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Typhoid Immunization Recommendations of the Advisory Committee on Immunization Practices (ACIP)

Advisory Committee on Immunization Practices

Membership List, October 1994

CHAIRMAN ACTING EXECUTIVE SECRETARY Jeffrey P. Davis, M.D. Dixie E. Snider, M.D., M.P.H. Chief Medical Officer (Acting) Associate Director Department of Health and for Science

Social Services Centers for Disease Control State of Wisconsin and Prevention (CDC) Madison, WI Atlanta, GA

MEMBERS

Barbara Ann DeBuono, M.D. Rudolph E. Jackson, M.D. Rhode Island Department of Health Morehouse School of Medicine Providence, RI Atlanta, GA

Kathryn M. Edwards, M.D. Stephen C. Schoenbaum, M.D. Vanderbilt University School of Harvard Community Health Plan of

Medicine New England Nashville, TN Providence, RI

Marie R. Griffin, M.D., M.P.H. Fred E. Thompson, Jr., M.D. Vanderbilt University Medical Center Mississippi State Department of Nashville, TN Health

Jackson, MS Fernando A. Guerra, M.D. San Antonio Metro Health District Joel Ira Ward, M.D. San Antonio, TX Harbor-UCLA Medical Center

Torrance, CA Neal A. Halsey, M.D. Johns Hopkins University

School of Hygiene and Public Health Baltimore, MD

EX OFFICIO MEMBERS

John La Montagne, Ph.D. Jerry Zelinger, M.D. National Institutes of Health Health Care Financing Administration Bethesda, MD Baltimore, MD

Carolyn Hardegree, M.D. Food and Drug Administration Bethesda, MD

LIAISON REPRESENTATIVES

American Academy of Family Canadian National Advisory Committee

Physicians on Immunization (NACI) Richard Zimmerman, M.D. David Scheifele, M.D. Pittsburgh, PA Vancouver, BC

American Academy of Pediatrics Department of Defense Georges Peter, M.D. William M. Butler, Mc.Usn Providence, RI Washington, DC Caroline B. Hall, M.D. Rochester, NY Department of Veterans Affairs

Kristin Lee Nichol, M.D., M.P.H. American College of Obstetricians and Minneapolis, MN

Gynecologists Stanley A. Gall, M.D. Hospital Infections Control Louisville, KY Practices Advisory Committee

David W. Fleming, M.D. American College of Physicians Portland, OR Pierce Gardner, M.D. Stonybrook, NY Infectious Diseases Society

of America American Hospital Association William P. Glezen, M.D. William Schaffner, M.D. Houston, TX Nashville, TN

National Vaccine Program American Medical Association (Acting) Chester Robinson Edward A. Mortimer, Jr., M.D. Washington, DC Cleveland, OH

Pharmaceutical Research and Association of Teachers of Manufacturers of America

Preventive Medicine Thomas L. Copmann, Ph.D. Richard D. Clover, M.D. Washington, DC Galveston, TX

The following CDC staff members prepared this report:

Paul R. Cieslak, MD Robert V. Tauxe, MD, MPH

Division of Bacterial and Mycotic Diseases

National Center for Infectious Diseases

John C. Watson, MD, MPH Epidemiology and Surveillance Division

National Immunization Program


Summary

These revised recommendations of the Advisory Committee on Immunization 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.

INTRODUCTION

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 of cases reported annually was 464. During that period, 57% of reported cases occurred among persons greater than or equal to 20 years of age; 62% of reported cases occurred among persons who had traveled to other countries. From 1967 through 1976, only 33% of reported cases occurred among travelers to other countries (1).

