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Jeffrey Weinstein, MD, FIDSA, CPHQ, Chief Quality Officer, Director, Antimicrobial Stewardship Program, Kettering Medical Center and Sycamore Hospital, Dayton, OH
Dean L. Winslow, MD, Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA
It started with a hypothesis. In the late 1700s, Edward Jenner had heard that milkmaids who were frequently exposed to cowpox seemed to be immune to smallpox (variola) infection. Although others had noted this, Jenner proved that immunity could be developed by injecting cowpox into subjects who he later challenged with smallpox.1 The Latin word for cow is vacca — thus the medical term for vaccines. Vaccines are among the single biggest scientific advance in human history, and Jenner’s work is credited with saving millions of lives. Over recent decades, new advances in vaccination continue to alter the epidemiology of common infectious diseases in ways previously unimaginable. For instance, childhood meningitis due to Haemophilus influenzae type B essentially has been eradicated in the United States since universal childhood vaccination against this pathogen began in 1991.2 Likewise, chickenpox has been reduced 90% with the widespread uptake of varicella vaccination.3
Since adults and children live together in communities, the beneficial effects of childhood vaccines have extended to elders in significant ways. The death rates among both children and adults declined after the introduction of the varicella vaccine.4 Similarly, the rate of invasive pneumococcal disease in adults caused by the serotypes in the newer pneumococcal conjugate vaccine decreased after the vaccine was given to children. In part, these findings are explained by the concept of herd immunity. When a large enough proportion of a population is immune to a pathogen, even those in the community who have not been vaccinated are afforded some protection.
Vaccinations to directly prevent disease in adults likewise have reduced morbidity and mortality from a wide variety of viral and bacterial infections. This article will review the vaccines recommended for all adults as well as those vaccines recommended for special populations, such as immunosuppressed patients and pregnant women. In addition, the article will examine strategies that can be employed to increase vaccination rates in adults. These strategies have assumed a larger role in the era of value-based purchasing and pay for performance reimbursement methods such as the Medicare Access and CHIP Reauthorization Act.
The vaccines recommended in healthy adults are listed in Figure 1. All shown shaded in light gray are universally recommended. These figures, along with the detailed footnotes, can be found at: . Those vaccines shaded in dark gray will be described in a later section of this article.
Influenza A and B cause annual epidemics worldwide, with severity determined by the degree of change in the hemagglutinin and, to a lesser degree, the neuraminidase antigens on the viral surface. Since 1968, the predominant strains have been H3N2, but a pandemic occurred in 2009, with an antigenic shift to the H1N1 (swine flu) strain.5 During inter-pandemic years, there is antigenic drift such that the prior year’s vaccine is unlikely to remain effective. Thus, influenza vaccination is recommended annually for all adults in the United States who lack a contraindication. The currently available vaccines include trivalent and quadrivalent intramuscular and intradermal preparations, as well as a high-dose form and a newer recombinant form that has no ovalbumin and, therefore, is safe for use in patients with severe egg allergies.6 The Advisory Committee on Immunization Practices (ACIP) does not state a preference of which vaccine should be given, although some experts favor high-dose influenza vaccination for those ≥ 65 years of age,7 as the efficacy may be better in this group. A live attenuated influenza vaccine that has been approved for use in those aged 2-49 years is no longer recommended, as preliminary data show only 3% protective efficacy vs. 63% efficacy of the standard inactivated vaccines in children aged 2-17 years.8 In adults, the efficacy of influenza vaccination depends on the status of the host as well as how well-matched the vaccine is with circulating strains. A recent meta-analysis determined the vaccine efficacy to be 60% in healthy adults,9 whereas studies in HIV-infected patients suggest efficacy to prevent laboratory confirmed influenza may be as high as 71-85%.10 The currently marketed influenza vaccines are extremely safe, with the most common side effect being pain at the injection site. Prior anaphylaxis to an influenza vaccine (which is a rare event) is the only absolute contraindication. As noted above, those with severe egg allergy can receive the recombinant influenza vaccine. The swine flu vaccine given in 1976 led to an increase in cases of Guillain-Barré syndrome (GBS), but a recent study suggests the current vaccine leads to very small increased rates of GBS that are lower than the rate of GBS seen after naturally occurring influenza infection.11
For several decades, the recommendation for diphtheria/tetanus (Td) vaccination in adults simply was for booster shots every 10 years. Although rare in the United States, tetanus is most common in older adults whose immunity has waned as a result of lack of receipt of the Td booster. While diphtheria also remains rare in the United States, there have been epidemics overseas in recent years. Vaccine refusal is one of the factors leading to a resurgence of pertussis in children and adults.12 This resurgence has led to a revision of the recommendations, as the Td booster does not protect against pertussis. As per Figure 2, the ACIP now recommends one tetanus/diphtheria/acellular pertussis (Tdap) booster for all adults in the United States followed by Td boosters every 10 years. Special consideration regarding Td boosters applies for tetanus-prone wounds. All patients who have received fewer than three doses of tetanus-containing vaccine should receive a booster. Those in this category with major tetanus-prone wounds also should receive tetanus immune globulin administered at a different site. Fully vaccinated patients with minor wounds only require a booster if the most recent tetanus-containing vaccine was given more than 10 years previously, while those with major wounds should receive a booster if their last dose was given more than five years previously. Neither of these groups requires tetanus immune globulin.13 As per the general ACIP recommendations, if adult patients with wounds in need of a booster have not had the Tdap, then this preparation should be given. Pain at the injection site is the most common side effect of Tdap vaccine in adults. Low-grade fever is relatively common, while higher grade fever of > 102° F is more common among children. The acellular pertussis vaccine has fewer side effects than the older whole-cell pertussis vaccines. The use of Tdap vaccines in pregnant women is discussed later.
