Benefits and Effectiveness of Administering Pneumococcal Polysaccharide Vaccine With Seasonal Influenza Vaccine: An Approach for Policymakers [American Journal of Public Health]

By Levine, Orin

Proquest LLC

For the influenza pandemic of 2009-2010, countries responded to the direct threat of influenza but may have missed opportunities and strategies to limit secondary pneumococcal infections. Delivering both vaccines together can potentially increase pneumococcal polysaccharide vaccine (PPV23) immunization rates and prevent additional hospitalizations and mortality in the elderly and other highrisk groups.

We used PubMed to review the literature on the concomitant use of PPV23 with seasonal influenza vaccines. Eight of 9 clinical studies found that a concomitant program conferred clinical benefits. The 2 studies that compared the cost-effectiveness of different strategies found concomitant immunization to be more cost-effective than either vaccine given alone.

Policymakers should consider a stepwise strategy to reduce the burden of secondary pneumococcal infections during seasonal and pandemic influenza outbreaks. (Am J Public Health. 2012;102: 596-605. doi:10.2105/AJPH. 2011.300512)

ON JUNE 11, 2009, THE WORLD Health Organization (WHO) declared the first influenza pandemic of the 21st century and escalated the global health alert to the highest possible level, phase 6.1 The heightened alert resulted in countries implementing preventive and treatment strategies for influenza management including expanded recommendations for influenza immunization and antiviral coverage in children and adults, and for the increased use of 23-valent pneumococcal polysaccharide vaccine (PPV23).2

Every year, Streptococcus pneumoniae infections account for approximately 1.6 million deaths worldwide.3 The incidence of pneumococcal infections rises and falls seasonally with the incidence of influenza. Pneumococcal infections secondary to influenza place a significant burden on health systems, which can be strained or overwhelmed during influenza epidemics, as evidenced by the 2009-2010 H1N1 influenza pandemic.4,5 The 2009-2010 H1N1 influenza pandemic also highlighted the importance of secondary pneumococcal infections6 and their association with adverse outcomes, including death.7

Current pneumococcal disease- control strategies include immunization of elderly populations ([double dagger] 65 years) and other high-risk groups (including cigarette smokers) with PPV23 and immunization of infants with conjugate pneumococcal vaccine (PCV). In the absence of pneumococcal immunization, these groups are particularly susceptible to infection.

Although routine pediatric pneumococcal immunization strategies have reduced the overall burden of pneumococcal disease in children, the remaining burden has shifted to older age groups, particularly the elderly.8-12 In the United States, 85% of invasive pneumococcal disease now occurs in adults.13

In general, adults and high-risk groups are known to have lower immunization coverage than the pediatric population, and can be harder to reach. Therefore, specific strategies to increase PPV23 immunization coverage are needed. One proposed strategy is to integrate a PPV23 program with seasonal influenza programs. Unlike influenza vaccine, which is administered annually, PPV23 is typically recommended to be repeated after 5 years in high-risk groups or the elderly who were immunized when younger than 65 years, but influenza immunization would nevertheless afford an ideal opportunity to access the elderly and other high-risk groups for initial and follow-up PPV23 administration.

THE LINK BETWEEN PNEUMOCOCCAL DISEASE AND INFLUENZA

In the United States, more than 185 million person-years of surveillance show that pneumococcal infections are more prevalent during spikes in the incidence of influenza.4,14-18 Pneumococcal infections secondary to influenza are predictive of a severe outcome of influenza infection and are a major cause of death in the elderly. Based on estimates of influenzaassociated deaths in the United States over 31 influenza seasons, almost 90% of annual deaths with underlying pneumonia and influenza causes are in persons older than 65 years and account for excess mortality during influenza epidemics.19

Coinfection with S. pneumoniae and influenza was first hypothesized by Laennec in 1803.20 It has subsequently been observed in several epidemics, as reported in McCullers16 and Brundage,21 including in the influenza pandemic of1918,22,23 the Boston epidemic of 1941,24 the "Asian flu" pandemic of 1957,25 the Hong Kong influenza epidemic of 1968-1969,26 and, most recently, in the 2009-2010 H1N1 pandemic.4 The frequent isolation of bacteria, most commonly, Haemophilus, Streptococcus, and Staphylococcus spp., led to the hypothesis that influenza was predisposing to bacterial pneumonia. 27 In a recent retrospective review of 109 autopsy reports from 8398 individual investigations and examination of 58 lung tissue sections from the 1918 influenza pandemic, Morens et al. confirmed that deaths were noted to occur almost exclusively from secondary bacterial infections.18