TYPHOID VACCINES

Three typhoid vaccines are currently available for use in the United States: a) an oral live-attenuated vaccine (Vivotif Berna-TM vaccine, manufactured from the Ty21a strain of Salmonella typhi (2) by the Swiss Serum and Vaccine Institute); b) a parenteral heat-phenol-inactivated vaccine that has been widely used for many years (Typhoid Vaccine, manufactured by Wyeth- Ayerst); and c) a newly licensed capsular polysaccharide vaccine for parenteral use (Typhim Vi, manufactured by Pasteur Merieux). A fourth vaccine, an acetone-inactivated parenteral vaccine, is currently available 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 demonstrated the efficacy of each vaccine. In controlled field trials conducted among schoolchildren in Chile, three doses of the Ty21a vaccine in enteric-coated capsules administered on alternate days reduced laboratory- confirmed infection by 66% over a period of 5 years (95% confidence interval {CI}=50%-77%) (3,4). In a subsequent trial in 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 the data were stratified by age in this trial, children greater than or equal to 10 years of age had a 53% reduction in incidence of culture-confirmed typhoid fever (95% CI=7%-77%), whereas children 5-9 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, a significant decrease in the incidence of clinical typhoid fever occurred among persons receiving four doses of vaccine compared with persons receiving two (p less than 0.001) or three (p=0.002) doses. Because no placebo group was included in this trial, absolute vaccine 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 capsules (5,7,8), but only enteric-coated capsules are available in the United States. The efficacy of vaccination with Ty21a has not been studied among persons from areas without endemic disease who travel to disease-endemic regions. The mechanism by which Ty21a vaccine confers protection is unknown; however, the vaccine does elicit both 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 vaccine), vaccine efficacy over the 2- to 3-year follow-up periods ranged from 51% to 77% (12-14). Efficacy for the acetone- inactivated parenteral vaccine, available only to the armed forces, ranges from 75% to 94% (12,14,15).

The newly licensed parenteral vaccine (Vi capsular polysaccharide {ViCPS}) is composed of purified Vi ("virulence") antigen, the capsular polysaccharide elaborated by S. typhi isolated from blood cultures (16). In recent studies, one 25-ug injection of purified 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). Two field trials in disease-endemic areas have demonstrated the efficacy of ViCPS in preventing typhoid fever. In a trial in Nepal, in which vaccine recipients were observed for 20 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 occurred with controls (19). In a trial involving schoolchildren in South Africa who were 5-15 years of age, one dose of ViCPS resulted in 55% (95% CI=30%-71%) fewer cases of blood-culture-confirmed typhoid fever over a period of 3 years than occurred with controls. The reduction in the number of cases in years 1, 2, and 3, was 61%, 52%, and 50%, respectively (20,21). The efficacy of vaccination with ViCPS has not been studied among persons from areas without endemic disease who travel to disease-endemic regions or among children less than 5 years of age. ViCPS has not been tested among children less than 1 year of age.

VACCINE USAGE

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 and drink (22). Multidrug-resistant strains of S. typhi have become common in some areas 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 be fatal. Travelers should be cautioned that typhoid vaccination is not a substitute for careful selection of food and drink. Typhoid vaccines are not 100% effective, and the vaccine's protection can be overwhelmed by large inocula of S. typhi.

  • Persons with intimate exposure (e.g., household contact) to a documented S. typhi carrier.

  • 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, typhoid vaccine is not indicated for persons attending rural summer camps or living in areas in which natural disasters (e.g., floods) have occurred (27). No evidence has indicated that typhoid vaccine is useful in controlling common-source outbreaks.

CHOICE OF VACCINE

The parenteral inactivated vaccine causes substantially more adverse reactions but is no more effective than Ty21a or ViCPS. Thus, when not contraindicated, either oral Ty21a 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 required for primary vaccination differs for each vaccine. Primary vaccination with ViCPS can be accomplished with a single injection, whereas 1 week is required for Ty21a, and 4 weeks are required to complete a primary series for parenteral inactivated vaccine (Table_1). Finally, the live-attenuated Ty21a vaccine should not be used for immunocompromised persons or persons taking antibiotics at the time of vaccination (see Precautions and Contraindications).

VACCINE ADMINISTRATION

Ty21a

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 must be kept refrigerated (not frozen), and all four doses must be taken to achieve maximum 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 are uncommon among children 1-5 years of age (28,29), data are unavailable regarding efficacy for this age group. This vaccine has not been studied among children less than 1 year of age. The vaccine manufacturer recommends that Ty21a not be administered to children less than 6 years of age.

ViCPS

Primary vaccination with ViCPS consists of one 0.5-mL (25-ug) dose administered intramuscularly. This vaccine has not been studied among children less than 1 year of age. The vaccine manufacturer does not recommend the vaccine for children less than 2 years of age.

