Travel Vaccines and Elderly Persons: Review of Vaccines Available in ...

INVITED ARTICLE

TRAVEL MEDICINE

Charles D. Ericsson and Robert Steffen, Section Editors

Travel Vaccines and Elderly Persons: Review of Vaccines Available in the United States Karin Leder,1,3 Peter F. Weller,1–3 and Mary E. Wilson3–5 Divisions of 1Infectious Diseases and 2Allergy and Inflammation, Beth Israel Deaconess Medical Center, 3Department of Medicine, Harvard Medical School, and 4Division of Population and International Health, Harvard School of Public Health, Boston; and 5Travel Resource Center, Mount Auburn Hospital, Cambridge, Massachusetts

Aging is associated with alterations in immune responses and may lead to clinically significant changes in the safety, immunogenicity, and protective efficacy of certain vaccines. This review summarizes published data regarding the effects of age on responses after immunization with vaccines generally administered before travel. The specific vaccines discussed in detail include hepatitis A, typhoid, yellow fever, Japanese encephalitis, and rabies vaccines. There is some evidence of diminished serological responses to hepatitis A and rabies vaccines in older individuals. In addition, increased toxic effects following yellow fever vaccination in elderly recipients have recently been reported. However, many travel-related vaccines have never been studied specifically in elderly populations. Consideration of potential age-related differences in responses to travel vaccines is becoming increasingly important as elderly persons more frequently venture to exotic destinations. As the number of elderly persons worldwide increases, it becomes increasingly important to understand the health implications of aging. Elderly persons have an increased susceptibility to cancer, autoimmune diseases, and infectious diseases, but the relative importance of increased age in isolation from the effects of other comorbidities remains debated. There is now evidence of a remodeling of the immune system, even in healthy elderly individuals [1], resulting in changes involving humoral, cellular, and innate immunity. Frequently, the net effect observed is a decrease in the quantity and quality of immune responses in older individuals [2, 3]. This review summarizes what is known about responses that follow immunization of elderly individuals with vaccines currently available in the United States, a topic that is becoming increasingly relevant as the number of aged people traveling to exotic destinations increases. It has been estimated that 13%–15% of travelers are 165 years of age [4–6]. In one study of 1416 travelers who attended a pretravel clinic in the United States, 48% were ⭓50 years of age, one-third were 160 years

Received 27 December 2000; revised 4 May 2001; electronically published 4 October 2001. Reprints or correspondence: Dr. Karin Leder, Infectious Disease Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Dana-617, Boston, MA 02215 (kleder @hotmail.com). Clinical Infectious Diseases 2001; 33:1553–66 2001 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2001/3309-0018$03.00

of age, and almost 1.5% were 180 years of age [7]. Elderly persons are more vulnerable to acquisition of certain infections as well as to severe outcomes. In addition, they may not develop the same degree of immunoprotection as that which occurs in younger individuals after vaccination. General immunization guidelines for travel vaccines have been developed primarily from studying responses in young volunteers. We review published information regarding the use of pretravel vaccines in older individuals, concentrating on data for individuals 160 years old but also reviewing results for those 40–60 years of age, and we highlight areas that have not yet been studied. It is possible that many aspects of immune response are affected by age, including the quality and magnitude of antibody and cellular responses, the duration of protection, the timing of seroresponses, and the adverse events that occur after vaccination (tables 1–6). HEPATITIS A VACCINE Travelers to developing countries have a risk of hepatitis A infection estimated to be 3–20 cases per 1000 persons per month of stay, varying with destination and with living conditions while abroad [8, 9]. Although clinical illness is usually mild in the young, the risk of severe infection increases with increasing age, and mortality rates are ∼2% for patients 140 years of age [8]. Consequently, hepatitis A vaccine is recomTRAVEL MEDICINE • CID 2001:33 (1 November) • 1553

Table 1.

Data concerning age-related effects on immune response to hepatitis A vaccine.

Response characteristic

Time after first vaccine dose

Age, years

15 days

20–39

“Young” patients Seroconversion, %, or GMT, mIU/mL

“Middle-aged” patients Age, years

Seroconversion, %, or GMT, mIU/mL

“Old” patients

Hepatitis A vaccine, a dose (dose schedule)

Reference(s)

Seroconversion NS

Havrix, 1440 EU (0, 6 months)

[18]

NS

Vaqta, 25U (0, 24 weeks)

[21]

NS

Vaqta, 25 U (1 dose)

[22]

84%

NSS

Havrix, 720 EU (0, 1, 12 months)

[19]

60%

NS

Havrix, 720 EU (0, 2 weeks, intragluteal)

[20]

262

NS

Havrix, 1440 EU (0, 6 b months)

[18]

NS Vaqta, 25U (0, 24 c weeks)

[21]

Havrix, 720 EU (0, 1, 2 b months)

[23]

NS

Vaqta, 25U (0, 2, 6 or c 0, 6 months)

[24]

97% 94%

88%

7 months

100%

100%

18–39

60%

4 weeks

91%

24 weeks

100%

52 weeks

95%–100%

97%

40–65

23% 70% 83% 95%–100%

2–9

99%

40–49

81%

10–19

94%

50–79

75%

20–29

90%

30–39

89%

1 month

18–39

94%

8 months

17–34

85%

15 days

20–39

282

⭓40 35–52 40–62

1 month

589

357

7 months

3629

2320

2 weeks

18–39

4 weeks

40–65

6.1

836

585 18–40

223

287 140

233

2 months

518

277

3 months

1743

826

1 month

NS

14.3

2032

52 weeks 1 month

12.9 29

28 weeks

21

7 months

17–40

4232

40–60

1991

NS

Havrix, 720 EU (0, 1, 6 b months)

