma  7580  759  [ 
Age 65 to 84  Gamma  7568  234  [ 
Age 85 and Over  Gamma  7698  240  [ 
General death  Triangular  6921  5191 – 9025  [ 
Treatment of vaccine side effects  Triangular  0.79  0.70 – 3.93  [ 
Median hourly wage  Point Estimate  15.57    [ 
 
 
 
Work hours per day    8    Assumption 
Absenteeism from influenza (days)  Uniform  3.2  1.5 – 4.9  [ 
Time being sick from the flu  Uniform  6  5 – 7  [ 
Time after having vaccine side effects  Uniform  0.75  0.5 – 1  [ 
 
 
 
 
Age 0 to 17  Point Estimate  1    [ 
Age 18 to 64  Point Estimate  0.92    [ 
Age 65 and Over  Point Estimate  0.84    [ 
Influenza with no hospitalization  Triangular  0.65  0.49 – 0.81  [ 
Influenza with hospitalization  Triangular  0.50  0.38 – 0.63  [ 
Vaccine side effects  Triangular  0.95  0.71 – 1.00  [ 
 
 
 
 
Influenza throughout the year  Triangular  0.125  0.05 – 0.2  [ 
 
Age 0 to 4  Beta  0.455  0.098  [ 
Age 5 to 17  Beta  0.318  0.061  [ 
Age 18 to 64  Beta  0.313  0.014  [ 
Age 65 and Over  Beta  0.620  0.027  [ 
Age 0 to 4 (Highrisk)  Beta  0.910  0.250  [ 
Age 5 to 17 (Highrisk)  Beta  0.635  0.167  [ 
Age 18 to 64 (Highrisk)  Beta  0.625  0.118  [ 
Age 65 and Over(Highrisk)  Beta  0.850  0.093  [ 
 
Age 0 to 4  Beta  0.0141  0.0047  [ 
Age 5 to 17  Beta  0.0006  0.0002  [ 
Age 18 to 49  Beta  0.0042  0.0014  [ 
Age 50 to 64  Beta  0.0193  0.0064  [ 
Age 65 and Over  Beta  0.0421  0.0140  [ 
 
Age 0 to 4  Beta  0.00004  0.00001  [ 
Age 5 to 17  Point Estimate  0.00001  [  
Age 18 to 49  Beta  0.00009  0.00003  [ 
Age 50 to 64  Beta  0.00134  0.00045  [ 
Age 65 and Over  Beta  0.01170  0.00390  [ 
Vaccine efficacy  Triangular  0.45  0.56 – 0.68  [ 
Vaccine side effects  Point Estimate  0.03    [ 
Cost, Effectiveness, and Incremental CostEffectiveness Ratio (ICER; Cost per QALY) of Switching from Annual to Universal Vaccine when Universal Vaccine Provides 5 years of Protection (50% Symptomatic Influenza Rate)
Annual Vaccine Compliance  Vaccination Strategy  Cost  Effectiveness  ICER  


 100%  Universal  1,580 – 2,120  25.52 – 28.29  Universal Dominates 
Annual  1,684 – 2,385  25.52 – 28.29  
75%  Universal  1,579 – 2,118  25.53 – 28.29  Universal Dominates  
Annual  1,649 – 2,560  25.52 – 28.29  
50%  Universal  1,579 – 2,120  25.52 – 28.29  Universal Dominates  
Annual  1,616 – 2,320  25.52 – 28.28  
25%  Universal  1,577 – 2,118  25.53 – 28.29  Universal Dominates  
Annual  1,578 – 2,286  25.52 – 28.28  
 
 100%  Universal  1,775 – 2,473  25.52 – 28.29  Annual Dominates  
Annual  1,685 – 2,387  25.52 – 28.30  
75%  Universal  1,777 – 2,474  25.53 – 28.29  
Annual  1,650 – 2,351  25.53 – 28.29  
50%  Universal  1,775 – 2,475  25.53 – 28.29  
Annual  1,612 – 2,320  25.53 – 28.29  
25%  Universal  1,775 – 2,474  25.53 – 28.29 
 
