Infection and chemotherapy

The Korean Society of Infectious Diseases (대한감염학회)
권호 표지

Immunogenicity and Safety of Oral Live Attenuated Salmonella typhi Vaccine

경구용 약독화 장티푸스 생균 백신의 면역원성과 안전성

Oh, Mee-Hye;Shin, Dong-Han;Pee, Dae-Hun;Shin, Young-Kyoo;Choi, Byung-Min;Sohn, Jang-Wook;Kim, Ik-Sang
오미혜;신동한;피대훈;신영규;최병민;손장욱;김익상

  • Published : 20040200
⟨ Previous Next ⟩

Abstract

Background: This study is aimed at evaluating immunogenicity by measuring immunoglobulin A (IgA) seroconversion rate through common mucosal immune system and adverse reactions after vaccination of oral live attenuated Salmonella typhi (S. typhi) Ty21a vaccine in Korean population. Methods: A commercially available oral live attenuated vaccine of S. typhi strain Ty21a ($Zerotyph^{\circledR}$) capsule, Boryung Biopharma Co., Seoul, Korea) was given to volunteers; children above 6 years, adolescents, and adults who have never infected with S. typhi nor received S. typhi vaccination. The vaccines were given in three doses, with two day interval between the doses. Seroconversion was determined by ELISPOT (enzyme-linked immunospot) assay. Adverse reactions after vaccination were evaluated in 12 institutions by direct interviewing with vaccinees. Results: A total of 93 volunteers for evaluation of seroconversion were enrolled. Seroconversion rate in the the below 16 year-old group was 73.8% (31/42) and that of over 16 year-old group was 86.3% (44/51), which was not statistically different. Adverse reaction were found in 8.6% (40/465). Gastrointestinal symptoms were most common (6.5%, 30/465). Adverse reactions were found in 5.2% (24/465) after 1st administration, 4.5% (21/462) after 2nd, and 2.6% (12/461) after 3rd. Frequency of adverse reactions was significantly higher after 1st administration (P<0.05). Conclusion: Oral live attenuated S. typhi vaccine, $Zerotyph^{\circledR}$ capsule, had good immnuogenicity and safety through intestinal immune system.

목 적: Salmonella typhi Ty21a 주로 만든 경구용 약독화 장티푸스 생균 백신 투여 후 위장관의 점막면역유도를 통한 장티푸스 특이 IgA 항체 양전율과 백신 투여 후 발생한 이상 반응을 조사함으로 백신의 면역원성과 안전성에 대해 알아보고자 이 연구를 시행하였다.재료 및 방법: 2001년 7월부터 2002년 3월까지 고려대학교 의과대학 안산병원에서 건강한 6세 이상의 소아, 청소년 및 성인 지원자를 93명을 모집하여 장티푸스 생균 백신(지로티프 캅셀, 보령신약)을 1캅셀씩 2일 간격으로 3회 경구 투여하였다. 투여 시작 후 6, 8, 10일째에 혈액을 채취하여 혈중에서 장티푸스 특이 IgA 분비세포를 측정하는 ELISPOT (enzyme-linked immunospot) 방법으로 면역형성 유무를 검사하였다. 또한 2001년 7월부터 2001년 11월까지 고대안산병원을 포함한 전국 12개 기관에서 모집한 465명의 소아 및 성인남녀 지원자를 대상으로 백신 투여 후 발생한 이상 반응을 조사 분석하였다. 결 과: 1)지원자 중 항체 양전율 연구를 마친 사람은 6-15세의 16세미만군 42명(남:22명, 여:20명), 16세이상군 51명(남:17명, 여:34명), 합계 93명(남:39명, 여:54명)이었으며, 평균 연령은 16세미만군 11.1$\pm$2.5세, 16세이상군 31.6$\pm$9.8세였다. 이상 반응 조사가 완료된 사람은 465명(남:187명, 여:278명)이었으며, 평균 연령은 31.3$\pm$16.9세였다. 2) 16세미만군의 항체 양전율은 73.8% (31/42명), 16세이상군의 양전율은 86.3% (44/51명)였으며, 양 군간에 통계적으로 유의한 차이는 없었다. 성, 연령, 알레르기력, 기존 질환, 병용약물 등 대상자의 제반 배경 인자 중에서 통계학적으로 유의하게 양전율에 영향을 미치는 요인은 없었다. 3)이상 반응의 발현 증례율은 8.6% (40/465명)였으며 증상별로는 복통, 설사, 구역 등 위장관계 이상이 6.5% (30/465명), 무력감, 발열 등의 전신 이상이 1.3% (6/465명), 두통이 0.6% (3/465), 피부발진이 0.2% (1/465명)에서 나타났다. 백신 복용 횟수에 따른 이상 반응 발현율은 1차 복용 후 5.2% (24/465명), 2차 복용 후 4.5% (21/ 462), 3차 복용 후 2.6% (12/461)로 처음 복용 후 유의하게 높았다(P<0.05). 대상자의 제반 배경 인자 중에서 통계학적으로 유의하게 이상 반응 발현율에 영향을 미치는 요인은 없었다. 결 론:경구용 약독화 장티푸스 생균 백신은 장점막 면역유도를 통한 우수한 면역원성을 가지고 있으며, 이상 반응 발생률이 낮고 이상 증상이 경미하여 소아 및 성인 모두에 안전한 백신으로 판단된다.