[25]

8 months

17–34

117

35–52

97

NS

Havrix, 720 EU (0, 2 weeks, intragluteal; 8 b months, in deltoid)

[20]

Havrix, 720 EU (0, 1, b 12 months)

[19]

NS

Havrix, 1440 EU

[17]

951

11 months 1 month

31–57

NSS

18–30

12 months

21

508

508

1252 18–39

224

769 ⭓40

132

2 months

420

299

13 months

5115

3197

20 years

20–39

d

99%

NSS

d

40–62

94%

d

30 years Protective efficacy

77%

6 months

4 weeks

Antibody persistence

40–62

1 month

15 days

GMT

90%

d

77%

58%

!16

94%–100%

NS

NS

Vaqta, 25U (1 dose)

[14]

!16

94%–100%

NS

NS

Havrix, 360 EU (2 doses)

[15]

NOTE. Seroconversion was defined as antibody levels of ⭓10–20 IU/mL. “Young” patients tended to be !40 years of age, “middle-aged” patients tended to be 40–60 years of age, and “old” patients tended to be 160 years of age. EU, enzyme units; GMT, geometric mean titer; NS, not studied; NSS, not specifically studied (there was no age breakdown). a b c d

Manufacturers: Havrix, GlaxoSmithKline Pharmaceuticals; Vaqta, Merck & Co. Levels determined by means of ELISA. Levels determined by means of RIA. Projected estimate of seroprotection.

1554

1555

Postvaccination Prevaccination Postvaccination

Nepalese Prevaccination Postvaccination

Before

French/US students

14–44

5–14

18–40

US nonimmune

1 week 1 month

5–14 14–44

Not stated

Age, years

Nepalese

French/US students


0.38 f 3.68

2.25 0.24 1.89e

d

0.06

60% 93%

76.9% 79%b

b

95.5%b

Seroconversion, %, or GMT, mg/mL

Nepalese

US students South African children

3 years 21 months 3 years 17 months 5–44

21–32 6–14

90% 64% 55% 75%

45–55

45–55

NS

NS

NS

NS

NS NS

NS

NS

NS NS

NS

NS

NS

NSS

4.44e

0.51

NS

NS

NSS

NSS

25 mg

25 mg 25 mg

25 mg

25 mg

25 mg

25 mg

25 mg

25 mg

[41]

[39, 108] [35, 40]

[35, 107]

[34]

[106]

a

[41]

[34]

[41]a

Dose of typhoid Vi Age, Seroconversion, %, “Old” polysaccharide years or GMT, mg/mL patients vaccine Reference(s) “Middle-aged”

g

f

e

d

c

b

a

Different responses seen in subjects from the United States and France (areas of nonendemicity) when compared with subjects from Nepal (area of endemicity). Timing not stated. Determined by use of radioimmunoassay. A 38-fold increase. A 8-fold increase. A 10-fold increase. Ongoing exposure complicates interpretation.

NOTE. Seroconversion was defined as a ⭓4-fold increase in titer. Seroresponse has not been proven to protect against infection. Only volunteer studies of immunogenicity involving small numbers of subjects have been performed in countries of nonendemicity. “Young” patients tended to be !40 years of age, “middle-aged” patients tended to be 40–60 years of age, and “old” patients tended to be 160 years of age. GMT, geometric mean titer; NS, not studied; NSS, not specifically studied (no age breakdown); US, United States.

Protective efficacy

Nonimmune Europeans Prevaccination Mean, 23.5 0.24 Postvaccination 3.41 Antibody persistence US Prevaccination 18–40 0.2 1 month 3.2; 93% were seroprotected 11 months 2.0; 64% were seroprotected 27 months 1.1; 38% were seroprotected South African children 3 years 64% seroprotected 10–11 years 58% seroprotectedg

GMTc

Seroconversion

Study population

“Young”

Data concerning age-related effects on immune response to typhoid Vi polysaccharide vaccine.


Table 2.

Table 3.

Data concerning age-related effects on immune response to oral typhoid vaccine.

“Young” patients

“Middle-aged” and “old” patients

Seroconversion in 69% of Thai children, 2–6 years

NS

3 doses of liquid suspensiona

Seroconversion in 64% of Chilean schoolchildren

NS

3 doses, entericcoated capsulea

Seroconversion in 62% of European volunteers aged 16–56 years (no age breakdown)

NS

3 doses of liquid formulationa

For Chilean schoolchildren, efficacy rates 3 years after vaccination were as follows: for those aged 5–9 years, 59%; 10–14 years, 67%; and ⭓15 years, 85%. Overall efficacy rate at followup of 7 years was 62%.

