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Keywords:

  • influenza;
  • vaccination;
  • vaccine efficacy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies

In 2010, the Centers for Disease Control and Prevention (CDC) expanded guidelines for annual influenza vaccine to recommend universal vaccination of everyone over the age of 6 months. In 2007, the CDC partnered with Families Fighting Flu, an industry-funded group, to create public service announcements promoting vaccination of healthy children, the segment of the population at the least risk of dying. The “everyone is at risk” message associated with universal influenza vaccination could undermine effective influenza prevention efforts. Most influenza-related deaths and hospitalizations occur in those aged 85 and older—a population in which influenza vaccine is not very effective. Herd immunity, integral to the effectiveness of other vaccines, is difficult to achieve with influenza vaccine, which is less effective than other vaccines, and must be given annually. Controlling pandemic or non-pandemic influenza may depend not only on vaccination but also on social distancing, handwashing, and wearing masks. Non-vaccine infection control techniques may work against influenza and other respiratory infections. Comparative effectiveness research is needed to determine the best methods for reducing deaths and hospitalizations for influenza and pneumonia. Discussion is needed about the extent to which public health recommendations are distorted by industry relationships. Public health messaging must be evidence-based.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies

Over the last two decades, major shifts in influenza vaccine recommendations have expanded substantially with limited rationale to support the guideline shift. Vaccination guidelines are released annually by the Centers for Disease Control and Prevention (CDC), which relies on the Advisory Committee on Immunization Practices (ACIP), a group of 15 experts appointed by the Secretary of the U.S. Department of Health and Human Services.

Since 1964, the CDC has recommended that annual influenza vaccination efforts target adults 65 years of age or older and people with asthma or other conditions that place them at higher risk of influenza-related complications (Doshi, 2013a). In 2000, CDC recommendations expanded to include everyone over the age of 50; in 2002, children 6–23 months were to be vaccinated “if feasible,” and in 2004 all children 6–23 months were added. In 2006, CDC guidelines expanded again to include children up to 5 years old, and in 2008 the CDC extended routine annual influenza vaccine recommendations to include all children aged 6 months to 19 years (Doshi, 2013a). In 2010, the ACIP recommended universal vaccination for everyone over the age of 6 months (Fiore et al., 2010).

This article will discuss the question of whether universal influenza vaccination will reduce influenza-related morbidity and mortality, and will make recommendations for more targeted use of influenza vaccine and increased use of non-vaccine infection control measures.

Who Is at Risk?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies

The CDC estimates that 23,607 influenza-related deaths occur annually (CDC, 2010). Approximately 226,054 people are hospitalized from influenza or influenza complications annually (Thompson et al., 2004). The vast majority of influenza hospitalizations and deaths are in the elderly; adults over 65 account for 87.9% of estimated influenza-attributable deaths in the United States (CDC, 2010; see Figure 1). The risk for hospitalization for influenza increases steeply in a linear fashion only after age 65 and is consistently highest among those aged 85 and older (628.6 per 100,000 person-years) (Thompson et al., 2004).

image

Figure 1. Age-Specific Average Annual Rate of Pneumonia and Influenza Hospitalizations.

Figure based on data from Figure 3 in Thompson et al. (2004).

Download figure to PowerPoint

It is difficult to estimate the number of deaths from influenza because patients may have pneumonia or other comorbidities; also, what clinicians report as causes of death varies over time. For example, ICD (International Classification of Disease) codes for deaths caused by influenza increase—and codes for deaths caused by pneumonia decrease—when clinicians are aware of pandemic influenza (Thompson et al., 2009). Deaths attributed to influenza and pneumonia are now combined and mathematical modeling used to estimate the proportion due to influenza, but this method has obvious drawbacks (Doshi, 2008; Thompson et al., 2009).

Vaccinating the Elderly

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies

To reduce deaths from influenza, protecting the elderly is paramount, but it is not clear how best to do this. Claims are sometimes made that influenza vaccination reduces overall mortality in the elderly by 50%, but this claim is implausible given that influenza is associated with only about 10% of wintertime deaths (Wong, Campitelli, Stukel, & Kwong, 2012). Deaths prevented by influenza vaccine are based on non-randomized retrospective cohort studies with known methodological problems, and the true benefit may be far lower, especially in the elderly (Doshi, 2013b).

