以實證為基礎之流感應變整備

Abstract

1.國際間針對2009年新型A型 H1N1 流感病毒（2009 pdm A / H1N1）引發之病例死亡率（CFR）研究，存在很大差異性。本文主要係為研究比較2009年至2011年間，台灣感染新型A型H1N1流感病毒病例的病例死亡率與感染季節性A型H3N2流感病毒的病例死亡率，加以調整干擾因素，以釐清新型A型H1N1流感病毒是否叫季節性流感病毒有更強的致死率。結果發現2009年7月至2011年6月期間我國感染新型A型H1N1流感病毒的2232位個案，比起831位感染季節性A型H3N2流感病毒個案，年齡較小，患慢性潛在疾病的個案較少。感染新型A型H1N1流感病毒病例的粗死亡率與H3N2流感病毒病例相近，在利用多變量邏輯式回歸分析後則顯示，經調整年齡，性別，慢性病史，抗病毒藥劑使用和疫苗史的影響後，新型A型H1N1流感病毒引起的致死率則顯著高於A型H3N2流感病毒（調整比值比1.2,95％信賴區間：1.0-1.9，p = 0.04）。 2.以鋁鹽作為流感大流行疫苗佐劑效用-系統性文獻回顧分析禽源性H5 / H7流感病毒有可能引發流感大流行，因此，流感大流行疫苗的使用與備製是整備工作中重要的一環。然而，人類對禽流感病毒表面抗原產生的免疫反應通常較差，因此疫苗製造過程中通常會以添加佐劑來的方式增加大流行前流感疫苗於人體產生的保護力。其中，鋁鹽是目前已經批准，安全夠且價格合理的佐劑，但其對流感疫苗的保護功效的提升程度仍未得到驗證文獻資料蒐集共有9項隨機對照試驗（2006-2013間共計有 22項臨床試驗比較資料，總計2,467名參與者）分別接種含鋁鹽佐劑H5N1疫苗與不含鋁鹽佐劑疫苗個案。單劑量含鋁鹽佐劑H5N1疫苗接種後其血清抗體生成保護率與細胞凝集抑制中和試驗的血清保護率之比為0.66（95％CI：0.53-0.83），與0.56（95％CI：0.42-0.74），且注射部位出現疼痛風險估計值為1.85（95％CI：1.56至2.19）。證據顯示，接種含鋁鹽佐劑的H5N1疫苗後，產生的血清抗體保護率比例顯著降低，且注射部位疼痛風險顯著增加，故代表鋁鹽降低了疫苗的免疫功效，但增加了接種部位出現局部反應的風險。 3.水包油乳劑佐劑流感疫苗對於兒童之接種疫苗效益討論-系統性文獻回顧分析減毒活性流感疫苗對於未曾感染過流感的健康幼兒能產生的保護效果有限，但該族群又是感染流感的高風險族群，因此，提供具有更好保護效益的流感疫苗被認為是兒童流感疫苗的重要議題。添加水包油乳劑佐劑流感疫苗是近年被認為有可能改善前揭問題的解決方式，但截至目前為止，臨床試驗產生了不一致的結果。因此本研究以系統性文獻回顧方法分析所有隨機對照試驗的疫苗功效數據（共有 3項試驗，n = 15,310）和血清抗體測驗數據（17項試驗，n = 9,062）。與無佐劑的疫苗相比，佐劑化的流感疫苗顯著有更好的保護功效（以RT-PCR接種含佐劑流感疫苗感染流感的風險為接種未含佐劑疫苗者的0.26），抗體測驗數據也顯示，對於未曾感染流感的兒童，血清抗體四倍以上上升的個案較接種未含佐劑組別的4.6-7.9倍。然而，在曾感染流感的兒童身上，則發現含佐劑和未含佐劑疫苗提供之保護效果類似。以上結果顯示，含水包油乳劑佐劑流感疫苗對於第一次接種流感疫苗的健康兒童提供更好的保護效果。

