Clinical Review

A majority of ovarian cancers are diagnosed at an advanced stage, requiring extensive surgical cytoreductive procedures.¹ Because the presence of residual macroscopic disease correlates highly with decreased survival,² these procedures can be lengthy, complicated, and risky for the patient. Many patients who undergo cytoreduction will be left with a suboptimal result despite surgery.

Better identification and improved treatment of patients who are at high risk of a suboptimal result are clearly needed. One treatment option is neoadjuvant chemotherapy, the administration of chemotherapy prior to the main treatment. Although early data suggested that it was associated with worse outcomes, recent studies have yielded new information:

• Neoadjuvant chemotherapy followed by interval debulking surgery is not inferior to primary debulking surgery followed by chemotherapy for patients who have bulky stage III or IV ovarian cancer
• In patients who have advanced ovarian cancer, neoadjuvant chemotherapy followed by surgical cytoreduction is associated with improved perioperative outcomes
• Postoperative intraperitoneal chemotherapy after neoadjuvant chemotherapy has not yet proved to be associated with improved survival.

Several questions prompted by these findings include:

• Will neoadjuvant chemotherapy improve surgical outcomes in patients who have advanced ovarian cancer and, thus, improve survival?
• Is neoadjuvant chemotherapy a better strategy for all patients?
• Will neoadjuvant chemotherapy reduce the surgical effort necessary to achieve an optimal result?
• What is the role of intraperitoneal chemotherapy in patients who undergo neoadjuvant chemotherapy?

Further national (or international) data are needed to confirm a survival advantage for patients who receive neoadjuvant chemotherapy, compared with those who undergo primary surgery before the administration of chemotherapy.

Neoadjuvant chemotherapy is an acceptable alternative to primary surgical cytoreduction

Vergote I, Tropé CG, Amant F, et al; European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC Clinical Trials Group. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943–953.

Historically, the standard of care in ovarian cancer treatment has been surgical cytoreduction followed by chemotherapy.^3-6 However, data from prospective randomized trials to support this practice are limited. Neoadjuvant chemotherapy is an alternative strategy that has been explored as a way to improve outcomes from interval surgical debulking in patients who have ovarian cancer in whom suboptimal cytoreduction is otherwise expected. Vergote and coworkers attempted to determine which strategy is better through a randomized trial of 632 patients.

Participants had to have biopsy-proven stage IIIc or IV ovarian, fallopian tube, or primary peritoneal cancer. The two treatment arms were:

• primary debulking surgery followed by at least 6 cycles of platinum-based chemotherapy
• 3 cycles of platinum-based neoadjuvant chemotherapy followed by interval debulking surgery in responders and those who had stable disease. These patients then received an additional 3 cycles of platinum-based chemotherapy post-operatively.

All surgical procedures were completed by qualified gynecologic oncologists, and all patients were evaluated for eligibility before randomization, with no additional selection criteria.

Postoperative death occurred in 2.5% of patients in the primary-surgery group, compared with 0.7% of patients in the neoadjuvant-chemotherapy group. Grade 3 or 4 hemorrhage occurred in 7.4% of patients after primary debulking, compared with 4.1% of patients after interval debulking. Patients who received neoadjuvant chemotherapy experienced a lower rate of infection (1.7% versus 8.1%) and venous complications (0% versus 2.6%).

Overall and progression-free survival rates were similar between the two groups. After multivariate analysis, the strongest predictors of survival were absence of residual disease after surgery (P<.001), small tumor size before randomization (P=.001), and endometrioid histology (P=.001)

Neoadjuvant chemotherapy improves perioperative outcomes

Milam MR, Tao X, Coleman RL, et al. Neoadjuvant chemotherapy is associated with prolonged primary treatment intervals in patients with advanced epithelial ovarian cancer. Int J Gynecol Cancer. 2011;21(1):66–71.

Milam and coworkers investigated chemotherapy-associated morbidity and timing in two groups of patients who had advanced epithelial ovarian cancer:

• those undergoing neoadjuvant chemotherapy followed by maximal cytoreductive surgery
• those undergoing primary surgery followed by chemotherapy.

Their retrospective study involved 263 consecutive patients who were treated at MD Anderson Cancer Center from 1993 to 2005. In this cohort, 47 women (18%) received neoadjuvant chemotherapy. These patients experienced less blood loss (400 mL versus 750 mL) and a shorter hospital stay (6 versus 8 days). Time to the initiation of chemotherapy from the date of diagnosis did not differ between groups, and the amount of residual disease and rate of survival were also similar between arms. However, patients who received neoadjuvant chemotherapy underwent more cycles of chemotherapy over a longer treatment period.

In the pipeline: Data on intraperitoneal chemotherapy after neoadjuvant chemotherapy

Le T, Latifah H, Jolicoeur L, et al. Does intraperitoneal chemotherapy benefit optimally debulked epithelial ovarian cancer patients after neoadjuvant chemotherapy? Gynecol Oncol. 2011;121(3):451–454.

Although several studies have demonstrated that intraperitoneal (IP) chemotherapy provides a survival advantage, compared with intravenous (IV) chemotherapy, after primary surgical debulking, it remains unclear whether IP chemotherapy would provide a similar superior survival outcome following neoadjuvant chemotherapy (FIGURE).

Intraperitoneal chemotherapy: How efficacious?
The jury is still out on whether intraperitoneal chemotherapy improves survival after neoadjuvant chemotherapy and interval debulking in stages III and IV ovarian cancer.The authors of this paper attempted to answer this question through a retrospective review of 71 patients. All patients were treated with neoadjuvant chemotherapy followed by interval debulking and either IP or IV chemotherapy. Overall, 17 patients (24%) received IP chemotherapy, and 54 patients (76%) received IV chemotherapy. The median number of cycles given prior to and after surgery was the same for both groups (3 for both neoadjuvant chemotherapy and chemotherapy following surgery).

Although patients who received IP chemotherapy had a higher overall response rate (82% versus 67%), there were no differences between groups in terms of progression-free (P=.42) and overall survival (P=.72).

One important limitation of this study was its small sample size and lack of statistical power. In addition, more patients in the IP group had macroscopic residual disease than in the IV group (71% versus 52%; P=.17).

A phase II/III study is under way to evaluate the use of IP chemotherapy following neoadjuvant chemotherapy in ovarian cancer patients.⁷ The two-stage randomized trial will compare IV chemotherapy with platinum-based IP chemotherapy in women who have undergone optimal surgical debulking (>1 cm) after 3 to 4 cycles of platinum-based neoadjuvant chemotherapy. This study is led by the US National Cancer Institute in collaboration with the Society of Gynecologic Oncologists of Canada, the UK National Cancer Research Institute, the Spanish Ovarian Cancer Research Group, and the US Southwest Oncology Group.

We want to hear from you! Tell us what you think.

A majority of ovarian cancers are diagnosed at an advanced stage, requiring extensive surgical cytoreductive procedures.¹ Because the presence of residual macroscopic disease correlates highly with decreased survival,² these procedures can be lengthy, complicated, and risky for the patient. Many patients who undergo cytoreduction will be left with a suboptimal result despite surgery.

Better identification and improved treatment of patients who are at high risk of a suboptimal result are clearly needed. One treatment option is neoadjuvant chemotherapy, the administration of chemotherapy prior to the main treatment. Although early data suggested that it was associated with worse outcomes, recent studies have yielded new information:

• Neoadjuvant chemotherapy followed by interval debulking surgery is not inferior to primary debulking surgery followed by chemotherapy for patients who have bulky stage III or IV ovarian cancer
• In patients who have advanced ovarian cancer, neoadjuvant chemotherapy followed by surgical cytoreduction is associated with improved perioperative outcomes
• Postoperative intraperitoneal chemotherapy after neoadjuvant chemotherapy has not yet proved to be associated with improved survival.

Several questions prompted by these findings include:

• Will neoadjuvant chemotherapy improve surgical outcomes in patients who have advanced ovarian cancer and, thus, improve survival?
• Is neoadjuvant chemotherapy a better strategy for all patients?
• Will neoadjuvant chemotherapy reduce the surgical effort necessary to achieve an optimal result?
• What is the role of intraperitoneal chemotherapy in patients who undergo neoadjuvant chemotherapy?

Further national (or international) data are needed to confirm a survival advantage for patients who receive neoadjuvant chemotherapy, compared with those who undergo primary surgery before the administration of chemotherapy.

Neoadjuvant chemotherapy is an acceptable alternative to primary surgical cytoreduction

Vergote I, Tropé CG, Amant F, et al; European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC Clinical Trials Group. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943–953.

Historically, the standard of care in ovarian cancer treatment has been surgical cytoreduction followed by chemotherapy.^3-6 However, data from prospective randomized trials to support this practice are limited. Neoadjuvant chemotherapy is an alternative strategy that has been explored as a way to improve outcomes from interval surgical debulking in patients who have ovarian cancer in whom suboptimal cytoreduction is otherwise expected. Vergote and coworkers attempted to determine which strategy is better through a randomized trial of 632 patients.

Participants had to have biopsy-proven stage IIIc or IV ovarian, fallopian tube, or primary peritoneal cancer. The two treatment arms were:

• primary debulking surgery followed by at least 6 cycles of platinum-based chemotherapy
• 3 cycles of platinum-based neoadjuvant chemotherapy followed by interval debulking surgery in responders and those who had stable disease. These patients then received an additional 3 cycles of platinum-based chemotherapy post-operatively.

All surgical procedures were completed by qualified gynecologic oncologists, and all patients were evaluated for eligibility before randomization, with no additional selection criteria.

Postoperative death occurred in 2.5% of patients in the primary-surgery group, compared with 0.7% of patients in the neoadjuvant-chemotherapy group. Grade 3 or 4 hemorrhage occurred in 7.4% of patients after primary debulking, compared with 4.1% of patients after interval debulking. Patients who received neoadjuvant chemotherapy experienced a lower rate of infection (1.7% versus 8.1%) and venous complications (0% versus 2.6%).

Overall and progression-free survival rates were similar between the two groups. After multivariate analysis, the strongest predictors of survival were absence of residual disease after surgery (P<.001), small tumor size before randomization (P=.001), and endometrioid histology (P=.001)

Neoadjuvant chemotherapy improves perioperative outcomes

Milam MR, Tao X, Coleman RL, et al. Neoadjuvant chemotherapy is associated with prolonged primary treatment intervals in patients with advanced epithelial ovarian cancer. Int J Gynecol Cancer. 2011;21(1):66–71.

Milam and coworkers investigated chemotherapy-associated morbidity and timing in two groups of patients who had advanced epithelial ovarian cancer:

• those undergoing neoadjuvant chemotherapy followed by maximal cytoreductive surgery
• those undergoing primary surgery followed by chemotherapy.

Their retrospective study involved 263 consecutive patients who were treated at MD Anderson Cancer Center from 1993 to 2005. In this cohort, 47 women (18%) received neoadjuvant chemotherapy. These patients experienced less blood loss (400 mL versus 750 mL) and a shorter hospital stay (6 versus 8 days). Time to the initiation of chemotherapy from the date of diagnosis did not differ between groups, and the amount of residual disease and rate of survival were also similar between arms. However, patients who received neoadjuvant chemotherapy underwent more cycles of chemotherapy over a longer treatment period.

In the pipeline: Data on intraperitoneal chemotherapy after neoadjuvant chemotherapy

Le T, Latifah H, Jolicoeur L, et al. Does intraperitoneal chemotherapy benefit optimally debulked epithelial ovarian cancer patients after neoadjuvant chemotherapy? Gynecol Oncol. 2011;121(3):451–454.

Although several studies have demonstrated that intraperitoneal (IP) chemotherapy provides a survival advantage, compared with intravenous (IV) chemotherapy, after primary surgical debulking, it remains unclear whether IP chemotherapy would provide a similar superior survival outcome following neoadjuvant chemotherapy (FIGURE).

Intraperitoneal chemotherapy: How efficacious?
The jury is still out on whether intraperitoneal chemotherapy improves survival after neoadjuvant chemotherapy and interval debulking in stages III and IV ovarian cancer.The authors of this paper attempted to answer this question through a retrospective review of 71 patients. All patients were treated with neoadjuvant chemotherapy followed by interval debulking and either IP or IV chemotherapy. Overall, 17 patients (24%) received IP chemotherapy, and 54 patients (76%) received IV chemotherapy. The median number of cycles given prior to and after surgery was the same for both groups (3 for both neoadjuvant chemotherapy and chemotherapy following surgery).

Although patients who received IP chemotherapy had a higher overall response rate (82% versus 67%), there were no differences between groups in terms of progression-free (P=.42) and overall survival (P=.72).

One important limitation of this study was its small sample size and lack of statistical power. In addition, more patients in the IP group had macroscopic residual disease than in the IV group (71% versus 52%; P=.17).

A phase II/III study is under way to evaluate the use of IP chemotherapy following neoadjuvant chemotherapy in ovarian cancer patients.⁷ The two-stage randomized trial will compare IV chemotherapy with platinum-based IP chemotherapy in women who have undergone optimal surgical debulking (>1 cm) after 3 to 4 cycles of platinum-based neoadjuvant chemotherapy. This study is led by the US National Cancer Institute in collaboration with the Society of Gynecologic Oncologists of Canada, the UK National Cancer Research Institute, the Spanish Ovarian Cancer Research Group, and the US Southwest Oncology Group.

We want to hear from you! Tell us what you think.

A majority of ovarian cancers are diagnosed at an advanced stage, requiring extensive surgical cytoreductive procedures.¹ Because the presence of residual macroscopic disease correlates highly with decreased survival,² these procedures can be lengthy, complicated, and risky for the patient. Many patients who undergo cytoreduction will be left with a suboptimal result despite surgery.

Better identification and improved treatment of patients who are at high risk of a suboptimal result are clearly needed. One treatment option is neoadjuvant chemotherapy, the administration of chemotherapy prior to the main treatment. Although early data suggested that it was associated with worse outcomes, recent studies have yielded new information:

• Neoadjuvant chemotherapy followed by interval debulking surgery is not inferior to primary debulking surgery followed by chemotherapy for patients who have bulky stage III or IV ovarian cancer
• In patients who have advanced ovarian cancer, neoadjuvant chemotherapy followed by surgical cytoreduction is associated with improved perioperative outcomes
• Postoperative intraperitoneal chemotherapy after neoadjuvant chemotherapy has not yet proved to be associated with improved survival.

Several questions prompted by these findings include:

• Will neoadjuvant chemotherapy improve surgical outcomes in patients who have advanced ovarian cancer and, thus, improve survival?
• Is neoadjuvant chemotherapy a better strategy for all patients?
• Will neoadjuvant chemotherapy reduce the surgical effort necessary to achieve an optimal result?
• What is the role of intraperitoneal chemotherapy in patients who undergo neoadjuvant chemotherapy?

Further national (or international) data are needed to confirm a survival advantage for patients who receive neoadjuvant chemotherapy, compared with those who undergo primary surgery before the administration of chemotherapy.

Neoadjuvant chemotherapy is an acceptable alternative to primary surgical cytoreduction

Vergote I, Tropé CG, Amant F, et al; European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC Clinical Trials Group. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943–953.

Historically, the standard of care in ovarian cancer treatment has been surgical cytoreduction followed by chemotherapy.^3-6 However, data from prospective randomized trials to support this practice are limited. Neoadjuvant chemotherapy is an alternative strategy that has been explored as a way to improve outcomes from interval surgical debulking in patients who have ovarian cancer in whom suboptimal cytoreduction is otherwise expected. Vergote and coworkers attempted to determine which strategy is better through a randomized trial of 632 patients.