Keywords

References

  1. 국립보건원:2000년 표준 예방접종 지침서. p99-104, 2000
  2. Groschel DH, Hornick RB:Who introduced typhoid vaccination:Almroth Write or Richard Pfeiffer? Rev Infect Dis 3:1251-1254, 1981
  3. Levine MM, Ferreccio C, Black RE, Tacket CO, Germanier R:Progress in vaccines against typhoid fever. Rev Infect Dis 11:552-567, 1989
  4. Wahdan MH, Serie C, Cerisier Y, Sallam S, Germanier R:A controlled field trial of live Salmonella typhi strain Ty21a oral vaccine against typhoid:Three-year results. J Infect Dis 145:292-295, 1982
  5. Levine MM, Ferreccio C, Black RE, Germanier R:Large-scale field trial of Ty21a live oral typhoid vaccine in enteric-coated capsule formation. Lancet 1:1049-1052, 1987
  6. Simanjuntak CH, Paleologo FP, Punjabi NH, Darmowigoto R, Soeprawoto, Totosudirjo H, Haryanto P, Suprijanto E, Witham ND, Hoffman SL:Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine. Lancet 338:1055-1059, 1991
  7. Engels EA, Falagas ME, Lan J, Bennish ML:Typhoid fever vaccines:a meta-analysis of studies on efficacy and toxicity. Br Med J 316:110-116, 1998
  8. Ashcroft MT, Ruchie JM, Nicholson CC:Controlled field trial in British Guiana school children of heat- killed phenolized and aceton-killed lyophilized vaccines. Am J Hyg 79:196-206, 1964
  9. Wong KH, Feeley JC, Northrup RS, Forline ME:Vi antigen from Salmonella typhi and immunity against thypoid fever. I, Isolation and immunologic properties in animals. Infect Immun 9:348-353, 1974
  10. Tacket CO, Ferreccio C, Robbins JB, Tsai CM, Schulz D, Cadoz M, Goudeau A, Levine MM:Safety and immunogenicity of two Salmonella typhi Vi capsular polysaccharide vaccines. J Infect Dis 154: 342-345, 1986
  11. Tacket CO, Levine MM, Robbins JB:Persistence of antibody titers three years after vaccination with Vi polysaccharide vaccine against thphoid fever. Vaccine 6:307-308, 1988
  12. Black RE, Levine MM, Ferreccio C, Clements ML, Lanata C, Rooney J, Germanier R:Efficacy of one or two doses of Ty21a Salmonella typhi vaccine in enteric- coated capsules in a controlled field trial. Chilean Typhoid Committee. Vaccine 8:81-84, 1990
  13. Ferreccio C, Levine MM, Rodriguez H, Contreras R: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 159:766-769, 1989
  14. 이환종:선별 예방접종. 대한의사협회지 40:1603-1634, 1997
  15. Cancellieri V, Fara GM:Demonstration of specific IgA in human feces after immunization with live Ty21a Salmonella typhi vaccine. J Infect Dis 151: 482-484, 1985
  16. D'Amelio R, Tagliabue A, Nencioni L, Di Addario A, Villa L, Manganaro M, Boraschi D, Le Moli S, Nisini R, Matricardi PM:Matricardi. Comparative analysis of immunological responses to oral (Ty21a) and parenteral (TAB) typhoid vaccines. Infect Immun 56:2731-2735, 1988
  17. Viret JF, Favre D, Wegmuller B, Herzog C, Que JU, Cryz SJ Jr, Lang AB:Mucosal and systemic immune response in human after primary and booster immunization with orally administered invasive andnoninvasive live attenuated bacteria. Infect Immun 67:3680-3685, 1999
  18. Forrest BD, LaBrooy JT:Effect of parenteral immunization on the intestinal immune response to Salmonella typhi Ty21a as measured using peripheral blood lymphocytes. Vaccine 11:136-139, 1993
  19. Kantele A, Hakkinen M, Moldoveanu Z, Lu A, Savilahti E, Alvarez RD, Michalek S, Mestecky J:Differences in immune responses induced by oral and rectal immunizations with Salmonella typhi Ty21a: Evidence for compartmentalization within the common mucosal immune system in humans. Infect Immune 66:5630-5635, 1998
  20. Forrest BD:Indirect measurement of intestinal immune responses to an orally administered attenuated bacterial vaccine. Infect Immun 60:2023-2029, 1992
  21. Kantele A, Arvilommi H, Jokinen I:Specific immunoglobulin-secreting human blood cells after peroral vaccination against Salmonella typhi. J Infect Dis 153:1126-1131, 1986
  22. Kantele A:Peirpheral blood antibody-secreting cells in the evaluation of immune response to an oral vaccine. J Biotech 44:217-224, 1996
  23. Kantele A:Antibody-secreting cells in the evaluation of the immunogenicity of an oral vaccine. Vaccine 8:321-326, 1990
  24. Czerkinsky CC, Nilsson LA, Nygren H, Ouchterlony O, Tarkowski A. A solid-phase enzyme-linked immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells. J Immunol Methods 16:109-121, 1983
  25. Sedgwick JD, Holt PG:A solid-phase immunoenzymatic technique for ther enumeration of specific antibody-secreting cells. J Immunol Methods 57:301- 309, 1983
  26. Cryz SJ Jr, Vanprapar N, Thisyakorn U, Olanratmanee T, Losonsky G, Levine MM, Chearskul S:Safety and immunicity of Salmonella typhi Ty21a vaccine in young Thai children. Infect Immun 61: 1149-1151, 1993