Varicella-zoster virus (VZV) is a herpesvirus that causes chickenpox in non-immune individuals and shingles when it reactivates later in life. Primary chickenpox in children can be a mild disease, but it also can be associated with severe disease and even death in children, primarily from Streptococcal toxic shock syndrome as a superinfection. Routine varicella vaccination not only can reduce morbidity and mortality in children,14 but by reducing the burden of disease in the community, there is lower likelihood of exposure in pregnant women and immunocompromised adults. This is an excellent example of the concept of herd immunity. These groups of adults not only have a higher risk for severe chickenpox but also have a contraindication to vaccination themselves. The ACIP does recommend varicella vaccination to all non-immune adults who do not have such a contraindication. The main side effects of varicella vaccination are pain at the injection site and the development of a small number of nearby vesicles. A more diffuse rash can occur, and those affected should avoid close contact with non-immune or immunocompromised individuals.15
The zoster vaccine was developed for use in adults to help prevent shingles, which is a reactivation of previously acquired VZV infection. As adults age or become immunocompromised, the risk of shingles increases. Shingles can present as dermatomal disease or disseminated disease. The latter can cause life-threatening manifestations in immunocompromised patients including pneumonia, ophthalmic infection, and central nervous system (CNS) involvement. In addition, postherpetic neuralgia with chronic pain is a complication more common in older adults. The zoster vaccine has an efficacy of approximately 50% for preventing shingles but nearly 70% for preventing postherpetic neuralgia.16 Although efficacy has been shown for adults age 50 years and older, the cost effectiveness for those aged 50-60 years is lower.17 Therefore, many payers will cover the zoster vaccine only for those ≥ 60 years of age. Contraindications to zoster vaccination include pregnancy and immunocompromised states. However, the vaccine is safe for HIV-infected patients with a CD4 count of > 200 cells/mL.3 The most common side effect of the zoster vaccine is pain at the injection site. The only difference between the varicella vaccine and the zoster vaccine is the dose and administration schedule. The varicella vaccine is lower dose and requires a two-dose schedule, whereas the zoster vaccine contains a higher concentration of the attenuated virus but is given as a single shot.
Measles and mumps are viral infections that had been nearly eliminated in the United States by the early 1980s because of successful vaccination strategies in children. Now both diseases occur in epidemics related to under-immunization in certain religious groups18 and the children of those philosophically opposed to vaccination (“anti-vaxxers”).19 The latter group has remained steadfastly against childhood vaccination for fear of a link to autism, despite multiple Institute of Medicine reports and other studies that have failed to find any causal links between either the measles, mumps, and rubella (MMR) or vaccine ingredients, such as thimerosal, and autism spectrum disorder.20 In fact, the original research purporting this link has been proven to be fraudulent.21
Measles, mumps, and rubella all can have serious health consequences in adults as well as children. In addition to the classic presentation with coryza, fever, and rash, measles can cause pneumonia, encephalitis, and subacute sclerosing panencephalitis. Mumps causes the classic parotitis and orchitis, but also can be associated with CNS disease. Although often mild in adults, rubella is feared, as it causes a variety of serious birth defects in infants born to mothers infected during pregnancy. The efficacy of the MMR vaccine approaches 95-100%.22 Because infection with measles and mumps was nearly universal before 1957, those born before that year generally are considered immune. Per the ACIP, all adults born in or after 1957 should have at least one dose of the MMR unless there is a contraindication such as immunosuppression. A second dose four weeks later is recommended for college students, healthcare workers, and international travelers. Serologic testing should be performed on women of childbearing age, and those not immune to rubella should be vaccinated if not pregnant; vaccination is contraindicated during pregnancy. The most common side effects of MMR vaccination in adults include fever, rash, lymphadenopathy, and joint pain.
