Please use this identifier to cite or link to this item:
標題: 利用血清學評估台灣地區國小學童對抗不同流感病毒亞型的群體免疫力及疫苗效益
Serological evaluation of herd immunity and vaccine effectiveness against different subtype of influenza viruses in children in Taiwan
作者: 廖郁昕
Liao, Yu-Hsin
關鍵字: 流感疫苗;influenza vaccination;學童;疫苗效益;血清流行病學;school-aged children;vaccine effectiveness;seroepidemiology;herd immunity
出版社: 微生物暨公共衛生學研究所
引用: Centers for Disease Control and Prevention. CDC (2009). "Update: Swine influenza A (H1N1) infections—California and Texas, April 2009. ." MMWR Morb Mortal Wkly Rep. 58: 435-437.Belongia, Edward A., Burney A. Kieke, et al. (2009). "Effectiveness of Inactivated Influenza Vaccines Varied Substantially with Antigenic Match from the 2004-2005 Season to the 2006-2007 Season." The Journal of Infectious Diseases 199(2): 159-167. Belshe, R. B. (2010). "The need for quadrivalent vaccine against seasonal influenza." Vaccine 28: D45-D53. Boni, M. F. (2008). "Vaccination and antigenic drift in influenza." Vaccine 26: C8-C14. Burnet, F. M. (1936). "Influenza virus on the developing egg. I. Changes associated with the development of an egg-passage strain of virus." Br J Exp Pathol 17: 282-293 Camilloni, B., M. Neri, et al. (2009). "Cross-reactive antibodies in middle-aged and elderly volunteers after MF59-adjuvanted subunit trivalent influenza vaccine against B viruses of the B/Victoria or B/Yamagata lineages." Vaccine 27(31): 4099-4103. Carrat, F. and A. Flahault (2007). "Influenza vaccine: The challenge of antigenic drift." Vaccine 25(39-40): 6852-6862. Chan, Y. J., C. L. Lee, et al. (2010). "Seroprevalence of antibodies to pandemic (H1N1) 2009 influenza virus among hospital staff in a medical center in Taiwan." J Chin Med Assoc 73(2): 62-66. Chen, M. I. C., V. J. M. Lee, et al. (2010). "2009 Influenza A(H1N1) Seroconversion Rates and Risk Factors Among Distinct Adult Cohorts in Singapore." JAMA: The Journal of the American Medical Association 303(14): 1383-1391. Chiu, S. S., Y. L. Lau, et al. (2002). "Influenza-related hospitalizations among children in Hong Kong." N Engl J Med 347(26): 2097-2103. Clark, T. W., M. Pareek, et al. (2009). "Trial of 2009 influenza A (H1N1) monovalent MF59-adjuvanted vaccine." N Engl J Med 361(25): 2424-2435. Colombo, C., L. Argiolas, et al. (2001). "Influenza vaccine in healthy preschool children." Rev Epidemiol Sante Publique 49(2): 157-162. Couch, R. B. (2008). "Seasonal inactivated influenza virus vaccines." Vaccine 26 Suppl 4: D5-9. Cox, N. J. and K. Subbarao (2000). "Global epidemiology of influenza: past and present." Annu Rev Med 51: 407-421. Davies, J. R. and E. A. Grilli (1989). "Natural or vaccine-induced antibody as a predictor of immunity in the face of natural challenge with influenza viruses." Epidemiol Infect 102(2): 325-333. Dawood, F. S., S. Jain, et al. (2009). "Emergence of a novel swine-origin influenza A (H1N1) virus in humans." N Engl J Med 360(25): 2605-2615. Englund, J. A., E. B. Walter, et al. (2006). "Immunization With Trivalent Inactivated Influenza Vaccine in Partially Immunized Toddlers." Pediatrics 118(3): e579-e585. Fedson, D. S., A. Wajda, et al. (1993). "Clinical effectiveness of influenza vaccination in Manitoba." JAMA 270(16): 1956-1961. Ferguson, N. M., D. A. Cummings, et al. (2006). "Strategies for mitigating an influenza pandemic." Nature 442(7101): 