Parenteral Inactivated Vaccine

Primary vaccination with parenteral inactivated vaccine consists of two 0.5-mL subcutaneous injections, each containing approximately 5 x 10 (sup) 8 killed bacteria, separated by greater than or equal to 4 weeks. The vaccine manufacturer does not recommend the vaccine for use among children less than 6 months of age. If the two doses of parenteral inactivated vaccine cannot be separated by greater than or equal to 4 weeks because of time constraints, common practice has been to administer three doses of the vaccine at weekly intervals in the volumes listed above. 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 the primary dose if continued or renewed exposure is expected. In a study in which efficacy was not examined, revaccination of U.S. adults at either 27 or 34 months after the primary vaccination increased mean antibody titers to the approximate levels achieved with the primary dose (17). The optimal booster schedule for persons administered Ty21a for primary vaccination has not been determined; however, the longest reported follow-up study of vaccine trial subjects indicated that efficacy continued for 5 years after vaccination (4). The manufacturer of Ty21a recommends revaccination with the entire four-dose series every 5 years if continued or renewed exposure to S. typhi is expected. This recommendation may change as more data become available about the period of protection produced by the Ty21a vaccine. If the parenteral inactivated vaccine is used initially, booster doses should be administered every 3 years if continued or renewed exposure is expected. A single booster dose of parenteral inactivated vaccine is sufficient, even if greater than 3 years have elapsed since the prior vaccination. When the heat-phenol-inactivated vaccine is used for booster vaccination, the intradermal route causes less reaction than the subcutaneous route (30). The acetone-inactivated vaccine should not be administered intradermally or by jet-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 of four doses of Ty21a or one dose of ViCPS for persons previously vaccinated with parenteral vaccine is a reasonable alternative to administration of a booster dose of parenteral inactivated vaccine.

ADVERSE REACTIONS

Ty21a produces fewer adverse reactions than either ViCPS or the parenteral inactivated vaccine. During volunteer studies and field trials with oral live-attenuated Ty21a vaccine, side effects were rare and consisted of abdominal discomfort, nausea, vomiting, fever, headache, and rash or urticaria (2,7,32) (Table_2). In placebo-controlled trials, monitored adverse reactions occurred with equal frequency among groups receiving vaccine and placebo.

In several trials, ViCPS produced fever (occurring in 0%-1% of vaccinees), headache (1.5%-3% of vaccinees), and erythema or induration greater than or equal to 1 cm (7% of vaccinees) (17,20,33) (Table_2). In the study conducted in Nepal, the ViCPS vaccine produced fewer local and systemic reactions than did the control (the 23-valent pneumococcal vaccine) (19). Among schoolchildren in South Africa, ViCPS produced less erythema and induration than did the control bivalent meningococcal vaccine (20). In a direct comparison, ViCPS produced reactions less than half as frequently as parenteral inactivated vaccine, probably because ViCPS contains negligible amounts of bacterial lipopolysaccharide (33).

Parenteral inactivated vaccines produce several systemic and local adverse reactions, including fever (occurring in 6.7%-24% of vaccinees), headache (9%-10% of vaccinees), 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, have been reported sporadically.

PRECAUTIONS AND CONTRAINDICATIONS

The theoretical possibility for decreased immunogenicity when Ty21a, a live bacterial vaccine, is administered concurrently with immunoglobulin, antimalarials, or viral vaccines has caused concern (35). However, because Ty21a is immunogenic even in persons with preexisting antibody titers (29), its immunogenicity should not be affected by simultaneous administration of immunoglobulin. Mefloquine can inhibit the growth of the live Ty21a strain in vitro; if this antimalarial is administered, vaccination with Ty21a should be delayed for 24 hours. The minimum inhibitory concentration of chloroquine for Ty21a is greater than 256 ug/mL; this antimalarial should not affect the immunogenicity of Ty21a (36,37). The vaccine manufacturer advises that Ty21a should not be administered to persons receiving sulfonamides or other antimicrobial agents; Ty21a should be administered greater than or equal to 24 hours after an antimicrobial dose. No data exist on the immunogenicity of Ty21a when administered concurrently or within 30 days of viral vaccines (e.g., oral polio, measles/mumps/rubella, or yellow fever vaccines). In the absence of such data, if typhoid vaccination is warranted, it should not be delayed because 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 immunocompromised persons, including those persons known to be infected with human immunodeficiency virus. The two available parenteral vaccines present theoretically safer alternatives for this group. The only contraindication to vaccination with either ViCPS or with parenteral inactivated vaccine is a history of severe local or systemic reactions following a previous dose.

References

  1. Ryan CA, Hargrett-Bean NT, Blake PA. Salmonella typhi infections in the United States, 1975-1984: increasing role of foreign travel. Rev Infect Dis 1989;11:1-8.

  2. Gilman RH, Hornick RB, Woodward WE, et al. Evaluation of a UDP-glucose-4- epimeraseless mutant of Salmonella typhi as a live oral vaccine. J Infect Dis 1977;136:717-23.

  3. Levine MM, Ferreccio C, Black RE, Germanier R, Chilean Typhoid Committee. Large-scale field trial of Ty21a live oral typhoid vaccine in enteric- coated capsule formulation. Lancet 1987;329:1049-52.

