臺灣博碩士論文加值系統

背景:對於預防百日咳疾病發生，有兩種疫苗，為全細胞性百日咳疫苗(Whole-Cell Pertussis Vaccines、wP Vaccines、WPVs)與非細胞性百日咳疫苗(Acellular Pertussis Vaccines、aP Vaccines、ACVs)。因為疫苗涵蓋率(Vaccination Coverage)高，百日咳疾病受到控制，但2014年台灣爆發百日咳流行疫情。從流行病學調查得知：1.百日咳重症個案多為未滿一歲的幼童，2.家庭環境(75%)為百日咳的傳染源，39% (95%CI 33–45%)來自母親，16% (95%CI 12–21%) 來自父親，(16–43%)來自手足，而母親們與手足們不知道自身已感染百日咳，此因素導致未接受百日咳疫苗或未完全接受百日咳疫苗的幼童成為受感染的高危險族群，因此探討追加劑量(booster)使用的全細胞性百日咳疫苗與追加劑量(booster)非細胞性百日咳疫苗的疫苗功用(Vaccine Effectiveness)與疫苗保護期(the duration of vaccine-induced protection)顯得重要。
材料與方法:此論文為橫段式研究，此研究為第一篇擷取墨西哥(Mexico)國民與加拿大Ontario省居民的血清數據且使用數理建模(Mathematical model)的方式，探討時間變化與百日咳疫苗的疫苗效益與疫苗保護期之研究。
結果:利用墨西哥(Mexico)國民血清數據與數理建模(Mathematical model)的方式分析，本研究得知追加劑量(booster)使用全細胞性百日咳疫苗時，其疫苗效益與疫苗保護期使用趨勢線分析後，發現隨著時間增長而疫苗效益與疫苗保護期會減弱。加拿大Ontario省居民的血清數據與數理建模(Mathematical model)的方式分析，本研究得知追加劑量(booster)使用非全細胞性百日咳疫苗，其疫苗效益範圍0.830(95%CI 0.7967 to 0.864)與疫苗保護期範圍6.31年(95%CI 5.417118–7.564297)。
討論:此研究發現追加劑量(booster)使用全細胞性百日咳疫苗接種者，其疫苗效益有逐漸降低的趨勢，若6歲時追加劑量(booster)接受全細胞性百日咳疫苗者，約在6.26年後可能面臨對百日咳疾病失去保護力的風險，因此青少年有追加注射疫苗的需求，以降低罹病機率。追加劑量(booster)使用非全細胞性百日咳疫苗接種者，經過數理建模(Mathematical model)方法分析後，疫苗效益與疫苗保護期各只有一個數值，其疫苗效益0.83(95%CI 0.7967 to 0.864)與疫苗保護期6.31年(95%CI 5.417118–7.564297)與各國的研究相近。而2017年世界衛生組織(WHO)亦提出此論點，且建議含有非細胞性百日咳成份的疫苗(aP-containing vaccines)施打於7歲以上的孩童。墨西哥(Mexico)國民血清數據是來自不同人，以研究時年齡5歲、6歲、7歲、8歲、9歲、10歲、11歲、12歲、13歲、14歲的年齡分群，因為不同族群，因此，數理建模(Mathematical model)後的數值無法做比較的探討。所以，若有很多人的長期血清學資料，此數理建模(Mathematical model)工具可用來探討時間變化與疫苗效益和疫苗保護期。