NS

3 doses of entericcoated capsule

For Chilean schoolchildren, efficacy rates 2 years after vaccination were 29% after 1 dose and 59% after 2 doses; 3-5 years after vaccination, it was not effective

NS

1 or 2 doses of enteric-coated capsule

[111]

For Chileans of 5–19 years of age, superior efficacy of liquid suspension (76.9%) at 3 years vs. capsules (33.2%); the liquid suspension had 79% efficacy at 5 years

NS

3 doses of liquid suspension or entericcoated capsules

[113, 114]

For Indonesians of 3–44 years of age, superior efficacy of liquid suspension (53%) vs. capsules (42%) at 30 months

NS

3 doses of liquid suspension or entericcoated capsules

[115]

For children in Egypt, 96% efficacy at 3 years

NS

93 doses of liquid formulation

[116]


Ty21a vaccine

Reference(s)

Seroconversion

Protective efficacy and persistence

[109] [37, 110, 111] [112] [110, 113]

NOTE, Only volunteer studies of immunogenicity that have involved small numbers of subjects have been performed in countries of nonendemicity. No efficacy trials have been performed in countries of nonendemicity. Mucosal IgA response may be the best marker of immunity. Serum IgG antibodies to Salmonella typhi O antigen have been shown to correlate with seroprotection, but they have not been proven to protect against infection. Serum IgA levels against both O and H antigens also increase after vaccination, but correlation with mucosal IgA and its significance for clinical immunity remain unclear [117]. Seroconversion was defined as an increase in OD of ⭓0.15 units in serum levels of IgG against S. typhi LPS or O antigen. “Young” patients tended to be !40 years of age, “middle-aged” patients tended to be 40–60 years of age, and “old” patients tended to be 160 years of age. LPS, lipopolysaccharide; NS, not studied; OD, optical density (OD units). a

Determined by means of ELISA.

mended for nonimmune elderly travelers, despite a paucity of data regarding protective efficacy of the vaccine in this population. The currently licensed hepatitis A vaccines in the United States are Havrix (GlaxoSmithKline) and Vaqta (Merck & Co.). Both have equivalent high immunogenicity and excellent safety profiles [10]. Cell-mediated reactions may play a minor role in the immune response to hepatitis A infection, but antibody alone is sufficient to protect against clinical disease, as has been clearly demonstrated by the excellent protection provided by passive immunization with Ig [11, 12]. Thus, measurement of serum antibody levels is useful for monitoring vaccination response, and a minimum level of 10 mIU/mL or 20 mIU/mL is generally considered necessary for protection [13]. Among young persons, seroconversion is seen in 80%–90% within 2 weeks of the first dose, and 95%–100% of vaccinees have had seroconversion by 4 weeks [13]. In large efficacy studies that involved children (1 study in Thailand and 1 study 1556 • CID 2001:33 (1 November) • TRAVEL MEDICINE

in the United States), protective efficacy against clinical disease was 95% and 100%, respectively [14, 15]. It has been projected that protective antibody levels will persist for 125 years after vaccination [16, 17]. Vaccination of elderly persons. A number of studies have looked at age-related effects on the immune response to hepatitis A vaccine (table 1). Some studies used the 2-dose vaccine regimen currently recommended for adults in the United States (Havrix [1440 enzyme units (EU)], or Vaqta [50 units/mL], at 0 and 6–12 months), but earlier studies used a half-dose, 3inoculation schedule that was recommended previously. In one study, Havrix (1440 EU) administered at 0 and 6 months to seronegative people aged 20–39 years or 40–62 years led to lower seropositivity rates at day 15 in the older group (90% vs. 77%; P ! .05) [18]. At 1 month after both the initial vaccination and after the booster, 97% and 100%, respectively, of the groups were seropositive. Similar results have been found in other studies: one showed that 94% of adults !40 years old

Table 4.

Data concerning age-related effects on immune response to yellow fever vaccine.



“Middle-aged” patients

“Old” patients

Yellow fever a vaccine Reference

Seroconversion Neutralizing antibody titer of ⭓1:10b

In volunteers from the UK aged 18–65 years (mean, 32 years), 87% had seroconversion by days 10–14, and 100% had seroconversion by day 28

NSS

NS

Stamaril

[51]

Plaque reduction of 180% with an initial serum dilution of 1:4c

In volunteers from the US aged 18–60 years (mean, 31.1 years), 56% had seroconversion by day 10, 92%, by day 35; and 100%, by month 7

NSS

NS

Stamaril

[118]

Titers 11:0.5%d

In European volunteers aged 18–39 years, 90% had seroconversion by day 14 and 96% had it by day 28

NS

NS

Stamaril

[57]

GMT, IU/mL

In volunteers from the UK aged 18–69 years (mean, 32 years), by days 10–14, the GMT was 26.0, and by day 28, it was 124

NSS

NS

Stamaril

[51]


In war veterans from the US, there was persistence of protective antibodies after 130 years in 78.4% of vaccinees

NSS

NS

Variable

[56]

Side effects

Encephalitis in children of !9 months of age

Patients aged 65–74 years were 5.8 times more likely to have serious adverse effects than were younger patients; patients aged ⭓75 years were 18 times more likely

Stamaril

[61]

NOTE. No prospective efficacy trial has been done, so direct correlation of seroresponse with protection from infection is not possible. “Young” patients tended to be !40 years of age, “middle-aged” patients tended to be 40–60 years of age, and “old” patients tended to be 160 years of age. GMT, geometric mean titer; NS, not studied; NSS, not specifically studied (no age breakdown); UK, United Kingdom; US, United States. a b c d

Stamaril is manufactured by Aventis Pasteur (Swiftwater, PA). Determined by means of plaque reduction neutralization testing. Determined by means of a serum dilution–plaque reduction test. Measured by testing neutralizing antibodies on mouse brains.