Participants had to have biopsy-proven stage IIIc or IV ovarian, fallopian tube, or primary peritoneal cancer. The two treatment arms were:

• primary debulking surgery followed by at least 6 cycles of platinum-based chemotherapy
• 3 cycles of platinum-based neoadjuvant chemotherapy followed by interval debulking surgery in responders and those who had stable disease. These patients then received an additional 3 cycles of platinum-based chemotherapy post-operatively.

All surgical procedures were completed by qualified gynecologic oncologists, and all patients were evaluated for eligibility before randomization, with no additional selection criteria.

Postoperative death occurred in 2.5% of patients in the primary-surgery group, compared with 0.7% of patients in the neoadjuvant-chemotherapy group. Grade 3 or 4 hemorrhage occurred in 7.4% of patients after primary debulking, compared with 4.1% of patients after interval debulking. Patients who received neoadjuvant chemotherapy experienced a lower rate of infection (1.7% versus 8.1%) and venous complications (0% versus 2.6%).

Overall and progression-free survival rates were similar between the two groups. After multivariate analysis, the strongest predictors of survival were absence of residual disease after surgery (P<.001), small tumor size before randomization (P=.001), and endometrioid histology (P=.001)

Neoadjuvant chemotherapy improves perioperative outcomes

Milam MR, Tao X, Coleman RL, et al. Neoadjuvant chemotherapy is associated with prolonged primary treatment intervals in patients with advanced epithelial ovarian cancer. Int J Gynecol Cancer. 2011;21(1):66–71.

Milam and coworkers investigated chemotherapy-associated morbidity and timing in two groups of patients who had advanced epithelial ovarian cancer:

• those undergoing neoadjuvant chemotherapy followed by maximal cytoreductive surgery
• those undergoing primary surgery followed by chemotherapy.

Their retrospective study involved 263 consecutive patients who were treated at MD Anderson Cancer Center from 1993 to 2005. In this cohort, 47 women (18%) received neoadjuvant chemotherapy. These patients experienced less blood loss (400 mL versus 750 mL) and a shorter hospital stay (6 versus 8 days). Time to the initiation of chemotherapy from the date of diagnosis did not differ between groups, and the amount of residual disease and rate of survival were also similar between arms. However, patients who received neoadjuvant chemotherapy underwent more cycles of chemotherapy over a longer treatment period.

In the pipeline: Data on intraperitoneal chemotherapy after neoadjuvant chemotherapy

Le T, Latifah H, Jolicoeur L, et al. Does intraperitoneal chemotherapy benefit optimally debulked epithelial ovarian cancer patients after neoadjuvant chemotherapy? Gynecol Oncol. 2011;121(3):451–454.

Although several studies have demonstrated that intraperitoneal (IP) chemotherapy provides a survival advantage, compared with intravenous (IV) chemotherapy, after primary surgical debulking, it remains unclear whether IP chemotherapy would provide a similar superior survival outcome following neoadjuvant chemotherapy (FIGURE).

Intraperitoneal chemotherapy: How efficacious?
The jury is still out on whether intraperitoneal chemotherapy improves survival after neoadjuvant chemotherapy and interval debulking in stages III and IV ovarian cancer.The authors of this paper attempted to answer this question through a retrospective review of 71 patients. All patients were treated with neoadjuvant chemotherapy followed by interval debulking and either IP or IV chemotherapy. Overall, 17 patients (24%) received IP chemotherapy, and 54 patients (76%) received IV chemotherapy. The median number of cycles given prior to and after surgery was the same for both groups (3 for both neoadjuvant chemotherapy and chemotherapy following surgery).

Although patients who received IP chemotherapy had a higher overall response rate (82% versus 67%), there were no differences between groups in terms of progression-free (P=.42) and overall survival (P=.72).

One important limitation of this study was its small sample size and lack of statistical power. In addition, more patients in the IP group had macroscopic residual disease than in the IV group (71% versus 52%; P=.17).

A phase II/III study is under way to evaluate the use of IP chemotherapy following neoadjuvant chemotherapy in ovarian cancer patients.⁷ The two-stage randomized trial will compare IV chemotherapy with platinum-based IP chemotherapy in women who have undergone optimal surgical debulking (>1 cm) after 3 to 4 cycles of platinum-based neoadjuvant chemotherapy. This study is led by the US National Cancer Institute in collaboration with the Society of Gynecologic Oncologists of Canada, the UK National Cancer Research Institute, the Spanish Ovarian Cancer Research Group, and the US Southwest Oncology Group.

We want to hear from you! Tell us what you think.

No question: Vitamin D plays a vital role in bone health. In recent years, the possibility that it plays a role in other aspects of health has prompted considerable speculation, fueled by both widespread media coverage and dissemination of conflicting information about the potential nonskeletal benefits of high-dose vitamin D supplementation. Controversy has emerged about:

• the appropriate criteria for defining vitamin D deficiency
• the extent to which vitamin D influences nonskeletal health conditions
• the optimal level of vitamin D supplementation.

In 2010, the Institute of Medicine (IOM) released a report that provided recommendations for vitamin D intake, which were also summarized in a recent article for clinicians.^1,2 The IOM report provided much-needed clinical guidance, but it has also fueled additional questions.

This article describes the IOM recommendations, explains what we know now about the effect of vitamin D on various health outcomes, and offers concrete recommendations on vitamin D measurement, intake, and supplementation.

How is vitamin D metabolized?

Vitamin D is produced endogenously in the skin in the form of vitamin D3 (cholecalciferol). It also can be ingested exogenously in the form of vitamin D3 or vitamin D2 (ergocalciferol). Cutaneous synthesis of vitamin D is stimulated by solar ultraviolet radiation.

Vitamin D2 and D3 are hydroxylated in the liver to form 25-hydroxyvitamin D (25OHD). Measurement of the serum 25OHD level is thought to be the most reliable indicator of vitamin D exposure.³ 25OHD is hydroxylated again, primarily in the kidneys, to the most active form of vitamin D (1,25-dihydroxyvitamin D).

The adverse skeletal effects of severe vitamin D deficiency are well established; those effects include calcium malabsorption, secondary hyperparathyroidism, bone loss, and increased risk of fracture. In this setting, secondary hyperparathyroidism results from both decreased gastrointestinal calcium absorption and decreased suppression of parathyroid hormone (PTH) production by the parathyroid glands from vitamin D metabolites. Secondary hyperparathyroidism leads to increased bone resorption and bone loss. Rickets, osteomalacia, hypocalcemia, hypophosphatemia, muscle weakness, and bone pain are less common effects that can occur with severe vitamin D deficiency.

It is worth noting that women of color are at increased risk of vitamin D deficiency as a result of greater skin pigmentation.³ Obesity is also a risk factor for vitamin D deficiency.³ Additional risk factors for vitamin D insufficiency are listed in TABLE 1.

TABLE 1

Risk factors for vitamin D insufficiency

How should vitamin D insufficiency be defined?

Biochemical criteria for defining vitamin D insufficiency vary. That makes it difficult to estimate the prevalence of vitamin D insufficiency.

Severe vitamin D deficiency is commonly defined as a serum 25OHD level below 10 ng/mL.³ Vitamin D insufficiency has been variably defined as a serum 25OHD level below 20 to 32 ng/mL,^3,4 and the lower limit of normal in most clinical laboratories is now typically 30 to 32 ng/mL. Many patients become concerned when their serum 25OHD level is flagged as “low” on a laboratory report, and it’s likely that you are called on from time to time to interpret and make recommendations about the appropriate response to this “abnormal” finding.

The broad definition of vitamin D insufficiency stems, in part, from the assessment of a wide range of outcomes. Measures that have been used include fracture risk, calcium absorptive capacity, and the serum concentration of PTH. In regard to calcium absorption, most studies suggest that maximal dietary calcium absorption occurs when the 25OHD level reaches 20 ng/mL, although some studies suggest a higher threshold.^1,3

The optimal level of 25OHD for PTH suppression remains unclear. Several studies have suggested that the PTH level increases when the 25OHD concentration falls below 30 ng/mL,^4,5 although this threshold has varied substantially across studies.⁶

How prevalent is vitamin D insufficiency?

Estimates of the prevalence of vitamin D insufficiency vary by the criteria used to define the condition. A recent report using data from the National Health and Nutrition Examination Survey (NHANES) estimated that approximately 30% of US adults 20 years of age or older have a 25OHD level below 20 ng/mL, and more than 70% of this age group has a 25OHD level below 32 ng/mL.⁷

The IOM committee noted that several reports have most likely overestimated the prevalence of vitamin D insufficiency through the use of 25OHD cut points higher than 20 ng/mL.

The data on vitamin D insufficiency and skeletal health

Many studies have examined the relationship between vitamin D supplementation or the 25OHD level and fracture risk, and conflicting results have emerged. Many trials have examined the combination of calcium and vitamin D supplementation, the effects of which are tightly interwoven, confounding interpretation.

Interpretation of large observational studies is further confounded by the inability to attribute association to causation. In the Women’s Health Initiative (WHI) study of calcium with vitamin D, treatment of healthy postmenopausal women with 1,000 mg of calcium and 400 IU of vitamin D daily led to improved bone density at the hip but no statistically significant reduction in hip fracture.⁸ However, a reduced risk of hip fracture was demonstrated in secondary analyses among women who adhered to treatment and among women 60 years or older. Meta-analyses of clinical trials have reported that treatment with varying doses of vitamin D (more than 400 IU daily) reduces the risk of vertebral,⁹ nonvertebral,¹⁰ and hip fractures.¹⁰

Several studies have examined the relationship between the 25OHD level and fracture risk, with inconsistent findings:

• A nested case-control study from the WHI found that the risk of hip fracture was significantly increased among postmenopausal women who had a 25OHD level of 19 ng/mL or lower.¹¹
• A 2009 report from the Agency for Healthcare Research and Quality (AHRQ) concluded that the association between the 25OHD level and the risk of fracture was inconsistent.¹²

After a comprehensive review of the available research, the IOM committee concluded that a serum 25OHD level of 20 ng/mL would meet the needs for bone health for at least 97.5% of the US and Canadian populations.

TABLE 2

Calcium and vitamin D dietary reference intakes for adults, by life stage

The data on vitamin D insufficiency and nonskeletal outcomes

Many observational studies have reported relationships between vitamin D insufficiency and myriad nonskeletal health outcomes, particularly cardiovascular disease, cancer, diabetes, and autoimmune disorders.³ However, well-designed randomized clinical trials that examine nonskeletal outcomes as primary pre-specified outcomes are lacking.¹³ Such studies will be essential to elucidate the relationship between vitamin D insufficiency and nonskeletal chronic diseases. The VITamin D and OmegA-3 TriaL (VITAL) is an ongoing large-scale, randomized clinical trial designed to evaluate the role of supplementation with 2,000 IU of vitamin D3 daily in the primary prevention of cancer and cardiovascular disease.¹⁴

What we recommend for treatment

The IOM report provided the medical community with evidence-based recommendations for vitamin D intake at the population level, based on a public health perspective.^1,2 However, the public health guideline model must be distinguished from the medical model, in which shared clinical decision-making between physician and patient occurs on an individual level and is informed by individual clinical risk factors. The public health recommendations detailed in the IOM report are not intended to replace or interfere with clinical judgment or preclude individualized clinical decision-making.

The debate over optimal levels of vitamin D supplementation for individual patients who have osteoporosis or other health conditions continues.¹⁵ Here, we provide general guidelines for treatment, based on the evidence available to date.

Clear benefits of vitamin D in bone health notwithstanding, advise your patients to avoid excessive intake because it can cause harm. See “More is not necessarily better”.

Recommendations for healthy adult nonpregnant women

Vitamin D intake: We recommend a daily vitamin D intake of 600 IU for healthy nonpregnant women up to age 70 years (and 800  IU daily for women older than 70 years) who are at average risk of vitamin D insufficiency and bone loss, consistent with the IOM recommendations. The IOM guidelines assume minimal to no sun exposure.

Measurement of 25OHD: It is not necessary to routinely measure the 25OHD level in these women. However, it is prudent to measure 25OHD in women who have risk factors for vitamin D insufficiency (TABLE 1) or a clinical condition associated with severe vitamin D deficiency. In these cases, if the 25OHD level is found to be below 20 ng/mL, vitamin D therapy should be initiated, with the goal of boosting the 25OHD level above the threshold of 20 ng/mL.

Treatment of vitamin D insufficiency: Options include daily vitamin D supplementation and higher-dose weekly preparations.

Many clinicians treat severe vitamin D insufficiency with 50,000 IU of vitamin D2 once weekly for 8 weeks, followed by a maintenance dose (described below) of vitamin D to preserve the target 25OHD level.⁵ An alternative is daily vitamin D supplementation, with the dosage based on the degree of insufficiency.

A general rule of thumb, for persons who have normal vitamin D absorption, is that every 1,000 IU of vitamin D3 ingested daily increases the 25OHD level by approximately 6 to 10 ng/mL.^4,16 However, the incremental increase in the 25OHD concentration varies among individuals, depending on the baseline 25OHD level, with a greater incremental increase occurring at lower baseline 25OHD levels.

Monitoring of the 25OHD level after adjustment of the dosage is necessary to ensure that the target level is achieved.

Maintaining an adequate vitamin D level: Once vitamin D insufficiency has been corrected, a maintenance dosage of vitamin D should be selected—commonly 800 to 1,000  IU daily. A higher maintenance dosage may be required for persons who have genetic or ongoing environmental factors that predispose them to vitamin D insufficiency.

Vitamin D3 is reportedly more potent than D2 in increasing the 25OHD level,¹⁷ although this finding has not been universal.¹⁸ Monthly or twice-monthly administration of 50,000 IU of vitamin D2 is another option for maintenance of vitamin D sufficiency,^5,16 although daily doses are more commonly used and are readily available in over-the-counter preparations.

Regardless of the regimen selected, the 25OHD level should be measured again approximately 3 months after a change in dosage to ensure that the target level has been achieved, with further dosage adjustments as indicated.

Recommendations for adult women at increased risk of skeletal disease

Measurement of 25OHD: The 25OHD level should be measured among women at increased risk of vitamin D insufficiency, bone loss, or fracture and among women who have established skeletal disease.

Vitamin D intake: We recommend that women at increased risk of osteoporosis and women older than 70 years receive at least 800 IU daily and, potentially, more if necessary to achieve the target 25OHD level.

Although the evidence to date does not support routine achievement of a 25OHD level substantially above 20 ng/mL in most women, many clinicians recommend that women in this higher-risk group maintain a 25OHD level above 30 ng/mL because of the possibly greater (although unproven) skeletal and nonskeletal benefits. As more data become available regarding the benefits and safety of vitamin D doses higher than those recommended by the IOM, these recommendations may be revised.

In 2010, the National Osteoporosis Foundation (NOF) recommended a vitamin D intake of 800 to 1,000 IU daily for all adults 50 years and older. Among persons at risk of deficiency, the NOF also recommended measurement of the serum 25OHD level, with vitamin D supplementation, as necessary, to achieve a 25OHD level of 30 ng/mL or higher.¹⁹ Also in 2010, the International Osteoporosis Foundation (IOF) recommended a target 25OHD level above 30 ng/mL for all older adults. The IOF also estimated that the average dosage required to achieve this level in older adults is 800 to 1,000 IU daily, noting that upward adjustment may be required in some people.⁴ It is unclear whether these guidelines will be revised in the future, based on the IOM report.

