在結核病控制上優化 BCG、ChAdOx1 85A 和 MVA85A疫苗策略

線上發布 2023 年 11 月 24 日 / www.thelancet.com/infection Vol 2024 年 3 月 24 日 / https://doi.org/10.1016/ S1473-3099(23)00514-5

結核病是由結核分枝桿菌引起的傳染病。 儘管卡介苗在預防嬰兒結核病方面效果顯著，但在高負擔地區和成人中其有效性卻很匱乏。因此，尋找新型、更有效的結核病疫苗已成為當前重要的研究方向之一。 活病毒載體具有誘導高水平細胞毒性T 淋巴細胞反應的獨特能力，有助於宿主清除細胞內結核分枝桿菌。 因此，活病毒已被廣泛用作結核疫苗的載體形式之一。 MVA85A 和ChAdOx1 85A疫苗在結核病候選疫苗中脫穎而出。

在《刺胳針傳染病》中，Anne Wajja 及其同事 對烏干達青少年進行了一項研究，評估 ChAdOx1 85A–MVA85A 免疫方案的安全性和免疫原性，並將其與 BCG 重新接種進行比較。 劑量遞增試驗的結果顯示，成人和青少年對兩劑（5×10⁹病毒顆粒[VP]至2·5×1010VP）的ChAdOx1 85A疫苗具有良好的耐受性。 此外，Ag85A 特異性和結核菌素試驗 (PPD) 特異性之γ干擾素酵素連結免疫斑點法 ( IFN-γ ELISpot ) 的反應呈現增加趨勢，在免疫後 14 天達到高峰。 有趣的是，與青少年相比，成年人在免疫後14 天的Ag85A 特異性之IFN-γ ELISpot 反應普遍較低，這可能是由於出生時接種BCG 疫苗所誘導的訓練有素的免疫力逐漸減弱所致。

此外，這項隨機、開放試驗的 2a 期臨床試驗招募了 60 名青少年，以評估和比較 ChAdOx1 85A–MVA85A 和 BCG 重新接種方案的安全性和免疫原性。 結果顯示，與BCG再接種組相比，ChAdOx1 85A–MVA85A組的不良事件較少，且嚴重程度均為輕至中度。 ChAdOx1 85A–MVA85A 組中 Ag85A 特異性和 PPD 特異性之 IFN-γ ELISpot 反應在 MVA85A 加強疫苗接種後第 63 天達到高峰。 這些發現與英國先前一項成人1 期臨床試驗的結果一致。 與BCG 重新接種組相比，ChAdOx1 85A–MVA85A 組在第63 天表現出顯著更高的Ag85A 特異性之IFN-γ ELISpot 反應（幾何平均比率 30.59 [95% CI 17·46–53.59]，p<0.001) 和整個追蹤期間（曲線下面積平均差 57091 [95% CI 40524–73658] , p< 0.001)；而PPD 特異性IFN-γ ELISpot 反應則沒有顯著差異。 這可能歸因於檢測到的基線 PPD 反應較高，這是 BCG 疫苗接種者的預期反應。 儘管該研究是 2a 期臨床試驗，但作者也使用 ESAT-6/CFP-10 ELISpot 來初步評估單次ChAdOx1 85A 加強疫苗、ChAdOx1 85A–MVA85A以及BCG 重新接種可預防潛伏性結核感染之療效。 結果顯示，接受單次 ChAdOx1 85A 加強免疫的成年人中有 25% 出現潛伏性結核感染，青少年未發現潛伏性結核感染病例。 在隨機試驗中，ChAdOx1 85A-MVA85A 組的 30 名參與者中有 14 名 (47%) 和 BCG 重新接種組的 30 名參與者中有 11 名 (38%) 出現潛伏性結核感染。 早在2009年，一項2b期臨床試驗發現，MVA85A疫苗對接種卡介苗且未感染HIV的新生兒的結核病有效率為17.3%，對結核病感染的有效率為–3.8%。 從這些初步數據可以推斷，組合式助推器很可能比單一ChAdOx1 85A 助推器具有更高的效率。