The co-occurrence of influenza and pneumococcal disease is also observed with seasonal influenza, and secondary bacterial pneumonias (mostly S. pneumoniae) are estimated to account for up to 50% of deaths during seasonal influenza in the United States.14,15,28,29 Mechanisms that account for coinfection have recently been elucidated. Influenza virus can damage the epithelial lining of airways16,17,30 or decrease mechanical clearance and improve the conditions for bacterial growth16 allowing carried bacteria to invade, or, conversely, bacterium-derived proteases may enhance viral virulence.31

An assessment of the benefits and effectiveness of administering pneumococcal polysaccharide vaccine with seasonal influenza vaccine can assist policymakers to develop strategies to reduce the burden of secondary pneumococcal infections during seasonal and pandemic influenza outbreaks.

METHODS

We conducted a review of the literature on concomitant use of PPV23 with seasonal influenza vaccine, by searching the PubMed database, to assess the added benefits. We used the combination of mesh words "benefits," "influenza," "pneumococcal," "vaccination," "elderly," and the combination "effectiveness," "influenza," "pneumococcal," "vaccination," "elderly." We excluded all articles that did not specifically make reference to immunization of the elderly or high-risk groups with PPV23 or influenza vaccines and included only articles published in the English language. Articles included in the review ranged in time from the earliest in the database, from 1988, to November 2010, the time of the search.

An identical search on the Cochrane Collaboration database did not reveal any reviews on the concomitant use of both vaccines in the elderly. We did not systematically review data on either vaccine when used alone. We reviewed each article for the presence or absence of evidence of effectiveness, or other benefits, from the concomitant administration of PPV23 and influenza vaccines in the elderly or other highrisk groups. Results from large randomized controlled clinical trials were considered best evidence of effectiveness, but all articles were reviewed for observed impacts. Based on the findings from the review, we developed a 5-step strategy for policymakers to potentially reduce the burden of secondary pneumococcal infections during seasonal outbreaks and pandemic influenza.

RESULTS

The searches yielded a total of 25 and 54 articles, respectively. Twenty articles were included from the first search and an additional 41 from the second, for a total of 61 articles. A total of 9 studies addressed the issue of concomitant administration and its clinical benefits: 2 were randomized controlled trials; the remainder were observational studies. Of the 7 observational studies, 4 were cohort studies in the elderly, 2 were cohort studies in the elderly with chronic illness, and 1 was a cohort study in HIV-infected participants. Eight of the 9 studies showed that a concomitant program conferred some clinical benefits, and these achieved statistical significance in 5 of the studies, whereas 1 article found no difference.

Eight studies generated costeffectiveness data. Six studies found PPV23 vaccination to be cost-effective with or without influenza. The other 2 studies compared the cost-effectiveness of a concomitant strategy to either vaccine given alone and found concomitant immunization to be more cost-effective.

Clinical Benefits

In the absence of pneumococcal immunization, children and the elderly are particularly susceptible to S. pneumoniae infections (Figure 1). The WHO advises that PPV23 may help reduce the incidence of the more severe bacteremic forms of pneumococcal disease in at-risk populations older than 2 years during epidemic or pandemic influenza.33 Furthermore, some studies have found that concomitant administration of PPV23 and influenza vaccine can prevent more hospitalizations for pneumonia and deaths in the elderly than either vaccine alone (Table 1),34,35 although study design varies greatly and not all have confirmed this finding.36

In a large, 3-year study in the United States, a cohort of 1898 elderly persons with chronic lung disease from a large managed care organization were followed prospectively over 3 influenza seasons from 1993 to 1996.34 Hospitalization for pneumonia or influenza, and death were compared between vaccinated and unvaccinated groups, with control for covariates and confounders. Influenza vaccination alone resulted in a statistically significant 52% (95% confidence interval [CI] = 18, 72) reduction in hospitalization for pneumonia and a statistically significant 70% (95% CI = 57, 89) reduction in death. PPV23 vaccination alone reduced hospitalizations for pneumonia by 27% (not significant) and reduced death by a significant 34% (95%CI = 6, 54). But when both vaccineswere given concomitantly, the effects against hospitalization for pneumonia (63%; 95% CI = 29, 80) and against death (81%; 95% CI = 68, 88) were higher than for either single vaccine.

