Typhoid Immunization
Recommendations of the Advisory
Committee on Immunization Practices (ACIP)
Public Health Service
The MMWR series of publications is published by the Epidemiology Program Office,Centers for Disease Control and Prevention (CDC), Public Health Service, U.S. Depart-ment of Health and Human Services, Atlanta, GA 30333.
Centers for Disease Control and Prevention. Typhoid immunization—recommen-dations of the Advisory Committee on Immunization Practices (ACIP). MMWR1994;43(No. RR-14):[inclusive page numbers].
Centers for Disease Control and Prevention . David Satcher, M.D., Ph.D.
The material in this report was prepared for publication by: National Center for Infectious Diseases. James M. Hughes, M.D.
Division of Bacterial and Mycotic Diseases . Mitchell L. Cohen, M.D.
The production of this report as an MMWR serial publication was coordinated in: Epidemiology Program Office. Stephen B. Thacker, M.D., M.Sc.
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Vol. 43 / No. RR-14
December 9, 1994
Advisory Committee on Immunization Practices
Membership List, October 1994
Neal A. Halsey, M.D.
Johns Hopkins University School of Hygiene and Public HealthBaltimore, MD EX OFFICIO MEMBERS
Carolyn Hardegree, M.D.
Food and Drug AdministrationBethesda, MD Vol. 43 / No. RR-14
Advisory Committee on Immunization Practices
Membership List, October 1994 — Continued
Vol. 43 / No. RR-14
The following CDC staff members prepared this report: Division of Bacterial and Mycotic Diseases Vol. 43 / No. RR-14
Typhoid Immunization
Recommendations of the Advisory Committee on
Immunization Practices (ACIP)
These revised recommendations of the Advisory Committee on Immuniza- tion Practices update previous recommendations (MMWR 1990;39[RR-10]:1–5).
They include information on the Vi capsular polysaccharide (ViCPS) vaccine,which was not available when the previous recommendations were published.
The incidence of typhoid fever declined steadily in the United States from 1900 to 1960 and has since remained low. From 1975 through 1984, the average number ofcases reported annually was 464. During that period, 57% of reported cases occurredamong persons ≥20 years of age; 62% of reported cases occurred among persons whohad traveled to other countries. From 1967 through 1976, only 33% of reported casesoccurred among travelers to other countries (1 ).
Three typhoid vaccines are currently available for use in the United States: a) an oral live-attenuated vaccine (Vivotif Berna vaccine, manufactured from the Ty21astrain of Salmonella typhi (2 ) by the Swiss Serum and Vaccine Institute); b) a paren-teral heat-phenol-inactivated vaccine that has been widely used for many years(Typhoid Vaccine, manufactured by Wyeth-Ayerst); and c) a newly licensed capsularpolysaccharide vaccine for parenteral use (Typhim Vi, manufactured by PasteurMérieux). A fourth vaccine, an acetone-inactivated parenteral vaccine, is currentlyavailable only to the armed forces.
Although no prospective, randomized trials comparing any of the three U.S.- licensed typhoid vaccines have been conducted, several field trials have demon-strated the efficacy of each vaccine. In controlled field trials conducted amongschoolchildren in Chile, three doses of the Ty21a vaccine in enteric-coated capsulesadministered on alternate days reduced laboratory-confirmed infection by 66% over aperiod of 5 years (95% confidence interval [CI]=50%–77%) (3,4 ). In a subsequent trialin Chile, efficacy appeared to be lower: three doses resulted in only 33% (95% CI=0%–57%) fewer cases of laboratory-confirmed infection over a period of 3 years. When thedata were stratified by age in this trial, children ≥10 years of age had a 53% reductionin incidence of culture-confirmed typhoid fever (95% CI=7%–77%), whereas children5–9 years of age had only a 17% reduction (95% CI=0%–53%). This difference in age-related efficacy, however, is not statistically significant (5 ). In another trial in Chile, asignificant decrease in the incidence of clinical typhoid fever occurred among personsreceiving four doses of vaccine compared with persons receiving two (p<0.001) or December 9, 1994
three (p=0.002) doses. Because no placebo group was included in this trial, absolutevaccine efficacy could not be calculated (6 ).
