Improving influenza and pneumococcal vaccination rates through outpatient standing order programs, which allow vaccination without physician orders, is economically favorable in older Americans.
Despite the benefits of vaccination and guidelines for their use, the rates for influenza and pneumococcal vaccination remain below the 90% goal set by Healthy People 2010 for persons 65 years and older. Standing order programs (SOPs) authorize vaccination administration without physician orders. Here we examine the cost-effectiveness of SOPs to improve both pneumococcal and influenza vaccination rates in outpatient settings for individuals 65 years and older.
Decision analysis-based cost-effectiveness analysis.
A Markov model was constructed to estimate the incremental cost-effectiveness of outpatient SOPs for pneumococcal polysaccharide vaccine (PPSV) and influenza vaccination in hypothetical US population cohorts 65 years and older. Vaccination rate improvement data were obtained from the medical literature. Centers for Disease Control and Prevention Active Bacterial Core surveillance data and US national databases were used to estimate costs and outcomes.
SOPs cost $14,171 per quality-adjusted life-year (QALY) gained compared with no program from a third-party payer perspective. In 1-way sensitivity analyses, the SOP strategy cost less than $50,000/QALY if SOPs increased absolute vaccination rates by 4% or more (base case: 18%), annual SOP costs were less than $21 per person (base case: $4.60), or annual influenza incidence was 4% or more (base case: 10%). Model results were insensitive to other individual parameter variations, and were supported by a probabilistic sensitivity analysis.
SOPs used to improve PPSV and influenza vaccination rates in outpatient settings is a promising and economically favorable investment, with cost-effectiveness analysis results remaining robust to parameter variation over clinically plausible ranges.
(Am J Manag Care. 2013;19(1):e30-e37)We examined the cost-effectiveness of using standing order programs (SOPs), which allow influenza and pneumococcal vaccination without a physician order, to improve the suboptimal vaccination rates in older US populations.
Pneumonia and influenza continue to be among the leading causes of death in the United States.1 Influenza is estimated to cause an average of 200,000 hospitalizations and 36,000 deaths annually.2 Because individuals 65 years and older are at increased risk for influenza complications, seasonal influenza vaccination is important. Invasive pneumococcal disease (IPD), which includes bacteremia and/or infection of the meninges, joints, bones, or body cavities, is a relatively common outcome following influenza, particularly among individuals with chronic illnesses.3,4 Each year pneumococcus causes about 500,000 cases of pneumonia, 50,000 cases of bacteremia, 3000 cases of meningitis, and up to 7000 to 12,500 deaths.5
The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) has recommended influenza vaccination for all persons 6 months and older; pneumococcal polysaccharide vaccine (PPSV) is recommended for all persons 65 years and older, and for persons with chronic medical conditions 18 years and older.6 Among persons 65 years and older in 2010, the annual seasonal influenza vaccination rate was 63.6%,7 while 59.4% reported ever receiving PPSV.8 Despite the benefits of adult vaccination and the availability of usage guidelines, vaccination rates for seasonal influenza and PPSV remain below the Healthy People 2020 goal of 90% for each vaccine among persons 65 years and older.9
Standing orders authorize nurses and pharmacists to administer vaccinations according to a protocol approved by an institution or physician without an individual order or examination by the physician.10 The Task Force on Community Preventive Services reviewed the evidence for standing orders and strongly recommended them.11,12 Several studies have reported the successful use of standing order programs (SOPs).13-15 Because both PPSV and influenza vaccination are recommended for persons 65 years and older, coadministration is another strategy to raise vaccination rates. Although Smith et al found that dual PPSV and influenza vaccination of all persons 50 years and older was economically reasonable,4 the cost-effectiveness of SOPs for vaccination of PPSV and influenza vaccine administered in outpatient settings for persons 65 years and older is unknown.