We recommend against achieving a 25OHD level above 50 ng/mL, based on evidence suggesting potential adverse health effects above this level.

We want to hear from you! Tell us what you think.

No question: Vitamin D plays a vital role in bone health. In recent years, the possibility that it plays a role in other aspects of health has prompted considerable speculation, fueled by both widespread media coverage and dissemination of conflicting information about the potential nonskeletal benefits of high-dose vitamin D supplementation. Controversy has emerged about:

• the appropriate criteria for defining vitamin D deficiency
• the extent to which vitamin D influences nonskeletal health conditions
• the optimal level of vitamin D supplementation.

In 2010, the Institute of Medicine (IOM) released a report that provided recommendations for vitamin D intake, which were also summarized in a recent article for clinicians.^1,2 The IOM report provided much-needed clinical guidance, but it has also fueled additional questions.

This article describes the IOM recommendations, explains what we know now about the effect of vitamin D on various health outcomes, and offers concrete recommendations on vitamin D measurement, intake, and supplementation.

How is vitamin D metabolized?

Vitamin D is produced endogenously in the skin in the form of vitamin D3 (cholecalciferol). It also can be ingested exogenously in the form of vitamin D3 or vitamin D2 (ergocalciferol). Cutaneous synthesis of vitamin D is stimulated by solar ultraviolet radiation.

Vitamin D2 and D3 are hydroxylated in the liver to form 25-hydroxyvitamin D (25OHD). Measurement of the serum 25OHD level is thought to be the most reliable indicator of vitamin D exposure.³ 25OHD is hydroxylated again, primarily in the kidneys, to the most active form of vitamin D (1,25-dihydroxyvitamin D).

The adverse skeletal effects of severe vitamin D deficiency are well established; those effects include calcium malabsorption, secondary hyperparathyroidism, bone loss, and increased risk of fracture. In this setting, secondary hyperparathyroidism results from both decreased gastrointestinal calcium absorption and decreased suppression of parathyroid hormone (PTH) production by the parathyroid glands from vitamin D metabolites. Secondary hyperparathyroidism leads to increased bone resorption and bone loss. Rickets, osteomalacia, hypocalcemia, hypophosphatemia, muscle weakness, and bone pain are less common effects that can occur with severe vitamin D deficiency.

It is worth noting that women of color are at increased risk of vitamin D deficiency as a result of greater skin pigmentation.³ Obesity is also a risk factor for vitamin D deficiency.³ Additional risk factors for vitamin D insufficiency are listed in TABLE 1.

TABLE 1

Risk factors for vitamin D insufficiency

How should vitamin D insufficiency be defined?

Biochemical criteria for defining vitamin D insufficiency vary. That makes it difficult to estimate the prevalence of vitamin D insufficiency.

Severe vitamin D deficiency is commonly defined as a serum 25OHD level below 10 ng/mL.³ Vitamin D insufficiency has been variably defined as a serum 25OHD level below 20 to 32 ng/mL,^3,4 and the lower limit of normal in most clinical laboratories is now typically 30 to 32 ng/mL. Many patients become concerned when their serum 25OHD level is flagged as “low” on a laboratory report, and it’s likely that you are called on from time to time to interpret and make recommendations about the appropriate response to this “abnormal” finding.

The broad definition of vitamin D insufficiency stems, in part, from the assessment of a wide range of outcomes. Measures that have been used include fracture risk, calcium absorptive capacity, and the serum concentration of PTH. In regard to calcium absorption, most studies suggest that maximal dietary calcium absorption occurs when the 25OHD level reaches 20 ng/mL, although some studies suggest a higher threshold.^1,3

The optimal level of 25OHD for PTH suppression remains unclear. Several studies have suggested that the PTH level increases when the 25OHD concentration falls below 30 ng/mL,^4,5 although this threshold has varied substantially across studies.⁶

How prevalent is vitamin D insufficiency?

Estimates of the prevalence of vitamin D insufficiency vary by the criteria used to define the condition. A recent report using data from the National Health and Nutrition Examination Survey (NHANES) estimated that approximately 30% of US adults 20 years of age or older have a 25OHD level below 20 ng/mL, and more than 70% of this age group has a 25OHD level below 32 ng/mL.⁷

The IOM committee noted that several reports have most likely overestimated the prevalence of vitamin D insufficiency through the use of 25OHD cut points higher than 20 ng/mL.

The data on vitamin D insufficiency and skeletal health

Many studies have examined the relationship between vitamin D supplementation or the 25OHD level and fracture risk, and conflicting results have emerged. Many trials have examined the combination of calcium and vitamin D supplementation, the effects of which are tightly interwoven, confounding interpretation.

Interpretation of large observational studies is further confounded by the inability to attribute association to causation. In the Women’s Health Initiative (WHI) study of calcium with vitamin D, treatment of healthy postmenopausal women with 1,000 mg of calcium and 400 IU of vitamin D daily led to improved bone density at the hip but no statistically significant reduction in hip fracture.⁸ However, a reduced risk of hip fracture was demonstrated in secondary analyses among women who adhered to treatment and among women 60 years or older. Meta-analyses of clinical trials have reported that treatment with varying doses of vitamin D (more than 400 IU daily) reduces the risk of vertebral,⁹ nonvertebral,¹⁰ and hip fractures.¹⁰

Several studies have examined the relationship between the 25OHD level and fracture risk, with inconsistent findings:

• A nested case-control study from the WHI found that the risk of hip fracture was significantly increased among postmenopausal women who had a 25OHD level of 19 ng/mL or lower.¹¹
• A 2009 report from the Agency for Healthcare Research and Quality (AHRQ) concluded that the association between the 25OHD level and the risk of fracture was inconsistent.¹²

After a comprehensive review of the available research, the IOM committee concluded that a serum 25OHD level of 20 ng/mL would meet the needs for bone health for at least 97.5% of the US and Canadian populations.

TABLE 2

Calcium and vitamin D dietary reference intakes for adults, by life stage

The data on vitamin D insufficiency and nonskeletal outcomes

Many observational studies have reported relationships between vitamin D insufficiency and myriad nonskeletal health outcomes, particularly cardiovascular disease, cancer, diabetes, and autoimmune disorders.³ However, well-designed randomized clinical trials that examine nonskeletal outcomes as primary pre-specified outcomes are lacking.¹³ Such studies will be essential to elucidate the relationship between vitamin D insufficiency and nonskeletal chronic diseases. The VITamin D and OmegA-3 TriaL (VITAL) is an ongoing large-scale, randomized clinical trial designed to evaluate the role of supplementation with 2,000 IU of vitamin D3 daily in the primary prevention of cancer and cardiovascular disease.¹⁴

What we recommend for treatment

The IOM report provided the medical community with evidence-based recommendations for vitamin D intake at the population level, based on a public health perspective.^1,2 However, the public health guideline model must be distinguished from the medical model, in which shared clinical decision-making between physician and patient occurs on an individual level and is informed by individual clinical risk factors. The public health recommendations detailed in the IOM report are not intended to replace or interfere with clinical judgment or preclude individualized clinical decision-making.

The debate over optimal levels of vitamin D supplementation for individual patients who have osteoporosis or other health conditions continues.¹⁵ Here, we provide general guidelines for treatment, based on the evidence available to date.

Clear benefits of vitamin D in bone health notwithstanding, advise your patients to avoid excessive intake because it can cause harm. See “More is not necessarily better”.

Recommendations for healthy adult nonpregnant women

Vitamin D intake: We recommend a daily vitamin D intake of 600 IU for healthy nonpregnant women up to age 70 years (and 800  IU daily for women older than 70 years) who are at average risk of vitamin D insufficiency and bone loss, consistent with the IOM recommendations. The IOM guidelines assume minimal to no sun exposure.

Measurement of 25OHD: It is not necessary to routinely measure the 25OHD level in these women. However, it is prudent to measure 25OHD in women who have risk factors for vitamin D insufficiency (TABLE 1) or a clinical condition associated with severe vitamin D deficiency. In these cases, if the 25OHD level is found to be below 20 ng/mL, vitamin D therapy should be initiated, with the goal of boosting the 25OHD level above the threshold of 20 ng/mL.

Treatment of vitamin D insufficiency: Options include daily vitamin D supplementation and higher-dose weekly preparations.

Many clinicians treat severe vitamin D insufficiency with 50,000 IU of vitamin D2 once weekly for 8 weeks, followed by a maintenance dose (described below) of vitamin D to preserve the target 25OHD level.⁵ An alternative is daily vitamin D supplementation, with the dosage based on the degree of insufficiency.

A general rule of thumb, for persons who have normal vitamin D absorption, is that every 1,000 IU of vitamin D3 ingested daily increases the 25OHD level by approximately 6 to 10 ng/mL.^4,16 However, the incremental increase in the 25OHD concentration varies among individuals, depending on the baseline 25OHD level, with a greater incremental increase occurring at lower baseline 25OHD levels.

Monitoring of the 25OHD level after adjustment of the dosage is necessary to ensure that the target level is achieved.

Maintaining an adequate vitamin D level: Once vitamin D insufficiency has been corrected, a maintenance dosage of vitamin D should be selected—commonly 800 to 1,000  IU daily. A higher maintenance dosage may be required for persons who have genetic or ongoing environmental factors that predispose them to vitamin D insufficiency.

Vitamin D3 is reportedly more potent than D2 in increasing the 25OHD level,¹⁷ although this finding has not been universal.¹⁸ Monthly or twice-monthly administration of 50,000 IU of vitamin D2 is another option for maintenance of vitamin D sufficiency,^5,16 although daily doses are more commonly used and are readily available in over-the-counter preparations.

Regardless of the regimen selected, the 25OHD level should be measured again approximately 3 months after a change in dosage to ensure that the target level has been achieved, with further dosage adjustments as indicated.

Recommendations for adult women at increased risk of skeletal disease

Measurement of 25OHD: The 25OHD level should be measured among women at increased risk of vitamin D insufficiency, bone loss, or fracture and among women who have established skeletal disease.

Vitamin D intake: We recommend that women at increased risk of osteoporosis and women older than 70 years receive at least 800 IU daily and, potentially, more if necessary to achieve the target 25OHD level.

Although the evidence to date does not support routine achievement of a 25OHD level substantially above 20 ng/mL in most women, many clinicians recommend that women in this higher-risk group maintain a 25OHD level above 30 ng/mL because of the possibly greater (although unproven) skeletal and nonskeletal benefits. As more data become available regarding the benefits and safety of vitamin D doses higher than those recommended by the IOM, these recommendations may be revised.

In 2010, the National Osteoporosis Foundation (NOF) recommended a vitamin D intake of 800 to 1,000 IU daily for all adults 50 years and older. Among persons at risk of deficiency, the NOF also recommended measurement of the serum 25OHD level, with vitamin D supplementation, as necessary, to achieve a 25OHD level of 30 ng/mL or higher.¹⁹ Also in 2010, the International Osteoporosis Foundation (IOF) recommended a target 25OHD level above 30 ng/mL for all older adults. The IOF also estimated that the average dosage required to achieve this level in older adults is 800 to 1,000 IU daily, noting that upward adjustment may be required in some people.⁴ It is unclear whether these guidelines will be revised in the future, based on the IOM report.

We recommend against achieving a 25OHD level above 50 ng/mL, based on evidence suggesting potential adverse health effects above this level.

We want to hear from you! Tell us what you think.

No question: Vitamin D plays a vital role in bone health. In recent years, the possibility that it plays a role in other aspects of health has prompted considerable speculation, fueled by both widespread media coverage and dissemination of conflicting information about the potential nonskeletal benefits of high-dose vitamin D supplementation. Controversy has emerged about:

• the appropriate criteria for defining vitamin D deficiency
• the extent to which vitamin D influences nonskeletal health conditions
• the optimal level of vitamin D supplementation.

In 2010, the Institute of Medicine (IOM) released a report that provided recommendations for vitamin D intake, which were also summarized in a recent article for clinicians.^1,2 The IOM report provided much-needed clinical guidance, but it has also fueled additional questions.

This article describes the IOM recommendations, explains what we know now about the effect of vitamin D on various health outcomes, and offers concrete recommendations on vitamin D measurement, intake, and supplementation.

How is vitamin D metabolized?

Vitamin D is produced endogenously in the skin in the form of vitamin D3 (cholecalciferol). It also can be ingested exogenously in the form of vitamin D3 or vitamin D2 (ergocalciferol). Cutaneous synthesis of vitamin D is stimulated by solar ultraviolet radiation.

Vitamin D2 and D3 are hydroxylated in the liver to form 25-hydroxyvitamin D (25OHD). Measurement of the serum 25OHD level is thought to be the most reliable indicator of vitamin D exposure.³ 25OHD is hydroxylated again, primarily in the kidneys, to the most active form of vitamin D (1,25-dihydroxyvitamin D).

The adverse skeletal effects of severe vitamin D deficiency are well established; those effects include calcium malabsorption, secondary hyperparathyroidism, bone loss, and increased risk of fracture. In this setting, secondary hyperparathyroidism results from both decreased gastrointestinal calcium absorption and decreased suppression of parathyroid hormone (PTH) production by the parathyroid glands from vitamin D metabolites. Secondary hyperparathyroidism leads to increased bone resorption and bone loss. Rickets, osteomalacia, hypocalcemia, hypophosphatemia, muscle weakness, and bone pain are less common effects that can occur with severe vitamin D deficiency.

It is worth noting that women of color are at increased risk of vitamin D deficiency as a result of greater skin pigmentation.³ Obesity is also a risk factor for vitamin D deficiency.³ Additional risk factors for vitamin D insufficiency are listed in TABLE 1.

TABLE 1

Risk factors for vitamin D insufficiency

How should vitamin D insufficiency be defined?

Biochemical criteria for defining vitamin D insufficiency vary. That makes it difficult to estimate the prevalence of vitamin D insufficiency.

Severe vitamin D deficiency is commonly defined as a serum 25OHD level below 10 ng/mL.³ Vitamin D insufficiency has been variably defined as a serum 25OHD level below 20 to 32 ng/mL,^3,4 and the lower limit of normal in most clinical laboratories is now typically 30 to 32 ng/mL. Many patients become concerned when their serum 25OHD level is flagged as “low” on a laboratory report, and it’s likely that you are called on from time to time to interpret and make recommendations about the appropriate response to this “abnormal” finding.

The broad definition of vitamin D insufficiency stems, in part, from the assessment of a wide range of outcomes. Measures that have been used include fracture risk, calcium absorptive capacity, and the serum concentration of PTH. In regard to calcium absorption, most studies suggest that maximal dietary calcium absorption occurs when the 25OHD level reaches 20 ng/mL, although some studies suggest a higher threshold.^1,3

The optimal level of 25OHD for PTH suppression remains unclear. Several studies have suggested that the PTH level increases when the 25OHD concentration falls below 30 ng/mL,^4,5 although this threshold has varied substantially across studies.⁶

How prevalent is vitamin D insufficiency?

Estimates of the prevalence of vitamin D insufficiency vary by the criteria used to define the condition. A recent report using data from the National Health and Nutrition Examination Survey (NHANES) estimated that approximately 30% of US adults 20 years of age or older have a 25OHD level below 20 ng/mL, and more than 70% of this age group has a 25OHD level below 32 ng/mL.⁷

The IOM committee noted that several reports have most likely overestimated the prevalence of vitamin D insufficiency through the use of 25OHD cut points higher than 20 ng/mL.