Many observational studies purport to show that elders who receive influenza vaccine are less likely to die, but it is clear that observational studies overestimate the benefit of influenza vaccination (Fireman et al., 2009; Simonsen et al., 2005). Healthy elders are more likely to receive influenza vaccine, and sick elders may be less likely to be vaccinated. One study that supports the concept that healthy user bias infests observational studies found that vaccination is associated with decreased mortality during the flu season but also, implausibly, decreased mortality before and after the flu season (Eurich, Thomas, Johnstone, & Majumdar, 2008).

Using statistical methods that reduce bias, Wong et al. (2012) determined that the true reduction in all-cause mortality attributable to influenza vaccine is about 6% (Doshi, 2013b). Another study found similar results (Fireman et al., 2009).

Vaccinating Healthy Adults

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies

Healthy adults are at low risk of dying from influenza. Reducing morbidity and absenteeism is still an important goal, but influenza vaccine is not highly effective in this group. A recent Cochrane systematic review of the influenza vaccine in healthy adults examined 50 reports with a total of more than 70,000 healthy people aged 14–60. The study found that when inactivated parenteral vaccines matched the circulating strain and met WHO recommendations for antigenic content and potency, they reduced symptoms from influenza-like illness 30% and symptoms from influenza 73%. When these conditions were not met, the vaccine was ineffective against symptoms from influenza-like illness and only 44% effective against symptoms of influenza (Jefferson et al., 2010). In absolute terms, influenza vaccine reduced influenza symptoms by 3% under the best of circumstances—when the vaccine was well-matched with the circulating strain and circulation was high. When those conditions were not met influenza symptoms were reduced only 1%. There was no significant effect on time taken off work, which was reduced by only 0.13 days. The authors concluded that “Inactivated influenza vaccines decrease the risk of symptoms of influenza and time off work, but their effects are minimal, especially if the vaccines and the circulating viruses are mismatched. There is no evidence that they affect complications or transmission” (Jefferson et al., 2010).

Little evidence supports the view that vaccinating healthy people protects more vulnerable groups through herd immunity. In fact, a recent Cochrane Collaboration systematic review found that vaccinating adults most at risk of vectoring influenza is ineffective for protecting a vulnerable population. The review evaluated four cluster-RCTs and one cohort study on the effect of vaccinating caretakers on influenza in adults over age 60 in long-term care facilities. Pooled data from three randomized cluster-controlled trials showed that although the incidence of influenza-like illness was reduced, there was no effect of vaccinating health-care workers on laboratory-proven influenza, lower respiratory tract infections, or hospital admissions and deaths from pneumonia among elderly residents in long-term care facilities (Thomas, Jefferson, & Lasserson, 2013).

Protecting the Herd

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies

One of the main reasons given for universal vaccination is that herd immunity may protect the elderly, who have a lowered immunological response to influenza vaccine (Goodwin, Viboud, & Simonsen 2006). The latest adjusted estimates of influenza vaccine effectiveness against influenza A found that vaccine efficacy was only 27% in persons aged ≥65 years—an estimate that did not reach statistical significance (CDC, 2013a). Vaccine efficacy was 56% overall. Even if everyone were vaccinated, herd immunity is impossible to achieve with the influenza vaccine, because vaccine efficacy is too low.

Focusing on Children

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies

Although elders are the group at highest risk of dying from influenza, public health efforts have targeted children. However, influenza-associated mortality in children is rare. Since influenza-associated pediatric mortality became a nationally notifiable condition in 2004, pediatric deaths have ranged from 35 to 282 deaths annually (the highest number occurred during the 2009 pandemic) (CDC, 2014).

Between 1976 and 2007, the CDC estimated that there were 97 influenza-associated deaths annually in those 18 years and younger, or 0.1 deaths per 100,000 children (CDC, 2010). In contrast, the mortality estimate for adults age 65 and older was 21,098 deaths annually or 17 deaths per 100,000 persons—a 170-fold difference (CDC, 2010).