448-452. Ferguson, N. M., A. P. Galvani, et al. (2003). "Ecological and immunological determinants of influenza evolution." Nature 422(6930): 428-433. Garten, R. J., C. T. Davis, et al. (2009). "Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans." Science 325(5937): 197-201. Govaert, T. M., C. T. Thijs, et al. (1994). "The efficacy of influenza vaccination in elderly individuals. A randomized double-blind placebo-controlled trial." JAMA 272(21): 1661-1665. Greenberg, M. E., M. H. Lai, et al. (2009). "Response to a monovalent 2009 influenza A (H1N1) vaccine." N Engl J Med 361(25): 2405-2413. Hancock, K., V. Veguilla, et al. (2009). "Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus." N Engl J Med 361(20): 1945-1952. Hannoun, C., F. Megas, et al. (2004). "Immunogenicity and protective efficacy of influenza vaccination." Virus Research 103(1-2): 133-138. Hannoun, C., F. Megas, et al. (2004). "Immunogenicity and protective efficacy of influenza vaccination." Virus Res 103(1-2): 133-138. Hu, J. J., C. L. Kao, et al. (2004). "Clinical features of influenza A and B in children and association with myositis." J Microbiol Immunol Infect 37(2): 95-98. Hurwitz, E. S., M. Haber, et al. (2000). "Studies of the 1996-1997 Inactivated Influenza Vaccine among Children Attending Day Care: Immunologic Response, Protection against Infection, and Clinical Effectiveness." The Journal of Infectious Diseases 182: 1218-1221. Itoh, Y., K. Shinya, et al. (2009). "In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses." Nature 460(7258): 1021-1025. Izurieta, H. S., W. W. Thompson, et al. (2000). "Influenza and the rates of hospitalization for respiratory disease among infants and young children." N Engl J Med 342(4): 232-239. Jackson C, Vynnycky E, Mangtani P (2010) Estimates of the transmissibility of the 1968 (Hong Kong) influenza pandemic: evidence of increased transmissibility between successive waves. Am J Epidemiol 171(4): 465-78. Jefferson, T., C. Di Pietrantonj, et al. (2010). "Vaccines for preventing influenza in the elderly." Cochrane Database Syst Rev(2): CD004876. Kelly, H. A., G. N. Mercer, et al. (2010). "Pandemic (H1N1) 2009 influenza community transmission was established in one Australian state when the virus was first identified in North America." PLoS One 5(6): e11341. Keren, G., S. Segev, et al. (1988). "Failure of influenza vaccination in the aged." J Med Virol 25(1): 85-89. King, J. C., Jr., J. J. Stoddard, et al. (2006). "Effectiveness of school-based influenza vaccination." N Engl J Med 355(24): 2523-2532. Koelle, K., S. Cobey, et al. (2006). "Epochal evolution shapes the phylodynamics of interpandemic influenza A (H3N2) in humans." Science 314(5807): 1898-1903. Kung, H. C., K. C. Huang, et al. (2010). "A clinical study to assess the immunogenicity and safety of a monovalent 2009 influenza A (H1N1) vaccine in an area with low-level epidemics of pandemic influenza." Vaccine 28(45): 7337-7343. Li, W. C., S. R. Shih, et al. (2008). "Clinical and genetic characterization of severe influenza B-associated diseases during an outbreak in Taiwan." J Clin Virol 42(1): 45-51. Longini, I. M., Jr., J. S. Koopman, et al. (1982). "Estimating household and community transmission parameters for influenza." Am J Epidemiol 115(5): 736-751. Lu, C.-Y., P.