A Markov model was constructed to estimate, from the third-party payer and societal perspectives, the incremental cost-effectiveness of an SOP intervention for PPSV and influenza immunization. The intervention is implementation of SOPs in outpatient practice, and the comparison is between a base case of current practice (including some SOP-using practices) and broader SOP implementation in primary care practices for hypothetical cohorts of patients 65 years and older in the United States.
presents a state transition diagram illustrating the Markov model, which was adapted from a prior study.4 During each monthly cycle, a person may stay well, develop nonsevere influenza, develop severe influenza, or develop IPD without influenza. Severe influenza was defined as requiring inpatient treatment while non-severe influenza was defined as those cases not requiring inpatient therapy. Inpatients with severe influenza may develop IPD, become disabled, or die due to influenza or other causes. We assumed that patients with non-severe influenza would recover and not go on to worse outcomes, depicted by arrows from the illness states to the well state. In the model, influenza occurs in 5-month seasons each year, with annual influenza vaccination at the start of each season, equal monthly incidence within that time frame, and constant yearly incidence over time. PPSV was given, based on the likelihood of vaccination, when patients entered the model; we assumed that no PPSV was given later in the model and no repeat PPSV vaccination. Patients who develop IPD may recover without disability, become disabled, or die. The cohort was followed monthly over their lifetimes until death. Age-specific mortality not associated with illness was based on US mortality tables.16
Generally, US national databases and published sources were used to estimate costs and outcomes, which were discounted at an annual rate of 3%.17,18 PPSV effectiveness was estimated based on an expert panel, consisting of present and former CDC ACIP members or liaisons and other pneumococcal disease experts (), as described previously.19 Because PPSV is generally thought to have little or no effectiveness against non-bacteremic pneumonia,20,21 we conservatively assumed no PPSV effectiveness against pneumonia. IPD data were obtained from the CDC’s active bacterial core (ABC) surveillance data ().22 Costs were derived from the medical literature, Medicare physician fees,23 and the 2006 nationwide inpatient sample (NIS) data. Hospitalization charges from NIS data were adjusted using costto- charge ratios from the Medicare cost report.24 Parameter values used in the model are summarized in .4,15,25-36 In addition, the following assumptions were included in the model: (1) equal likelihood and severity of side effects for each vaccine, (2) patients with immunocompromising conditions gain no benefit from PPSV,4,19,37 (3) 60.1% vaccine uptake for both vaccines, based on National Health Interview Survey (NHIS) data,38 (4) yearly SOP costs remain constant through the lifetime of the modeled patient cohort, and 5) vaccination rates remain constant at the improved rate resulting from SOP use.
The numerator of the cost-effectiveness ratio represents per patient change in resources associated with the SOP including vaccine and administration costs, disease costs, and SOP costs. Details about the estimation of those costs are published elsewhere.4,15,21,24,35,36 SOP costs are derived from time and motion studies of an inpatient program,15 and thus may over- or under-estimate the costs of outpatient programs; for this reason, these costs were varied widely in sensitivity analyses. SOP costs in the model are per person in contact with the implemented program, not per person vaccinated. The denominator of cost-effectiveness ratio represents differences in quality-adjusted life-years (QALYs) resulting from increased vaccination rates due to SOP use. QALYs account for changes in both duration and quality of life, and are the product of time spent in a healthy state and the quality of life utility value for that healthy state summed over all healthy states and over time.
In addition to the base case cost-effectiveness analysis, 1-way sensitivity analyses and Monte Carlo probabilistic sensitivity analyses were performed to examine the robustness of cost-effectiveness estimates. One-way sensitivity analyses were conducted for all model parameters in Table 1, varying them over their listed ranges to evaluate influence on model results. In these analyses, the parameter of interest was varied while all other variables remained unchanged from their base case values. The probabilistic sensitivity analysis varied all input parameters simultaneously across their ranges; 10,000 model iterations were performed over specific distributions selected based on the level of parameter value certainty. Tree- Age Pro 2009 (TreeAge Software, Williamstown, Massachusetts) was used to perform the analysis.
From a third-party payer perspective, SOPs cost $14,171 per QALY gained compared with no SOP when the SOPrelated absolute increase in vaccination rate was at its base case level, 18% (, top). When the societal perspective is taken, which adds costs that patients incur while seeking or receiving care,18 SOPs cost $12,718 per QALY gained. We report all subsequent results from the third-party payer perspective.