Abstract:The best way to prevent pertussis is to get pertussis vaccines. And there are two different kinds of vaccines - Whole-Cell Pertussis Vaccines/wP Vaccines/WPVs along with Acellular Pertussis Vaccines/aP Vaccines/ACVs. Whooping cough disease is under control because of the high coverage rate of the vaccines, however, an outbreak of pertussis happened in Taiwan in 2014. Epidemiological investigations show that 1. The majority of severe cases of pertussis are young children under one year of age, 2. Family environment (75%) is the source of whooping cough infection, 33% from mothers, and most mothers do not know that they have whooping cough, which leads to young children who do not receive vaccines or not fully receive the vaccines have a higher risk for severe illness. Therefore, to analyze the vaccine effectiveness and the duration of vaccine-induced protection turns into important.
Materials and Methods:This paper is a cross-sectional study. This study is the first one to take the serum data from Mexican nationals and Canadian nationals (Ontario) populations to explore temporal change and pertussis vaccines using mathematical modeling.
Result:When Mexico''s national serum data and mathematical model analysis were used, this study learned that when whole-cell pertussis vaccine was took as a booster shot, the vaccine effectiveness and the duration of vaccine-induced protection would wane over time.Analysis of serum data and mathematical modeling of residents in Ontario, Canada, this study found that booster uses non-whole-cell pertussis vaccine, and the vaccine effectiveness was 0.830 (95% CI 0.7967 to 0.864). The duration of vaccine-induced protection is 6.31 years (95%CI 5.417118-7.564297).
Conclusion:The study found that someone received the aP vaccine as a booster shot was at risk of losing protection against whooping cough disease after several years. If someone received the whole-cell pertussis vaccine as a booster at the age of 6 years old, he may face a risk of losing protection against whooping cough disease after about 6.26 years. Therefore, the additional vaccinations were needed to reduce the risk of disease before immunity was reduced to non-protective. For those who took non-whole-cell pertussis vaccines for booster, the vaccine effectiveness and the duration of vaccine-induced protection have only one value by mathematical modeling, and the vaccine effectiveness is 0.83 (95%CI 0.7967 to 0.864)together with the duration of vaccine-induced protection is 6.31 years (95%CI 5.417118–7.564297), which is similar to studies in various countries. In 2017, the World Health Organization (WHO) also put forward this argument and recommended that aP-containing vaccines containing acellular pertussis components be administered to children over 7 years old. Mexico''s national serum data are from different people, grouped by ages of 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 at the time of the study. Because of the different ethnic groups, the numerical value from the mathematical modeling cannot be compared. Therefore, if long-term serology-based studies exist, this tool of mathematical model could be a good way to explore time changes and vaccine effectiveness and the duration of vaccine-induced protection.

目錄
第一章 緒論
第一節 研究背景與研究動機 1
第二節 研究的重性 4
第三節 研究目的 5
第四節 研究問題 5
第五節 名詞界定 6

第二章 文獻查證
第一節 百日咳疾病 6
第二節 百日咳的發生率 7
第三節 百日咳疫苗的差異性 7
第四節 百日咳的數理模式 8
第五節 研究架構 12
第六節 研究流程 12

第三章 研究方法
第一節 研究設計 13
第二節 研究對象 13
第三節 研究工具的擬定 17
第四節 資料收集過程 17
第五節 資料處理 18

第四章 研究結果
第一節 百日咳疫苗效用(The Vaccine Effectiveness)隨時間變化
18
第二節 百日咳疫苗衰退率(The Waning Rate of Vaccine-derived Protection)隨時間變化 19
第三節 百日咳疫苗保護期(The Duration of Vaccine-induced Protection)隨時間變化 20

第五章 討論
第一節 百日咳疫苗效用(The Vaccine Effectiveness)與各國的相關研究
21
第二節 百日咳疫苗保護期(The Duration of
Pertussis-vaccine-derived Protection)與各國的相關研究
22
第六章 結論與建議
第一節 結論 24
第二節 研究限制 25
第三節 應用與建議 26