In 2007, the CDC joined forces with an industry-funded group called Families Fighting Flu (FFF). The stated aim of FFF is to “improve the rates of childhood influenza vaccinations and help reduce the number of childhood illnesses and deaths caused by the influenza each year” (FFF, 2009). The FFF “operates solely on donations from organizations.” The CDC may be the only non-corporate organization involved; the FFF website is “made possible by unrestricted grants from MedImmune, Inc., Novartis Vaccines, Sanofi Pasteur, CSL Biotherapies, and The Clorox Company” (FFF, 2009). Four of these companies manufacture influenza vaccine (CDC, 2013b); Clorox makes disinfectant products. In 2010, Sanofi Pasteur gave FFF $200,000 (Sanofi-Aventis, 2011).

A joint CDC-FFF Public Service Announcement (PSA) focuses on healthy children who died suddenly after developing influenza symptoms (CDC, 2008a). In the PSA, one parent says, “The influenza has changed our lives … the influenza can kill your healthy children” while another parent, referring to the influenza vaccine, advises, “Please get it. I don't want you sitting here having to talk about the loss of your child.”

The PSA warns that, “Children have the highest rates of influenza infection of any age group, yet they are rarely vaccinated” and, “Every year children die in the United States from influenza and its complications. The majority of these children have no high-risk medical conditions” (CDC, 2008a).

In fact, relatively few healthy children die from influenza, and almost half of pediatric deaths occur in high-risk children, including those with asthma, seizures, or cerebral palsy. Of 166 influenza-associated pediatric deaths reported from 39 states and 2 local health departments in the United States between 2004 and 2007, 73 deaths (45%) were in children with underlying respiratory or neurological conditions that placed them in a high-risk group (Finelli et al., 2008). Despite longstanding recommendations, only one out of five (21%) of these high-risk children had been vaccinated (Finelli et al., 2008). It is unclear how much industry influence affects CDC messages.

Possible Adverse Effects

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies

Many vaccines, including influenza vaccine, have been linked to Guillain–Barre syndrome, but recent studies have also linked influenza vaccine to febrile seizures in children, and narcolepsy in adolescents, although the exact mechanism is unknown (Wong et al., 2012). It is also possible that seasonal influenza vaccination increases susceptibility to pandemic influenza. Case-control studies in Canada, involving 1,226 laboratory-confirmed cases of pandemic influenza H1N1 (pH1N1) and 1,505 controls, indicate that prior vaccination with the 2008–09 trivalent influenza vaccine was associated with an increased risk of acquiring pandemic influenza H1N1 (odds ratios ranged from 1.4 to 2.5) in 2009 (Skowronski et al., 2010).

Non-Vaccine Public Health Measures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies

Non-vaccine prevention measures include social isolation (avoiding others while ill), wearing a mask when ill, covering the mouth when sneezing or coughing, and handwashing. These interventions can be very effective; frequent handwashing, for example, can reduce the spread of respiratory viruses by half (Jefferson et al., 2011). Vaccines by their nature protect against targeted pathogens, but non-vaccine infection control measures reduce transmission of all viral and bacterial infections spread by the respiratory route. A simulation model estimates that isolation measures such as household quarantine and school closures could reduce influenza spread by 63.7–94.7%, with household quarantine alone reducing spread by 48.7% (Yong, Atkinson, & Ettema, 2011). School closings and household quarantine are difficult to implement and have their own societal costs to families and the workplace. And simulation models have limitations. But fostering a culture in which workers, students, and caretakers are encouraged to stay home is an achievable goal with both individual and societal benefits.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies

While is it clear that influenza presents a danger to the health of the population, vaccines have not been proven to be completely efficacious in preventing the spread of influenza. Vaccinating healthy adults and children makes sense only if disrupting their role as vectors of disease to the elderly and chronically ill has been proven to be effective. For influenza, herd immunity is not the most successful or direct way to prevent influenza-related deaths.