-L. Shao, et al. (2010). "Immunogenicity and safety of a monovalent vaccine for the 2009 pandemic influenza virus A (H1N1) in children and adolescents." Vaccine 28(36): 5864-5870. Manzoli, L., F. Schioppa, et al. (2007). "The efficacy of influenza vaccine for healthy children: a meta-analysis evaluating potential sources of variation in efficacy estimates including study quality." Pediatr Infect Dis J 26(2): 97-106. McCullers, J. A., T. Saito, et al. (2004). "Multiple genotypes of influenza B virus circulated between 1979 and 2003." J Virol 78(23): 12817-12828. Miller, E., K. Hoschler, et al. (2010). "Incidence of 2009 pandemic influenza A H1N1 infection in England: a cross-sectional serological study." Lancet 375(9720): 1100-1108. Morio, S., N. Okamoto, et al. (1994). "Three year follow up study of national influenza vaccination practices in Japan." J Epidemiol Community Health 48(1): 46-51. Mossad, S. B. (2003). "Demystifying FluMist, a new intranasal, live influenza vaccine." Cleve Clin J Med 70(9): 801-806. Neuzil, K. M., C. Hohlbein, et al. (2002). "Illness among schoolchildren during influenza season: effect on school absenteeism, parental absenteeism from work, and secondary illness in families." Arch Pediatr Adolesc Med 156(10): 986-991. Neuzil, K. M., L. A. Jackson, et al. (2006). "Immunogenicity and Reactogenicity of 1 versus 2 Doses of Trivalent Inactivated Influenza Vaccine in Vaccine-Naive 5-8-Year-Old Children." J Infect Dis 194: 1032-1039. Neuzil, K. M., B. G. Mellen, et al. (2000). "The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children." N Engl J Med 342(4): 225-231. Nichol, K. (2003). "The efficacy, effectiveness and cost-effectiveness of inactivated influenza virus vaccines." Vaccine 21(16): 1769-1775. Nichol, K. L., K. P. Mallon, et al. (2003). "Cost benefit of influenza vaccination in healthy, working adults: an economic analysis based on the results of a clinical trial of trivalent live attenuated influenza virus vaccine." Vaccine 21(17-18): 2207-2217. Nicholls, H. (2006). "Pandemic influenza: the inside story." PLoS Biol 4(2): e50. Nicholls, J. M., A. J. Bourne, et al. (2007). "Sialic acid receptor detection in the human respiratory tract: evidence for widespread distribution of potential binding sites for human and avian influenza viruses." Respir Res 8: 73. Noah, D. L. and R. M. Krug (2005). "Influenza virus virulence and its molecular determinants." Adv Virus Res 65: 121-145. Nolan, T., J. McVernon, et al. (2010). "Immunogenicity of a monovalent 2009 influenza A(H1N1) vaccine in infants and children: a randomized trial." JAMA 303(1): 37-46. Nolan, T., P. C. Richmond, et al. (2008). "Safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in infants and children." Vaccine 26(50): 6383-6391. Novartis, T. (2010). from http: // Olson, D. R., R. T. Heffernan, et al. (2007). "Monitoring the impact of influenza by age: emergency department fever and respiratory complaint surveillance in New York City." PLoS Med 4(8): e247. Organization., W. H. "Global Alert and Response (GAR) " Peacey, M., R. J. Hall, et al. (2010). "Pandemic (H1N1) 2009 and seasonal influenza A (H1N1) co-infection, New Zealand, 2009." Emerg Infect Dis 16(10): 1618-1620. Piedra, P. A., M. J. Gaglani, et al. (2007). "Trivalent Live Attenuated Intranasal Influenza Vaccine Administered During the 2003 2004 Influenza Type A (H3N2) Outbreak