Althouse, B. M. and S. V. Scarpino (2015). "Asymptomatic transmission and the resurgence of Bordetella pertussis." BMC Med 13: 146.
Amirthalingam, G., S. Gupta and H. Campbell (2013). "Pertussis immunisation and control in England and Wales, 1957 to 2012: a historical review." Euro Surveill 18(38).
Ausiello, C. and A. Cassone (2014). "Acellular Pertussis Vaccines and Pertussis Resurgence: Revise or Replace?" mBio 5.
Ausiello, C. M. and A. Cassone (2014). "Acellular pertussis vaccines and pertussis resurgence: revise or replace?" MBio 5(3): e01339-01314.
Barkoff, A. M., K. Grondahl-Yli-Hannuksela and Q. He (2015). "Seroprevalence studies of pertussis: what have we learned from different immunized populations." Pathog Dis 73(7).
Bisgard, K. M., F. B. Pascual, K. R. Ehresmann, C. A. Miller, C. Cianfrini, C. E. Jennings, C. A. Rebmann, J. Gabel, S. L. Schauer and S. M. Lett (2004). "Infant pertussis: who was the source?" Pediatr Infect Dis J 23(11): 985-989.
Campbell, H., G. Amirthalingam, N. Andrews, N. K. Fry, R. C. George, T. G. Harrison and E. Miller (2012). "Accelerating control of pertussis in England and Wales." Emerg Infect Dis 18(1): 38-47.
Campbell, P. T., J. M. McCaw and J. McVernon (2015). "Pertussis models to inform vaccine policy." Hum Vaccin Immunother 11(3): 669-678.
Cassels, S., S. J. Clark and M. Morris (2008). "Mathematical models for HIV transmission dynamics: tools for social and behavioral science research." Journal of acquired immune deficiency syndromes (1999) 47 Suppl 1(Suppl 1): S34-S39.
Chit, A., H. Zivaripiran, T. Shin, J. K. H. Lee, A. Tomovici, D. Macina, D. R. Johnson, M. D. Decker and J. Wu (2018). "Acellular pertussis vaccines effectiveness over time: A systematic review, meta-analysis and modeling study." PLoS One 13(6): e0197970.
Choi, Y. H., H. Campbell, G. Amirthalingam, A. J. van Hoek and E. Miller (2016). "Investigating the pertussis resurgence in England and Wales, and options for future control." BMC Med 14(1): 121.
Chow, M. Y., G. Khandaker and P. McIntyre (2016). "Global Childhood Deaths From Pertussis: A Historical Review." Clin Infect Dis 63(suppl 4): S134-S141.
Conde-Glez, C., E. Lazcano-Ponce, R. Rojas, R. DeAntonio, L. Romano-Mazzotti, Y. Cervantes and E. Ortega-Barria (2014). "Seroprevalence of Bordetella pertussis in the Mexican population: a cross-sectional study." Epidemiol Infect 142(4): 706-713.
de Greeff, S. C., H. E. de Melker, A. Westerhof, J. F. Schellekens, F. R. Mooi and M. van Boven (2012). "Estimation of household transmission rates of pertussis and the effect of cocooning vaccination strategies on infant pertussis." Epidemiology 23(6): 852-860.
Domenech de Celles, M., M. A. Riolo, F. M. Magpantay, P. Rohani and A. A. King (2014). "Epidemiological evidence for herd immunity induced by acellular pertussis vaccines." Proc Natl Acad Sci U S A 111(7): E716-717.
Doroshenko, A., W. Qian and N. D. Osgood (2016). "Evaluation of outbreak response immunization in the control of pertussis using agent-based modeling." PeerJ 4: e2337.
Elomaa, A., Q. He, N. N. Minh and J. Mertsola (2009). "Pertussis before and after the introduction of acellular pertussis vaccines in Finland." Vaccine 27(40): 5443-5449.
Esposito, S. and N. Principi (2016). "Immunization against pertussis in adolescents and adults." Clinical Microbiology and Infection 22: S89-S95.
Gambhir, M., T. A. Clark, S. Cauchemez, S. Y. Tartof, D. L. Swerdlow and N. M. Ferguson (2015). "A change in vaccine efficacy and duration of protection explains recent rises in pertussis incidence in the United States." PLoS Comput Biol 11(4): e1004138.
Gill, C., P. Rohani and D. M. Thea (2017). "The relationship between mucosal immunity, nasopharyngeal carriage, asymptomatic transmission and the resurgence of Bordetella pertussis." F1000Res 6: 1568.
Guiso, N., C. Levy, O. Romain, S. Guillot, A. Werner, M. C. Rondeau, S. Béchet and R. Cohen (2017). "Whooping cough surveillance in France in pediatric private practice in 2006–2015." Vaccine 35(45): 6083-6088.
Haller, S., M. Dehnert, I. Karagiannis, T. Rieck, C. Siffczyk, O. Wichmann, C. Poethko-Mueller and W. Hellenbrand (2015). "Effectiveness of routine and booster pertussis vaccination in children and adolescents, federal state of brandenburg, Germany, 2002-2012." Pediatr Infect Dis J 34(5): 513-519.
Healy, C. M., M. A. Rench, S. H. Wootton and L. A. Castagnini (2015). "Evaluation of the Impact of a Pertussis Cocooning Program on Infant Pertussis Infection." Pediatric Infectious Disease Journal 34(1): 22-26.