In 1-way sensitivity analyses, individual variation of the vaccination rate increase due to SOPs (Table 4) showed that the incremental cost-effectiveness ratio remained less than $50,000 per QALY gained if absolute vaccination rates increased more than or equal to 4%. The effects of varying other selected parameter values in 1-way sensitivity analyses are shown in . Of these, program costs and annual influenza probability had the greatest effects on results; however, SOPs cost less than $50,000/QALY if program costs were not greater than $21 per person per year (base case = $4.6015) or annual influenza incidence was more than or equal to 4% (base case = 10%). Varying PPSV effectiveness had little impact on model results, given the relatively low incidence of invasive pneumococcal disease when compared with influenza incidence. With PPSV effectiveness at its low range estimate (Table 1), SOPs cost $14,694/QALY gained, $523 more than the base case value; if PPSV was completely ineffective, SOPs cost $15,577/QALY. Individual variation of the other listed parameters had little effect on model results.
In the probabilistic sensitivity analysis, which varied all parameter values simultaneously over distributions, SOPs were favored in greater than 82% of model iterations if the willingness-to-pay acceptability threshold was $50,000/QALY or more. In this analysis, SOPs were cost saving in 9.6% of iterations and were more costly and less effective than no program in 0.7% of the model iterations.
We found that SOPs for influenza and pneumococcal vaccination were cost-effective under a wide range of assumptions. When using the frequently cited $50,000 per QALY gained acceptability threshold, which probably underestimates willingness to pay for healthcare gains in the United States,19,39,40 $21 per person spent on program costs or 4% absolute increases in vaccination rates would still meet this criterion. The analysis was relatively insensitive to variation of other parameters, and simultaneous variation of all parameters in a probabilistic sensitivity analysis showed a high likelihood that SOPs would be favored.
Missed opportunities for vaccination during outpatient visits contribute to low vaccination rates and unnecessary disease burden. Failure to assess and offer vaccines at visits, as well as low rates of preventive care visits, contribute to missed opportunities to vaccinate.41,42 SOPs are a powerful way to reduce missed opportunities and to raise immunization rates. The CDC has recommended SOPs for adult vaccination since 2000.10 However, the Center for Medicare & Medicaid Services (CMS) prohibited SOPs for all medications until 2002 when CMS allowed SOPs for influenza and pneumococcal polysaccharide vaccines.43 The ACIP,10 the Task Force for Community Preventive Services,12 and the Southern California Evidence-Based Practice Center-RAND44 have endorsed SOPs for improving immunization rates.
However, only 42% of primary care physicians who immunized adults in their practices reported consistent use of SOPs.45 Factors associated with consistent use of SOPs include awareness about CDC/CMS stance on standing-order policies, physician perception about the power of SOPs, staffing levels (ie, number of assistants to help each clinician), and use of electronic medical records (EMRs).45,46 Record keeping and tracing of vaccination status is facilitated by the EMR. In some settings, the EMR can send alerts, make ordering and billing of vaccinations easy, or pull the most recent vaccination status into nursing, thereby facilitating the use of SOP protocols by nursing personnel.46 CMS has incentives for EMR usage which may further facilitate SOPs.
Given that the SOPs are effective in raising vaccination rates and economically reasonable, why are they not used more? Physicians and practice managers may be unaware of the economics of SOPs, which we estimate will cost less than $5 per person per year to implement; in contrast, the administration fee by Medicare for influenza and pneumococcal vaccines is about $21, depending on the locale.47 Several benefits can occur through SOP use, including reduced office visits for respiratory infections, decreasing both patient illness burden and strains on office manpower and flow during the influenza season. Another benefit is that adult immunization is a quality measure that can lead to bonus payments48 in some settings. The balance between SOP cost and the reimbursement that can occur through its use appears sufficient to justify SOPs.
Another possible reason for limited SOP use is unfamiliarity with resources. Peer-reviewed SOP tool kits, suggested related resources, and protocols are available at www.immunizationed.org49 and protocols for SOPs for various vaccines areavailable at www.immunize.org/standingorders.
Strengths and Limitations
Although inpatient SOP costs have been published for PPSV,15 to our knowledge, this is the first paper examining the cost-effectiveness of outpatient SOPs for both PPSV and influenza vaccination. The results of our study should facilitate planning by healthcare providers and administrators, office managers, insurers, and government officials.