Most “flu” is not influenza; only a small proportion of influenza-like illness (ILI) is true influenza. Vaccine efficacy for serologically confirmed influenza varies widely, ranging from about 44% to 90% for any given season (CDC, 2008b); in 2012–13, vaccine efficacy was 56% (CDC, 2013a). Vaccine efficacy is the ability of a vaccine to reduce the incidence of proven disease in a vaccinated population compared to an unvaccinated population, but the term does not connote a reduction in hospitalizations or deaths. Available since the mid-1940s, the influenza vaccine is reformulated annually from the preceding year's influenza strains, using two subtypes from Type A and one subtype from Type B (Hilleman, 2003). Because of antigenic drift, individuals immune to last year's influenza strains may not be fully (or at all) immune to new strains; therefore annual vaccination is necessary.

Not only does influenza vaccine have to be readministered annually, but the efficacy of influenza vaccine is far below the efficacy of other widely used vaccines. For example, a single dose of measles, mumps, rubella (MMR) vaccine provides at least 95% effectiveness in preventing clinical measles and 69–81% protection against mumps. MMR also has results in herd immunity; for example, a single dose is 92% effective in preventing secondary cases of measles among household contacts (Demicheli, Rivetti, Debalini, & Pietrantonj, 2012).

Pandemic influenza, because it is the result of antigenic shift, not drift (CDC, 2011), will always predate a highly effective vaccine. While vaccination will be important in a pandemic, social isolation and other non-vaccine methods of prevention must not be ignored.

Promotion of influenza vaccine may mislead the public into believing that influenza vaccine is highly effective. A false sense of security could even increase transmission rates if vaccinated individuals who develop influenza-like symptoms fail to take precautions against infecting others because they believe they could not possibly have “flu.”

Policy Implications

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies

The development and rational use of vaccines is an important part of public health. However, it is important to rely on randomized controlled trials, not observational studies, for claims of benefit, and not to overstate efficacy claims. It is also important to have adjunct preventive health measures in place until more reliable analyses are done.

An “everyone is at risk” message misrepresents reality and could undermine effective influenza prevention efforts. Vaccine campaigns are effective in increasing vaccination rates, but the goal should be reducing mortality and hospitalizations, not merely increasing vaccination coverage. Expanding influenza vaccine recommendations to include low-risk groups, and promoting to low-risk groups, may divert educational efforts and financing away from the elderly and other populations who are at the highest risk of dying from influenza. Influenza vaccines are innately limited, and should be an adjunct to hygiene, not the other way around. Routine use of non-vaccine infection control techniques (including social isolation, handwashing, and mask-wearing) may be effective against not only influenza, but other infections spread by the respiratory route. Comparative effectiveness research is needed to determine the best methods for reducing deaths and hospitalizations for influenza and pneumonia in the elderly. There is a dearth of randomized controlled trials comparing the effect of vaccination to non-vaccine infection control techniques, and comparing the effect of different vaccine policies. Industry has a clear interest in promoting vaccines to the exclusion of other infection control measures, but this perspective should be resisted by public health agencies. Discussion is needed about the extent to which public health recommendations are distorted by relationships with industry.

Notes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies

Alicia M. Bell, MS, contributed valuable insights to this article. Nicole Dubowitz assisted with formatting and fact-checking.

Dr. Fugh-Berman directs PharmedOut, a Georgetown University Medical Center-based research and education project that promotes rational prescribing.

Dr. Fugh-Berman is a paid expert witness on behalf of plaintiffs in litigation regarding pharmaceutical marketing practices. Dr. Richards and Ms. Tran have no conflicts of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies

Biographies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Who Is at Risk?
  5. Vaccinating the Elderly
  6. Vaccinating Healthy Adults
  7. Protecting the Herd
  8. Focusing on Children
  9. Possible Adverse Effects
  10. Non-Vaccine Public Health Measures
  11. Discussion
  12. Policy Implications
  13. Notes
  14. References
  15. Biographies
  • Carly Noel Richards, MD, MPH, is an intern in general surgery at Tripler Army Medical Center, Hawaii.

  • Christine Tran, MS, is a former intern for PharmedOut.

  • Adriane Fugh-Berman, MD, (corresponding author) is an Associate Professor in the Department of Pharmacology and Physiology at Georgetown University Medical Center and Director of PharmedOut, a GUMC research and education project.