Human papillomavirus (HPV) is the major cause of genital warts and urogenital cancers. Because types 16 and 18 are the major etiologic agents of cervical cancer, vaccines initially were developed and approved for use in girls and women. Now the vaccines are recommended for both sexes for several reasons. Obviously, reduction of infections in males likewise reduces infection in their sexual partners. Also, HPV is a cause of penile, anal, and oral cancers as well as respiratory papillomatosis. Vaccination to prevent HPV infection is most effective if given before the period of risk — before the onset of sexual activity. For boys and girls, the vaccine series should be given at ages 11-12 years. However, since there are many different serotypes, catch-up vaccination is recommended for women up until age 26 years and in men until age 21 years (26 years if HIV infected). The ACIP currently recommends the use of either the 2-valent, 4-valent, or newer 9-valent vaccine in girls/women but only the 4-valent or 9-valent vaccine in boys/men. (See Figure 1.)
Much of the efficacy data on HPV vaccination comes from Australia, which was the first country to establish a national government-funded vaccine campaign. Rates of infection with the four vaccine serotypes (6, 11, 16, 18) fell among women from 28.7% to 6.7% from the pre-vaccine period to the post-vaccine period.23 In the United States, the prevalence of infection in females with these serotypes has been reduced by 64% in the 14- to 19-year-old age group and by 34% in the 20- to 24-year-old age group.24 In males, the efficacy for preventing genital warts among the four vaccine serotypes was 65% in a large international trial.25
The HPV vaccines are very safe, with the main adverse effect being pain at the injection site. There have been reports of syncopal episodes after receipt of the vaccine, and the ACIP now recommends a 15-minute waiting period in a sitting or supine position following vaccination.26
Streptococcus pneumoniae is a virulent bacterial pathogen that causes pneumonia, bacteremia, and bacterial meningitis in adults and children. Initial pneumococcal vaccines were directed at capsular polysaccharides of the many serotypes of the bacteria. The polysaccharide vaccines are poorly immunogenic in younger children and the immunosuppressed and, therefore, pneumococcal conjugate vaccines have been developed. These vaccines include protein antigens to help induce type-specific antibody production. At present, the two major vaccines available in the United States are the pneumococcal polysaccharide 23 valent (PPSV23) and the pneumococcal conjugate 13 valent (PCV13) preparations. The serotypes covered include those most commonly associated with invasive pneumococcal disease in humans. Dosing and sequencing of these vaccines vary depending on age of the patient and indication for vaccination. In general, the PCV13 should be given before the PPSV23 in those never previously vaccinated. Those requiring more than one dose of PPSV23 should not receive the subsequent doses within five years of the previous dose. The ACIP has determined that the pneumococcal vaccine algorithms for adults will be scheduled for review again in 2018. Detailed algorithms are found online at the ACIP Recommended Adult Immunization Schedule: .
The efficacy of the PPSV23 vaccine in older adults has been established in a number of trials and confirmed in a recent meta-analysis.27 The vaccine efficacy to prevent invasive pneumococcal disease was between 45-73% and to prevent pneumococcal pneumonia was between 48-64%. Although these numbers are similar to the efficacy of PCV13, the PPSV23 still has a role in adults, as it provides protection against pneumococcal strains not included in PCV13. A very large trial of the PCV13 vaccine in 85,000 adults 65 years of age and older found vaccine efficacy to be 45% at reducing vaccine type pneumococcal pneumonia and 75% at preventing invasive pneumococcal disease.28
Adverse effects of the pneumococcal vaccine include pain, swelling, and/or erythema at the injection site. The only known contraindication to vaccination is a history of anaphylaxis to a previous pneumococcal vaccine.