Limitations include a number of estimated variables, as well as SOP cost and cost-effectiveness estimates that may not remain stable during these times of substantial change in healthcare. In addition, certain parameters, such as vaccine effectiveness estimates, are controversial.25,32,50-53 For these reasons, we varied all parameters in sensitivity analyses, finding in particular that PPSV effectiveness values had little influence on model results. Models based on national data provide estimates but do not necessarily reflect the costs in a particular locale. We assume that yearly SOP costs, and the improved vaccination rates that occur through their use, remain constant; thus our analysis will not be correct if SOP costs or effects change significantly over time. Finally, although a new vaccine, the pneumococcal conjugate vaccine, is now licensed in the United States,54 the ACIP has thus far declined to make recommendations for its routine use in adults; for this reason we have not considered it in our analysis.
With these limitations in mind, we conclude that SOP implementation for both PPSV and influenza vaccination in outpatient settings, targeting patients 65 years and older, is a promising and economically favorable investment, with costeffectiveness analysis results remaining robust to parameter variation over clinically plausible ranges.Author Affiliations: From Department of Family Medicine (CJL, RKZ), Department of Internal Medicine (KJS), University of Pittsburgh School of Medicine, Pittsburgh, PA.
Funding Source: This study was supported by the Centers for Disease Control and Prevention (CDC) through Association for Prevention Teaching and Research Grant No TS-1432 and by the National Institute of Allergy and Infectious Diseases (R01AI076256). Its contents are the responsibility of the authors and do not necessarily reflect the official views of the CDC or the Association for Prevention Teaching and Research.
Author Disclosures: Drs Lin and Zimmerman report receiving consultancies from MedImmune and grants from MedImmune, Merck, and sanofiaventis. Dr Smith reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Authorship Information: Concept and design (CJL, RKZ, KJS); acquisition of data (CJL); analysis and interpretation of data (CJL, KJS); drafting of the manuscript (KJS); critical revision of the manuscript for important intellectual content (CJL, RKZ, KJS); statistical analysis (CJL, KJS); obtaining funding (RKZ); and supervision (KJS).
Address correspondence to: Chyongchiou Jeng Lin, PhD, Department of Family Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA. E-mail: email@example.com. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Deaths and mortality. http://www.cdc.gov/nchs/fastats/deaths.htm. Revised 2012. Accessed September 15, 2011.
2. Aldrich N, Keyser CM, Benson WF. CDC says immunizations reduce deaths from influenza and pneumococcal disease among older adults. http://www.cdc.gov/vaccines/vpd-vac/pneumo/downloads/influ-pneudisease-2008-508.pdf. Published 2008. Accessed September 15, 2011.
3. McCullers JA. Insights into the interaction between influenza virus and pneumococcus. Clin Microbiol Rev. 2006;19(3):571-582.
4. Smith KJ, Lee BY, Nowalk MP, Raymund M, Zimmerman RK. Costeffectiveness of dual influenza and pneumococcal vaccination in 50-year-olds. Vaccine. 2010;28(48):7620-7625.
5. National Foundation for Infectious Diseases. Facts about pneumococcal disease for adults. http://www.adultvaccination.com/vpd/pneumococcal/ facts.html. Updated October 2012. Accessed July 13, 2012.
6. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. CDC’s advisory committee on immunization practices (ACIP) recommends universal annual influenza vaccination. http://www.cdc.gov/media/ pressrel/2010/r100224.htm. Published 2010. Accessed September 1, 2011.
7. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Annual percentage of adults aged 65 years and over who had received influenza vaccination during past 12 months. http://www.cdc.gov/ nchs/data/nhis/earlyrelease/201106_04.pdf. Published 2011. Accessed September 10, 2011.
8. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Annual percentage of adults aged 65 years and over who had ever received a pneumococcal vaccination. http://www.cdc.gov/nchs/data/nhis/earlyrelease/ 201106_05.pdf. Published 2011. Accessed September 10, 2011.
9. US Department of Health and Human Services. 2020 topics and objectives. http://www.healthypeople.gov/2020/topicsobjectives2020/pdfs/HP2020objectives.pdf. Published 2012. Accessed February 1, 2012.
10. US Department of Health and Human Services. Use of standing orders programs to increase adult vaccination rates. MMWR Morb Mortal Wkly Rep. 2000;49(1):15-26.