Provided Immediate, Direct, and Indirect Protection in Children." Pediatrics 120(3): e553-e564. Potter, C. W. (2001). "A history of influenza." J Appl Microbiol 91(4): 572-579. Reichert, T. A., N. Sugaya, et al. (2001). "The Japanese experience with vaccinating schoolchildren against influenza." N Engl J Med 344(12): 889-896. Ross, T., S. Zimmer, et al. (2010). "Seroprevalence Following the Second Wave of Pandemic 2009 H1N1 Influenza." PLoS Curr 2: RRN1148. Rota, P. A., T. R. Wallis, et al. (1990). "Cocirculation of two distinct evolutionary lineages of influenza type B virus since 1983." Virology 175(1): 59-68. Russell, C. A., T. C. Jones, et al. (2008). "The Global Circulation of Seasonal Influenza A (H3N2) Viruses." Science 320(5874): 340-346. Schweiger, B., L. Bruns, et al. (2006). "Reassortment between human A(H3N2) viruses is an important evolutionary mechanism." Vaccine 24(44-46): 6683-6690. Skowronski, D., C. Masaro, et al. (2007). "Estimating vaccine effectiveness against laboratory-confirmed influenza using a sentinel physician network: Results from the 2005-2006 season of dual A and B vaccine mismatch in Canada." Vaccine 25(15): 2842-2851. Skowronski, Danuta M., G. De Serres, et al. (2009). "Component‐Specific Effectiveness of Trivalent Influenza Vaccine as Monitored through a Sentinel Surveillance Network in Canada, 2006-2007." The Journal of Infectious Diseases 199(2): 168-179. Smith, D. J., A. S. Lapedes, et al. (2004). "Mapping the antigenic and genetic evolution of influenza virus." Science 305(5682): 371-376. Smith, S., V. Demicheli, et al. (2006). "Vaccines for preventing influenza in healthy children." Cochrane Database Syst Rev(1): CD004879. Thompson, W. W., D. K. Shay, et al. (2003). "Mortality associated with influenza and respiratory syncytial virus in the United States." JAMA 289(2): 179-186. Treanor, J. (2004). "Influenza vaccine--outmaneuvering antigenic shift and drift." N Engl J Med 350(3): 218-220. Vajo, Z., F. Tamas, et al. (2010). "Safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 2009-10 influenza season: a multicentre, randomised controlled trial." Lancet 375(9708): 49-55. Walter, E. B., K. M. Neuzil, et al. (2006). "Influenza Vaccine Immunogenicity in 6- to 23-Month-Old Children: Are Identical Antigens Necessary for Priming?" Pediatrics 118(3): e570-e578. Wang, C. S., S. T. Wang, et al. (2002). "Efficacy and cost-effectiveness of influenza vaccination of the elderly in a densely populated and unvaccinated community." Vaccine 20(19-20): 2494-2499. Wang, C. S., S. T. Wang, et al. (2004). "Reducing major cause-specific hospitalization rates and shortening hospital stays after influenza vaccination." Clin Infect Dis 39(11): 1604-1610. Wang, S. T., L. T. Lee, et al. (2005). "Economic evaluation of vaccination against influenza in the elderly: an experience from a population-based influenza vaccination program in Taiwan." Vaccine 23(16): 1973-1980. White, T., S. Lavoie, et al. (1999). "Potential cost savings attributable to influenza vaccination of school-aged children." Pediatrics 103(6): e73. WHO. (2009). "Pandemic (H1N1) vaccines and vaccination." from Wood, J. M. (2002). "Selection of influenza vaccine strains and developing pandemic vaccines." Vaccine 20 Suppl 5: B40-44. Yamaguchi, S., S. Ohfuji, et al. (2010). "Influenza vaccine effectiveness in primary school children in Japan: a prospective cohort study using rapid diagnostic test results." Journal of Infection and Chemotherapy 16(6): 407-413. Yang, J.-R., C.-H. Lin, et al. (2010). "A new antigenic variant of human influenza A (H3N2) virus isolated from airport and community surveillance in Taiwan in early 2009." Virus Research 151(1): 33-38.
