摘要:根據歐美和非洲地區的研究,肺炎球菌是大多數國家、地區引起愛滋病毒感染者的菌血症和細菌性肺炎等呼吸道感染最常見的病原;在18 歲到64 歲年齡層中,愛滋病毒感染者發生侵犯性的肺炎球菌感染(invasive pneumococcal diseases)的機會,較未感染愛滋病毒者高達46 到100 倍。因此,美國疾病管制與預防中心(Centers forDisease Control and Prevention;CDC)參考以美國地區為主進行的回溯性觀察研究,建議愛滋病毒感染者應接種肺炎球菌疫苗(pneumococcal vaccine)。但是,愛滋病毒感染者接種肺炎球菌疫苗後,產生抗體的能力較未感染愛滋病毒者來得差,而且,CD4+淋巴球數越低的感染者,產生抗體的能力越差。因此,美國疾病管制與預防中心建議愛滋病毒感染者在接受抗病毒治療CD4+淋巴球數上升到200/μL以後,應再追加疫苗接種。自從2000 年6 月起,我們已經針對在臺大醫院追蹤的450 多位愛滋病毒感染者進行含23 價肺炎雙球菌抗原的疫苗(23-valent pneumococcal polysaccharidevaccine)接種(Hung CC, CROI, 2004; Hung CC, et al. Vaccine, 2004)。但是,在長達五年的血清抗體效價(PPS 14, 19F, 23F, 和6B)追蹤研究中(2005/7/1-2006/6/30、2007/8/1-2010/7/30 國科會研究計畫;Hung CC, et al. International AIDS Congress,Toronto, 2006; Hung CC, HIV Medicine 2010),我們發現愛滋病毒感染者接種疫苗後,接種時CD4+淋巴球數低於100 cells/μL的患者,其血清抗體效價遠低於接種時CD4+淋巴球數高於200 cells/μL的患者;其次,隨著時間逐年下降;不論接種時CD4+淋巴球數高低,血清抗體在第五年時都有顯著的下降;在逐年的多變項分析,我們也發現,能否在五年後維持有效的血清抗體反應,和愛滋病毒是否受到有效控制與接種時CD4+淋巴球數高低相關。針對接受過23 價肺炎球菌疫苗接種五年以上的愛滋病毒感染者,國外專家的建議是給予相同的疫苗追加接種。但是,對於此建議,目前文獻中尚缺乏長期追蹤的研究。對於這個臨床問題,我們在持續的研究中(2007/8/1-2010/7/30 國科會研究計畫;Hung CC, et al. European Congress ofMicrobiology and Infectious Diseases, Helsinki, 2009),針對129 位患者已經在初次接種肺炎球菌疫苗的五年後,再追加接種一次23 價肺炎雙球菌抗原的疫苗,我們持續在固定時間(每3 個月)收集病患定期返院就診接受病毒量和CD4+淋巴球數常規檢驗餘留的血清檢體,進行血清肺炎球菌抗體的檢驗,每一位患者至少接受一年以上的追蹤,同時也接受抗愛滋病毒藥物治療。透過長期的血清抗體變化的追蹤,我們同時發現血清中肺炎球菌抗體的變化仍然和接種時CD4+淋巴球數和初次接種疫苗後三到六個月的血清中肺炎球菌抗體的量有關(Hung CC, et al. European Congress ofMicrobiology and Infectious Diseases, Helsinki, 2009)。在這些一系列追蹤的研究中,我們發現愛滋病毒感染者因為免疫功能的缺損,對於多醣體抗原的免疫反應較差,因此,過去一年中,我們在國科會的研究贊助下(2007/8/1-2010/7/30 國科會研究計畫),開始針對於未曾接受肺炎疫苗接種的感染者,和已經在五年前接受過23 價多醣體抗原肺炎雙球菌的愛滋病毒感染者,提供七價接合蛋白質肺炎疫苗(7-valent conjugatepneumococcal vaccine)。疫苗的接種,包括一劑和兩劑(間隔一個月)的接種方式。這個三年的研究計劃在明年七月結案時,我們預期會有250 位初次接種七價接合蛋白質肺炎疫苗的感染者完成接種(其中大約130 接種二劑,120 接種一劑),並且其中有六成的患者會陸續完成一年的定期(每3 個月)追蹤;其次,我們也預期會有80 位已經在五年前接受過23 價多醣體抗原肺炎雙球菌的愛滋病毒感染者,陸續完成追加接種一劑或兩劑(間隔一個月)的七價接合蛋白質肺炎疫苗(其中大約40 接種二劑,40 接種一劑)。我們希望在未來三年中,有機會再度獲得國科會支持,目標是完成450 位感染者初次接種七價接合蛋白質肺炎疫苗和120 位感染者追加接種七價接合蛋白質肺炎疫苗,並且接種疫苗後(包括450 位初次接種和120 位感染者追加接種的感染者)至少二年的血清抗體追蹤,我們將同時和過去已經完成的接種23 價多醣體抗原肺炎球菌疫苗的血清抗體反應比較。期待這些研究能協助釐清對於愛滋病毒感染者,不論是初次接種或者是追加接種肺炎疫苗,七價接合蛋白質肺炎疫苗是否優於23 價多醣體抗原肺炎球菌疫苗。我們預期未來三年陸續發表3 篇論文,希望本研究成果能針對國際間對於免疫缺損的愛滋病毒感染者的肺炎疫苗接種的建議,提供足夠的血清抗體反應長期追蹤的證據。
Abstract: Patients with HIV infection are at higher risk for invasive infections due toStreptococcus pneumoniae as compared with those without HIV infection. The USCenters for Disease Control and Prevention (CDC) has strongly recommended thatpneumococcal vaccination be given to patients with HIV infection who are aged 2years and a CD4+ count 200 cells/μL. In addition, revaccination is recommendedwhen the CD4+ count increases to 200 cells/μL in patients with an initial CD4+ countof <200 cells/μL after receiving antiretroviral therapies. In previous study, we haveevaluated the clinical benefits of vaccination with the 23-valent pneumococcal vaccineon HIV-infected patients who were receiving highly active antiretroviral therapy(HAART). Our data suggested that vaccination with 23-valent pneumococcalpolysaccharide vaccine (PPV) reduced risks for pneumococcal disease and wasassociated with a lower risk for death among HIV-1-infected patients receiving HAARTand PPV. Vaccination did not increase the risks of all-cause community-acquiredpneumonia and HIV