他們的研究的主要限制在於，它採用了 ChAdOx1 85A–MVA85A 免疫策略，而沒有利用先前顯示的 BCG–ChAdOx1 85A–MVA85A 免疫策略的優勢。 2015 年，Stylianou 及其同事在小鼠中比較了 BCG ChAdOx1 85A–MVA85A 疫苗接種方案與 BCG 疫苗接種組的有效性。 結果發現，接受BCG–ChAdOx1 85A–MVA85A 方案的小鼠肺部集落形成單位顯著低於接受ChAdOx1 85A–MVA85A 方案的小鼠。 在 2021 年的一項研究中，BCG–ChAdOx1 85A–MVA85A 的保護性免疫反應在小鼠模型中評估了疫苗方案。 結果顯示，該方案在全身和肺部的 CD4 和 CD8 T 細胞中誘導了強烈的 Ag85A 特異性細胞因子反應。 此外，與單獨使用 BCG 免疫的小鼠相比，BCG–ChAdOx1 85A–MVA85A 疫苗接種的小鼠的肺駐留 CXCR3+ KLRG1-Ag85A 特異性 CD4 T 細胞記憶顯著增加。兩項小鼠研究均顯示，BCG–ChAdOx1 85A–MVA85A 疫苗接種策略有望預防結核病，而 ChAdOx1 85A–MVA85A 疫苗方案可能不那麼有效。 有鑑於此背景，建議未來的臨床試驗採用BCG–ChAdOx1 85A–MVA85A疫苗接種方案，以增強免疫原性和保護功效。 此外，在接受BCG 重新接種的30 名參與者中，只有18 名(60%) 參與者表現出明顯的BCG 疤痕，這顯示12 名(40%) 人可能在出生時沒有接受BCG 疫苗接種或疫苗接種無效。 儘管並非每個接受 BCG 疫苗接種的人都會出現疤痕，但先前的研究顯示，BCG 疫苗接種疤痕的存在可以作為疫苗接種的高度敏感且可重複的指標， 並且患有 BCG 疤痕的兒童所提到的限制可能會導致該小樣本臨床試驗結果的異質性增加。 因此，有必要透過大規模臨床試驗進一步驗證以支持本研究得出的結論。

這項研究的最大優勢在於比較了ChAdOx1 85A–MVA85A與卡介苗再接種的安全性和免疫原性，為優化未來疫苗免疫策略提供了新的見解。 未來的研究應納入更嚴格的納入和排除標準，增加樣本量，並探索ChAdOx1 85A–MVA85A、BCG–ChAdOx1 85A–MVA85A和BCG再接種策略在安全性、免疫原性和保護功效方面的優勢。 這些努力將有助於結核病疫苗的開發和全球結核病的控制。

我們聲明不存在競爭利益。 本評論由國家重點研發計畫（2022YFA1303503）、健康與防疫專案研究（22FYFH13）和解放軍總醫院第八醫學中心（MS202211002）資助。

*龔文平、杜靜麗 gwp891015@whu.edu.cn

中國人民解放軍總醫院第八醫學中心結核病高級部門，結核病診療新技術北京市重點實驗室，北京 100091

Optimising the vaccine strategy of BCG, ChAdOx1 85A, and MVA85A for tuberculosis control

Published Online November 24, 2023 / www.thelancet.com/infection Vol 24 March 2024 / https://doi.org/10.1016/ S1473-3099(23)00514-5

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Despite the remarkable efficacy of the BCG vaccine in preventing tuberculosis in infants, its effectiveness is scarce in high-burden areas and in adults. Therefore, the search for new and more effective tuberculosis vaccines has become one of the current important research directions. Live viral vectors possess a unique ability to induce high-level cytotoxic T lymphocyte responses, which assist the host in clearing intracellular M tuberculosis. Thus, live viruses have been widely used as one of the carrier forms for tuberculosis vaccines.3 MVA85A and ChAdOx1 85A vaccines stand out among the candidate vaccines for tuberculosis.

In The Lancet Infectious Diseases, Anne Wajja and colleagues4 did a study in adolescents in Uganda to assess the safety and immunogenicity of the ChAdOx1 85A–MVA85A immunisation regimen and compared it with BCG revaccination. The results of the dose escalation trial showed that both adults and adolescents had good tolerability to two doses (5 × 10⁹ viral particles [VP] to 2·5 × 1010 VP) of the ChAdOx1 85A vaccine. Furthermore, there was an increasing trend in Ag85A specific and PPD-specific IFN-γ ELISpot responses, which peaked 14 days after immunisation. Interestingly, adults generally had lower Ag85A-specific IFN-γ ELISpot responses 14 days after immunisation compared with adolescents, which might be attributed to the gradual waning of the trained immunity induced by BCG vaccination at birth.