The hepatitis B vaccine is highly effective at preventing infection, as can be evidenced by the epidemiology of hepatitis B infection in healthcare workers, all of whom are vaccinated. Hepatitis B is much more transmissible than hepatitis C or HIV, but there has been an approximate 30-fold reduction in hepatitis B infections among healthcare workers since universal vaccination began.29 However, rates of vaccination in other adults are low, and those who were not vaccinated in childhood remain at risk via sexual exposure or the sharing of needles used for intravenous (IV) drug injection.30 Although a large proportion of patients with acute hepatitis B clear the infection spontaneously, those who develop chronic infection are at risk of progressing to cirrhosis or developing hepatocellular carcinoma. Given the safety of this vaccine, the high burden of disease, and ease of transmission, the hepatitis B vaccine is now a routine childhood vaccine. Adults who should be vaccinated are described in Table 1 as well as in Figures 1 and 2.
The hepatitis B vaccine is given as a series of three injections over six months, alone or in combination with the hepatitis A vaccine. Response rates are high though not universal, and titers should be drawn after vaccination of healthcare workers or others with ongoing risk, such as IV drug users or hemodialysis patients. In general, non-responders require an additional three-dose series. Severe adverse reactions to hepatitis B vaccination are rare.31
Hepatitis A virus does not cause chronic disease, but acute infection produces a miserable illness characterized by nausea, malaise, and occasionally severe liver dysfunction. Although less common in the United States than in developing countries, the virus is transmitted via the fecal oral route so everyone is at risk. Most infections are transmitted by food handlers, so common source outbreaks occur. The vaccine is recommended as per Figure 2 for patients with chronic liver disease including hepatitis B or C infections, men who have sex with men, IV drug users, and travelers. For the latter group, the first injection provides protection for a trip, but a second shot six months after the first completes the series and provides prolonged protection.32 If more than six months has elapsed between doses, the series does not need to be re-started; the second shot is sufficient. Soreness at the injection site is the most common side effect of this vaccine and severe reactions are extremely uncommon.
Neisseria meningitidis is a feared pathogen that can cause meningitis or severe sepsis with purpura fulminans. Those with deficiencies in the terminal components of complement are at significantly elevated risk, but healthy adolescents and adults can be affected. Disease can be sporadic or can occur in outbreaks among those living in close quarters such as a college dorm. For several decades, the available meningococcal vaccines only covered three of the main four strains: A, C, Y, and W135. A vaccine for type B strains available in Europe was imported into the United States in 2013 to help contain meningococcal outbreaks at two major U.S. universities.33 Two meningococcal B vaccines are now FDA-approved in the United States, along with three quadrivalent vaccines for strains A, C, Y, and W135. Current recommendations from the ACIP include the use of both meningococcal vaccines in adolescents and young adults, and most colleges require these for either all incoming students or those residing on campus. The routine childhood vaccine schedule calls for the initial quadrivalent meningococcal vaccine at 11-12 years of age and a booster at age 16 years, because efficacy seems to wane prior to the age of high school graduation.34
The meningococcal vaccines are all extremely safe, with minor reactions reported. There had been early concerns about a causal relationship between the Menactra quadrivalent meningococcal vaccine and GBS, but large-scale studies have revealed no significant increased risk.35
The H. influenzae type B vaccine (Hib) is not indicated routinely for healthy adults. As previously noted, the vaccine has had a tremendous effect on childhood meningitis, but H. influenzae is not a common cause of bacterial meningitis in adults. The vaccine is recommended in limited situations for adults: asplenic patients (including those with sickle cell disease as they are functionally asplenic) and adults status-post-hematopoietic stem cell transplantation. In patients undergoing splenectomy, the vaccine should be administered 14 days before surgery; if the surgery is for traumatic rupture, the vaccine should be given 14 days postoperatively.36 A full three-shot series is not required except for following stem cell transplantation.
Vaccines recommended for immunosuppressed patients are listed in Figure 2. However, it is always critical to remember that not all immunosuppressed patients are alike. Asplenic patients are at unique risk for life-threatening infections with encapsulated organisms and thus require meningococcal and Hib vaccines in addition to pneumococcal vaccines. As a rule of thumb, live vaccines, such as MMR, zoster, and yellow fever, should be avoided in immunosuppressed patients. However, certain live attenuated vaccines are safe and recommended for HIV-infected patients with CD4 counts > 200 since their immune system is strong enough. Live vaccines also may be acceptable in patients status-post-hematopoietic stem cell transplant after two years, but never in solid organ transplant patients.37 The Hib vaccine also is recommended after hematopoietic stem cell transplant.38 All immunosuppressed adults should receive annual influenza vaccination as well as pneumococcal vaccination, regardless of age. This includes cancer patients actively undergoing chemotherapy treatments.39 They also should receive the Tdap vaccine once then the Td booster every 10 years.40
The recommended vaccines for patients with chronic diseases such as cardiopulmonary, renal, or liver disease or alcoholism also are listed in Figure 2. In general, everyone should receive annual influenza vaccination as well as pneumococcal vaccination as per the proper schedule. The recommendation for Tdap once followed by the Td booster every 10 years still applies. Based on the tables, the MMR vaccine should be given to those without proof of immunity. A zoster vaccine is safe to administer at age 60 years unless the patient is immunocompromised. The most significant difference among these groups is that patients with end-stage renal disease,41 chronic liver disease, and diabetes all should be vaccinated against hepatitis B if not already immune, whereas this is not universally needed for those patients with chronic cardiopulmonary diseases and alcoholism. Non-immune patients with chronic liver disease also should receive the hepatitis A vaccine series.