The data on vitamin D insufficiency and skeletal health

Many studies have examined the relationship between vitamin D supplementation or the 25OHD level and fracture risk, and conflicting results have emerged. Many trials have examined the combination of calcium and vitamin D supplementation, the effects of which are tightly interwoven, confounding interpretation.

Interpretation of large observational studies is further confounded by the inability to attribute association to causation. In the Women’s Health Initiative (WHI) study of calcium with vitamin D, treatment of healthy postmenopausal women with 1,000 mg of calcium and 400 IU of vitamin D daily led to improved bone density at the hip but no statistically significant reduction in hip fracture.⁸ However, a reduced risk of hip fracture was demonstrated in secondary analyses among women who adhered to treatment and among women 60 years or older. Meta-analyses of clinical trials have reported that treatment with varying doses of vitamin D (more than 400 IU daily) reduces the risk of vertebral,⁹ nonvertebral,¹⁰ and hip fractures.¹⁰

Several studies have examined the relationship between the 25OHD level and fracture risk, with inconsistent findings:

• A nested case-control study from the WHI found that the risk of hip fracture was significantly increased among postmenopausal women who had a 25OHD level of 19 ng/mL or lower.¹¹
• A 2009 report from the Agency for Healthcare Research and Quality (AHRQ) concluded that the association between the 25OHD level and the risk of fracture was inconsistent.¹²

After a comprehensive review of the available research, the IOM committee concluded that a serum 25OHD level of 20 ng/mL would meet the needs for bone health for at least 97.5% of the US and Canadian populations.

TABLE 2

Calcium and vitamin D dietary reference intakes for adults, by life stage

The data on vitamin D insufficiency and nonskeletal outcomes

Many observational studies have reported relationships between vitamin D insufficiency and myriad nonskeletal health outcomes, particularly cardiovascular disease, cancer, diabetes, and autoimmune disorders.³ However, well-designed randomized clinical trials that examine nonskeletal outcomes as primary pre-specified outcomes are lacking.¹³ Such studies will be essential to elucidate the relationship between vitamin D insufficiency and nonskeletal chronic diseases. The VITamin D and OmegA-3 TriaL (VITAL) is an ongoing large-scale, randomized clinical trial designed to evaluate the role of supplementation with 2,000 IU of vitamin D3 daily in the primary prevention of cancer and cardiovascular disease.¹⁴

What we recommend for treatment

The IOM report provided the medical community with evidence-based recommendations for vitamin D intake at the population level, based on a public health perspective.^1,2 However, the public health guideline model must be distinguished from the medical model, in which shared clinical decision-making between physician and patient occurs on an individual level and is informed by individual clinical risk factors. The public health recommendations detailed in the IOM report are not intended to replace or interfere with clinical judgment or preclude individualized clinical decision-making.

The debate over optimal levels of vitamin D supplementation for individual patients who have osteoporosis or other health conditions continues.¹⁵ Here, we provide general guidelines for treatment, based on the evidence available to date.

Clear benefits of vitamin D in bone health notwithstanding, advise your patients to avoid excessive intake because it can cause harm. See “More is not necessarily better”.

Recommendations for healthy adult nonpregnant women

Vitamin D intake: We recommend a daily vitamin D intake of 600 IU for healthy nonpregnant women up to age 70 years (and 800  IU daily for women older than 70 years) who are at average risk of vitamin D insufficiency and bone loss, consistent with the IOM recommendations. The IOM guidelines assume minimal to no sun exposure.

Measurement of 25OHD: It is not necessary to routinely measure the 25OHD level in these women. However, it is prudent to measure 25OHD in women who have risk factors for vitamin D insufficiency (TABLE 1) or a clinical condition associated with severe vitamin D deficiency. In these cases, if the 25OHD level is found to be below 20 ng/mL, vitamin D therapy should be initiated, with the goal of boosting the 25OHD level above the threshold of 20 ng/mL.

Treatment of vitamin D insufficiency: Options include daily vitamin D supplementation and higher-dose weekly preparations.

Many clinicians treat severe vitamin D insufficiency with 50,000 IU of vitamin D2 once weekly for 8 weeks, followed by a maintenance dose (described below) of vitamin D to preserve the target 25OHD level.⁵ An alternative is daily vitamin D supplementation, with the dosage based on the degree of insufficiency.

A general rule of thumb, for persons who have normal vitamin D absorption, is that every 1,000 IU of vitamin D3 ingested daily increases the 25OHD level by approximately 6 to 10 ng/mL.^4,16 However, the incremental increase in the 25OHD concentration varies among individuals, depending on the baseline 25OHD level, with a greater incremental increase occurring at lower baseline 25OHD levels.

Monitoring of the 25OHD level after adjustment of the dosage is necessary to ensure that the target level is achieved.

Maintaining an adequate vitamin D level: Once vitamin D insufficiency has been corrected, a maintenance dosage of vitamin D should be selected—commonly 800 to 1,000  IU daily. A higher maintenance dosage may be required for persons who have genetic or ongoing environmental factors that predispose them to vitamin D insufficiency.

Vitamin D3 is reportedly more potent than D2 in increasing the 25OHD level,¹⁷ although this finding has not been universal.¹⁸ Monthly or twice-monthly administration of 50,000 IU of vitamin D2 is another option for maintenance of vitamin D sufficiency,^5,16 although daily doses are more commonly used and are readily available in over-the-counter preparations.

Regardless of the regimen selected, the 25OHD level should be measured again approximately 3 months after a change in dosage to ensure that the target level has been achieved, with further dosage adjustments as indicated.

Recommendations for adult women at increased risk of skeletal disease

Measurement of 25OHD: The 25OHD level should be measured among women at increased risk of vitamin D insufficiency, bone loss, or fracture and among women who have established skeletal disease.

Vitamin D intake: We recommend that women at increased risk of osteoporosis and women older than 70 years receive at least 800 IU daily and, potentially, more if necessary to achieve the target 25OHD level.

Although the evidence to date does not support routine achievement of a 25OHD level substantially above 20 ng/mL in most women, many clinicians recommend that women in this higher-risk group maintain a 25OHD level above 30 ng/mL because of the possibly greater (although unproven) skeletal and nonskeletal benefits. As more data become available regarding the benefits and safety of vitamin D doses higher than those recommended by the IOM, these recommendations may be revised.

In 2010, the National Osteoporosis Foundation (NOF) recommended a vitamin D intake of 800 to 1,000 IU daily for all adults 50 years and older. Among persons at risk of deficiency, the NOF also recommended measurement of the serum 25OHD level, with vitamin D supplementation, as necessary, to achieve a 25OHD level of 30 ng/mL or higher.¹⁹ Also in 2010, the International Osteoporosis Foundation (IOF) recommended a target 25OHD level above 30 ng/mL for all older adults. The IOF also estimated that the average dosage required to achieve this level in older adults is 800 to 1,000 IU daily, noting that upward adjustment may be required in some people.⁴ It is unclear whether these guidelines will be revised in the future, based on the IOM report.

We recommend against achieving a 25OHD level above 50 ng/mL, based on evidence suggesting potential adverse health effects above this level.

We want to hear from you! Tell us what you think.

Reported incidence rates of certain vaccine-preventable diseases—measles, rubella, diphtheria, polio, and tetanus—are low in the United States.¹ However, as was demonstrated during the 2009-2010 flu season and the outbreak of H1N1 influenza,² we cannot afford to be complacent in our attitudes toward vaccines and vaccination. New virus strains exist and can become endemic quickly and ravenously. Furthermore, certain vaccine-preventable illnesses are frequently reported among adult patients, including hepatitis B, herpes zoster, human papillomavirus infection, influenza, pertussis, and pneumococcal infection.³

Vigilance regarding vaccination of children and adults was addressed by the CDC’s Office of Disease Prevention and Health Promotion in Healthy People 2010.⁴ These target objectives are proposed to be retained in Healthy People 2020,⁵ as the objectives from 2010 have not been met. The Healthy People 2010 target for administration of the pneumococcal vaccine in adults ages 65 and older, for example, is 90%. As of 2008, research has shown, only 60% of that population was immunized.⁶

There are subgroups of immunocompromised people who will probably never achieve adequate antibody levels to ensure immunity to vaccine-preventable diseases (for example, measles and influenza can be deadly to the immunocompromised person, as they can be to the very young and the very old). This is an important reason why vaccination of the healthy population is essential: the concept of herd immunity.⁷ Herd immunity (or community immunity) suggests that if most people around you are immune to an infection and do not become ill, then there is no one who can infect you—even if you are not immune to the infection.

WHY SOME ADULTS MIGHT NEED VACCINES

Adults who were vaccinated as children may incorrectly assume that they are protected from disease for life. In the case of some diseases, this may be true. However:

• Some adults were never vaccinated as children

• Newer vaccines have been developed since many adults were children

• Immunity can begin to fade over time

• As we age, we become more susceptible to serious disease caused by common infections (eg, influenza, pneumococcus).⁸

Barriers to Vaccination

Barriers to vaccination are varied, but none is insurmountable. Some of these barriers include^8-15:

Missed opportunities. Providers should address vaccination needs for both adults and children at each visit or encounter. According to the CDC, studies have shown that eliminating missed opportunities could increase vaccination coverage by as much as 20%.^8,11

Provider misconceptions regarding vaccine contraindications, schedules, and simultaneous vaccine administration. These misconceptions may prompt providers to forego an opportunity to vaccinate. Up-to-date information about vaccinations and ongoing provider education are imperative to improve immunity among both adults and children against vaccine-preventable disease.⁸ Numerous Web sites and publications are instrumental and essential in furnishing the health care provider with the most current information about vaccinations (see Table 1, above, and Table 2,^10,12-14).

A belief on patients’ part that they are fully vaccinated when they are not. It is important to provide a vaccination record and a return date at every vaccination encounter, even if just one vaccination has been administered on a given day. Participating in Immunization Information System,¹⁵ if one is available, is an efficient way to access computerized vaccine records easily at the point of contact.

Just as parents should be encouraged to bring their child’s vaccine record with them to every health care visit, adults are also called upon to maintain a record of all their vaccinations. Each entry in the immunization record should include:

• The type of vaccine and dose

• The site and route of administration

• The date that the vaccine was administered

• The date that the next dose is due

• The manufacturer and lot number

• The name, address, and title of the person who administered the vaccine.¹⁵

PRINCIPLES OF VACCINATION

There are two ways to acquire immunity: active and passive.

Active immunity is produced by the individual’s own immune system and usually represents a permanent immunity toward the antigen.^10,16

Passive immunity is produced when the individual receives products of immunity made by another animal or a human and transferred to the host. Passive immunity can be accomplished by injection of these products or through the placenta in infants. This type of immunity is not permanent and wanes over time—usually within weeks or months.^10,16

This article will concentrate on active immunity, acquired through the administration of vaccines.

CLASSIFICATION OF VACCINES

Vaccines are classified as either live, attenuated vaccine (viral or bacterial) or inactivated vaccine.

Live, attenuated vaccines are derived from “wild” or disease-causing viruses and bacteria. Through procedures conducted in the laboratory, these wild organisms are weakened or attenuated. The live, attenuated vaccine must grow and replicate in the vaccinated person in order to stimulate an immune response.  However, because the organism has been weakened, it usually does not cause disease or illness.^10,16 

The immune response to a live, attenuated vaccine is virtually identical to a response produced by natural infection. In rare instances, however, live, attenuated vaccines may cause severe or fatal reactions as a result of uncontrolled replication of the organism. This occurs only in individuals who are significantly immunocompromised.^10,16

Inactivated vaccines are produced by growing the viral or bacterial organism in a culture medium, then using heat and/or chemicals to inactivate the organism. Because inactivated vaccines are not alive, they cannot replicate, and therefore cannot cause disease, even in an immunodeficient patient. The immune response to an inactivated vaccine is mostly humoral (in contrast to the natural infection response of a live vaccine), and little or no cellular immunity is produced.^10,16

 Inactivated vaccines always require multiple doses, gradually building up a protective immune response. The antibody titers diminish over time, so some inactivated vaccines may require periodic doses to “boost” or increase the titers.¹⁶

Some vaccines, such as hepatitis B vaccine, lead to the development of immune memory, which stays intact for at least 20 years following immunization. Immune memory occurs during replication of B cells and T cells; some cells will become long-lived memory cells that will “remember” the pathogen and produce an immune response if the pathogen is detected again. In this case, boosters are not recommended.¹⁰

Toxoids are a type of vaccine made from the inactivated toxin of a bacterium—not the bacterium itself. Tetanus and diphtheria vaccines are examples of toxoid vaccines.^10,16

Subunit and conjugate vaccines are segments of the pathogen. A subunit vaccine can be created via genetic engineering. The end result is a recombinant vaccine that can stimulate cell memory (eg, hepatitis B vaccine).^10,16 Conjugate vaccines, which are similar to recombinant vaccines, are made by combining two different components to prompt a more powerful, combined immune response.¹⁰

Spacing of Live-Virus and Inactivated Vaccines

There are almost no spacing requirements between two or more inactivated vaccines⁸ (see Table 3^8,14 for spacing recommendations from the Advisory Committee on Immunization Practices [ACIP]). The only vaccines that must be spaced at least four weeks apart are live-virus vaccines—that is, if they are not given on the same day. Studies have shown that the immune response to a live-virus vaccine may be impaired if it is administered within 30 days of another live-virus vaccine. Inactivated vaccines, on the other hand, may usually be administered at any time after or before a live-virus vaccine.⁸

One exception to this statement is the administration of Zostavax (zoster live-virus vaccine) with Pneumovax 23 (inactivated pneumococcal vaccine, polyvalent, MSD).^17-19 The manufacturer of the two vaccines recommends a spacing of at least four weeks between them, based on research showing that concomitant use may result in reduced immunogenicity for Zostavax.²⁰ However, as of this writing, ACIP has not revised its statement that both vaccines can be given at the same time or at any time before or after each other.²¹

Live-virus vaccines currently licensed in the US provide protection against diseases including measles/mumps/rubella, varicella, zoster (ie, shingles), influenza, and yellow fever.

ADULT VACCINATION HIGHLIGHTS

A summary of 2011 recommendations for adult immunization from ACIP is shown in Table 4^12,21. The following information is specific to each of the vaccine-preventable illnesses of concern in adults.^12,13,22

Seasonal Influenza

The options to protect the adult patient against seasonal influenza are a trivalent, inactivated influenza vaccine (TIV; Fluzone, high-dose Fluzone for adults ages 65 and older, Fluvirin, Fluarix, FluLaval, Afluria, Agriflu) or a live, attenuated influenza vaccine (LAIV; FluMist).^2,23 Dosage of TIV for adults is 0.5 mL IM in the deltoid once annually. For adults ages 49 and younger, LAIV is administered at 0.2 mL intranasally, once per year.