11. US Department of Health and Human Services. Vaccine-preventable diseases: improving vaccination coverage in children, adolescents, and adults: a report on recommendations of the Task Force on Community Preventive Services. MMWR Morb Mortal Wkly Rep. 1999;48:1-15.
12. Centers for Disease Control and Prevention. Vaccine-preventable diseases: improving vaccination coverage in children, adolescents, and adults. MMWR Recomm Rep. 2000.
13. Rhew DC, Glassman PA, Goetz MB. Improving pneumococcal vaccine rates: nurse protocols versus clinical reminders. J Gen Intern Med. 1999;14:351-356.
14. Dexter PR. Inpatient computer-based standing orders vs physician
reminders to increase influenza and pneumococcal vaccination rates.
J Am Med Assoc. 2004;292(19):2366-2371.
15. Middleton DB, Lin CJ, Smith KJ, et al. Economic evaluation of standing order programs for pneumococcal vaccination of hospitalized elderly patients. Infect Control Hosp Epidemiol. 2008;29(5):385-394.
16. US Department of Health and Human Services, Centers for Disease Control and Prevention. National Vital Statistics Reports. 2010;58(21): 7-8.
17. Gold M, Siegel J, Russell LB, Weinstein M. Cost-Effectiveness in Health and Medicine. New York: Oxford University Press; 1996.
18. Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the panel on cost-effectiveness in health and medicine. J Am Med Assoc. 1996;276(15):1253-1258.
19. Smith KJ, Zimmerman RK, Lin CJ, et al. Alternative strategies for adult pneumococcal polysaccharide vaccination: a cost-effectiveness analysis. Vaccine. 2008;26(11):1420-1431.
20. Huss A, Scott P, Stuck AE, Trotter C, Egger M. Efficacy of pneumococcal vaccination in adults: a meta-analysis. Canadian Med Ass J. 2009;180(1):48-58.
21. Moberley SA, Holden J, Tatham DP, Andrews RM. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev. 2008;(1):CD000422.
22. Centers for Disease Control and Prevention. Active bacterial core surveillance (ABCs). http://www.cdc.gov/abcs/index.html. Accessed February 10, 2012.
23. US Department of Health and Human Services, Centers for Medicare & Medicaid Services. Medicare Physician Fee Schedule look-up (CPT 90471). http://www.cms.gov/apps/physician-fee-schedule/. Published 2006. Accessed March 23, 2012.
24. Agency for Healthcare Research and Quality. Cost-to-charge ratio files: healthcare cost and utilization project (HCUP). http://www.hcupus. ahrq.gov/db/state/costtocharge.jsp. Published 2007. Accessed July 1, 2007.
25. Jefferson TO, Rivetti D, Pietrantonj DC, Rivetti A, Demicheli V. Vaccines for preventing influenza in healthy adults (Review). Cochrane Database Syst Rev. 2007(2).
26. 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(12):840-843.
27. Lee BY, Brown ST, Cooley PC, et al. A computer simulation of employee vaccination to mitigate an influenza epidemic. Am J Prev Med. 2010;38(3):247-257.
28. Lee BY, Tai JHY, Bailey RR, Smith KJ. The timing of influenza vaccination for older adults (65 years and older). Vaccine. 2009;27(50): 7110-7115.
29. Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: a systematic review and metaanalysis. Lancet Infect Dis. 2012;12(1):36-44.
30. Zhou H, Thompson WW, Viboud CG, et al. Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993-2008. Clin Infect Dis. 2012;54(10):1427-1436.
31. Community Preventive Services Task Force. Universally Recommended Vaccinations: Standing Orders. http://www.thecommunityguide. org/vaccines/universally/RRstandingorders.html. Published 2012.Accessed June 5, 2012.
32. Jackson LA, Benson P, Sneller VP, et al. Safety of revaccination with pneumococcal polysaccharide vaccine. J Am Med Assoc. 1999;281(3): 243-248.
33. IOM Report. Patient safety - achieving a new standard for care. Acad Emerg Med. 2005;12(10):1011-1012.
34. Gold MR, Franks P, McCoy KI, Fryback DG. Toward consistency in cost-utility analyses-using national measures to create conditionspecific values. Med Care. 1998;36(6):778-792.
35. Sisk JE, Whang W, Butler JC, Sneller VP, Whitney CG. Cost-effectiveness of vaccination against invasive pneumococcal disease among people 50 through 64 years of age: role of comorbid conditions and race. Ann Intern Med. 2003;138(12):960-968.