  4. Levine MM, Taylor DN, Ferreccio C. Typhoid vaccines come of age. Pediatr Infect Dis J 1989;8:374-81.

  5. Levine MM, Ferreccio C, Cryz S, Ortiz E. Comparison of enteric-coated capsules and liquid formulation of Ty21a typhoid vaccine in randomised controlled field trial. Lancet 1990; 336:891-4.

  6. Ferreccio C, Levine MM, Rodriguez H, Contreras R, Chilean Typhoid Committee. Comparative efficacy of two, three, or four doses of TY21a live oral typhoid vaccine in enteric-coated capsules: a field trial in an endemic area. J Infect Dis 1989;159:766-9.

  7. Simanjuntak CH, Paleologo FP, Punjabi NH, et al. Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine. Lancet 1991;338: 1055-9.

  8. Wahdan MH, Serie C, Cerisier Y, Sallam S, Germanier R. A controlled field trial of live Salmonella typhi strain Ty 21a oral vaccine against typhoid: three-year results. J Infect Dis 1982;145:292-5.

  9. Hornick RB, Dupont HL, Levine MM, et al. Efficacy of a live oral typhoid vaccine in human volunteers. Dev Biol Stand 1976;33:89-92.

  10. Cancellieri V, Fara GM. Demonstration of specific IgA in human feces after immunization with live Ty21a Salmonella typhi vaccine. J Infect Dis 1985;151:482-4.

  11. Murphy JR, Baqar S, Munoz C, et al. Characteristics of humoral and cellular immunity to Salmonella typhi in residents of typhoid-endemic and typhoid-free regions. J Infect Dis 1987;156:1005-9.

  12. Yugoslav Typhoid Commission. A controlled field trial of the effective- ness of acetone-dried and inactivated and heat-phenol-inactivated typhoid vaccines in Yugoslavia. Bull WHO 1964;30:623-30.

  13. Hejfec LB, Salmin LV, Lejtman MZ, et al. A controlled field trial and laboratory study of five typhoid vaccines in the USSR. Bull WHO 1966;34: 321-9.

  14. Ashcroft MT, Singh B, Nicholson CC, Ritchie JM, Sobryan E, Williams F. A seven-year field trial of two typhoid vaccines in Guyana. Lancet 1967;290:1056-9.

  15. Polish Typhoid Committee. Controlled field trials and laboratory studies on the effectiveness of typhoid vaccines in Poland, 1961-64. Bull WHO 1966;34:211-22.

  16. Robbins JD, Robbins JB. Reexamination of the protective role of the capsular polysaccharide (Vi antigen) of Salmonella typhi. J Infect Dis 1984;150:436-49.

  17. Keitel WA, Bond NL, Zahradnik JM, Cramton TA, Robbins JB. Clinical and serological responses following primary and booster immunization with Salmonella typhi Vi capsular polysaccharide vaccines. Vaccine 1994;12: 195-9.

  18. Ambrosch F, Fritzell B, Gregor J, et al. Combined vaccination against yellow fever and typhoid fever: a comparative trial. Vaccine 1994;12: 625-8.

  19. Acharya IL, Lowe CU, Thapa R, et al. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi. N Engl J Med 1987;317:1101-4.

  20. Klugman KP, Gilbertson IT, Koornhof HJ, et al. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever. Lancet 1987;330: 1165-9.

  21. Klugman KP, Koornhof HJ, Robbins JB. Immunogenicity and protective efficacy of Vi vaccine against typhoid fever three years after immuniza- tion {Abstract}. Bangkok, Thailand: Second Asia-Pacific Symposium on Typhoid Fever and Other Salmonellosis, 1994.

  22. Edelman R, Levine MM. Summary of an international workshop on typhoid fever. Rev Infect Dis 1986;8:329-49.

  23. Rao PS, Rajashekar V, Varghese GK, Shivananda PG. Emergence of multidrug- resistant Salmonella typhi in rural southern India. Am J Trop Med Hyg 1993;48:108-11.

  24. Wallace M, Yousif AA. Spread of multiresistant Salmonella typhi (letter). Lancet 1990; 336:1065-6.

  25. Elshafie SS, Rafay AM. Chloramphenicol-resistant typhoid fever -- an emerging problem in Oman. Scand J Infect Dis 1992;24:819-20.

  26. Blaser MJ, Hickman FW, Farmer III JJ, Brenner DJ, Balows A, Feldman RA. Salmonella typhi: the laboratory as a reservoir of infection. J Infect Dis 1980;142:934-8.