ACIP now recommends universal influenza vaccination for all persons ages 6 months and older with no contraindications.^2,8 Strong consideration should be given to concurrent administration of influenza vaccine and pneumococcal vaccine to high-risk persons not previously vaccinated against pneumococcal disease.¹²

Note: When influenza and pneumococcal vaccines are given at the same time, they should be administered in opposite arms to reduce the risk of adverse reactions or a decreased antibody response to either vaccine.^18,19

Pneumococcal Polysaccharide (PPSV)

Pneumovax 23¹⁹ is administered as a 0.5-mL dose IM in the deltoid or subcutaneously in the upper arm. The vaccine is recommended for^8,19,24:

• Adults ages 65 and older who have not been previously vaccinated

• Adults now 65 and older who received PPSV vaccine at least five years ago and were younger than 65 at that time

• Adults ages 19 through 64 years who have asthma or who smoke²⁴

• Any adult with the following underlying medical conditions: chronic heart or lung disease, diabetes mellitus, cerebrospinal fluid leaks, cochlear implants, chronic liver disease, cirrhosis, chronic alcoholism, functional or anatomic asplenia, and immunocompromising conditions (HIV infection, diseases that require immunosuppressive therapy, chemotherapy, or radiation therapy; congenital immunodeficiency).²⁴

A one-time revaccination is recommended after five years for persons ages 19 to 64 who have chronic renal failure, nephrotic syndrome, or functional or anatomic asplenia, and for those who are immunocompromised.²⁴

Note: According to the manufacturer of Zostavax¹⁸ and Pneumovax,^23,19 these vaccines should not be given at the same time, as research has shown that Zostavax immunogenicity is reduced as a result.^18-20

Zoster

For adults ages 60 and older, Zostavax¹⁸ is administered in a single 0.65-mL dose, subcutaneously in the upper arm. Providers are not required to ask about varicella vaccination history or history of varicella disease before administering the vaccine. Adults ages 60 and older who have previously had shingles can still be vaccinated during a routine health care visit.^10,21,22

Immunization is contraindicated in adults with a previous anaphylactic reaction to neomycin or gelatin, although a nonanaphylactic reaction to neomycin (most commonly, contact dermatitis) is not considered a contraindication.⁸

Any adult patient who has close household or occupational contact with persons at risk for severe varicella (eg, infants) need not take precautions after receiving the zoster vaccine, except in the rare case in which a varicella-like rash develops.^10,21,22

Note: Review the note appearing in “Pneumococcal Polysaccharide (PPSV),” above, regarding coadministration of Zostavax and Pneumovax 23.^18-20

Varicella

Adults who were born in the US before 1980 are considered immune to varicella and don’t need to be vaccinated, with the exception of health care workers, pregnant women, and immunocompromised persons. Nonimmune healthy adults who have not previously undergone vaccination should receive two 0.5-mL doses of Varivax, administered subcutaneously, four to eight weeks apart.²⁵

Immunization is contraindicated in adults with a previous anaphylactic reaction to neomycin or gelatin, although a nonanaphylactic reaction to neomycin (eg, contact dermatitis) is not considered a contraindication.⁸

Measles, Mumps, Rubella (MMR)

The MMR vaccine is administered at 0.5 mL, given subcutaneously in the posterolateral fat of the upper arm.⁸

MMR-susceptible adults who were born during or since 1957 and are not at increased risk (see below) need only one dose of the MMR vaccine; those considered at increased risk need two doses, and a second dose can also be considered during an outbreak. Adults who require two doses should wait at least four weeks between the first and second doses.¹²

The following factors place adults at increased risk for MMR:

• Anticipated international travel

• Being a student in a post–secondary educational setting

• Working in a health care facility

• Recent exposure to measles, or an outbreak of measles or mumps

• Previous vaccination with killed measles vaccine

• Previous vaccination with an unknown measles vaccine between 1963 and 1967.

Also at risk are health care workers born before 1957 who have no evidence of immunity, and women who plan to become pregnant and have no evidence of immunity.^8,12

Tetanus, Diphtheria, Pertussis

Options for adults include a vaccine against tetanus and diphtheria (Td; Decavac); or a vaccine that protects against tetanus, diphtheria, and acellular pertussis (Tdap; Adacel, Boostrix). Adults who have not been previously vaccinated should receive one dose of Tdap and two doses of Td (the first, one month after Tdap; the second at six to 12 months after the Tdap). Each is administered as a 0.5-mL dose IM in the deltoid. A booster dose is recommended every 10 years but can be given earlier in patients who sustain wounds or who anticipate international travel.^8,12

Adults ages 19 through 64 should receive a single dose of Tdap in place of a booster dose if the last Td dose was administered at least 10 years earlier and the patient has not previously received Tdap. Additionally, a dose of Tdap (if not previously given) is recommended for postpartum women, close contacts of infants younger than 12 months, and all health care workers with direct patient contact. An interval as short as two years from the last Td is suggested; shorter intervals may be appropriate.^8,12

According to the new 2011 recommendations, persons ages 65 and older who have close contact with an infant younger than 12 months should be vaccinated with Tdap, and any person age 65 or older may be vaccinated with Tdap. Also added is a recommendation to administer Tdap, regardless of the interval since the patient received his or her most recent Td-containing vaccine.^8,12

Human Papillomavirus (HPV)

Gardasil²⁶ protects both female and male patients against HPV infection; Cervarix²⁷ is indicated only for female patients. Either quadrivalent vaccine or bivalent vaccine is recommended for female patients.¹²

In women ages 26 and younger, Gardasil (0.5 mL IM, administered in the deltoid at 0 month, 2 months, and 6 months) provides protection against diseases caused by HPV types 6, 11, 16, and 18 (including cervical, vaginal, and vulvar cancer caused by HPV types 16 and 18). In men ages 26 and younger, Gardasil provides protection against genital warts caused by HPV types 6 and 11.²⁶

Cervarix,²⁷ administered at 0 month, 1 month, and 6 months (0.5 mL IM in the deltoid), provides protection for women ages 25 and younger against cervical cancer and precancerous lesions caused by HPV types 16 and 18.

Caution: Patients should be advised to sit or lie down when the HPV vaccine is administered, and they should be observed for the subsequent 15 minutes. Syncope can occur after vaccination—most commonly among adolescents and young adults.²⁸ Convulsive syncope has been reported.

Meningococcal Disease

Two vaccines are available to protect against meningococcal disease: Menactra²⁹ (meningococcal groups A, C, Y, and W-135 polysaccharide diphtheria toxoids conjugate vaccine); and Menveo³⁰ (meningococcal groups A, C, Y, and W-135 oligosaccharide diphtheria CRM₁₉₇ conjugate vaccine). Both are administered in the deltoid, 0.5 mL IM.

The following patients should be considered for vaccination:

• College freshmen living in dormitories, as well as college students with immune deficiencies, as they are at higher risk for meningococcal disease

• Patients who travel to or reside in countries in which Neisseria meningitidis is epidemic (particularly those with the potential for prolonged contact with the local population)

• Travelers to Saudi Arabia for pilgrimage to Mecca (the Hajj)

• Patients with anatomical or functional asplenia (two-dose series).

A two-dose series of meningococcal conjugate vaccine is also recommended for adults with persistent complement component deficiencies, and for those with HIV infection who are vaccinated.¹²

Hepatitis A

Two hepatitis A vaccines (both inactivated) can be used interchangeably: Havrix³¹ and Vaqta.³² Dosing for both vaccines in 18-year-old patients is 0.5 mL IM in the deltoid at 0 months, then at 6 to 12 months. In patients ages 19 and older, administration is the same, with the exception of increased dosing (1.0 mL IM).

Vaccination against hepatitis A is recommended for men who have sex with men, and for all adult patients who¹²:

• Travel to or work in areas where risk for hepatitis A transmission is high (especially those who take frequent trips or experience prolonged stays)

• Use injection drugs

• Have chronic liver disease

• Receive clotting factor concentrates for treatment of a blood-clotting disorder

• May have been exposed to hepatitis A in the previous two weeks

• Wish to be vaccinated against hepatitis A to avoid future infection.

Hepatitis B

Recombivax HB³³ and Engerix-B³⁴ are the two vaccines available to protect patients against hepatitis B (HBV), and they can be used interchangeably.¹² In patients from birth through age 19, Recombivax HB³³ or Engerix-B³⁴ is given as 0.5 mL IM in the deltoid at 0, 1, and 6 months; patients ages 20 and older receive an increased dose (1.0 mL IM), with administration otherwise the same. According to the manufacturer of Recombivax HB,³³ patients age 11 through 15 may be given either three doses of 0.5 mL or two doses of 1.0 mL.

The following adults are advised to undergo vaccination for HBV:

• At-risk, unvaccinated adults

• Those requesting protection against HBV infection

• Those planning to travel to areas where HBV is common

• Household contacts of a patient with chronic HBV infection, and sexual partners of a patient with HBV infection

• Adults with chronic liver disease

• Men who have sex with men

• Sexually active adults who are not in a long-term, mutually monogamous relationship

• Adults who are being evaluated or treated for a sexually transmitted disease, including HIV infection

• Health care or public safety workers who may be exposed to blood or blood-contaminated body fluids

• Workers and residents in facilities for developmentally disabled persons

• Patients undergoing or anticipating dialysis

• Adults who inject illegal drugs or who have done so recently.¹²

CONTRAINDICATIONS AND PRECAUTIONS FOR VACCINES COMMONLY USED IN ADULTS

See Table 5,^8,22 for a summary of contraindications and precautions from ACIP and the Immunization Action Coalition that are associated with vaccinations mentioned in this article. A more complete summary can be found at www.im munize.org/catg.d/p3072a.pdf.

Conclusion

The adult patient’s vaccination status should be addressed at each health care encounter, and current recommendations should be followed. The duration of efficacy for vaccines is not an exact science. Many vaccines licensed in the US are relatively new, and recommendations for boosters for some of these vaccines will be forthcoming as more data are gathered. For example, the recommendation that a booster dose of Tdap be given to adults resulted from the recent increase in reported pertussis cases.³⁵

Providers armed with the most current information and resources represent the forefront in ensuring that the US adult population is adequately immunized.

REFERENCES

1. World Health Organization. Immunization surveillance, assessment, and monitoring (2010). www.who.int/immunization_monitor ing/en. Accessed May 12, 2011.

2. Fiore AE, Uyeki TM, Broder K, et al; Centers for Disease Control and Prevention. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep. 2010;59(RR-08);1-62.

3. Schaffner W. Update on vaccine-preventable diseases: are adults in your community adequately protected? J Fam Pract. 2008;57(4 suppl):S1-S11.

4. CDC. Healthy People 2010: Objectives for Improving Health. www.healthypeople.gov. Accessed May 6, 2011.

5. US Department of Health and Human Services. Developing Healthy People 2020: immunization and infectious diseases. www.healthy people.gov/2020. Accessed May 12, 2011.

6. Lu PJ, Nuorti JP. Pneumococcal polysaccharide vaccination among adults aged 65 years and older, United States, 1989-2008. Am J Prev Med. 2010;39(4):287-295.

7. National Institute of Allergy and Infectious Diseases, NIH. Community immunity (“herd” immunity) (2010). www.niaid.nih.gov/topics/pages/communityimmunity.aspx. Accessed May 12, 2011.

8. National Center for Immunization and Respiratory Diseases. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ADIP). MMWR Recomm Rep. 2011;60(2):1-64.

9. High KP. Overcoming barriers to adult immunization. J Am Osteopath Assoc. 2009;109(6): 525-528.

10. CDC; Atkinson W, Wolfe S, Hamborsky J, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases (Pink Book). 12th ed. Washington, DC: Public Health Foundation, 2011.

11. CDC. Vaccine-preventable diseases: improving vaccination coverage in children, adolescents, and adults: a report on recommendations from the Task Force on Community Preventive Services. MMWR Recomm Rep. 1999;48(RR-8):1-15.

12. CDC. Recommended adult immunization schedule: United States, 2011. MMWR Morb Mortal Wkly Rep. 2011;60(4):1-4.

13. Thompson RF. Travel & Routine Immunizations: A Practical Guide for the Medical Office. 19th ed. Milwaukee, WI: Shoreland, Inc: 2001.

14. American Academy of Pediatrics. Pertussis. In: Pickering LK, Backer, CJ, Long SS, McMillan J, eds. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics.

15. CDC. Immunization information systems (IIS). www.cdc.gov/vaccines/programs/iis/default.htm. Accessed May 12, 2011.

16. College of Physicians of Philadelphia. The history of vaccines: a project of the College of Physicians of Philadelphia (2011). www.history ofvaccines.org/content/articles/different-types-vaccines. Accessed May 12, 2011.

17. US Food and Drug Administration. Vaccines, blood, and biologics: December 18, 2009 Approval Letter—Zostavax. www.fda.gov/
BiologicsBloodVaccines/Vaccines/Approved Products/ucm195993.htm. Accessed May 12, 2011.

18. Merck & Co, Inc. Zostavax^® (zoster vaccine live; product insert). www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/Approved Products/UCM132831.pdf. Accessed May 12, 2011.

19. Merck & Co, Inc. Pneumovax^® 23 (pneumococcal vaccine, polyvalent, MSD; product information). www.merck.com/product/usa/pi_circulars/p/pneumovax_23/pneumovax_pi.pdf. Accessed May 16, 2011.

20. Macintyre CR, Egerton T, McCaughey M, et al. Concomitant administration of zoster and pneumococcal vaccines in adults ≥60 years old. Hum Vaccin. 2010;6(11):18-26.

21. CDC. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1–30.

22. Immunization Action Coalition. Vaccinate Adults. 2010 Aug;14(5). www.immunize.org/va. Accessed May 12, 2011.

23. CDC. Update: recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding use of CSL seasonal influenza vaccine (Afluria) in the United States during 2010–2011. MMWR Morb Mortal Wkly Rep. 2010;59(31);989-992.

24. CDC. Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR Morb Mortal Wkly Rep. 2010;59(RR-34):1102-1106.

25. Merck & Co, Inc. Varivax^® varicella virus vaccine live (product information). www.merck
.com/product/usa/pi_circulars/v/varivax/varivax_pi.pdf. Accessed May 12, 2011.

26. Merck & Co, Inc. Gardasil^® (human papillomavirus quadrivalent [types 6, 11, 16, and 18] vaccine, recombinant; product information). www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_ppi.pdf. Accessed May 12, 2011.

27. GlaxoSmithKline Biologicals. Cervarix (human papillomavirus bivalent [types 16 and 18] vaccine, recombinant; product information). http://us.gsk.com/products/assets/us_cervarix.pdf. Accessed May 12, 2011.

28. CDC. Syncope after vaccination—United States, January 2005-July 2007. MMWR Morb Mortal Wkly Rep. 2008;57(17):457-460.

29. Sanofi Pasteur. Meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria
toxoids conjugate vaccine Menactra^® for intramuscular injection. www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/Approved
Products/UCM131170.pdf. Accessed May 12, 2011.

30. Novartis Vaccines and Diagnostics, Inc. Menveo^® (meningococcal [groups A, C, Y and W-135] oligosaccharide diphtheria CRM₁₉₇ conjugate vaccine solution for intramuscular injection; prescribing information highlights). www .fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm201349.pdf. Accessed May 12, 2011.

31. GlaxoSmithKline Biologicals. Havrix (hepatitis A vaccine, suspension for intramuscular injection; prescribing information highlights). http://us.gsk.com/products/assets/us_havrix .pdf. Accessed May 12, 2011.

32. Merck & Co, Inc. Vaqta (hepatitis A vaccine, inactivated; suspension for intramuscular injection; highlighted prescribing information). www.merck.com/product/usa/pi_circulars/v/vaqta/vaqta_pi.pdf. Accessed May 12, 2011.

33. Merck & Co, Inc. Recombivax HB^® hepatitis B vaccine (recombinant; product information). www.merck.com/product/usa/pi_circulars/r/recombivax_hb/recombivax_pi.pdf. Accessed May 12, 2011.