had seroconversion 1 month after a single dose of Havrix (720 EU), compared with 84% of adults 140 years old (P p.08) [19], and a second study showed that 8 months after 2 doses of Havrix (720 EU), seroconversion rates were 85% and 60% for adults ⭐35 years and 135 years, respectively (P ! .05 ) [20]. The same trend has also been seen after immunization with Vaqta (25 U): one study showed healthy adults aged 18–39 and 40–65 years had seroconversion at 2 weeks at rates of 60% and 23% (P ! .017), respectively, and at 4 weeks at rates of 91% and 70% (P p .044) [21]. Another study that used varying Vaqta doses also showed that the 4-week seroconversion rate after immunization decreased progressively by age for each decade, with 99% seroconversion among 2–9-year-olds and 75% among 50–79-year-olds [22]. In addition to lower seroconversion rates, many studies have shown that titers of antibody to hepatitis A virus achieved after

vaccination are inversely proportional to age, as shown in table 1 [18–21, 23–29]. None of these studies noted more severe adverse reactions to vaccination in the older groups. Overall, 2 conclusions can be drawn. First, the antibody response tends to be slower in older people, and this may have implications on the timing of pretravel vaccination. The Centers for Disease Control and Prevention (CDC) currently recommends that the vaccine be given 4 weeks before travel; however, in clinical practice it is often administered ⭐2 weeks prior to departure. Second, significantly lower peak titers are reached after vaccination in elderly recipients. The distribution of responses appears to be unimodal, because most older individuals have a relatively low response when compared with younger populations, but there is no evidence of completely unresponsive subpopulations (table 1) [16, 30]. The clinical significance of this is unclear, because titers still exceed those required for TRAVEL MEDICINE • CID 2001:33 (1 November) • 1557

1558 NS

NS

For Thai children aged 1–14 years (area of endemicity), the protective efficacy rate was 91% For children in China (mean age, 4.7 years), the protective efficacy rate was 80% after 1 dose and 97.5% after 2 doses

NS

NS

NS

NS

NS

NS

NS

NS

Of Japanese adults aged ⭓60 years (area of nonendemicity), 35% had ⭓2fold increase in titer at 4 weeks

NS

NS

“Old” patients

Live-attenuated vaccine, 1 or 2 doses

Inactivated vaccine, 2 doses


Bikenc

[65]

[83]

[82]

[76]

[79, 120]

[80]

Biken,c 3 doses (days 0, 1, and 30) Bikenc vaccine, 3 doses (weeks 0 and 1 and month 4)

[75]

[119]

[84]

[80]

[76]

Reference(s)



Experimental inactivated vaccine, 1 dose

Biken,c 3 doses

Biken

c

Japanese encephalitis vaccinea

c

b

a

It is unclear how well antibody levels correlate with immunity from infection. Determined by means of plaque reduction neutralization testing. Biken is distributed by Aventis-Pasteur.

NOTE. “Young” patients tended to be !40 years of age, “middle-aged” patients tended to be 40–60 years of age, and “old” patients tended to be 160 years of age. GMT, geometric mean titer; NS, not studied; NSS, not specifically studied (no age breakdown); US, United States.

NS

For children in Taiwan, the protective efficacy rate at 1 year was 80%

NSS

Of adults in the US (age not stated), 37% had protective antibodies 6–12 months after 2 doses

Protective efficacy

NS

Of US soldiers (age not stated), 85% had antibody persistence at 8 weeks, 33% had it at 4 months, 100% had it at 5 months, and 94% had it at 3 years


NS

NS

Of Asian children aged ⭓5 years (area of endemicity), 97%–99% had seroconversion after 2 doses Of US soldiers (mean age, 23 years), the GMT at month 2 was 4074; at month 6, it was 1230

NS

Of infants aged 12 months who were likely nonimmune, 67% had seroconversion at 3 months

GMT, IU/mL

NS

Of Japanese high school students aged 12–13 years (area of nonendemicity), 20.4% had a ⭓2-fold increase in titer at 4 weeks

Neutralizing antibody titers ⭓1:10b

NS

NSS

Of adults from the US (age not stated), 77% developed titers ⭓1:8 after 2 doses; after 3 doses, the rate was 99%b


Variable definitions in For US soldiers (mean age, 23 years), different laboratories the rate was 100% at 2 months

Seroconversion


Data concerning age-related effects on immune response to Japanese encephalitis vaccine.


Table 5.

1559

1–20 21–40

28.65 24.02

Following PDEV and HDCV, the GMTs were 13.6 and 13.7, respectively

11–25 Following PDEV and HDCV, the GMTs were 7.4 and 7.7, respectively

100%

20%–40% 95%–100% 96%–100%

Seroconversion, %, or GMT, IU/mL


2–3 years 185% of recipients are seroprotected; if a booster dose is given at 12 months, seroprotection may last 110 years No randomized trials have been performed, but the protective efficacy rates are estimated to be close to 100% after receipt of cell vaccines, if guidelines are followed; the efficacy rates after receipt of nerve tissue vaccines are lower (estimated to be 80%–85%)

18 days

90 days

30 days

11–25

!40

Age, years

100%

NS

Seroconversion, %, or GMT, IU/mL


NS

NS

“Old” patients

NS

NS

NS

NS

Following PDEV and HDCV, NS the GMTs were 4.8 and 5.1, respectively, which was 52% lower than the levels for the younger group The GMTs were 9.8 and 10.0, respectively, which was 37% lower than the levels for the younger group 41–60 19.51 For patients aged 160 years, the GMT was 8.9 IU/mL

150

150

Age, years

2 or 3 doses

HDCV, 2-dose postexposure doses (days 0 and 3)

PDEV and HDCV, 6-dose postexposure schedule (days 0, 3, 7, 14, 30, and 90)

PDEV and HDCV, 6-dose postexposure schedule (days 0, 3, 7, 14, 30, and 90)

Cell culture vaccines; 1, 2, or 3 doses administered IM/ID (multiple different preexposure schedules)

Rabies vaccine (dose schedule)

[89, 121]

[100, 102]

[94]

[93]

[93]

[96–98, 101, 103]

Reference(s)

a

Determined by means of indirect fluorescent antibody test.

