小劑量黃熱病疫苗的免疫原性和安全性不劣於標準劑量
作者：
小柯機器人發布時間：2021/1/9 21:09:47
法國巴黎Epicentre生物技術公司Rebecca F Grais團隊研究了部分劑量黃熱病疫苗的免疫原性和安全性。2021年1月9日，該研究發表在《柳葉刀》雜誌上。
黃熱病疫苗的庫存不足以滿足疫情應對的特殊需求。分次給藥已顯示出療效，但證據僅限於17DD亞株疫苗。研究組評估了五分之一劑量的黃熱病疫苗與標準劑量的黃熱病疫苗的免疫原性和安全性。
研究組在烏幹達姆巴拉和肯亞基利菲的研究中心進行了這項隨機、雙盲、非劣效性試驗，招募年齡在18-59歲、沒有接種疫苗禁忌症、非孕期或哺乳期、沒有黃熱病疫苗接種或感染史、旅行時不需要接種黃熱病疫苗的參與者。
將這些參與者隨機分為8組，分別接種標準劑量或小劑量的4種疫苗。主要結局是接種後28天血清轉化的參與者比例，其中血清轉化定義為接種後中和抗體滴度至少為接種前的4倍，通過50%菌斑減少中和試驗（PRNT50）測量。研究組將非劣效性定義為接種後28天，與標準劑量組相比，小劑量組血清轉化率降低不到10%。
2017年11月6日至2018年2月21日，共有1029名參與者接種後納入評估。69人不合格，960名參與者被登記並隨機分配至8組，每組120人，分別接受四種製造商疫苗標準劑量和小劑量接種。49名受試者在基線檢查時可檢測到PRNT50，11名受試者在基線檢查或28天時未檢測到PRNT50結果。
900人被納入方案分析。959名參與者被納入安全性分析。四種製造商疫苗標準劑量和小劑量接種後血清轉化率的絕對差異分別為1.71%、0.90%、1.82%和0.0%，均符合非劣效性標準。最常見的治療相關不良事件為頭痛（22.2%）、疲勞（13.7%）、肌痛（13.3%）和自述發熱（9.0%）。未發生與研究疫苗相關的嚴重不良事件。
研究結果表明，接種世衛組織所有通過資格預審的黃熱病疫苗的部分劑量後，28天的誘導血清轉化率不低於標準劑量，沒有重大安全問題。這些結果支持在疫苗短缺的情況下，在普通成人人群中使用部分劑量來應對疫情。
附：英文原文
Title: Immunogenicity and safety of fractional doses of yellow fever vaccines: a randomised, double-blind, non-inferiority trial
Author: Aitana Juan-Giner, Derick Kimathi, Kyra H Grantz, Mainga Hamaluba, Patrick Kazooba, Patricia Njuguna, Gamou Fall, Moussa Dia, Ndeye S Bob, Thomas P Monath, Alan D Barrett, Joachim Hombach, Edgar M Mulogo, Immaculate Ampeire, Henry K Karanja, Dan Nyehangane, Juliet Mwanga-Amumpaire, Derek A T Cummings, Philip Bejon, George M Warimwe, Rebecca F Grais
Issue&Volume: 2021/01/09
Abstract:
Background
Stocks of yellow fever vaccine are insufficient to cover exceptional demands for outbreak response. Fractional dosing has shown efficacy, but evidence is limited to the 17DD substrain vaccine. We assessed the immunogenicity and safety of one-fifth fractional dose compared with standard dose of four WHO-prequalified yellow fever vaccines produced from three substrains.
Methods
We did this randomised, double-blind, non-inferiority trial at research centres in Mbarara, Uganda, and Kilifi, Kenya. Eligible participants were aged 18–59 years, had no contraindications for vaccination, were not pregnant or lactating, had no history of yellow fever vaccination or infection, and did not require yellow fever vaccination for travel. Eligible participants were recruited from communities and randomly assigned to one of eight groups, corresponding to the four vaccines at standard or fractional dose. The vaccine was administered subcutaneously by nurses who were not masked to treatment, but participants and other study personnel were masked to vaccine allocation. The primary outcome was proportion of participants with seroconversion 28 days after vaccination. Seroconversion was defined as post-vaccination neutralising antibody titres at least 4 times pre-vaccination measurement measured by 50% plaque reduction neutralisation test (PRNT50). We defined non-inferiority as less than 10% decrease in seroconversion in fractional compared with standard dose groups 28 days after vaccination. The primary outcome was measured in the per-protocol population, and safety analyses included all vaccinated participants. This trial is registered with ClinicalTrials.gov, NCT02991495.
Findings
Between Nov 6, 2017, and Feb 21, 2018, 1029 participants were assessed for inclusion. 69 people were ineligible, and 960 participants were enrolled and randomly assigned to vaccine manufacturer and dose (120 to Bio-Manguinhos-Fiocruz standard dose, 120 to Bio-Manguinhos-Fiocruz fractional dose, 120 to Chumakov Institute of Poliomyelitis and Viral Encephalitides standard dose, 120 to Chumakov Institute of Poliomyelitis and Viral Encephalitides fractional dose, 120 to Institut Pasteur Dakar standard dose, 120 to Institut Pasteur Dakar fractional dose, 120 to Sanofi Pasteur standard dose, and 120 to Sanofi Pasteur fractional dose). 49 participants had detectable PRNT50 at baseline and 11 had missing PRNT50 results at baseline or 28 days. 900 were included in the per-protocol analysis. 959 participants were included in the safety analysis. The absolute difference in seroconversion between fractional and standard doses by vaccine was 1·71% (95% CI 2·60 to 5·28) for Bio-Manguinhos-Fiocruz, 0·90% (–4·24 to 3·13) for Chumakov Institute of Poliomyelitis and Viral Encephalitides, 1·82% (–2·75 to 5·39) for Institut Pasteur Dakar, and 0·0% (–3·32 to 3·29) for Sanofi Pasteur. Fractional doses from all four vaccines met the non-inferiority criterion. The most common treatment-related adverse events were headache (22·2%), fatigue (13·7%), myalgia (13·3%) and self-reported fever (9·0%). There were no study-vaccine related serious adverse events.
Interpretation
Fractional doses of all WHO-prequalified yellow fever vaccines were non-inferior to the standard dose in inducing seroconversion 28 days after vaccination, with no major safety concerns. These results support the use of fractional dosage in the general adult population for outbreak response in situations of vaccine shortage.
DOI: 10.1016/S0140-6736(20)32520-4
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32520-4/fulltext