簡介:流行性感冒是每年冬季好發的呼吸道傳染病,病原體流感病毒(Influenza virus)具有抗原性轉移及抗原性漂移之特性,使其每年幾乎都會產生抗原變異,因此評估體內流感病毒特異性的抗體、發展流感疫苗及評估疫苗之效益為近年來廣受公共衛生探討的議題。其中孩童是流感病毒的易感受者之一,易在得到流感之後傳播病毒給其他孩童或家中同住的年長者,因此我國的衛生疫苗政策在2007年開始實施國小1-2年級免費施打季節流感疫苗,到了2008年開始國小1-4年級學童均可免費施打;此外在2009年4月開始,新型流感在全球造成大流行,接著全球各地也開始大規模的施打新型流感疫苗。
研究目的:本研究從2008到2010年進行連續兩年流感流行季中國小學童體內流感病毒特異性的抗體及疫苗效益的評估,主要分成三大研究主軸:(1) 「國小學童及其家人對2009新型流感抗體分佈及相關因子」之研究 (2) 「國小學童施打新型流感疫苗後的免疫反應」之研究 (3) 「2008-2010流感流行季中國小學童體內對於季節流感病毒抗體分布情形及評估疫苗效益」之研究。
材料方法:收集來自台中及南投地區國小學童及其家人的血清樣本,利用血球凝集抑制試驗(Hemagglutination inhibition assay, HI)進行流感特異性抗體的偵測,藉由凝集紅血球的能力計算其HI抗體力價,接著利用不同的抗體評估指標來評估體內流感特異性抗體,包括幾何平均抗體力價、血清抗體保護率,及血清抗體四倍上升率等,並同時利用統計方法計算出疫苗效益,此外配合問卷及症狀日誌的填寫,了解研究期間類流感發生的比率。
結果:(1)針對2009年新型流感抗體之研究主軸:以306名國小學童及其家人為一追蹤族群(longitudinal cohort),追蹤期間橫跨新型流感大流行台灣第一名確診病患前,到新型流感在台灣地區流行早期,總共採集三次的血液樣本(2008年12月、2009年4-6月及9-10月)。利用HI抗體力價大於等於40為切點(cutoff)當作是否感染新型流感病毒之指標, 該族群在4-6月期間之感染率為14.1%;而到9-10月期間之感染率為31.7%。利用4-6月份及9-10月份的兩個不同抽血時間,在夏季第一波(summer wave)流行期間該族群有25.37%兩次血清抗體有顯著的4倍上升的情形,其中又以5-18歲年齡層抗體4倍上升比率較高(25.9%)、19-60歲為25.2%、60歲以上年齡層為25%,經統計分析後發現,家中若有人血清抗體有陽轉的情形,其他的家庭成員則有很高的血清抗體陽轉比例,且台中地區血清抗體陽性率明顯的高於南投地(p<0.05)。
(2)針對國小學童施打新型流感疫苗(pH1N1疫苗)後免疫反應之研究主軸:193名學童施打pH1N1疫苗並擁有疫苗施打前後配對血清,其中131名學童僅施打pH1N1疫苗,而有62名學童同時施打pH1N1疫苗及季節流感疫苗(TIV),對於所有施打pH1N1疫苗的學童而言,施打一劑pH1N1疫苗後一個月,血清保護率超過90%,且血清陽轉率也超過50%,此外,若是進一步利用疫苗前的抗體力價來進行比較,當pH1N1疫苗施打前對於疫苗株的抗體力價較低時(HI抗體力價小於40),僅施打pH1N1疫苗的學童與同時施打pH1N1疫苗及TIV的學童比較之下,擁有較高的血清抗體陽轉率(86%及55%),且達統計上顯著差異。而在pH1N1疫苗施打後僅有8.8%的學童產生發燒或類流感等副作用,其中又以發燒的比例較高3.6%。進一步利用6個月後的血清樣本進行疫苗效益的評估,對於pH1N1疫苗株而言,疫苗效益達87% (95% CI為84.6%-89.3%),對於台灣地區所分離的pH1N1野生株疫苗效益為57% (95% CI為39.3%-69.6%)。
(3)針對評估連續兩個流感流行季中季節流感疫苗效益之研究主軸:兩個流行季中所有參與研究的國小學童若是該年有接種季節流感疫苗,前一年也有較高比率的流感疫苗接種率,而利用研究期間不同時間點對於不同流感病毒的血清抗體力價也發現,就H3N2而言,利用學童的幾何平均抗體力價所繪製出的抗體時間曲線圖,對於不同的抗原飄移所產生的變異株(V0, V1及V3)所繪製出抗體曲線圖也有互相消長的情形,對於A/Taiwan/480/2008(V0)的GMT從142.17下降至55.73,再下降為21.54、 17.79。學童體內對抗A/Taiwan/736/2008(V1)的GMT也呈現類似的曲線圖,相反的,學童體內對於2009年出現的新變異株A/Taiwan/3982/2009(V3)之抗體GMT呈現相反的曲線圖,從8.6上升至14.83之後又再度上升至39.97、91.1及 102.8。整體疫苗效益在2008-2009流感流行季時為-27% (95% CI為-106%~22%),2009-2010流感流行季時為29% (95% CI為7%~46%)。就B型流感而言,連續兩個流行季的研究中均顯示疫苗施打後對於B型流感疫苗株的血清保護率(69%及64%)均比H3N2(約90%)來的低,且對於不同lineages(Yamagada 及Victoria)的B型流感間的交叉保護力是很低的,此外,利用不同lineage所計算出的感染率也顯示,兩個lineage是共同存在於環境中,連續兩年的疫苗效益為20%到30%,但並沒有達到統計上之意義。
結論: 利用血清學的方式評估不同時間點流感特異性的抗體力價,不論對於季節流感或是新型流感皆可與病毒分離率的資料相符合,顯示利用血清抗體對於以社區為背景的流感相關研究在評估流感疫苗效益及群體免疫方面是很重要的,由此研究也發現了群體免疫確實是影響流感病毒產生抗原飄移的一項重要因子。

Background: Trivalent inactivated influenza vaccine (TIV) is reformulated annually to contain representative strains of 2 influenza A subtypes (H1N1 and H3N2) and 1 B subtype for protection, but the impact of antigenic drift on vaccine effectiveness varies between seasons. Vaccination of children in school is one strategy to reduce the spread of influenza in households and communities. Focusing efforts for influenza vaccination on healthy children may therefore be an effective and practical method of reducing the burden of influenza in the community. Since 2008, children grades 1-4 in elementary school in Taiwan receive free TIV vaccination; moreover, during the 2009 pandemic H1N1 (pH1N1) period, anextra monovalent vaccine was used in Taiwan for protection against the 2009 pH1N1 virus. In this study, we described a serological cohort study to evaluate the dynamic change of herd immunity to different influenza viruses and component specific vaccine effectiveness (VE) during 2 consecutive influenza seasons of 2008-09 and 2009-10.