Hendrikx, L. H., L. G. de Rond, K. Ozturk, R. H. Veenhoven, E. A. Sanders, G. A. Berbers and A. M. Buisman (2011). "Impact of infant and preschool pertussis vaccinations on memory B-cell responses in children at 4 years of age." Vaccine 29(34): 5725-5730.
Hethcote, H. W. (2000). "The Mathematics of Infectious Diseases." SIAM Review 42(4): 599-653.
Kilgore, P. E., A. M. Salim, M. J. Zervos and H. J. Schmitt (2016). "Pertussis: Microbiology, Disease, Treatment, and Prevention." Clin Microbiol Rev 29(3): 449-486.
Kim, S. Y. (2013). "Efficacy versus Effectiveness." Korean journal of family medicine 34(4): 227-227.
Klein, N. P., J. Bartlett, A. Rowhani-Rahbar, B. Fireman and R. Baxter (2012). "Waning protection after fifth dose of acellular pertussis vaccine in children." N Engl J Med 367(11): 1012-1019.
Libster, R. and K. Edwards (2012). "Re-emergence of pertussis: what are the solutions?" Expert review of vaccines 11: 1331-1346.
Mahmood, K., S. Pelkowski, D. Atherly, R. D. Sitrin and J. J. Donnelly (2013). "Hexavalent IPV-based combination vaccines for public-sector markets of low-resource countries." Hum Vaccin Immunother 9(9): 1894-1902.
McGirr, A. and D. N. Fisman (2015). "Duration of Pertussis Immunity After DTaP Immunization: A Meta-analysis." Pediatrics 135(2): 331-343.
Melvin, J. A., E. V. Scheller, J. F. Miller and P. A. Cotter (2014). "Bordetella pertussis pathogenesis: current and future challenges." Nat Rev Microbiol 12(4): 274-288.
Mooi, F. R., N. A. Van Der Maas and H. E. De Melker (2014). "Pertussis resurgence: waning immunity and pathogen adaptation - two sides of the same coin." Epidemiol Infect 142(4): 685-694.
Ntezayabo, B., G. De Serres and B. Duval (2003). "Pertussis resurgence in Canada largely caused by a cohort effect." Pediatr Infect Dis J 22(1): 22-27.
Octavia, S., V. Sintchenko, G. L. Gilbert, A. Lawrence, A. D. Keil, G. Hogg and R. Lan (2012). "Newly Emerging Clones of Bordetella pertussis Carrying prn2 and ptxP3 Alleles Implicated in Australian Pertussis Epidemic in 2008–2010." The Journal of Infectious Diseases 205(8): 1220-1224.
Quinn, H. E. and P. B. McIntyre (2011). "The impact of adolescent pertussis immunization, 2004-2009: lessons from Australia." Bull World Health Organ 89(9): 666-674.
Schwartz, K. L., J. C. Kwong, S. L. Deeks, M. A. Campitelli, F. B. Jamieson, A. Marchand-Austin, T. A. Stukel, L. Rosella, N. Daneman, S. Bolotin, S. J. Drews, H. Rilkoff and N. S. Crowcroft (2016). "Effectiveness of pertussis vaccination and duration of immunity." CMAJ 188(16): E399-E406.
Sheridan, S. L., K. Frith, T. L. Snelling, K. Grimwood, P. B. McIntyre and S. B. Lambert (2014). "Waning vaccine immunity in teenagers primed with whole cell and acellular pertussis vaccine: recent epidemiology." Expert Rev Vaccines 13(9): 1081-1106.
van Boven, M., H. E. de Melker, J. F. Schellekens and M. Kretzschmar (2000). "Waning immunity and sub-clinical infection in an epidemic model: implications for pertussis in The Netherlands." Math Biosci 164(2): 161-182.
Vilajeliu, A., A. Gonce, M. Lopez, J. Costa, L. Rocamora, J. Rios, I. Teixido, J. M. Bayas and P. W. Group (2015). "Combined tetanus-diphtheria and pertussis vaccine during pregnancy: transfer of maternal pertussis antibodies to the newborn." Vaccine 33(8): 1056-1062.
Warfel, J. M. and K. M. Edwards (2015). "Pertussis vaccines and the challenge of inducing durable immunity." Curr Opin Immunol 35: 48-54.
Wearing, H. J. and P. Rohani (2009). "Estimating the duration of pertussis immunity using epidemiological signatures." PLoS Pathog 5(10): e1000647.
Wendelboe, A. M., E. Njamkepo, A. Bourillon, D. D. Floret, J. Gaudelus, M. Gerber, E. Grimprel, D. Greenberg, S. Halperin, J. Liese, F. Munoz-Rivas, R. Teyssou, N. Guiso, A. Van Rie and G. Infant Pertussis Study (2007). "Transmission of Bordetella pertussis to young infants." Pediatr Infect Dis J 26(4): 293-299.
Wendelboe, A. M., A. Van Rie, S. Salmaso and J. A. Englund (2005). "Duration of immunity against pertussis after natural infection or vaccination." Pediatr Infect Dis J 24(5 Suppl): S58-61.
Wiley, K. E., Y. Zuo, K. K. Macartney and P. B. McIntyre (2013). "Sources of pertussis infection in young infants: A review of key evidence informing targeting of the cocoon strategy." Vaccine 31(4): 618-625.
Xu, J., S. Liu, Q. Liu, R. Rong, W. Tang, Q. Wang, S. Kuang and C. Zhou (2019). "The effectiveness and safety of pertussis booster vaccination for adolescents and adults: A systematic review and meta-analysis." Medicine (Baltimore) 98(16): e15281.
Yeung, K. H. T., P. Duclos, E. A. S. Nelson and R. C. W. Hutubessy (2017). "An update of the global burden of pertussis in children younger than 5 years: a modelling study." Lancet Infect Dis 17(9): 974-980.