Additionally, this randomised, open-label, phase 2a clinical trial recruited 60 adolescents to evaluate and compare the safety and immunogenicity of the ChAdOx1 85A–MVA85A and BCG revaccination regimens. The results showed that, compared with the BCG revaccination group, the ChAdOx1 85A–MVA85A group had fewer adverse events, all of which were mild to moderate in severity. The Ag85A-specific and PPD-specific IFN-γ ELISpot responses in the ChAdOx1 85A–MVA85A group reached their peak on day 63 after MVA85A booster vaccination. These findings are consistent with the results of a previous phase 1 clinical trial of adults in the UK. Compared with the BCG revaccination group, the ChAdOx1 85A–MVA85A group showed significantly higher Ag85A-specific IFN-γ ELISpot responses on day 63 (geometric mean ratio 30·59 [95% CI 17·46–53·59], p<0·001) and throughout the follow-up period (area under the curve mean difference 57 091 [95% CI 40 524–73 658], p<0·001), while there was no significant difference in PPD-specific IFN-γ ELISpot responses. This might be attributed to the higher baseline PPD responses detected, which is an expected reaction in BCG vaccine recipients. Although the study was a phase 2a clinical trial, the authors also used ESAT-6/CFP-10 ELISpot to preliminarily assess the efficacy of the single ChAdOx1 85A booster, ChAdOx1 85A–MVA85A, and BCG revaccination in preventing latent tuberculosis infection. The results showed that 25% of adults receiving the single ChAdOx1 85A booster developed latent tuberculosis infection, whereas no latent tuberculosis infection cases were found in adolescents. In the randomised trial, 14 (47%) of 30 participants in the ChAdOx1 85A–MVA85A group and 11 (38%) of 30 participants in the BCG revaccination group developed latent tuberculosis infection. As early as 2009, a phase 2b clinical trial found that the efficacy of the MVA85A vaccine against tuberculosis disease in newborns who had received the BCG vaccination and were not infected with HIV was 17·3%, and the efficacy against tuberculosis infection was –3·8%. From these preliminary data, it can be inferred that the combined booster most likely has higher effiacy than the single ChAdOx1 85A booster.

The major limitation of their study is that it employed the ChAdOx1 85A–MVA85A immunisation strategy without taking advantage of the previously shown benefits of the BCG–ChAdOx1 85A–MVA85A immunisation strategy. In 2015, Stylianou and colleagues8 compared the effectiveness of the BCG ChAdOx1 85A–MVA85A vaccination regimen to the BCG vaccination group in mice. It was found that mice receiving the BCG–ChAdOx1 85A–MVA85A regimen had significantly lower pulmonary colony-forming units than those receiving the ChAdOx1 85A–MVA85A regimen. In a 2021 study, the protective immune responses of the BCG–ChAdOx1 85A–MVA85A vaccine regimen were evaluated in a mouse model. The results showed that this regimen induced strong Ag85A specific cytokine responses in both CD4 and CD8 T cells, both systemically and in the lungs. Further more, BCG–ChAdOx1 85A–MVA85A vaccinated mice showed a significant increase in lung-resident CXCR3+ KLRG1- Ag85A-specific CD4 T cell memory compared with mice immunised with BCG alone. Both mouse studies suggest that the BCG–ChAdOx1 85A–MVA85A vaccination strategy holds promise for tuberculosis prevention, whereas the ChAdOx1 85A–MVA85A vaccine regimen might not be as effective. Given this background, it is recommended that future clinical trials adopt the BCG–ChAdOx1 85A–MVA85A vaccination regimen to enhance immunogenicity and protective efficacy. Additionally, of the 30 individuals receiving BCG revaccination, only 18 (60%) participants showed visible BCG scars, suggesting that 12 (40%) individuals might not have received BCG vaccination at birth or had a vaccination that was not effective. Although it is true that not every individual who receives a BCG vaccination will develop a scar, previous studies have indicated that the presence of a BCG vaccination scar serves as a highly sensitive and reproducible indicator of vaccine administration, and children with BCG scars have been shown to have higher survival rates. The limitations mentioned might potentially contribute to increased heterogeneity in the results of this small-sample clinical trial. Therefore, further validation through large-scale clinical trials is necessary to support the conclusions drawn from this study.

The greatest strength of this study lies in its comparison of the safety and immunogenicity of ChAdOx1 85A–MVA85A and BCG revaccination, providing new insights for optimising future vaccine immune strategies. Future research should incorporate stricter inclusion and exclusion criteria, increase sample sizes, and explore the advantages of ChAdOx1 85A–MVA85A, BCG–ChAdOx1 85A–MVA85A, and BCG revaccination strategies in terms of safety, immunogenicity, and protective efficacy. These efforts will contribute to the development of tuberculosis vaccines and the global control of tuberculosis.

We declare no competing interests. This Comment was funded by the National Key Research and Development Program of China (2022YFA1303503), Special Research on Health and Epidemic Prevention (22FYFH13), and the Eighth Medical Center of PLA General Hospital (MS202211002).

*Wenping Gong, Jingli Du gwp891015@whu.edu.cn

Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, Eighth Medical Center of PLA General Hospital, Beijing 100091, China