34. GlaxoSmithKline Biologicals. Engerix-B^® (hepatitis B vaccine, recombinant; prescribing information). http://us.gsk.com/products/assets/us_engerixb.pdf. Accessed May 12, 2011.

35. CDC. Tetanus and pertussis vaccination coverage among adults aged ≥ 18 years—United States, 1999 and 2008. MMWR Morb Mortal Wkly Rep. 2010;59(40):1302-1306.

Reported incidence rates of certain vaccine-preventable diseases—measles, rubella, diphtheria, polio, and tetanus—are low in the United States.¹ However, as was demonstrated during the 2009-2010 flu season and the outbreak of H1N1 influenza,² we cannot afford to be complacent in our attitudes toward vaccines and vaccination. New virus strains exist and can become endemic quickly and ravenously. Furthermore, certain vaccine-preventable illnesses are frequently reported among adult patients, including hepatitis B, herpes zoster, human papillomavirus infection, influenza, pertussis, and pneumococcal infection.³

Vigilance regarding vaccination of children and adults was addressed by the CDC’s Office of Disease Prevention and Health Promotion in Healthy People 2010.⁴ These target objectives are proposed to be retained in Healthy People 2020,⁵ as the objectives from 2010 have not been met. The Healthy People 2010 target for administration of the pneumococcal vaccine in adults ages 65 and older, for example, is 90%. As of 2008, research has shown, only 60% of that population was immunized.⁶

There are subgroups of immunocompromised people who will probably never achieve adequate antibody levels to ensure immunity to vaccine-preventable diseases (for example, measles and influenza can be deadly to the immunocompromised person, as they can be to the very young and the very old). This is an important reason why vaccination of the healthy population is essential: the concept of herd immunity.⁷ Herd immunity (or community immunity) suggests that if most people around you are immune to an infection and do not become ill, then there is no one who can infect you—even if you are not immune to the infection.

WHY SOME ADULTS MIGHT NEED VACCINES

Adults who were vaccinated as children may incorrectly assume that they are protected from disease for life. In the case of some diseases, this may be true. However:

• Some adults were never vaccinated as children

• Newer vaccines have been developed since many adults were children

• Immunity can begin to fade over time

• As we age, we become more susceptible to serious disease caused by common infections (eg, influenza, pneumococcus).⁸

Barriers to Vaccination

Barriers to vaccination are varied, but none is insurmountable. Some of these barriers include^8-15:

Missed opportunities. Providers should address vaccination needs for both adults and children at each visit or encounter. According to the CDC, studies have shown that eliminating missed opportunities could increase vaccination coverage by as much as 20%.^8,11

Provider misconceptions regarding vaccine contraindications, schedules, and simultaneous vaccine administration. These misconceptions may prompt providers to forego an opportunity to vaccinate. Up-to-date information about vaccinations and ongoing provider education are imperative to improve immunity among both adults and children against vaccine-preventable disease.⁸ Numerous Web sites and publications are instrumental and essential in furnishing the health care provider with the most current information about vaccinations (see Table 1, above, and Table 2,^10,12-14).

A belief on patients’ part that they are fully vaccinated when they are not. It is important to provide a vaccination record and a return date at every vaccination encounter, even if just one vaccination has been administered on a given day. Participating in Immunization Information System,¹⁵ if one is available, is an efficient way to access computerized vaccine records easily at the point of contact.

Just as parents should be encouraged to bring their child’s vaccine record with them to every health care visit, adults are also called upon to maintain a record of all their vaccinations. Each entry in the immunization record should include:

• The type of vaccine and dose

• The site and route of administration

• The date that the vaccine was administered

• The date that the next dose is due

• The manufacturer and lot number

• The name, address, and title of the person who administered the vaccine.¹⁵

PRINCIPLES OF VACCINATION

There are two ways to acquire immunity: active and passive.

Active immunity is produced by the individual’s own immune system and usually represents a permanent immunity toward the antigen.^10,16

Passive immunity is produced when the individual receives products of immunity made by another animal or a human and transferred to the host. Passive immunity can be accomplished by injection of these products or through the placenta in infants. This type of immunity is not permanent and wanes over time—usually within weeks or months.^10,16

This article will concentrate on active immunity, acquired through the administration of vaccines.

CLASSIFICATION OF VACCINES

Vaccines are classified as either live, attenuated vaccine (viral or bacterial) or inactivated vaccine.

Live, attenuated vaccines are derived from “wild” or disease-causing viruses and bacteria. Through procedures conducted in the laboratory, these wild organisms are weakened or attenuated. The live, attenuated vaccine must grow and replicate in the vaccinated person in order to stimulate an immune response.  However, because the organism has been weakened, it usually does not cause disease or illness.^10,16 

The immune response to a live, attenuated vaccine is virtually identical to a response produced by natural infection. In rare instances, however, live, attenuated vaccines may cause severe or fatal reactions as a result of uncontrolled replication of the organism. This occurs only in individuals who are significantly immunocompromised.^10,16

Inactivated vaccines are produced by growing the viral or bacterial organism in a culture medium, then using heat and/or chemicals to inactivate the organism. Because inactivated vaccines are not alive, they cannot replicate, and therefore cannot cause disease, even in an immunodeficient patient. The immune response to an inactivated vaccine is mostly humoral (in contrast to the natural infection response of a live vaccine), and little or no cellular immunity is produced.^10,16

 Inactivated vaccines always require multiple doses, gradually building up a protective immune response. The antibody titers diminish over time, so some inactivated vaccines may require periodic doses to “boost” or increase the titers.¹⁶

Some vaccines, such as hepatitis B vaccine, lead to the development of immune memory, which stays intact for at least 20 years following immunization. Immune memory occurs during replication of B cells and T cells; some cells will become long-lived memory cells that will “remember” the pathogen and produce an immune response if the pathogen is detected again. In this case, boosters are not recommended.¹⁰

Toxoids are a type of vaccine made from the inactivated toxin of a bacterium—not the bacterium itself. Tetanus and diphtheria vaccines are examples of toxoid vaccines.^10,16

Subunit and conjugate vaccines are segments of the pathogen. A subunit vaccine can be created via genetic engineering. The end result is a recombinant vaccine that can stimulate cell memory (eg, hepatitis B vaccine).^10,16 Conjugate vaccines, which are similar to recombinant vaccines, are made by combining two different components to prompt a more powerful, combined immune response.¹⁰

Spacing of Live-Virus and Inactivated Vaccines

There are almost no spacing requirements between two or more inactivated vaccines⁸ (see Table 3^8,14 for spacing recommendations from the Advisory Committee on Immunization Practices [ACIP]). The only vaccines that must be spaced at least four weeks apart are live-virus vaccines—that is, if they are not given on the same day. Studies have shown that the immune response to a live-virus vaccine may be impaired if it is administered within 30 days of another live-virus vaccine. Inactivated vaccines, on the other hand, may usually be administered at any time after or before a live-virus vaccine.⁸

One exception to this statement is the administration of Zostavax (zoster live-virus vaccine) with Pneumovax 23 (inactivated pneumococcal vaccine, polyvalent, MSD).^17-19 The manufacturer of the two vaccines recommends a spacing of at least four weeks between them, based on research showing that concomitant use may result in reduced immunogenicity for Zostavax.²⁰ However, as of this writing, ACIP has not revised its statement that both vaccines can be given at the same time or at any time before or after each other.²¹

Live-virus vaccines currently licensed in the US provide protection against diseases including measles/mumps/rubella, varicella, zoster (ie, shingles), influenza, and yellow fever.

ADULT VACCINATION HIGHLIGHTS

A summary of 2011 recommendations for adult immunization from ACIP is shown in Table 4^12,21. The following information is specific to each of the vaccine-preventable illnesses of concern in adults.^12,13,22

Seasonal Influenza

The options to protect the adult patient against seasonal influenza are a trivalent, inactivated influenza vaccine (TIV; Fluzone, high-dose Fluzone for adults ages 65 and older, Fluvirin, Fluarix, FluLaval, Afluria, Agriflu) or a live, attenuated influenza vaccine (LAIV; FluMist).^2,23 Dosage of TIV for adults is 0.5 mL IM in the deltoid once annually. For adults ages 49 and younger, LAIV is administered at 0.2 mL intranasally, once per year.

ACIP now recommends universal influenza vaccination for all persons ages 6 months and older with no contraindications.^2,8 Strong consideration should be given to concurrent administration of influenza vaccine and pneumococcal vaccine to high-risk persons not previously vaccinated against pneumococcal disease.¹²

Note: When influenza and pneumococcal vaccines are given at the same time, they should be administered in opposite arms to reduce the risk of adverse reactions or a decreased antibody response to either vaccine.^18,19

Pneumococcal Polysaccharide (PPSV)

Pneumovax 23¹⁹ is administered as a 0.5-mL dose IM in the deltoid or subcutaneously in the upper arm. The vaccine is recommended for^8,19,24:

• Adults ages 65 and older who have not been previously vaccinated

• Adults now 65 and older who received PPSV vaccine at least five years ago and were younger than 65 at that time

• Adults ages 19 through 64 years who have asthma or who smoke²⁴

• Any adult with the following underlying medical conditions: chronic heart or lung disease, diabetes mellitus, cerebrospinal fluid leaks, cochlear implants, chronic liver disease, cirrhosis, chronic alcoholism, functional or anatomic asplenia, and immunocompromising conditions (HIV infection, diseases that require immunosuppressive therapy, chemotherapy, or radiation therapy; congenital immunodeficiency).²⁴

A one-time revaccination is recommended after five years for persons ages 19 to 64 who have chronic renal failure, nephrotic syndrome, or functional or anatomic asplenia, and for those who are immunocompromised.²⁴

Note: According to the manufacturer of Zostavax¹⁸ and Pneumovax,^23,19 these vaccines should not be given at the same time, as research has shown that Zostavax immunogenicity is reduced as a result.^18-20

Zoster

For adults ages 60 and older, Zostavax¹⁸ is administered in a single 0.65-mL dose, subcutaneously in the upper arm. Providers are not required to ask about varicella vaccination history or history of varicella disease before administering the vaccine. Adults ages 60 and older who have previously had shingles can still be vaccinated during a routine health care visit.^10,21,22

Immunization is contraindicated in adults with a previous anaphylactic reaction to neomycin or gelatin, although a nonanaphylactic reaction to neomycin (most commonly, contact dermatitis) is not considered a contraindication.⁸

Any adult patient who has close household or occupational contact with persons at risk for severe varicella (eg, infants) need not take precautions after receiving the zoster vaccine, except in the rare case in which a varicella-like rash develops.^10,21,22

Note: Review the note appearing in “Pneumococcal Polysaccharide (PPSV),” above, regarding coadministration of Zostavax and Pneumovax 23.^18-20

Varicella

Adults who were born in the US before 1980 are considered immune to varicella and don’t need to be vaccinated, with the exception of health care workers, pregnant women, and immunocompromised persons. Nonimmune healthy adults who have not previously undergone vaccination should receive two 0.5-mL doses of Varivax, administered subcutaneously, four to eight weeks apart.²⁵

Immunization is contraindicated in adults with a previous anaphylactic reaction to neomycin or gelatin, although a nonanaphylactic reaction to neomycin (eg, contact dermatitis) is not considered a contraindication.⁸

Measles, Mumps, Rubella (MMR)

The MMR vaccine is administered at 0.5 mL, given subcutaneously in the posterolateral fat of the upper arm.⁸

MMR-susceptible adults who were born during or since 1957 and are not at increased risk (see below) need only one dose of the MMR vaccine; those considered at increased risk need two doses, and a second dose can also be considered during an outbreak. Adults who require two doses should wait at least four weeks between the first and second doses.¹²

The following factors place adults at increased risk for MMR:

• Anticipated international travel

• Being a student in a post–secondary educational setting

• Working in a health care facility

• Recent exposure to measles, or an outbreak of measles or mumps

• Previous vaccination with killed measles vaccine

• Previous vaccination with an unknown measles vaccine between 1963 and 1967.

Also at risk are health care workers born before 1957 who have no evidence of immunity, and women who plan to become pregnant and have no evidence of immunity.^8,12

Tetanus, Diphtheria, Pertussis

Options for adults include a vaccine against tetanus and diphtheria (Td; Decavac); or a vaccine that protects against tetanus, diphtheria, and acellular pertussis (Tdap; Adacel, Boostrix). Adults who have not been previously vaccinated should receive one dose of Tdap and two doses of Td (the first, one month after Tdap; the second at six to 12 months after the Tdap). Each is administered as a 0.5-mL dose IM in the deltoid. A booster dose is recommended every 10 years but can be given earlier in patients who sustain wounds or who anticipate international travel.^8,12

Adults ages 19 through 64 should receive a single dose of Tdap in place of a booster dose if the last Td dose was administered at least 10 years earlier and the patient has not previously received Tdap. Additionally, a dose of Tdap (if not previously given) is recommended for postpartum women, close contacts of infants younger than 12 months, and all health care workers with direct patient contact. An interval as short as two years from the last Td is suggested; shorter intervals may be appropriate.^8,12

According to the new 2011 recommendations, persons ages 65 and older who have close contact with an infant younger than 12 months should be vaccinated with Tdap, and any person age 65 or older may be vaccinated with Tdap. Also added is a recommendation to administer Tdap, regardless of the interval since the patient received his or her most recent Td-containing vaccine.^8,12

Human Papillomavirus (HPV)

Gardasil²⁶ protects both female and male patients against HPV infection; Cervarix²⁷ is indicated only for female patients. Either quadrivalent vaccine or bivalent vaccine is recommended for female patients.¹²

In women ages 26 and younger, Gardasil (0.5 mL IM, administered in the deltoid at 0 month, 2 months, and 6 months) provides protection against diseases caused by HPV types 6, 11, 16, and 18 (including cervical, vaginal, and vulvar cancer caused by HPV types 16 and 18). In men ages 26 and younger, Gardasil provides protection against genital warts caused by HPV types 6 and 11.²⁶

Cervarix,²⁷ administered at 0 month, 1 month, and 6 months (0.5 mL IM in the deltoid), provides protection for women ages 25 and younger against cervical cancer and precancerous lesions caused by HPV types 16 and 18.

Caution: Patients should be advised to sit or lie down when the HPV vaccine is administered, and they should be observed for the subsequent 15 minutes. Syncope can occur after vaccination—most commonly among adolescents and young adults.²⁸ Convulsive syncope has been reported.

Meningococcal Disease

Two vaccines are available to protect against meningococcal disease: Menactra²⁹ (meningococcal groups A, C, Y, and W-135 polysaccharide diphtheria toxoids conjugate vaccine); and Menveo³⁰ (meningococcal groups A, C, Y, and W-135 oligosaccharide diphtheria CRM₁₉₇ conjugate vaccine). Both are administered in the deltoid, 0.5 mL IM.

The following patients should be considered for vaccination:

• College freshmen living in dormitories, as well as college students with immune deficiencies, as they are at higher risk for meningococcal disease

• Patients who travel to or reside in countries in which Neisseria meningitidis is epidemic (particularly those with the potential for prolonged contact with the local population)

• Travelers to Saudi Arabia for pilgrimage to Mecca (the Hajj)

• Patients with anatomical or functional asplenia (two-dose series).