2.Centers for Disease Control, Taiwan.(Kilgore, Salim et al. 2016)
https://www.cdc.gov.tw/Disease/SubIndex/gJ7r9uf6cgWWczRSeMRibA
3.Centers for Disease Control, Taiwan. http://www.cdc.gov.tw/professional/themanet.aspx?did=654&treeid=F60D469E29C652FB&nowtreeid=F60D469E29C652FB
4. Center for Disease Control, Taiwan. Final Pertussis Surveillance Report. Available at: www.cdc.gov/pertussis/downloads/pertussis-surveillance-report.pdf. Accessed March 10, 2014.
5.百日咳預防與治療 許馨尹 黃偉新 家庭醫學與基層醫療第三十卷第五期Available at file:///C:/Users/User/AppData/Local/Temp/02-300504.pdf
6. WHO Information Sheet: Observed rate of vaccine reactions – Diphtheria, pertussis,tetanus vaccines, May 2014. Available at http://www.who.int/vaccine_safety/initiative/tools/DTP_vaccine_rates_information_sheet.pdf?ua=1; accessed July 2015.
7.臨床療效及功效 (Clinical effectiveness & Efficacy) Available at: https://nihta.cde.org.tw/Knowledge/cyclopedia_more?id=25
8.白日咳確定病例與接種百日咳疫苗之關係　王志銘　
9.Centers for Disease Control, Taiwan. 疫苗、藥品費用及取得方式 Available at: https://www.cdc.gov.tw/Category/ListContent/YipvR33b32K-dsMI2eIrIg?uaid=7xJffAe-293ImV5qeweoeQ
10. Etymologia:Bordetella pertussis. Emerg Infect Dis [serial on the Internet]. 2010, Aug [date cited]. Available at: http://dx.doi.org/10.3201/eid1608.ET1608
11. 微生物知識Bordetella pertussis. Available at:
http://microbiology.scu.edu.tw/MIB/micro/bacteria/B8.htm
12. Immunization, Vaccines and Biologicals Pertussis? Available at: https://www.who.int/immunization/monitoring_surveillance/burden/vpd/surveillance_type/passive/pertussis/en/
13. WHO. Immunization, Vaccines and Biologicals: pertussis. Available from: www.who.int/immunization/topics/pertussis/en/index.html [Last accessed 30 March 2014]
14. Wyman O. The supply landscape and economics of IPV-containing combination vaccines: key findings. Commissioned by the Bill & Melinda Gates Foundation; 2010