Methods: Children from elementary schools in Taichung city and Nantou county were enrolled during 2008-2009 and 2009-2010 seasons. The influenza viruses used in this study included vaccine strains and wildtype component H1N1, H3N2, influenza B viruses and pH1N1 virus, which represented the majority of isolations from clinical specimens collected in the corresponding seasons in Taiwan. Serum samples were taken from three different time periods to detect the antibody titers by using hemagglutination inhibition (HI) assay.

Results: Starting in the winter of 2008, age-specific 2009 pandemic H1N1 seroprevalence was calculated based on the antibodies against pH1N1 virus with an HI titer of 1:40 or more during three periods: seroprevalence in all age groups were 0% in December, 2008; seroprevalence in the age group of 5-18 years old was13.3%, 19-60 years old was 14.3%, above 60 years old was 18.8% in April-June, 2009 ; seroprevalence in the age group of 5-18 years old was 30.8%, 19-60 years old was 33.3%, above 60 years old was 25% in September- October, 2009. After the pH1N1 vaccination, seroprotecion rate among school-aged children who received 1 dose pH1N1vaccine was over 90% andthe seroconversion rate was over 50%.
We also evaluated the herd immunity and component specific vaccine effectiveness (VE), it revealed that the herd immunity against one of H3N2 variants (V0) decreased from 142.17 to 55.73 and further to 17.79; in contrast, the immunity against the other H3N2 variants (V3) increased from 8.6 to 14.83 and further up to 91.1 during December, 2008, April, and December, 2009, respectively. VE for A/H3N2 components was -27% (95% CI, -106%~22%),and 29% (95% CI,7%~46%) in the 2008/09 and 2009/10 influenza seasons, respectively. On the other hand, after receiving seasonal TIV, immunogenicity to influenza B virus was not as good as that to other vaccine components. The seroprotection rate of influenza B after vaccination were about 60% in both two influenza seasons while H3N2 were about 90%. Based on the serology data, low cross protection between two lineages (Yamagada and Victoria) was observed. VEs for influenza B subtype component were only at the range of 20% to 30% in 2008/09 and 2009/10 influenza season.

Conclusion: Our serological data suggested that the herd immunity results corresponded to the numbers of virus isolation of different antigenic drifted H3N2 strains according to Taiwan-CDC. It also confirmed that the immune selection pressure is the major driving force of H3N2 evolution and there were no or little cross protection between two influenza B lineages. Therefore, keep monitoring the herd immunity in different influenza viruses among children will be crucial to understand the VE of TIV.
其他識別: U0005-0808201115320400
Appears in Collections:微生物暨公共衛生學研究所

Show full item record

Google ScholarTM


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.