A two-dose series of meningococcal conjugate vaccine is also recommended for adults with persistent complement component deficiencies, and for those with HIV infection who are vaccinated.¹²

Hepatitis A

Two hepatitis A vaccines (both inactivated) can be used interchangeably: Havrix³¹ and Vaqta.³² Dosing for both vaccines in 18-year-old patients is 0.5 mL IM in the deltoid at 0 months, then at 6 to 12 months. In patients ages 19 and older, administration is the same, with the exception of increased dosing (1.0 mL IM).

Vaccination against hepatitis A is recommended for men who have sex with men, and for all adult patients who¹²:

• Travel to or work in areas where risk for hepatitis A transmission is high (especially those who take frequent trips or experience prolonged stays)

• Use injection drugs

• Have chronic liver disease

• Receive clotting factor concentrates for treatment of a blood-clotting disorder

• May have been exposed to hepatitis A in the previous two weeks

• Wish to be vaccinated against hepatitis A to avoid future infection.

Hepatitis B

Recombivax HB³³ and Engerix-B³⁴ are the two vaccines available to protect patients against hepatitis B (HBV), and they can be used interchangeably.¹² In patients from birth through age 19, Recombivax HB³³ or Engerix-B³⁴ is given as 0.5 mL IM in the deltoid at 0, 1, and 6 months; patients ages 20 and older receive an increased dose (1.0 mL IM), with administration otherwise the same. According to the manufacturer of Recombivax HB,³³ patients age 11 through 15 may be given either three doses of 0.5 mL or two doses of 1.0 mL.

The following adults are advised to undergo vaccination for HBV:

• At-risk, unvaccinated adults

• Those requesting protection against HBV infection

• Those planning to travel to areas where HBV is common

• Household contacts of a patient with chronic HBV infection, and sexual partners of a patient with HBV infection

• Adults with chronic liver disease

• Men who have sex with men

• Sexually active adults who are not in a long-term, mutually monogamous relationship

• Adults who are being evaluated or treated for a sexually transmitted disease, including HIV infection

• Health care or public safety workers who may be exposed to blood or blood-contaminated body fluids

• Workers and residents in facilities for developmentally disabled persons

• Patients undergoing or anticipating dialysis

• Adults who inject illegal drugs or who have done so recently.¹²

CONTRAINDICATIONS AND PRECAUTIONS FOR VACCINES COMMONLY USED IN ADULTS

See Table 5,^8,22 for a summary of contraindications and precautions from ACIP and the Immunization Action Coalition that are associated with vaccinations mentioned in this article. A more complete summary can be found at www.im munize.org/catg.d/p3072a.pdf.

Conclusion

The adult patient’s vaccination status should be addressed at each health care encounter, and current recommendations should be followed. The duration of efficacy for vaccines is not an exact science. Many vaccines licensed in the US are relatively new, and recommendations for boosters for some of these vaccines will be forthcoming as more data are gathered. For example, the recommendation that a booster dose of Tdap be given to adults resulted from the recent increase in reported pertussis cases.³⁵

Providers armed with the most current information and resources represent the forefront in ensuring that the US adult population is adequately immunized.

REFERENCES

1. World Health Organization. Immunization surveillance, assessment, and monitoring (2010). www.who.int/immunization_monitor ing/en. Accessed May 12, 2011.

2. Fiore AE, Uyeki TM, Broder K, et al; Centers for Disease Control and Prevention. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep. 2010;59(RR-08);1-62.

3. Schaffner W. Update on vaccine-preventable diseases: are adults in your community adequately protected? J Fam Pract. 2008;57(4 suppl):S1-S11.

4. CDC. Healthy People 2010: Objectives for Improving Health. www.healthypeople.gov. Accessed May 6, 2011.

5. US Department of Health and Human Services. Developing Healthy People 2020: immunization and infectious diseases. www.healthy people.gov/2020. Accessed May 12, 2011.

6. Lu PJ, Nuorti JP. Pneumococcal polysaccharide vaccination among adults aged 65 years and older, United States, 1989-2008. Am J Prev Med. 2010;39(4):287-295.

7. National Institute of Allergy and Infectious Diseases, NIH. Community immunity (“herd” immunity) (2010). www.niaid.nih.gov/topics/pages/communityimmunity.aspx. Accessed May 12, 2011.

8. National Center for Immunization and Respiratory Diseases. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ADIP). MMWR Recomm Rep. 2011;60(2):1-64.

9. High KP. Overcoming barriers to adult immunization. J Am Osteopath Assoc. 2009;109(6): 525-528.

10. CDC; Atkinson W, Wolfe S, Hamborsky J, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases (Pink Book). 12th ed. Washington, DC: Public Health Foundation, 2011.

11. CDC. Vaccine-preventable diseases: improving vaccination coverage in children, adolescents, and adults: a report on recommendations from the Task Force on Community Preventive Services. MMWR Recomm Rep. 1999;48(RR-8):1-15.

12. CDC. Recommended adult immunization schedule: United States, 2011. MMWR Morb Mortal Wkly Rep. 2011;60(4):1-4.

13. Thompson RF. Travel & Routine Immunizations: A Practical Guide for the Medical Office. 19th ed. Milwaukee, WI: Shoreland, Inc: 2001.

14. American Academy of Pediatrics. Pertussis. In: Pickering LK, Backer, CJ, Long SS, McMillan J, eds. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics.

15. CDC. Immunization information systems (IIS). www.cdc.gov/vaccines/programs/iis/default.htm. Accessed May 12, 2011.

16. College of Physicians of Philadelphia. The history of vaccines: a project of the College of Physicians of Philadelphia (2011). www.history ofvaccines.org/content/articles/different-types-vaccines. Accessed May 12, 2011.

17. US Food and Drug Administration. Vaccines, blood, and biologics: December 18, 2009 Approval Letter—Zostavax. www.fda.gov/
BiologicsBloodVaccines/Vaccines/Approved Products/ucm195993.htm. Accessed May 12, 2011.

18. Merck & Co, Inc. Zostavax^® (zoster vaccine live; product insert). www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/Approved Products/UCM132831.pdf. Accessed May 12, 2011.

19. Merck & Co, Inc. Pneumovax^® 23 (pneumococcal vaccine, polyvalent, MSD; product information). www.merck.com/product/usa/pi_circulars/p/pneumovax_23/pneumovax_pi.pdf. Accessed May 16, 2011.

20. Macintyre CR, Egerton T, McCaughey M, et al. Concomitant administration of zoster and pneumococcal vaccines in adults ≥60 years old. Hum Vaccin. 2010;6(11):18-26.

21. CDC. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1–30.

22. Immunization Action Coalition. Vaccinate Adults. 2010 Aug;14(5). www.immunize.org/va. Accessed May 12, 2011.

23. CDC. Update: recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding use of CSL seasonal influenza vaccine (Afluria) in the United States during 2010–2011. MMWR Morb Mortal Wkly Rep. 2010;59(31);989-992.

24. CDC. Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR Morb Mortal Wkly Rep. 2010;59(RR-34):1102-1106.

25. Merck & Co, Inc. Varivax^® varicella virus vaccine live (product information). www.merck
.com/product/usa/pi_circulars/v/varivax/varivax_pi.pdf. Accessed May 12, 2011.

26. Merck & Co, Inc. Gardasil^® (human papillomavirus quadrivalent [types 6, 11, 16, and 18] vaccine, recombinant; product information). www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_ppi.pdf. Accessed May 12, 2011.

27. GlaxoSmithKline Biologicals. Cervarix (human papillomavirus bivalent [types 16 and 18] vaccine, recombinant; product information). http://us.gsk.com/products/assets/us_cervarix.pdf. Accessed May 12, 2011.

28. CDC. Syncope after vaccination—United States, January 2005-July 2007. MMWR Morb Mortal Wkly Rep. 2008;57(17):457-460.

29. Sanofi Pasteur. Meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria
toxoids conjugate vaccine Menactra^® for intramuscular injection. www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/Approved
Products/UCM131170.pdf. Accessed May 12, 2011.

30. Novartis Vaccines and Diagnostics, Inc. Menveo^® (meningococcal [groups A, C, Y and W-135] oligosaccharide diphtheria CRM₁₉₇ conjugate vaccine solution for intramuscular injection; prescribing information highlights). www .fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm201349.pdf. Accessed May 12, 2011.

31. GlaxoSmithKline Biologicals. Havrix (hepatitis A vaccine, suspension for intramuscular injection; prescribing information highlights). http://us.gsk.com/products/assets/us_havrix .pdf. Accessed May 12, 2011.

32. Merck & Co, Inc. Vaqta (hepatitis A vaccine, inactivated; suspension for intramuscular injection; highlighted prescribing information). www.merck.com/product/usa/pi_circulars/v/vaqta/vaqta_pi.pdf. Accessed May 12, 2011.

33. Merck & Co, Inc. Recombivax HB^® hepatitis B vaccine (recombinant; product information). www.merck.com/product/usa/pi_circulars/r/recombivax_hb/recombivax_pi.pdf. Accessed May 12, 2011.

34. GlaxoSmithKline Biologicals. Engerix-B^® (hepatitis B vaccine, recombinant; prescribing information). http://us.gsk.com/products/assets/us_engerixb.pdf. Accessed May 12, 2011.

35. CDC. Tetanus and pertussis vaccination coverage among adults aged ≥ 18 years—United States, 1999 and 2008. MMWR Morb Mortal Wkly Rep. 2010;59(40):1302-1306.

Reported incidence rates of certain vaccine-preventable diseases—measles, rubella, diphtheria, polio, and tetanus—are low in the United States.¹ However, as was demonstrated during the 2009-2010 flu season and the outbreak of H1N1 influenza,² we cannot afford to be complacent in our attitudes toward vaccines and vaccination. New virus strains exist and can become endemic quickly and ravenously. Furthermore, certain vaccine-preventable illnesses are frequently reported among adult patients, including hepatitis B, herpes zoster, human papillomavirus infection, influenza, pertussis, and pneumococcal infection.³

Vigilance regarding vaccination of children and adults was addressed by the CDC’s Office of Disease Prevention and Health Promotion in Healthy People 2010.⁴ These target objectives are proposed to be retained in Healthy People 2020,⁵ as the objectives from 2010 have not been met. The Healthy People 2010 target for administration of the pneumococcal vaccine in adults ages 65 and older, for example, is 90%. As of 2008, research has shown, only 60% of that population was immunized.⁶

There are subgroups of immunocompromised people who will probably never achieve adequate antibody levels to ensure immunity to vaccine-preventable diseases (for example, measles and influenza can be deadly to the immunocompromised person, as they can be to the very young and the very old). This is an important reason why vaccination of the healthy population is essential: the concept of herd immunity.⁷ Herd immunity (or community immunity) suggests that if most people around you are immune to an infection and do not become ill, then there is no one who can infect you—even if you are not immune to the infection.

WHY SOME ADULTS MIGHT NEED VACCINES

Adults who were vaccinated as children may incorrectly assume that they are protected from disease for life. In the case of some diseases, this may be true. However:

• Some adults were never vaccinated as children

• Newer vaccines have been developed since many adults were children

• Immunity can begin to fade over time

• As we age, we become more susceptible to serious disease caused by common infections (eg, influenza, pneumococcus).⁸

Barriers to Vaccination

Barriers to vaccination are varied, but none is insurmountable. Some of these barriers include^8-15:

Missed opportunities. Providers should address vaccination needs for both adults and children at each visit or encounter. According to the CDC, studies have shown that eliminating missed opportunities could increase vaccination coverage by as much as 20%.^8,11

Provider misconceptions regarding vaccine contraindications, schedules, and simultaneous vaccine administration. These misconceptions may prompt providers to forego an opportunity to vaccinate. Up-to-date information about vaccinations and ongoing provider education are imperative to improve immunity among both adults and children against vaccine-preventable disease.⁸ Numerous Web sites and publications are instrumental and essential in furnishing the health care provider with the most current information about vaccinations (see Table 1, above, and Table 2,^10,12-14).

A belief on patients’ part that they are fully vaccinated when they are not. It is important to provide a vaccination record and a return date at every vaccination encounter, even if just one vaccination has been administered on a given day. Participating in Immunization Information System,¹⁵ if one is available, is an efficient way to access computerized vaccine records easily at the point of contact.

Just as parents should be encouraged to bring their child’s vaccine record with them to every health care visit, adults are also called upon to maintain a record of all their vaccinations. Each entry in the immunization record should include:

• The type of vaccine and dose

• The site and route of administration

• The date that the vaccine was administered

• The date that the next dose is due

• The manufacturer and lot number

• The name, address, and title of the person who administered the vaccine.¹⁵

PRINCIPLES OF VACCINATION

There are two ways to acquire immunity: active and passive.

Active immunity is produced by the individual’s own immune system and usually represents a permanent immunity toward the antigen.^10,16

Passive immunity is produced when the individual receives products of immunity made by another animal or a human and transferred to the host. Passive immunity can be accomplished by injection of these products or through the placenta in infants. This type of immunity is not permanent and wanes over time—usually within weeks or months.^10,16

This article will concentrate on active immunity, acquired through the administration of vaccines.

CLASSIFICATION OF VACCINES

Vaccines are classified as either live, attenuated vaccine (viral or bacterial) or inactivated vaccine.

Live, attenuated vaccines are derived from “wild” or disease-causing viruses and bacteria. Through procedures conducted in the laboratory, these wild organisms are weakened or attenuated. The live, attenuated vaccine must grow and replicate in the vaccinated person in order to stimulate an immune response.  However, because the organism has been weakened, it usually does not cause disease or illness.^10,16 

The immune response to a live, attenuated vaccine is virtually identical to a response produced by natural infection. In rare instances, however, live, attenuated vaccines may cause severe or fatal reactions as a result of uncontrolled replication of the organism. This occurs only in individuals who are significantly immunocompromised.^10,16

Inactivated vaccines are produced by growing the viral or bacterial organism in a culture medium, then using heat and/or chemicals to inactivate the organism. Because inactivated vaccines are not alive, they cannot replicate, and therefore cannot cause disease, even in an immunodeficient patient. The immune response to an inactivated vaccine is mostly humoral (in contrast to the natural infection response of a live vaccine), and little or no cellular immunity is produced.^10,16

 Inactivated vaccines always require multiple doses, gradually building up a protective immune response. The antibody titers diminish over time, so some inactivated vaccines may require periodic doses to “boost” or increase the titers.¹⁶

Some vaccines, such as hepatitis B vaccine, lead to the development of immune memory, which stays intact for at least 20 years following immunization. Immune memory occurs during replication of B cells and T cells; some cells will become long-lived memory cells that will “remember” the pathogen and produce an immune response if the pathogen is detected again. In this case, boosters are not recommended.¹⁰

Toxoids are a type of vaccine made from the inactivated toxin of a bacterium—not the bacterium itself. Tetanus and diphtheria vaccines are examples of toxoid vaccines.^10,16

Subunit and conjugate vaccines are segments of the pathogen. A subunit vaccine can be created via genetic engineering. The end result is a recombinant vaccine that can stimulate cell memory (eg, hepatitis B vaccine).^10,16 Conjugate vaccines, which are similar to recombinant vaccines, are made by combining two different components to prompt a more powerful, combined immune response.¹⁰

Spacing of Live-Virus and Inactivated Vaccines

There are almost no spacing requirements between two or more inactivated vaccines⁸ (see Table 3^8,14 for spacing recommendations from the Advisory Committee on Immunization Practices [ACIP]). The only vaccines that must be spaced at least four weeks apart are live-virus vaccines—that is, if they are not given on the same day. Studies have shown that the immune response to a live-virus vaccine may be impaired if it is administered within 30 days of another live-virus vaccine. Inactivated vaccines, on the other hand, may usually be administered at any time after or before a live-virus vaccine.⁸

One exception to this statement is the administration of Zostavax (zoster live-virus vaccine) with Pneumovax 23 (inactivated pneumococcal vaccine, polyvalent, MSD).^17-19 The manufacturer of the two vaccines recommends a spacing of at least four weeks between them, based on research showing that concomitant use may result in reduced immunogenicity for Zostavax.²⁰ However, as of this writing, ACIP has not revised its statement that both vaccines can be given at the same time or at any time before or after each other.²¹

Live-virus vaccines currently licensed in the US provide protection against diseases including measles/mumps/rubella, varicella, zoster (ie, shingles), influenza, and yellow fever.