In a similar trial in Sweden, more than 124 000 participants aged 65 years and older were enrolled in a 3-year prospective intervention study from 1998 to 2000 to receive influenza vaccine, PPV23, or both, and were compared with an unvaccinated cohort. 35 Effectiveness was measured against incidence of hospitalization, length of hospital stay, and death from influenza, pneumonia, and invasive pneumococcal disease (IPD) from December 1999 to November 2000. Both vaccines were administered to 72 107 participants, whereas 29 346 received only influenza vaccine and 23 249 received only PPV23. Just as in the study by Nichol, the Swedish study found an additive effect of both vaccines.34 Influenza vaccine and PPV23 given alone reduced the incidence of hospital admissions for influenza and pneumonia, respectively, but the risk of being hospitalized for influenza was significantly lower (37%; 95% CI = 19, 50) in the group that received both vaccines compared with the unvaccinated. Likewise, the risks of being admitted for pneumonia were significantly lower (29%; 95% CI = 25, 35) in the group that received both vaccines compared with the unvaccinated. Reductions in hospitalization for IPD were important for vaccines given alone or together-44% in the group that received both vaccines, 58% in the group that received influenza vaccine only, and 73% in the group who received PPV23 vaccine only-but numbers of cases were too small to achieve statistical significance. A significant decrease (35%; 95% CI = 22, 46) in mortality from pneumonia was observed in the group that received both vaccines, compared with the unvaccinated group. A 71% decrease in mortality from influenza was observed in the group that received both vaccines, compared with the unvaccinated group, but there were too few deaths to achieve significance. The group that received both vaccines also had significantly shorter duration of hospitalization than did the unvaccinated group: 5.2 versus 7.5 days for influenza, and 9.9 versus 11.3 days for pneumonia. Overall, both vaccines given together significantly reduced hospital admissions for all outcomes during the influenza season, compared with the group who received neither vaccination.

Reactions to the coadministration of PPV23 and influenza vaccines have been found to be mild and simultaneous administration is considered safe.37

Cost-Effectiveness

The rate of hospitalizations related to community-acquired pneumonia (CAP) is considerable, estimated at about 1.6% for the elderly in the United States.38 The elderly have the highest per capita cost for hospital admissions and hospitalization for CAP,39 and in an employed population in the United States, CAP is estimated to cost $10 227 6 $15 342 per case.40 Even outpatient costs for CAP can be considerable, averaging $953 in 2006 dollars in the United States.41 These direct costs do not account for the additional costs to employers and society for absenteeism and loss of productivity.

Where costs of hospitalization may be relatively high (e.g., the United States, Western Europe, Japan) PPV23 immunization of the elderly has been shown to be costeffective in several European countries and the United States,42-45 even after accounting for the introduction of PCV in the United States.46 In addition, routine immunization of all elderly may be more cost-effective than targeting the high-risk elderly alone.47

Because of the additive effect of influenza vaccine and PPV23, greater cost-effectiveness can be achieved by the coadministration of influenza and PPV23. Given together, these vaccines prevent more hospitalizations and deaths in the elderly and improve the cost-effectiveness over either vaccine given alone. In the United States, Weaver et al. found that the cost-effectiveness ratio for concomitant influenza vaccine and PPV23 in the elderly was $35 486 per quality-adjusted life year (QALY) compared with $53 547 per QALY for PPV23 and $130 908 per QALY for influenza vaccine given alone.38

In Japan, Cai et al. found that the cost-effectiveness ratio of influenza- only vaccination was ¥ 516 332 per years of life saved (YOLS; about US$ 6187 converted on November 22, 2010) compared with ¥ 459 874 per YOLS (about US$ 5511) for influenza vaccine with PPV23.48 The incremental cost-effectiveness ratio of concomitant PPV23 with influenza vaccine was ¥ 426 698 per YOLS (about US$ 5113) for 100 000 people.

Several countries that immunize annually against seasonal influenza in the elderly also routinely immunize against pneumococcal disease (Table 2). No other adult immunization offers as great an opportunity to access the same target groups with minimal investment.