NOTE. Antibody levels seems to correlate well with protective immunity. “Young” patients tended to be !40 years of age, “middle-aged” patients tended to be 40–60 years of age, and “old” patients tended to be 160 years of age. GMT, geometric mean titer; HDCV, human dipthoid cell vaccine; IM/ID, intramuscularly/intradermally; NS, not studied; PDEV, purified duck embryo vaccine.

Protective efficacy


GMT

30 days

Seroconversion 7 days 14 days 28 days


Data concerning age-related effects on immune response to rabies vaccine.


Table 6.

seroprotection. Whether it translates into a shorter duration of immunoprotection is unknown. In addition, no study has examined hepatitis A vaccine responses in those patients aged 165 years; thus, it is not known whether the trend of poorer immune responses would become clinically significant in older patients. Finally, large clinical efficacy studies to date have involved only children.

TYPHOID FEVER VACCINE Typhoid fever remains a significant public health problem in many developing countries. The risk of infection varies according to the country visited and length of stay, but estimates range from 1.3 to 812 cases per million persons who travel from the United States to low-income countries [31]. Approximately 75% of cases of typhoid fever in the United States are acquired during a trip abroad [31, 32]. The mortality rate is significantly higher among individuals ⭓50 years old than among those !50 years old (3.3% vs. 0.4%; P p .009) [33]. Particularly with the additional risk conferred by the rising prevalence of multidrug-resistant organisms, typhoid vaccination should be considered for elderly travelers, especially those staying 12–3 weeks in countries with endemic or epidemic disease. Killed whole-cell parenteral typhoid vaccines were used in the past, but because of significant side effects, they are no longer commercially available. A purified Vi polysaccharide parenteral vaccine (Aventis Pasteur) and a live-attenuated oral vaccine (Swiss Serum and Vaccine Institute) are currently licensed in North America. In addition, Vi conjugate vaccines have recently been developed, but they are still undergoing clinical trials and thus are not yet approved. There is no measurable immunologic response that clearly correlates with protective efficacy after vaccination. Following typhoid Vi polysaccharide vaccination, Vi antibody levels can be measured, but the minimum titer required for protection from infection has not been defined (1.0–1.5 mg/mL is considered a conservative estimate) [34, 35]. Instead, seroconversion is generally defined by a 4-fold increase in serum Vi antibody titer. For the live-attenuated oral vaccine, mucosal IgA and cellmediated responses are likely to be responsible for most of the protection conferred, but methods used to measure these are not widely available. Instead, the serum O antibody level is often used as a surrogate marker and has been shown to have some correlation with protection [36, 37]. Neither prior Salmonella typhi infection nor vaccination confers complete protection from (re)infection or clinical disease. Purified Vi Polysaccharide Parenteral Vaccine

The purified polysaccharide typhoid Vi vaccine is well tolerated, inducing only minor reactions in !10% of vaccinees [38]. Ad1560 • CID 2001:33 (1 November) • TRAVEL MEDICINE

ministration of booster doses after 2 years is recommended by the manufacturer. The vaccine elicits serum IgG Vi antibody responses in 85%–95% of children and young adults [38, 39]. Two large randomized, controlled field trials assessing vaccine efficacy have been performed: one involved South African schoolchildren and the other involved Nepalese individuals aged 5–55 years. The rate of protective efficacy against clinical infection was 64% at 21 months and 75% at 17 months after vaccination, respectively (table 2) [40, 41]. Vaccination of elderly persons. Most studies of immune response and vaccine efficacy have involved children in countries where typhoid is endemic. However, there is evidence of different antibody responses after vaccination, depending on past exposure to S. typhi, and immune responses in persons living in areas of endemicity are boosted by intervening infections [40, 41]. In addition, no studies have specifically addressed seroresponses in older adults. Close examination of the data from the Nepalese efficacy study shows that, at 1 month, children aged 5–14 years had a 77% seroconversion rate, adults aged 15–44 years had a 79% seroconversion rate, and adults 45–55 years had a 62.5% seroconversion rate, but this data cannot be extrapolated to nonimmune individuals (table 2) [41]. Because efficacy studies have also involved only young individuals in countries where typhoid is endemic, the relevance of this data to older travelers from countries of nonendemicity is unknown [42]. Ty21a Live-Attenuated Oral Vaccine