progression; and CD4+ continued to increase and PVL decreaseamong HIV-1-infected patients receiving HAART (Hung CC, et al. Vaccine 2004). Inaddition, we have evaluated the long-term antibody responses to pneumococcalcapsular polysaccharides (PPS 14, 19F, 23F, or 6B) in a longitudinal follow-up studysponsored by NSC (2005/7/1-2006/6/30 and 2007/8/1-2010/7/30). We have foundthat the proportion of responders to the three serotypes (PPS 14, 19F, 23F) wassignificantly lower among patients with baseline CD4<100 cells/μL compared withthose with CD4 counts of 100 cells/μLor greater during yearly follow-up. Much fasterloss of antibody responses was observed in among patients with baseline CD4<100cells/μL, although the rate of decline varied with serotypes studied in the four studygroups. Compared with the non-responders, more responders had CD4+ count >100cells/L at vaccination and achieved a better virological suppression throughout the5-year period, while the absolute increases of CD4 counts after HAART were notstatistically significantly different. We concluded that despite continued increases ofCD4+ counts after HAART, the proportion of patients who maintained antibodyresponses to PPV among the HIV-infected patients declined significantly over the5-year follow-up period, especially those who had CD4+ count <100 cells/L atvaccination and who failed to achieve virological suppression. (16th International AIDSCongress. Abstract no. THPE0054. Toronto 12-17 August, 2006 Hung CC, HIVMedicine 2010). With the continued sponsor from NSC, we have also providedbooster vaccination using 23-valent PPV to 129 HIV-infected patients. We have foundthat the serological responses 1 year after booster vaccination was associated withbaseline CD4 counts at primary vaccination and serological response 3-6 monthsafter booster vaccination (Hung CC, et al. European Congress of Microbiology andInfectious Diseases, Helsinki, 2009). Recent publications of studies investigating theserological responses to 7-valent conjugate pneumococcal vaccine among elderlyand immunocompromised hosts have prompted us to initiate another two studies toinvestigate the serological responses to investigating the serological responses to7-valent conjugate pneumococcal vaccine among HIV-infected patients who arereceiving HAART. In the past 1 year, we have completed primary vaccination in 250HIV-infected patients and booster vaccination in 80 HIV-infected patients who hadreceived 23-valent PPV 5 years earlier. In the next three years, we anticipate tocomplete primary vaccination and follow-up for at least 1 to 2 years 450 patients andbooster vaccination in 120 patients. All of the vaccines will receive regular follow-upand blood sampling will be performed every 3 months in the first 12 months and 6months every year for the next 5 years to assess the trends of changes ofanti-capsular antibodies following primary vaccination and booster vaccination.Comparisons of serological responses will be made between patients receiving23-valent PPV and those receiving 7-valent conjugate pneumococcal vaccine.Through the determinations of the antibodies, we will be able to understand the bestvaccine in terms of serological responses among HIV-infected patients who continueto receive HAART.