36. Centers for Disease Control and Prevention. National Immunization Program. CDC Price list. http://www.cdc.gov/vaccines/programs/ vfc/downloads/archived-pricelists/2006.pdf. Published 2006. Accessed March 1, 2007.
37. Jackson LA, Neuzil KM. Pneumococcal polysaccharide vaccines. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines. 5th ed. Saunders Elsevier Inc; 2008:569-604.
38. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Self-reported pneumococcal vaccination coverage trends 1989-2008 among adults by age group, risk group, race/ethnicity, health-care worker status, and pregnancy status, United States, National Health Interview Survey (NHIS). http://www.cdc.gov/flu/professionals/vaccination/pdf/NHIS89_08ppvvaxtrendtab.pdf. Accessed September 1, 2011.
39. Ubel PA, Hirth RA, Chernew ME, Fendrick AM. What is the price of life and why doesn’t it increase at the rate of inflation? Arch Intern Med. 2003;163(14):1637-1641.
40. Braithwaite RS, Meltzer DO, King JT, Leslie D, Roberts MS. What does the value of modern medicine say about the $50,000 per qualityadjusted life-year decision rule? Med Care. 2008;46(4):349-356.
41. Nowalk MP, Zimmerman RK, Feghali J. Missed opportunities for adult immunization in diverse primary care office settings. Vaccine. 2004;22(25-26):3457-3463.
42. Nowalk MP, Zimmerman RK, Cleary SM, Bruehlman RD. Missed opportunities to vaccinate older adults in primary care. J Am Board Fam Pract. 2005;18(1):20-27.
43. Centers for Medicare & Medicaid Services. Medicare and Medicaid programs; conditions of participation: immunization standards for hospitals, long-term care facilities, and home health agencies: final rule with comment period. Fed Reg. 2002;67:61808-61814.
44. Administration HCF. Evidence Report and Evidence-Based Recommendations: Interventions that Increase the Utilization of Medicare- Funded Preventive Service for Persons Age 65 and Older. Baltimore, MD: Health Care Financing Administration; 1999.
45. Zimmerman RK, Albert SM, Nowalk MP, Yonas MA, Ahmed F. Use of standing orders for adult influenza vaccination: a national survey of primary care physicians. Am J Prev Med. 2011;40(2):144-148.
46. Zimmerman RK, Nowalk MP, Raymund M, et al. Tailored interventions to increase influenza vaccination in neighborhood health centers serving the disadvantaged. Am J Public Health. 2003;93(10): 1699-1705.
47. Services HM. 2011 Reimbursement Fees—Flu, Pneumococcal and Hepatitis B Vaccines. https://www.highmarkmedicareservices.com/ partb/reimbursement/flu-pnu-hep-11.html. Published 2011. Accessed November 23, 2011.
48. Agency for Healthcare Research and Quality. Using quality measures. http://www.qualitymeasures.ahrq.gov/selecting-and-using/using. aspx. Published 2012. Accessed March 1, 2012.
49. Centers for Disease Control and Prevention. STFM Group on Immunization Education. http://www.immunizationed.org/Default.aspx. Accessed February 1, 2012.
50. Dear K, Holden J, Andrews R, Tatham D. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev. 2003(4): CD000422.
51. Fedson DS, Musher DM. Pneumococcal Polysaccharide Vaccine. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines. 4th ed. Philadephia: Elsevier; 2004:529-588.
52. Fedson DS, Liss C. Precise answers to the wrong question: prospective clinical trials and the meta-analyses of pneumococcal vaccine in elderly and high-risk adults.
53. Vila-Corcoles A, Ochoa-Gondar O, Hospital I, et al. Protective effects of the 23-valent pneumococcal polysaccharide vaccine in the elderly population: the EVAN-65 Study. Clin Infect Dis. 2006;43(7):860-868.
54. Smith KJ, Wateska AR, Nowalk MP, Raymund M, Nuorti JP, Zimmerman RK. Cost-effectiveness of adult vaccination strategies using pneumococcal conjugate vaccine compared with pneumococcal polysaccharide vaccine. J Am Med Assoc. 2012;307(8):804-812.