DISCUSSION

We did not conduct a metaanalysis of the existing data, but both the qualitative and quantitative data reviewed here indicate that there is an evidence base to support efforts that emphasize concomitant administration of PPV23 and influenza vaccines as part of a comprehensive diseasecontrol strategy for pneumonia and influenza in the elderly and other high-risk groups. In 2010, the European Center for Disease Control and Prevention published reports from 16 European countries on evaluations and lessons learned from the influenza pandemic. 52 One key message across reports was that national agencies have the authority to develop strategies for coordination and responsibilities for planning and oversight of how best to provide vaccination services to the public. Although recommended national guidelines are necessary for the introduction of PPV23 and influenza, they alone are not sufficient to increase immunization rates in adult populations.53

On the basis of these insights, we propose a 5-step comprehensive strategy for policymakers to integrate the administration of PPV23 into new or existing influenza programs on a national and subnational scale. Step 1- Governments should convene a scientific panel to synthesize the findings on concomitant use of PPV23 and influenza vaccines and submit an evidence-based report to policymakers. Step 2-Governments should assess and recommend appropriate financing mechanisms that will encourage concomitant PPV23 and influenza immunization. Step 3-National and subnational governments should lead communication efforts and provide effective messaging and tools to advocate, educate, and communicate the importance of concomitant PPV23 and influenza immunization to health care professionals and the general public. Step 4-National, state, and local health administrators should leverage influenza vaccine delivery channels to increase uptake for PPV23 vaccine. Step 5-Governments and health administrations should monitor and evaluate the impact of the concomitant administration of PPV23 with influenza vaccines.

The key for successful implementation of any new program requires the integration of knowledge and resources from key stakeholders, including governments, researchers, health system experts, and industry.

Step 1

National and subnational health departments should commission a scientific consensus panel to collect and analyze data on current PPV23 and influenza vaccines' practices and policies. The panel will need to synthesize all findings including the following factors:

* Disease burden and mortality from influenza and pneumonia,

* Vaccine efficacy and effectiveness,

* Current use and coverage rates,

* Barriers for adult immunization,

* Effective communication channels, and

* Options for supply and distribution.

Policymakers can then weigh the strengths of the data and limitations of incomplete, imperfect, or even contradictory data. This comprehensive analysis will provide policymakers with the evidence, rationale, and confidence in decision-making.

Recognizing the international scope of the burden of pneumococcal disease complicating influenza, countries could also seek guidance from international organizations such as the WHO that routinely issue international recommendations. The Strategic Advisory Group of Experts, the principal advisory group to WHO on overall global policies for vaccines and immunization, has a specific working group for influenza vaccines and immunization programs including underutilized vaccines such as PPV23. This working group reviews data on a rolling basis specific to the challenges of influenza and immunization programs. By sharing country-specific findings on PPV23 and influenza with the Strategic Advisory Group of Experts and other global key stakeholders, policymakers have the opportunity to guide new programs and strengthen existing ones for PPV23 and influenza immunization.

Step 2

Governments and health administrators will need to assess either existing or proposed financial mechanisms that are appropriate and affordable for the elderly and other high-risk groups. Removing or minimizing financial barriers to adult immunization has been shown to be an effective means of improving vaccine coverage levels.54 In 2007, a US State Legislator Policy Brief stated that every person aged 65 years or older who gets vaccinated with influenza and PPV23 vaccines could save a total of $190.87 in societal medical costs: $182.00 and $8.87, respectively.55 State policies implementing concomitant administration of both vaccines could potentially pay for the program.

There are typically 3 primary mechanisms used to finance adult immunization efforts: the government, private insurance companies, and private pay (individual out-of-pocket).54 National or subnational government financing programs have an important role to play in increasing the number of adults who get immunized against PPV23 and influenza. Several options in which national, state, or local governments can lessen or remove barriers to adult PPV23 immunization exist: increased program funding including adequate reimbursement to physicians and health care providers on administration costs; in developing countries, where resources may be scarce, the use of purchasing power to reduce vaccine prices by pooling orders and placing bulk purchase orders with suppliers, which has been shown to reduce vaccine prices; introducing policies requiring health insurers to cover immunizations with reduced or no cost-sharing requirements for adults; and instituting national programs to cover uninsured adult immunization, similar to those provided for pediatric populations.55

Step 3

Broad, informative national communication strategies for the public and health care providers were the main components of the influenza pandemic preparedness plans. Nationally coordinated communications activities with state and local health communications staff, combined with advocacy and education strategies for the public, physicians, and health care workers on the safety and economic benefits of the PPV23 vaccine can reduce knowledge gaps and sort fact from fiction. Specifically, providing guidance and education to local and state health officials and community health care workers on best practices for adult and high-risk group immunizations is a core communication strategy to increase uptake for PPV23 and influenza vaccines.