Weekly and triweekly dosing regimens have been less effective than alternate-day dosing (3 ). A liquid formulation of Ty21a is more effective than enteric-coated cap-sules (5,7,8 ), but only enteric-coated capsules are available in the United States. Theefficacy of vaccination with Ty21a has not been studied among persons from areaswithout endemic disease who travel to disease-endemic regions. The mechanism bywhich Ty21a vaccine confers protection is unknown; however, the vaccine does elicitboth serum (2,9 ) and intestinal (10 ) antibodies and cell-mediated immune responses(11 ). Vaccine organisms can be shed transiently in the stool of vaccine recipients (2,9 ).
However, secondary transmission of vaccine organisms has not been documented.
In field trials involving a primary series of two doses of heat-phenol-inactivated typhoid vaccine (which is similar to the currently available parenteral inactivated vac-cine), vaccine efficacy over the 21⁄2- to 3-year follow-up periods ranged from 51% to77% (12–14 ). Efficacy for the acetone-inactivated parenteral vaccine, available only tothe armed forces, ranges from 75% to 94% (12,14,15 ).
The newly licensed parenteral vaccine (Vi capsular polysaccharide [ViCPS]) is com- posed of purified Vi (“virulence”) antigen, the capsular polysaccharide elaborated byS. typhi isolated from blood cultures (16 ). In recent studies, one 25-µg injection ofpurified ViCPS produced seroconversion (i.e., at least a fourfold rise in antibody titers)in 93% of healthy U.S. adults (17 ); similar results were observed in Europe (18 ). Twofield trials in disease-endemic areas have demonstrated the efficacy of ViCPS in pre-venting typhoid fever. In a trial in Nepal, in which vaccine recipients were observed for20 months, one dose of ViCPS among persons 5–44 years of age resulted in 74% (95%CI=49%–87%) fewer cases of typhoid fever confirmed by blood culture than occurredwith controls (19 ). In a trial involving schoolchildren in South Africa who were 5–15years of age, one dose of ViCPS resulted in 55% (95% CI=30%–71%) fewer cases ofblood-culture-confirmed typhoid fever over a period of 3 years than occurred withcontrols. The reduction in the number of cases in years 1, 2, and 3, was 61%, 52%, and50%, respectively (20,21 ). The efficacy of vaccination with ViCPS has not been studiedamong persons from areas without endemic disease who travel to disease-endemicregions or among children <5 years of age. ViCPS has not been tested among children<1 year of age.
Routine typhoid vaccination is not recommended in the United States. However, vaccination is indicated for the following groups:• Travelers to areas in which there is a recognized risk of exposure to S. typhi. Risk is greatest for travelers to developing countries (e.g., countries in Latin America, Asia,and Africa) who have prolonged exposure to potentially contaminated food anddrink (22 ). Multidrug-resistant strains of S. typhi have become common in someareas of the world (e.g., the Indian subcontinent [23 ] and the Arabian peninsula[24,25 ]), and cases of typhoid fever that are treated with ineffective drugs can befatal. Travelers should be cautioned that typhoid vaccination is not a substitute forcareful selection of food and drink. Typhoid vaccines are not 100% effective, andthe vaccine’s protection can be overwhelmed by large inocula of S. typhi. Vol. 43 / No. RR-14
• Persons with intimate exposure (e.g., household contact) to a documented S. typhi • Microbiology laboratorians who work frequently with S. typhi (26 ).
Routine vaccination of sewage sanitation workers is not warranted in the United States and is indicated only for persons living in typhoid-endemic areas. Also, typhoidvaccine is not indicated for persons attending rural summer camps or living in areasin which natural disasters (e.g., floods) have occurred (27 ). No evidence has indicatedthat typhoid vaccine is useful in controlling common-source outbreaks.