Pregnancy is a relatively immunocompromising state and, as such, live vaccines, such as MMR and varicella, are contraindicated. Despite this recommendation, fetal infection in women who inadvertently were given a dose of MMR has never been documented.42 Influenza vaccine should be given to all pregnant women lacking a contraindication during the season when the vaccine is available. In addition, protection against diphtheria, pertussis, and tetanus is essential in pregnant women. Although diphtheria has mainly re-emerged outside of the United States, pertussis (whooping cough) has had a significant resurgence here this decade, affecting both young children and adults.43 Guidelines now recommend that all pregnant women be vaccinated against these pathogens. Those women who previously have not completed the vaccine series should have a full three-shot series, including one dose of the Tdap. All previously vaccinated pregnant women should have a Tdap booster with each pregnancy, even when there is a short time interval between pregnancies,44 as young infants need maternal antibody for protection during the first six months of life.
Well-established guidelines have been published for the vaccinations recommended (and often required) for healthcare personnel.45 All healthcare workers should be vaccinated against hepatitis B, as this is the most transmissible virus in healthcare settings. Annual influenza vaccination also is critical for healthcare workers. Measles can be transmitted via an airborne route, and outbreaks have occurred in hospital settings in the United States. Since immunity from childhood vaccines often wanes, the MMR is recommended for non-immune healthcare workers.45 All healthcare personnel also should be updated with the Tdap if they have not had this formulation previously. Finally, immunity against varicella is important for healthcare workers, as this is an airborne virus and also because severe disease can ensue in adults.
International travelers may be at risk for a variety of infectious diseases, some of which are not present in the United States. Vaccination of travelers is beyond the scope of this review. Information for healthcare providers regarding travel medicine can be found at .
It is well-documented that rates of adult vaccination in the United States are lower than desired. For example, 2014 CDC data show that only 43.2% of adults older than19 years of age received the influenza vaccine and only 61.3% of adults older than 65 years of age had appropriate pneumococcal vaccination coverage.46 This compares to goal rates of vaccination under the Healthy People 2020 program of 70% and 90%, respectively.47 This problem is not new, and a variety of methods have been studied to increase vaccine coverage rates in adults both in outpatient and inpatient settings. Recent data show that a program utilizing the 4 PillarsTM Practice Transformation Program may reduce missed opportunities for vaccination in outpatient primary care practices.48 The strategies used included creating easy access to vaccine services, improving communication with patients about vaccination, enhancing office systems including the use of electronic medical record alerts, and designating an office immunization champion. Other studies have looked at interventions as varied as sending patients leaflets/postcards, entering patients in a lottery to win free groceries, and even paying physicians.49 In the inpatient arena, the missed chances for vaccination also are well described. Prior to the push to take advantage of hospital stays as a chance to vaccinate, the rate of pneumococcal vaccination of inpatients was found to be only 0.4%.50 These concerns have been addressed in part by the IMM-2 Core Measure from the Centers for Medicare and Medicaid Services, which translate into financial penalties for hospitals that fall below a threshold influenza vaccination rate before patient discharge. Many hospitals now have standing orders for not only influenza vaccination in season but also for pneumococcal vaccination year round for appropriate patients.
Financial Disclosure: To reveal any potential bias in this publication, and in accordance with Accreditation Council for Continuing Medical Education guidelines, Dr. Wise (editor) reports he is involved with sales for CNS Vital Signs. Dr. Weinstein (author), Dr. Winslow (peer reviewer), Ms. Coplin (executive editor), Ms. Mark (executive editor), and Ms. Hatcher (AHC Media Editorial Group Manager) report no financial relationships with companies related to the field of study covered by this CME activity.