On a national level, policymakers can use existing resources such as the WHO's communication strategy for the H1N1 pandemic, the CDC's dedicated Web site for seasonal flu information and facts, and the US Government Health and Human Services pandemic influenza Web site.56-58 These communication tools can be amended to include PPV23 as part of a comprehensive strategy for preventing pneumonia and influenza and to coordinate media messages to ensure consistency. Leveraging national coordinated campaigns such as a National Influenza Vaccination Week, similar to the US strategy, provides the opportunity to further educate the public on the safety and benefits of PPV23 and influenza vaccinations.59 Increasing media campaigns, television educational advertising, and public service announcement campaigns has been shown to enhance awareness among health care providers and the general public to increase uptake of a new vaccine.58

On a subnational level, education, specifically targeting physicians and health care providers, is the most effective strategy to increase adult immunization rates. Studies over the past decade have shown that physicians' and health care providers' knowledge, attitudes, and practices highly influence adult decisions on immunization, especially for the elderly. In the United States, a nationwide survey found that physicians routinely failed to strongly recommend influenza and pneumococcal vaccinations to their elderly and high-risk patients even though physicians were found to be the "most trusted source" of information on immunization.54,57 A study by Opstelten et al.60 further showed that patient noncompliance was attributed to a perceived lack of recommendation for a pneumococcal vaccine by the physician, and results from household surveys performed by telephone interviews between the 2001 and 2007 influenza seasons in the United Kingdom, showed that the lack of a recommendation by a family physician for an influenza vaccination was themain reason for not getting immunized.61

There are several activities that state and local governments can implement to raise public awareness and increase education of physicians, health care workers, and patients. Use of preprinted influenza and PPV23 suppliers' product pamphlets and product profiles provides education materials for physicians and health care workers on the safety and effectiveness of influenza and PPV23 vaccines. Training health care workers to conduct comprehensive, on-site interventions at physician offices, local public health clinics, senior centers, and pharmacies, focusing on the impact of concomitant administration in reducing illness, hospitalization, and death from influenza and pneumonia, promotes the health benefits of immunization. The goals are to have physicians and health care workers recommend concomitant administration of influenza and PPV23 vaccines and to have patients ask for the vaccines.

Early, interdisciplinary communication and educational strategies at a national level and strengthening and emphasizing education and advocacy with physicians and health care workers on a subnational level will increase adult immunization specifically in the elderly and high-risk populations.

Step 4

Building upon existing influenza delivery channels can reduce programmatic costs and resources associated with the implementation of a PPV23 program. Several delivery options offer immediate access to the elderly and high-risk groups including physicians' offices, hospital settings, and longterm nursing facilities. One of the most important delivery pathways for elderly adult immunizations is physicians' offices, and those that use standing orders have been shown to be most effective in increasing vaccination for the elderly and high-risk populations.62 The results of the 2001 study conducted by Opstelten et al. showed that general practitioners who introduced PPV23 into existing influenza programs for elderly patients and used standing orders resulted in high vaccination rates for both vaccines; 2529 adult patients in the study (75%) received pneumococcal vaccine and 2812 (84%) received the influenza vaccine. 60 Furthermore, studies have shown that nurses and other health care staff who were assertive in implementing standing orders proved to be more effective for increasing vaccination coverage rates in adult populations than other institution-based strategies.63

Other options that have played a key role in reaching adults for influenza vaccine administration and suitable for including PPV23 vaccination are pharmacies, walkin health clinics, senior centers, grocery stores, and other nonmedical locations.64 These locations are gaining popularity specifically for their reduced administration costs, walk-in convenience, and extended hours outside physicians' office hours. In the United States, 33% of seasonal influenza vaccinations during the 2009-2010 vaccination season occurred outside the physician's office in health departments, pharmacies or drugstores, workplaces, and other alternative settings. 64

A recent study conducted in New York State showed that mass telephoning for patient-provider reminders improved uptake of PPV23.65 In 2007, a similar study conducted in a diverse managed care population that had already received mailed reminders showed like results. Telephone reminders, initiated by a nurse, informed patients that pneumococcal vaccination was recommended and a covered benefit of their insurance. Patients who received telephone reminders were 2.3 times more likely to be vaccinated during the study period than those that received mailed reminders only (P < .001).66

Lastly, mandatory immunization has been shown to be successful. A recent study conducted among health care workers in Canada showed that mandatory influenza vaccination rules in 3 hospitals increased immunization coverage among workers to almost 100%.67 Although this strategy has limitations for the general population, inpatients aged 65 years and older and high-risk groups, including staff in hospital settings, nursing, or long-term-care facilities, could benefit from mandatory policies requiring PPV23 and influenza vaccinations.