The parenteral inactivated vaccine causes substantially more adverse reactions but is no more effective than Ty21a or ViCPS. Thus, when not contraindicated, either oralTy21a or parenteral ViCPS is preferable.
Each of the three vaccines approved by the Food and Drug Administration has a different lower age limit for use among children (Table 1). In addition, the time re-quired for primary vaccination differs for each vaccine. Primary vaccination withViCPS can be accomplished with a single injection, whereas 1 week is required forTy21a, and 4 weeks are required to complete a primary series for parenteral inacti-vated vaccine (Table 1). Finally, the live-attenuated Ty21a vaccine should not be usedfor immunocompromised persons or persons taking antibiotics at the time of vaccina-tion (see Precautions and Contraindications).
TABLE 1. Dosage and schedules for typhoid fever vaccination
Dose/mode of Number of
Oral live-attenuated
Ty21a vaccine
Primary series
Vi capsular poly-
saccharide vaccine
Primary series
Primary series
*Each orally administered capsule contains contains 2–6 x 109 viable S. typhi Ty21a and 5–50 x 109 nonviable S. typhi Ty21a.
† Intramuscularly.
§ Subcutaneously.
¶ Intradermally.
December 9, 1994
Primary vaccination with live-attenuated Ty21a vaccine consists of one enteric- coated capsule taken on alternate days for a total of four capsules. The capsules mustbe kept refrigerated (not frozen), and all four doses must be taken to achieve maxi-mum efficacy (6 ). Each capsule should be taken with cool liquid no warmer than 37 C(98.6 F), approximately 1 hour before a meal. Although adverse reactions to Ty21a areuncommon among children 1–5 years of age (28,29 ), data are unavailable regardingefficacy for this age group. This vaccine has not been studied among children <1 yearof age. The vaccine manufacturer recommends that Ty21a not be administered tochildren <6 years of age.
Primary vaccination with ViCPS consists of one 0.5-mL (25-µg) dose administered intramuscularly. This vaccine has not been studied among children <1 year of age. Thevaccine manufacturer does not recommend the vaccine for children <2 years of age.
Parenteral Inactivated Vaccine
Primary vaccination with parenteral inactivated vaccine consists of two 0.5-mL sub- cutaneous injections, each containing approximately 5 x 108 killed bacteria, separatedby ≥4 weeks. The vaccine manufacturer does not recommend the vaccine for useamong children <6 months of age. If the two doses of parenteral inactivated vaccinecannot be separated by ≥4 weeks because of time constraints, common practice hasbeen to administer three doses of the vaccine at weekly intervals in the volumes listedabove. Vaccines administered according to this schedule may be less effective,however.
Booster Doses
If continued or repeated exposure to S. typhi is expected, booster doses of vaccine are required to maintain immunity after vaccination with parenteral typhoid vaccines(Table 1). The ViCPS manufacturer recommends a booster dose every 2 years after theprimary dose if continued or renewed exposure is expected. In a study in which effi-cacy was not examined, revaccination of U.S. adults at either 27 or 34 months after theprimary vaccination increased mean antibody titers to the approximate levelsachieved with the primary dose (17 ). The optimal booster schedule for persons ad-ministered Ty21a for primary vaccination has not been determined; however, thelongest reported follow-up study of vaccine trial subjects indicated that efficacy con-tinued for 5 years after vaccination (4 ). The manufacturer of Ty21a recommendsrevaccination with the entire four-dose series every 5 years if continued or renewedexposure to S. typhi is expected. This recommendation may change as more databecome available about the period of protection produced by the Ty21a vaccine. If theparenteral inactivated vaccine is used initially, booster doses should be administeredevery 3 years if continued or renewed exposure is expected. A single booster dose ofparenteral inactivated vaccine is sufficient, even if >3 years have elapsed since theprior vaccination. When the heat-phenol-inactivated vaccine is used for booster Vol. 43 / No. RR-14
vaccination, the intradermal route causes less reaction than the subcutaneous route(30 ). The acetone-inactivated vaccine should not be administered intradermally or byjet- injector gun because of the potential for severe local reactions (31 ).