Annual  1,579 – 2,282  25.52 – 28.29  
 

 100%  Universal  2,019 – 2,718  25.52 – 28.30  77,108 – 124,575 
Annual  1,684 – 2,384  25.53 – 28.29  
75%  Universal  2,214 – 2,893  25.52 – 28.29  171,099 – 319,601  
Annual  1,648 – 2,353  25.52 – 28.28  
50%  Universal  2,020 – 2,717  25.53 – 28.29  79,422 – 81,349  
Annual  1,614 – 2,317  25.52 – 28.29  
25%  Universal  2,018 – 2,718  25.53 – 28.30 
 
Annual  1,579 – 2,288  25.52 – 28.28  
 
 100%  Universal  2,411 – 3,072  25.53 – 28.29  Annual Dominates  
Annual  1,682 – 2,387  25.53 – 28.29  
75%  Universal  2,411 – 3,071  25.53 – 28.29  Annual Dominates – 495,957  
Annual  1,650 – 2,353  25.52 – 28.29  
50%  Universal  2,413 – 3,073  25.52 – 28.29  257,930 – 806,958  
Annual  1,614 – 2,560  25.52 – 28.29  
25%  Universal  2,412 – 2,284  25.53 – 28.29  144,542 – 172,231  
Annual  1,580 – 3,073  25.52 – 28.29 
Note: Bold ICER values are costeffective.
Cost, Effectiveness, and Incremental costeffectiveness ratio (ICER) of Switching from Annual to Universal Vaccine when Universal Vaccine Provides 10 years of Protection (50% Symptomatic Influenza Rate)
Annual Vaccine Compliance  Vaccination Strategy  Cost  Effectiveness  ICER  


 100%  Universal  1,287 – 2,021  25.53 – 28.29  Universal Dominates 
Annual  1,685 – 2,385  25.52 – 28.29  
75%  Universal  1,286 – 2,021  25.52 – 28.29  Universal Dominates  
Annual  1,648 – 2,353  25.52 – 28.29  
50%  Universal  1,286 – 2,019  25.53 – 28.29  Universal Dominates  
Annual  1,613 – 2,319  25.52 – 28.29  
25%  Universal  1,286 – 2,022  25.53 – 28.29  Universal Dominates  
Annual  1,581 – 2,283  25.52 – 28.29  
 
 100%  Universal  1,483 – 2,197  25.53 – 28.29  Universal Dominates  
Annual  1,685 – 2,386  25.52 – 28.29  
75%  Universal  1,485 – 2,201  25.53 – 28.29  Universal Dominates  
Annual  1,649 – 2,351  25.53 – 28.29  
50%  Universal  1,482 – 2,200  25.52 – 28.29  Universal Dominates  
Annual  1,615 – 2,316  25.52 – 28.29  
25%  Universal  1,484 – 2,200  25.52 – 28.29  Universal Dominates  
Annual  1,579 – 2,282  25.52 – 28.29  
 

 100%  Universal  1,630 – 2,347  25.53 – 28.29 

Annual  1,683 – 2,386  25.53 – 28.29  
75%  Universal  1,649 – 2,348  25.52 – 28.29 
 
Annual  1,629 – 2,354  25.53 – 28.29  
50%  Universal  1,615 – 2,348  25.52 – 28.29 
 
Annual  1,616 – 2,378  25.52 – 28.29  
25%  Universal  1,629 – 2,346  25.53 – 28.30 
 
Annual  1,580 – 2,285  25.52 – 28.29  
 
 100%  Universal  1,829 – 2,526  25.53 – 28.29  Annual Dominates  
Annual  1,684 – 2,384  25.53 – 28.29  
75%  Universal  1,827 – 2,530  25.52 – 28.29  Annual Dominates  
Annual  1,651 – 2,350  25.52 – 28.29  
50%  Universal  1,827 – 2,527  25.52 – 28.29  69,797 – 380,364  
Annual  1,613 – 2,322  25.52 – 28.29  
25%  Universal  1,827 – 2,527  25.53 – 28.29  59,443 – 74,421  
Annual  1,580 – 2,286  25.52 – 28.28 
Note: Bold ICER values are costeffective.