The live-attenuated oral vaccine comes in 2 formulations: an enteric-coated capsule (which is licensed but currently unavailable) and a liquid suspension (not licensed in the United States). The recommended schedule is administration of 4 doses on alternate days, with reimmunization after 5 years. All major immunogenicity and efficacy studies of the Ty21a vaccine have been performed in countries where typhoid is endemic (table 3). A meta-analysis of published studies concluded that the overall rate of efficacy of vaccination for protection against illness was 71% for people aged 5–9 years and 63% for individuals aged 10–14 years [43]. The efficacy data for travelers is sparse, but one case-control study of travelers to India showed the protective efficacy of the oral vaccine to be only ∼23% [44]. Another study showed that ∼10% of travelers to Indonesia who developed typhoid had received prior Ty21a vaccination [45]. Vaccination of elderly persons. There is no information on age-related effects on the safety, immunogenicity, or efficacy of the oral typhoid vaccine in elderly persons. YELLOW FEVER VACCINE Most yellow fever vaccine is administered to young children living in areas where the disease is endemic. Yellow fever is rare

in travelers, although there have been 4 recent deaths caused by yellow fever in unvaccinated travelers from the United States and Europe, and the incidence of infection with yellow fever is increasing in many regions [46–50]. Neonates and adults 150 years of age are both at increased risk of severe disease, and mortality rates after infection are highest in these age groups. All yellow fever vaccines are live-attenuated vaccines derived from the 17D strain of the virus, and all are produced in embryonated eggs. There are currently multiple active manufacturers worldwide, but the only vaccine distributed in the United States is produced by Aventis Pasteur. The seroconversion rates, efficacy, duration of immune response, safety, and tolerability appear to be similar for each preparation, although comparative efficacy studies have not been performed [51, 52]. Mild local or systemic reactions are reported to occur in 5%–40% of vaccinees. Anaphylaxis after vaccination is estimated to occur in ∼1 of 131,000 recipients [53]. Encephalitis has been documented in 22 cases, from among 1300 million doses of vaccine administered [54]. Three-quarters of these cases occurred in children aged !9 months, but at least 3 cases of encephalitis have been reported in adults [52, 55]. Although protective levels of antibody may persist for decades [56], revaccination is needed every 10 years to satisfy official entry requirements. The exact mechanism of protective immunity is poorly understood, and documentation of antibodies may not equate perfectly with protection from clinical infection [52]. Antibody responses following vaccination have been measured by use of many different assays, but estimated seroconversion rates are similar in most studies, irrespective of the method used for detection [52]. On the basis of animal studies that have involved challenge with virulent yellow fever virus, it is presumed that a neutralizing antibody titer of ⭓1:10 or a log10 neutralization index of ⭓0.7 equates with protection from infection [52]. However, no cutoff correlating with protective antibodies, as measured by the plaque reduction neutralization test (the method used for antibody detection in most studies), has been established. After vaccination, neutralizing antibodies appear within 7–10 days in 190% of young adult recipients. Peak titers are found at 3–4 weeks, and seroconversion occurs by day 28 in 96%–100% of vaccinees (table 4) [51, 57]. Immune responses to vaccination are qualitatively different in people with prior flavivirus immunity, in comparison with responses in flavivirusnaı¨ve individuals [58–60]. As a result, the findings of studies in countries where flaviviruses are endemic can be difficult to interpret and thus cannot be extended to populations in which flaviviruses are not endemic. For ethical reasons, protective efficacy against infection has never been tested in a controlled trial; however, only rare cases of primary vaccine failure have been reported [52].

Vaccination of elderly persons. No studies of seroconversion rates, timing of seroresponse, antibody titers, or protective efficacy of the vaccine have involved elderly subjects. However, preliminary data suggest that serious adverse reactions after vaccination may be more common in older individuals than they are in younger individuals [61, 62]. An analysis of data from the Vaccine Adverse Events Reporting System showed that persons aged 65–74 years were 5.8 times more likely to experience serious adverse events after vaccination than were persons aged 25–44 years, and patients aged ⭓75 years had an 18fold greater risk. Death or hospitalization was 3.5 times more common among those aged 65–74 years and 9 times more likely among those aged ⭓75 years. Confusion, renal failure, and thrombocytopenia were also more likely after vaccination of elderly individuals. This has not been confirmed by a prospective trial.

JAPANESE ENCEPHALITIS VACCINE The risk of developing Japanese encephalitis (JE) is very low for travelers; only 25 cases have been reported from among several million persons from the United States and Europe who have traveled to Asia during the past 20 years [63, 64]. Advanced age has been shown to increase the incidence, morbidity, and mortality of infection with JE virus [65]. Three JE vaccines are in widespread use worldwide, including a live-attenuated vaccine, and newer preparations are being developed. Currently only an inactivated Biken vaccine (distributed by Aventis Pasteur), produced in mouse brain, is available in the United States. Local side effects are seen in up to 20% of vaccine recipients, and mild systemic side effects are seen in up to 10% [66–68]. Severe reactions, including temporally related acute demyelinating encephalitis, have been reported to occur in 1 person per 50,000–75,000 vaccinees in some series [69–72]. In addition, allergic reactions, such as urticaria and angioedema, have been estimated to occur in 2.5–104 persons per 10,000 recipients of the Biken vaccine [64, 68, 72, 73]. Antibodies to JE virus are most commonly measured with a plaque reduction neutralization test, but other techniques are also available, and there is good overall correlation between the different methods [74]. No international standard for protective antibody units has been established; however, a neutralizing antibody titer of 11:10 is generally considered to indicate seroconversion [75]. It is unclear exactly how antibody levels correlate with immunity from infection, and failure to produce detectable neutralizing antibody titer may not correlate with lack of protection [76]. It is likely that T cell memory also contributes to protection after exposure. Most serological studies following immunization have involved children aged !15 years in areas where JE is endemic and vaccination is routine. Serological responses differ between TRAVEL MEDICINE • CID 2001:33 (1 November) • 1561