ADULT VACCINATION HIGHLIGHTS

A summary of 2011 recommendations for adult immunization from ACIP is shown in Table 4^12,21. The following information is specific to each of the vaccine-preventable illnesses of concern in adults.^12,13,22

Seasonal Influenza

The options to protect the adult patient against seasonal influenza are a trivalent, inactivated influenza vaccine (TIV; Fluzone, high-dose Fluzone for adults ages 65 and older, Fluvirin, Fluarix, FluLaval, Afluria, Agriflu) or a live, attenuated influenza vaccine (LAIV; FluMist).^2,23 Dosage of TIV for adults is 0.5 mL IM in the deltoid once annually. For adults ages 49 and younger, LAIV is administered at 0.2 mL intranasally, once per year.

ACIP now recommends universal influenza vaccination for all persons ages 6 months and older with no contraindications.^2,8 Strong consideration should be given to concurrent administration of influenza vaccine and pneumococcal vaccine to high-risk persons not previously vaccinated against pneumococcal disease.¹²

Note: When influenza and pneumococcal vaccines are given at the same time, they should be administered in opposite arms to reduce the risk of adverse reactions or a decreased antibody response to either vaccine.^18,19

Pneumococcal Polysaccharide (PPSV)

Pneumovax 23¹⁹ is administered as a 0.5-mL dose IM in the deltoid or subcutaneously in the upper arm. The vaccine is recommended for^8,19,24:

• Adults ages 65 and older who have not been previously vaccinated

• Adults now 65 and older who received PPSV vaccine at least five years ago and were younger than 65 at that time

• Adults ages 19 through 64 years who have asthma or who smoke²⁴

• Any adult with the following underlying medical conditions: chronic heart or lung disease, diabetes mellitus, cerebrospinal fluid leaks, cochlear implants, chronic liver disease, cirrhosis, chronic alcoholism, functional or anatomic asplenia, and immunocompromising conditions (HIV infection, diseases that require immunosuppressive therapy, chemotherapy, or radiation therapy; congenital immunodeficiency).²⁴

A one-time revaccination is recommended after five years for persons ages 19 to 64 who have chronic renal failure, nephrotic syndrome, or functional or anatomic asplenia, and for those who are immunocompromised.²⁴

Note: According to the manufacturer of Zostavax¹⁸ and Pneumovax,^23,19 these vaccines should not be given at the same time, as research has shown that Zostavax immunogenicity is reduced as a result.^18-20

Zoster

For adults ages 60 and older, Zostavax¹⁸ is administered in a single 0.65-mL dose, subcutaneously in the upper arm. Providers are not required to ask about varicella vaccination history or history of varicella disease before administering the vaccine. Adults ages 60 and older who have previously had shingles can still be vaccinated during a routine health care visit.^10,21,22

Immunization is contraindicated in adults with a previous anaphylactic reaction to neomycin or gelatin, although a nonanaphylactic reaction to neomycin (most commonly, contact dermatitis) is not considered a contraindication.⁸

Any adult patient who has close household or occupational contact with persons at risk for severe varicella (eg, infants) need not take precautions after receiving the zoster vaccine, except in the rare case in which a varicella-like rash develops.^10,21,22

Note: Review the note appearing in “Pneumococcal Polysaccharide (PPSV),” above, regarding coadministration of Zostavax and Pneumovax 23.^18-20

Varicella

Adults who were born in the US before 1980 are considered immune to varicella and don’t need to be vaccinated, with the exception of health care workers, pregnant women, and immunocompromised persons. Nonimmune healthy adults who have not previously undergone vaccination should receive two 0.5-mL doses of Varivax, administered subcutaneously, four to eight weeks apart.²⁵

Immunization is contraindicated in adults with a previous anaphylactic reaction to neomycin or gelatin, although a nonanaphylactic reaction to neomycin (eg, contact dermatitis) is not considered a contraindication.⁸

Measles, Mumps, Rubella (MMR)

The MMR vaccine is administered at 0.5 mL, given subcutaneously in the posterolateral fat of the upper arm.⁸

MMR-susceptible adults who were born during or since 1957 and are not at increased risk (see below) need only one dose of the MMR vaccine; those considered at increased risk need two doses, and a second dose can also be considered during an outbreak. Adults who require two doses should wait at least four weeks between the first and second doses.¹²

The following factors place adults at increased risk for MMR:

• Anticipated international travel

• Being a student in a post–secondary educational setting

• Working in a health care facility

• Recent exposure to measles, or an outbreak of measles or mumps

• Previous vaccination with killed measles vaccine

• Previous vaccination with an unknown measles vaccine between 1963 and 1967.

Also at risk are health care workers born before 1957 who have no evidence of immunity, and women who plan to become pregnant and have no evidence of immunity.^8,12

Tetanus, Diphtheria, Pertussis

Options for adults include a vaccine against tetanus and diphtheria (Td; Decavac); or a vaccine that protects against tetanus, diphtheria, and acellular pertussis (Tdap; Adacel, Boostrix). Adults who have not been previously vaccinated should receive one dose of Tdap and two doses of Td (the first, one month after Tdap; the second at six to 12 months after the Tdap). Each is administered as a 0.5-mL dose IM in the deltoid. A booster dose is recommended every 10 years but can be given earlier in patients who sustain wounds or who anticipate international travel.^8,12

Adults ages 19 through 64 should receive a single dose of Tdap in place of a booster dose if the last Td dose was administered at least 10 years earlier and the patient has not previously received Tdap. Additionally, a dose of Tdap (if not previously given) is recommended for postpartum women, close contacts of infants younger than 12 months, and all health care workers with direct patient contact. An interval as short as two years from the last Td is suggested; shorter intervals may be appropriate.^8,12

According to the new 2011 recommendations, persons ages 65 and older who have close contact with an infant younger than 12 months should be vaccinated with Tdap, and any person age 65 or older may be vaccinated with Tdap. Also added is a recommendation to administer Tdap, regardless of the interval since the patient received his or her most recent Td-containing vaccine.^8,12

Human Papillomavirus (HPV)

Gardasil²⁶ protects both female and male patients against HPV infection; Cervarix²⁷ is indicated only for female patients. Either quadrivalent vaccine or bivalent vaccine is recommended for female patients.¹²

In women ages 26 and younger, Gardasil (0.5 mL IM, administered in the deltoid at 0 month, 2 months, and 6 months) provides protection against diseases caused by HPV types 6, 11, 16, and 18 (including cervical, vaginal, and vulvar cancer caused by HPV types 16 and 18). In men ages 26 and younger, Gardasil provides protection against genital warts caused by HPV types 6 and 11.²⁶

Cervarix,²⁷ administered at 0 month, 1 month, and 6 months (0.5 mL IM in the deltoid), provides protection for women ages 25 and younger against cervical cancer and precancerous lesions caused by HPV types 16 and 18.

Caution: Patients should be advised to sit or lie down when the HPV vaccine is administered, and they should be observed for the subsequent 15 minutes. Syncope can occur after vaccination—most commonly among adolescents and young adults.²⁸ Convulsive syncope has been reported.

Meningococcal Disease

Two vaccines are available to protect against meningococcal disease: Menactra²⁹ (meningococcal groups A, C, Y, and W-135 polysaccharide diphtheria toxoids conjugate vaccine); and Menveo³⁰ (meningococcal groups A, C, Y, and W-135 oligosaccharide diphtheria CRM₁₉₇ conjugate vaccine). Both are administered in the deltoid, 0.5 mL IM.

The following patients should be considered for vaccination:

• College freshmen living in dormitories, as well as college students with immune deficiencies, as they are at higher risk for meningococcal disease

• Patients who travel to or reside in countries in which Neisseria meningitidis is epidemic (particularly those with the potential for prolonged contact with the local population)

• Travelers to Saudi Arabia for pilgrimage to Mecca (the Hajj)

• Patients with anatomical or functional asplenia (two-dose series).

A two-dose series of meningococcal conjugate vaccine is also recommended for adults with persistent complement component deficiencies, and for those with HIV infection who are vaccinated.¹²

Hepatitis A

Two hepatitis A vaccines (both inactivated) can be used interchangeably: Havrix³¹ and Vaqta.³² Dosing for both vaccines in 18-year-old patients is 0.5 mL IM in the deltoid at 0 months, then at 6 to 12 months. In patients ages 19 and older, administration is the same, with the exception of increased dosing (1.0 mL IM).

Vaccination against hepatitis A is recommended for men who have sex with men, and for all adult patients who¹²:

• Travel to or work in areas where risk for hepatitis A transmission is high (especially those who take frequent trips or experience prolonged stays)

• Use injection drugs

• Have chronic liver disease

• Receive clotting factor concentrates for treatment of a blood-clotting disorder

• May have been exposed to hepatitis A in the previous two weeks

• Wish to be vaccinated against hepatitis A to avoid future infection.

Hepatitis B

Recombivax HB³³ and Engerix-B³⁴ are the two vaccines available to protect patients against hepatitis B (HBV), and they can be used interchangeably.¹² In patients from birth through age 19, Recombivax HB³³ or Engerix-B³⁴ is given as 0.5 mL IM in the deltoid at 0, 1, and 6 months; patients ages 20 and older receive an increased dose (1.0 mL IM), with administration otherwise the same. According to the manufacturer of Recombivax HB,³³ patients age 11 through 15 may be given either three doses of 0.5 mL or two doses of 1.0 mL.

The following adults are advised to undergo vaccination for HBV:

• At-risk, unvaccinated adults

• Those requesting protection against HBV infection

• Those planning to travel to areas where HBV is common

• Household contacts of a patient with chronic HBV infection, and sexual partners of a patient with HBV infection

• Adults with chronic liver disease

• Men who have sex with men

• Sexually active adults who are not in a long-term, mutually monogamous relationship

• Adults who are being evaluated or treated for a sexually transmitted disease, including HIV infection

• Health care or public safety workers who may be exposed to blood or blood-contaminated body fluids

• Workers and residents in facilities for developmentally disabled persons

• Patients undergoing or anticipating dialysis

• Adults who inject illegal drugs or who have done so recently.¹²

CONTRAINDICATIONS AND PRECAUTIONS FOR VACCINES COMMONLY USED IN ADULTS

See Table 5,^8,22 for a summary of contraindications and precautions from ACIP and the Immunization Action Coalition that are associated with vaccinations mentioned in this article. A more complete summary can be found at www.im munize.org/catg.d/p3072a.pdf.

Conclusion

The adult patient’s vaccination status should be addressed at each health care encounter, and current recommendations should be followed. The duration of efficacy for vaccines is not an exact science. Many vaccines licensed in the US are relatively new, and recommendations for boosters for some of these vaccines will be forthcoming as more data are gathered. For example, the recommendation that a booster dose of Tdap be given to adults resulted from the recent increase in reported pertussis cases.³⁵

Providers armed with the most current information and resources represent the forefront in ensuring that the US adult population is adequately immunized.

REFERENCES

1. World Health Organization. Immunization surveillance, assessment, and monitoring (2010). www.who.int/immunization_monitor ing/en. Accessed May 12, 2011.

2. Fiore AE, Uyeki TM, Broder K, et al; Centers for Disease Control and Prevention. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep. 2010;59(RR-08);1-62.

3. Schaffner W. Update on vaccine-preventable diseases: are adults in your community adequately protected? J Fam Pract. 2008;57(4 suppl):S1-S11.

4. CDC. Healthy People 2010: Objectives for Improving Health. www.healthypeople.gov. Accessed May 6, 2011.

5. US Department of Health and Human Services. Developing Healthy People 2020: immunization and infectious diseases. www.healthy people.gov/2020. Accessed May 12, 2011.

6. Lu PJ, Nuorti JP. Pneumococcal polysaccharide vaccination among adults aged 65 years and older, United States, 1989-2008. Am J Prev Med. 2010;39(4):287-295.

7. National Institute of Allergy and Infectious Diseases, NIH. Community immunity (“herd” immunity) (2010). www.niaid.nih.gov/topics/pages/communityimmunity.aspx. Accessed May 12, 2011.

8. National Center for Immunization and Respiratory Diseases. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ADIP). MMWR Recomm Rep. 2011;60(2):1-64.

9. High KP. Overcoming barriers to adult immunization. J Am Osteopath Assoc. 2009;109(6): 525-528.

10. CDC; Atkinson W, Wolfe S, Hamborsky J, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases (Pink Book). 12th ed. Washington, DC: Public Health Foundation, 2011.

11. CDC. Vaccine-preventable diseases: improving vaccination coverage in children, adolescents, and adults: a report on recommendations from the Task Force on Community Preventive Services. MMWR Recomm Rep. 1999;48(RR-8):1-15.

12. CDC. Recommended adult immunization schedule: United States, 2011. MMWR Morb Mortal Wkly Rep. 2011;60(4):1-4.

13. Thompson RF. Travel & Routine Immunizations: A Practical Guide for the Medical Office. 19th ed. Milwaukee, WI: Shoreland, Inc: 2001.

14. American Academy of Pediatrics. Pertussis. In: Pickering LK, Backer, CJ, Long SS, McMillan J, eds. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics.

15. CDC. Immunization information systems (IIS). www.cdc.gov/vaccines/programs/iis/default.htm. Accessed May 12, 2011.

16. College of Physicians of Philadelphia. The history of vaccines: a project of the College of Physicians of Philadelphia (2011). www.history ofvaccines.org/content/articles/different-types-vaccines. Accessed May 12, 2011.

17. US Food and Drug Administration. Vaccines, blood, and biologics: December 18, 2009 Approval Letter—Zostavax. www.fda.gov/
BiologicsBloodVaccines/Vaccines/Approved Products/ucm195993.htm. Accessed May 12, 2011.

18. Merck & Co, Inc. Zostavax^® (zoster vaccine live; product insert). www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/Approved Products/UCM132831.pdf. Accessed May 12, 2011.

19. Merck & Co, Inc. Pneumovax^® 23 (pneumococcal vaccine, polyvalent, MSD; product information). www.merck.com/product/usa/pi_circulars/p/pneumovax_23/pneumovax_pi.pdf. Accessed May 16, 2011.

20. Macintyre CR, Egerton T, McCaughey M, et al. Concomitant administration of zoster and pneumococcal vaccines in adults ≥60 years old. Hum Vaccin. 2010;6(11):18-26.

21. CDC. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1–30.

22. Immunization Action Coalition. Vaccinate Adults. 2010 Aug;14(5). www.immunize.org/va. Accessed May 12, 2011.

23. CDC. Update: recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding use of CSL seasonal influenza vaccine (Afluria) in the United States during 2010–2011. MMWR Morb Mortal Wkly Rep. 2010;59(31);989-992.

24. CDC. Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR Morb Mortal Wkly Rep. 2010;59(RR-34):1102-1106.

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