1.Case Fatality Rate of 2009 Pandemic H1N1 Influenza：Using Seasonal H3N2 Influenza as Comparison Group: We aimed to compare CFRs of 2009 pdm A/H1N1 influenza cases with that of seasonal influenza A/H3N2 cases, with adjustment for confounding factors. This is a retrospective cohort study, which used all virologically confirmed cases which met the surveillance definition of severe influenza from Taiwan nationwide public health surveillance to analyze 2009 pdm A/H1N1 influenza-related mortality.A total of 2232 2009 pdm A/H1N1 cases and 831 A/H3N2 cases during the period from July 2009 to June 2011 were included. H1N1 cases were younger and less likely to have chronic underlying disease than H3N2 cases. The 2009 H1N1 cases had a similar crude CFR than H3N2 (9.2% vs. 8.5, p=0.76). Multivariate logistic regression show that after adjusting for the effect of age, sex, chronic disease history, oseltamivir use, and vaccine history, H1N1 had a significantly higher adjusted CFR than H3N2 (adjust OR 1.2, 95% CI: 1.0-1.9, p=0.04). We concluded that the virulence of H1N1/09pdm is only slightly higher than seasonal influenza, and people with comorbidity beer the most impact from the 2009 H1N1 epidemic. 2.Aluminum salts as an adjuvant for pre-pandemic influenza vaccines: a meta-analysis: Availability of effective vaccines is an essential part of pre-pandemic preparedness. However, avian influenza surface antigens are poorly immunogenic to humans, which necessitates the use of adjuvants to augment the immunogenicity of pre-pandemic influenza vaccines. Aluminum salts are approved, safe, and affordable adjuvants, but their adjuvanticity for influenza vaccines remains unverified. We conducted the first meta-analysis on this issue. A total of nine randomized controlled trials (2006–2013, 22 comparisons, 2,467 participants in total) compared aluminum-adjuvanted H5N1 vaccines versus non-adjuvanted counterparts. The weighted estimate for the ratio of the seroprotection rate after a single dose of H5N1 vaccine is 0.66 (95% CI: 0.53 to 0.83) by hemagglutination-inhibition assay or 0.56 (95% CI: 0.42 to 0.74) by neutralizing titer assay. The weighted estimate for the risk ratio of pain/tenderness at injection sites is 1.85 (95% CI: 1.56 to 2.19). The quality of evidence is low to very low for seroprotection and moderate for pain/tenderness, respectively. The significantly lower seroprotection rate after aluminum-adjuvanted H5N1 vaccines and the significantly higher risk of pain at injection sites indicate that aluminum salts decrease immunogenicity but increase local reactogenicity of pre-pandemic H5N1 vaccines in humans. 3.Oil-in-water emulsion adjuvants for pediatric influenza vaccines: a systematic review and meta-analysis:Standard inactivated influenza vaccines are poorly immunogenic in immunologically naive healthy young children. For them, there is an unmet need for better influenza vaccines. Oil-in-water emulsion-adjuvanted influenza vaccines are promising candidates, but clinical trials yielded inconsistent results. Here, we meta-analyzed all randomized controlled trials with efficacy data (3 trials, n=15,310) and immunogenicity data (17 trials, n=9,062). Compared with non-adjuvanted counterparts, adjuvanted influenza vaccines provided a significantly better protection (weighted estimate for risk ratio of RT-PCR-confirmed influenza: 0.26) and were significantly more immunogenic (weighted estimates for seroprotection rate ratio: 4.6 to 7.9) in healthy immunologically naive young children. Nevertheless, in immunologically non-naive children, adjuvanted and non-adjuvanted vaccines provided similar protection and were similarly immunogenic. These results indicated that oil-in-water emulsion adjuvant is highly effective in improving the efficacy of inactivated influenza vaccines in healthy young children at the first-time seasonal influenza vaccination.