populations in areas where JE is endemic versus areas where it is not endemic, because previous exposure to JE or other flaviviruses results in augmentation of antibody titers. In children in countries where JE is endemic, subcutaneous administration of 2 doses of JE vaccine 1–4 weeks apart leads to development of neutralizing antibodies in 94%–100% [75, 77, 78]. This contrasts with the !85% seroconversion among young people after administration of 2 doses in areas of nonendemicity [76, 77]. In addition, the geometric mean titers are lower in subjects in areas of nonendemicity, and protective antibody titers are less persistent [76, 79]. Thus, administration of 3 doses is recommended for flavivirus-nonimmune subjects, such as travellers from the United States, resulting in 90%–100% seroconversion rates among young adults (table 5) [76, 80, 81]. The protective efficacy of JE vaccine against clinical infection has also been studied, predominantly among persons in areas where JE is endemic. Two randomized, placebo-controlled trials (one in Taiwan and the other in Thailand) that involved children showed 80% and 91% efficacy rates, respectively, against infection at 1 year [82, 83]. However, these efficacy studies may not be applicable to travelers from countries where JE is not endemic. Vaccination of elderly patients. A number of reports published in the Japanese literature have suggested that older people’s capacity to respond to JE vaccination is variable and not universal. Only one study in the English-language literature has compared the immune responses of aged people with those of younger subjects (table 5) [84]. In this study, a group of people aged ⭓60 years who lived in an area in Japan where JE is not endemic were vaccinated with 1 dose of different types of JE vaccines and had neutralizing antibody levels measured before and 4 weeks after vaccination. Of those persons who had negative serological findings before vaccination, 35% had at least a 2-fold increase in antibody titer, and 2.7% had at least a 4fold increase in titer. These results were compared with those of a study of high school students, which showed an increase in titer of at least 2-fold in 20% of subjects and an increase of at least 4-fold in 2%. The study concluded that the capacity of older people to respond to JE vaccine did not seem to be inferior to that of high school students, although the number of subjects included was small. It is difficult to extrapolate these results to nonimmune populations, but no study of age-related effects on immune responses or efficacy of the JE vaccine has specifically involved travelers. The results of a Danish study suggested that allergic reactions were more common in individuals aged 15–30 years than they were in those aged 130 years, but this was a small study and it included few individuals aged 150 years [85].

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RABIES VACCINE Because the overall risk of rabies in travelers is low [86], vaccination should be considered predominantly for travelers planning to spend significant periods of time in remote areas of high-risk countries. There are multiple rabies vaccines available; varying preexposure and postexposure schedules have been tested, and different doses, sites of administration, and routes of injection (intramuscular, subcutaneous, or intradermal) have been used. Three different vaccines are currently licensed in the United States: a human diploidcell vaccine (HDCV; Aventis Pasteur), a rhesus diploid cell adsorbed vaccine (BioPort), and a purified chick embryo cell culture vaccine (Chiron Therapeutics). Vaccines available in other countries include a purified duck embryo vaccine, a primary hamster kidney cell rabies vaccine, and a Vero cell rabies vaccine. Nerve tissue vaccines, which are still used in many developing countries, have less efficacy and are associated with an allergic encephalomyelitis in up to 0.5% of recipients. The newer cell culture vaccines are generally well tolerated and have similar immunogenicity and protective efficacy. Antibody responses are generally used to demonstrate immunity, although they are imperfect markers of protection. The minimum protective antibody titer has been designated as either 10.5 IU/mL (by means of the mouse neutralization test) or 11:5 (by means of the rapid fluorescent focus inhibition technique) [86]. Most studies have shown that serum neutralizing antibodies are detectable in ∼20%–40% of young healthy vaccine recipients by day 7 after vaccination and that close to 100% of healthy vaccine recipients have rabies antibodies by 14 days after receiving 2 doses of the HDCV or rhesus diploid cell adsorbed vaccine [87–89]. The duration of protection after vaccination is variable, but adequate antibody titers are detectable in 88%–99% of recipients for ⭓1.5–2 years after intramuscular vaccination [90]. Use of the intradermal route results in slightly lower antibody titers and less-sustained immunity than does use of the intramuscular route, and the CDC does not endorse use of the intradermal route after exposure [86]. There have been no placebo-controlled trials of vaccine efficacy, so efficacy data are mainly from case reports of “failures.” Postexposure administration of various vaccines in various countries has generally yielded excellent efficacy; most treatment failures have been associated with incomplete adherence to the treatment guidelines of the World Health Organization (WHO) [91]. The overall failure rate for cell culture vaccines is estimated to be !1 case per 80,000 treatments [89, 92]. Vaccination of elderly persons. Two studies have specifically looked at the response to vaccination in elderly individuals (table 6). In one of these studies, responses to 2 antirabies vaccines (purified duck embryo vaccine and HDCV) in 260