No information has been reported concerning the use of one vaccine as a booster after primary vaccination with a different vaccine. However, using either the series offour doses of Ty21a or one dose of ViCPS for persons previously vaccinated withparenteral vaccine is a reasonable alternative to administration of a booster dose ofparenteral inactivated vaccine.
Ty21a produces fewer adverse reactions than either ViCPS or the parenteral inacti- vated vaccine. During volunteer studies and field trials with oral live-attenuated Ty21avaccine, side effects were rare and consisted of abdominal discomfort, nausea, vom-iting, fever, headache, and rash or urticaria (2,7,32 ) (Table 2). In placebo-controlledtrials, monitored adverse reactions occurred with equal frequency among groups re-ceiving vaccine and placebo.
In several trials, ViCPS produced fever (occurring in 0%–1% of vaccinees), head- ache (1.5%–3% of vaccinees), and erythema or induration ≥1 cm (7% of vaccinees)(17,20,33 ) (Table 2). In the study conducted in Nepal, the ViCPS vaccine producedfewer local and systemic reactions than did the control (the 23-valent pneumococcalvaccine) (19 ). Among schoolchildren in South Africa, ViCPS produced less erythemaand induration than did the control bivalent meningococcal vaccine (20 ). In a directcomparison, ViCPS produced reactions less than half as frequently as parenteral inac-tivated vaccine, probably because ViCPS contains negligible amounts of bacteriallipopolysaccharide (33 ).
Parenteral inactivated vaccines produce several systemic and local adverse reac- tions, including fever (occurring in 6.7%–24% of vaccinees), headache (9%–10% ofvaccinees), and severe local pain and/or swelling (3%–35% of vaccinees) (Table 2);21%–23% of vaccinees missed work or school because of adverse reactions(12,13,34 ). More severe reactions, including hypotension, chest pain, and shock, havebeen reported sporadically.
TABLE 2. Common adverse reactions of typhoid fever vaccines
Local reactions
*The side effects of Ty21a are rare and mainly consist of abdominal discomfort, nausea, December 9, 1994
The theoretical possibility for decreased immunogenicity when Ty21a, a live bacte- rial vaccine, is administered concurrently with immunoglobulin, antimalarials, or viralvaccines has caused concern (35 ). However, because Ty21a is immunogenic even inpersons with preexisting antibody titers (29 ), its immunogenicity should not be af-fected by simultaneous administration of immunoglobulin. Mefloquine can inhibit thegrowth of the live Ty21a strain in vitro; if this antimalarial is administered, vaccinationwith Ty21a should be delayed for 24 hours. The minimum inhibitory concentration ofchloroquine for Ty21a is >256 µg/mL; this antimalarial should not affect the immuno-genicity of Ty21a (36,37 ). The vaccine manufacturer advises that Ty21a should not beadministered to persons receiving sulfonamides or other antimicrobial agents; Ty21ashould be administered ≥24 hours after an antimicrobial dose. No data exist on theimmunogenicity of Ty21a when administered concurrently or within 30 days of viralvaccines (e.g., oral polio, measles/mumps/rubella, or yellow fever vaccines). In theabsence of such data, if typhoid vaccination is warranted, it should not be delayedbecause of the administration of viral vaccines.
No data have been reported on the use of any of the three typhoid vaccines among pregnant women. Live-attenuated Ty21a should not be used among immunocom-promised persons, including those persons known to be infected with humanimmunodeficiency virus. The two available parenteral vaccines present theoreticallysafer alternatives for this group. The only contraindication to vaccination with eitherViCPS or with parenteral inactivated vaccine is a history of severe local or systemicreactions following a previous dose.
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