Step 5

Policymakers should identify criteria to assess the impact and determine the thresholds of impact that would justify a concomitant immunization program. These criteria could include reductions in morbidity, mortality, and hospitalizations in the elderly and high-risk groups during influenza outbreaks increasing cost-effectiveness.

The H1N1 influenza pandemic has provided policymakers with an ideal opportunity to review existing surveillance policies for the use of PPV23 and influenza vaccines. Proactively documenting the deaths and hospitalizations in the elderly and other high-risk groups from influenza and pneumococcal disease, and monitoring yearly, will provide the necessary evidence to measure the impact of the program and assess its benefits. On the basis of the existing literature, policymakers can expect reductions in both hospitalizations and deaths from these causes.

Many countries have recently improved surveillance for influenza and therefore already have an infrastructure from which to expand surveillance. Adding onto an existing influenza surveillance program can help to minimize the costs of pneumococcal surveillance in the elderly and other high-risk groups. The European Centre for Disease Prevention and Control recommends that surveillance data collection for pneumococcal disease include

* Invasive pneumococcal disease (bacteremia, meningitis),

* Nonbacteremic pneumococcal pneumonia and all-cause pneumonia, and

* Antimicrobial resistance among S. pneumoniae isolates and pneumococcal serotype distribution. 68

Monitoring vaccination coverage will be essential for maximizing the benefits of the program, and strategies may have to be adjusted to increase coverage. Specific barriers to immunization should be assessed on an ongoing basis to determine where the program can be improved.

Conclusions

Our review of the literature suggests that additional control strategies for pneumococcal disease in the elderly and other highrisk groups are needed specifically during influenza seasonal and pandemic outbreaks. Coadministering PPV23 and influenza vaccine can have a greater protective effect in the elderly and high-risk groups and be more cost-effective than programs aimed at just 1 of the vaccines alone.

Policymakers could potentially control 2 diseases that co-occur, provide proactive protection against secondary infections in the event of an influenza pandemic, and possibly improve the costeffectiveness of PPV23 and influenza immunization programs.

Leveraging existing or new influenza programs is an efficient strategy to increase PPV23 coverage for the elderly and high-risk groups. Following a systematic 5-step approach can help policymakers to comprehensively implement a dual program.

For countries not currently recommending PPV23 for the elderly, policymakers should reassess the benefits of concomitant influenza vaccine and PPV23, and leverage the current global attention on influenza pandemic preparedness to review existing policies on the use of influenza and PPV23 vaccines.

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Shawn A. N. Gilchrist, MD, MSc, DTM&H, Angeline Nanni, MBA, and Orin Levine, PhD

About the Authors

Shawn A. N. Gilchrist is with S. Gilchrist Consulting Services, Brampton, Ontario, Canada. Angeline Nanni is with ALN Consulting, Ellicott City, MD. Orin Levine is with International Vaccine Access Center, and International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Correspondence should be sent to Shawn Andre Ngeva Gilchrist, S Gilchrist Consulting Services Inc, 8 Covebank Crescent, Brampton, Ontario, Canada, L6P 2X5 (e-mail: [email protected]). Reprints can be ordered at http://www.ajph. org by clicking the "Reprints/Eprints" link.

This article was accepted October 14, 2011.

Contributors

S. A. N. Gilchrist developed the methodology, and drafted the article's introduction, results, and key findings. A. Nanni drafted the discussion and recommendations. O. Levine contributed to the development of the article including writing, editing, and interpreting findings from the review.

Acknowledgments

S. A. N. Gilchrist and A. Nanni have received an unrestricted grant from Sanofi Pasteur that has been applied toward the development of this paper.

Human Participant Protection

No human participant protection was required because no human participants were enrolled in our study.

Copyright:	(c) 2012 American Public Health Association
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