European subjects aged 11–25 years were compared with responses in subjects aged 150 years [93]. All patients received vaccine on a 6-dose postexposure schedule. Serological examinations were performed on day 0, on day 30 (just before the fifth dose), and on day 90 (just before the sixth dose). All subjects from both age groups had adequate responses and developed protective antibody titers after the fourth dose, but the older subjects produced antibody titer levels 52% lower than those of the younger group (95% CI, 26%–84%). It is unclear whether this equates with reduced protective efficacy. The authors suggested that a sixth dose should be considered for elderly individuals, but this is not recommended by the CDC or WHO. The second study involved 60 patients who were divided into 4 age groups: 1–20 years, 21–40 years, 41–60 years, and 160 years [94]. After 2 dosings of HDCV, antibody titers were significantly lower for each successively older cohort. Comparison of the individual results for the older and younger subjects revealed that the geometric mean titers reflected a continuum of response that was uniformly lower in older patients, but recipients of all ages developed protective antibody titers. No assessment of the durability of the response was performed. A number of other studies of rabies vaccine have included some elderly patients, but the studies were not specifically designed to analyze age-related effects. In one report on antibody titers following postexposure prophylaxis with a human diploid cell rabies vaccine (Wyeth Laboratories), it was observed that inadequate titers were seen in a group of patients with a median age of 42 years, whereas responders had a median age of 21 years [95]. Other studies that have included a few elderly vaccine recipients have either found no age-related effects or have made no comment about any differences in immunogenicity in relation to age [96–103]. Allergic reactions to the vaccine are reported to be unrelated to age [89, 104]. One consideration relevant to elderly individuals is that intradermal injections may be difficult if the dermis is thin.

OTHER VACCINES Administration of additional vaccines may also be considered for travelers. There is evidence that many routine vaccines that are frequently administered before travel, including tetanusdiphtheria-toxoid, hepatitis B, pneumococcal, and influenza vaccines, are associated with decreased immunogenicity in elderly recipients. For many other vaccines, including cholera (parenteral or oral), polio (parenteral or oral), and measles-mumpsrubella vaccines, there is no published information specifically about the immunogenicity, protective efficacy, or side effects in elderly recipients. The same is essentially true regarding the meningococcal vaccine, although investigators in a study in

Nigeria reported that the 1-month postvaccination antibody titers were not significantly different after administration to persons aged 6–25 years, 26–45 years, and 46–65 years [105].

DISCUSSION Review of the vaccine literature shows that delayed development of immune responses, decreased peak antibody responses, more rapid waning of protective antibodies, decreased protective efficacy, and increased side effects have all been noted in elderly individuals after the administration of certain vaccines. Many vaccines currently in use—in particular, many of the vaccines given prior to travel—have never been specifically studied in elderly subjects, and many questions remain unanswered. Previous exposure to certain antigens via natural infection is more likely in elderly persons for some pathogens, such as hepatitis A virus, so elderly individuals may already be protected. However, older people have a greater risk of complications from certain travel-related infections, including JE, yellow fever, hepatitis A, and typhoid fever; therefore, immunization against these infections may be particularly important for older travelers. Determination of the magnitude of serological responses following vaccination does not necessarily provide adequate information on the degree of protection conferred against clinical infection. Differences in antibody avidity, other qualitative aspects of humoral responses, and variations in cellular immune responses also contribute to protection from infection. Which of these measures is most important differs for each vaccine—a circumstance that complicates assessment of age effects on immunity. Even antibody titer, the simplest of these measures, has not been systematically studied in a significant number of elderly travelers for any of the vaccines we have discussed, despite evidence suggesting that extrapolation from data obtained for young individuals and/or persons in countries of endemicity may be unreliable. In particular, there is no information regarding the immunogenicity of hepatitis A vaccine in travelers 165 years of age, and no serological studies specifically about vaccination of adult travelers of any age against typhoid, yellow fever, or JE have been performed. The interval before development of adequate responses and the durability of responses may also affect guidelines about vaccine administration. Timing of adequate immune responses is of particular relevance to travelers, because slower development of immunoprotection implies that earlier administration of travel vaccines may be required. Antibodies to hepatitis A develop more slowly in elderly patients, yet this has not been studied prospectively for any of the other travel vaccines. There is also a potential for more-rapid waning of protective antibodies in elderly persons, particularly for vaccines associated

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with lower antibody titers in older individuals, such as hepatitis A and rabies vaccines. The outcome measure of most practical importance is the degree of protection against clinical infection following vaccination. As we have shown, there is no information regarding clinical efficacy in elderly recipients of any of the travel vaccines in common use. The infrequency of disease acquisition makes such studies involving travelers very difficult. Extrapolation from responses in individuals from countries of endemicity may be unreliable because of numerous potential confounders, such as differences in number and timing of prior exposures and variations in underlying nutritional and health status. Finally, the safety of certain vaccines in elderly individuals, particularly live vaccines, remains under question. The suggestion of increased adverse events after administration of yellow fever vaccine is particularly relevant, and this needs to be studied in a more controlled fashion. Despite the lack of data pertaining to elderly individuals, physicians are still faced with the clinical decisions of who to vaccinate, how safe vaccination is for individual patients, and what level of protective efficacy a vaccine is likely to offer. Existing evidence suggests that immune responses are at least in part age-dependent, and this could translate into a requirement for altered vaccine schedules for elderly persons, as already are used for many vaccines administered to infants. In addition, interactions among vaccines in elderly recipients have not been adequately studied. These issues are becoming increasingly important as the number of elderly persons in the community increases, as more elderly persons travel to exotic destinations, as drug resistance to many organisms becomes more prevalent, and as new vaccines are developed. The only way to provide definitive answers is to prospectively study both immunologic responses and the protective efficacy of vaccines in different communities and in different age groups.

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