  27. Blake PA. Communicable disease control. In: Gregg MB, ed. The public health consequences of disasters. Atlanta: US Department of Health and Human Services, Public Health Service, CDC, 1989;7-12.

  28. Murphy JR, Grez L, Schlesinger L, et al. Immunogenicity of Salmonella typhi Ty21a vaccine for young children. Infect Immun 1991;59:4291-3.

  29. Cryz SJ, Vanprapar N, Thisyakorn U, et al. Safety and immunogenicity of Salmonella-typhi Ty21a vaccine in young Thai children. Infect Immun 1993;61:1149-51.

  30. Iwarson S, Larsson P. Intradermal versus subcutaneous immunization with typhoid vaccine. J Hyg (Lond) 1978;84:11-6.

  31. Edwards EA, Johnson DP, Pierce WE, Peckinpaugh RO. Reactions and serologic responses to monovalent acetone-inactivated typhoid vaccine and heat-killed TAB when given by jet-injection. Bull WHO 1974;51:501-5.

  32. Cryz SJ,Jr. Post-marketing experience with live oral Ty21a vaccine (letter). Lancet 1993; 341:49-50.

  33. Cumberland NS, Roberts JS, Arnold WSG, Patel RK, Bowker CH. Typhoid Vi: a less reactogenic vaccine. J Int Med Res 1992;20:247-53.

  34. Ashcroft MT, Ritchie JM, Nicholson CC. Controlled field trial in British Guiana school children of heat-killed-phenolized and acetone-killed lyophilized typhoid vaccines. Amer J Hyg 1964;79:196-206.

  35. Wolfe MS. Precautions with oral live typhoid (Ty 21a) vaccine (letter). Lancet 1990;336:631-2.

  36. Brachman PS, Metchock B, Kozarsky PE. Effects of antimalarial chemopro- phylactic agents on the viability of the Ty21a typhoid vaccine strain (letter). Clin Infect Dis 1992;15:1057-8.

  37. Horowitz H, Carbonaro CA. Inhibition of the Salmonella-typhi oral vaccine strain, Ty21a, by mefloquine and chloroquine (letter). J Infect Dis 1992;166:1462-4.


Table_1
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TABLE 1. Dosage and schedules for typhoid fever vaccination
=================================================================================================
                                                            Dosage
                          ---------------------------------------------------------------------
                                                                        Interval
                                          Dose/mode of     Number of    between      Boosting
Vaccination                    Age       administration      doses       doses       interval
-----------------------------------------------------------------------------------------------
Oral live-attenuated
  Ty21a vaccine
  Primary series               >=6 yrs     1 capsule *         4         2 days         --
  Booster                      >=6 yrs     1 capsule *         4         2 days     every 5 yrs

Vi capsular poly-
  saccharide vaccine
  Primary series               >=2 yrs     0.50 mL +           1           --           --
  Booster                      >=2 yrs     0.50 mL +           1           --       every 2 yrs

Heat-phenol-
  inactivated
  parenteral
  vaccine
  Primary series          6 mos-10 yrs     0.25 mL &           2         >=4 wks        --
                              >=10 yrs     0.50 mL &           2         >=4 wks        --
  Booster                 6 mos-10 yrs     0.25 mL &           1           --       every 3 yrs
                              >=10 yrs     0.50 mL &           1           --       every 3 yrs
                               >=6 mos     0.10 mL @           1           --       every 3 yrs
-----------------------------------------------------------------------------------------------
* Each orally administered capsule contains contains 2-6 x 10 (sup) 9 viable S. typhi Ty21a and
  5-50 x 10 (sup) 9 nonviable S. typhi Ty21a.
+ Intramuscularly.
& Subcutaneously.
@ Intradermally.
-- Not applicable.
=================================================================================================

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Table_2
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TABLE 2. Common adverse reactions of typhoid fever vaccines
==========================================================================================
                                                   Reactions
                                -----------------------------------------------
Vaccine                          Fever       Headache     Local reactions
-------------------------------------------------------------------------------
Ty21a *                           0%- 5%       0%- 5%     Not applicable

ViCPS                             0%- 1%     1.5%- 3%     Erythema or
                                                          induration >=1 cm: 7%

Parenteral inactivated          6.7%-24%       9%-10%     Severe local pain or
                                                          swelling: 3%-35%
-------------------------------------------------------------------------------
* The side effects of Ty21a are rare and mainly consist of abdominal discomfort, nausea,
  vomiting, and rash or urticaria.
==========================================================================================


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