BACKGROUND Immune responses induced by several important vaccines differ between populations, with reduced responses in low-income and rural settings compared with high-income and urban settings. BCG immunisation boosts immune responses to some unrelated vaccines in high-income populations. We aimed to test the hypothesis that BCG revaccination can enhance responses to unrelated vaccines in Ugandan schoolchildren. METHODS We conducted an open-label, randomised controlled trial to compare the effects of BCG revaccination versus no BCG revaccination on the immunogenicity of subsequent unrelated vaccines among adolescents aged 13-17 years who are participants in an urban Ugandan birth cohort study, in which BCG vaccination was documented at birth. Participants were excluded if they had received any of the trial vaccines or related agents when aged 5 years or older. Computer-generated 1:1 randomisation was implemented in REDCap. Participants were excluded if they were concurrently enrolled in other trials; had a clinically significant history of immunodeficiency, or serious psychiatric conditions or moderate to severe acute illnesses; were taking immunosuppressive medications; had allergies to vaccine components, a predisposition towards developing keloid scarring; positive HIV tests or pregnancy tests; were female participants who were lactating; or if they planned to use investigational drugs, vaccines, blood products, or any combination thereof. Trial participants assigned to the BCG revaccination group received the live parenteral BCG-Russia vaccine (Serum Institute of India, Pune, India; 0·1 mL intradermally, right upper arm) at week 0. All participants received yellow fever vaccine (YF-17D; Sanofi Pasteur, Lyon, France; 0·5 mL intramuscularly, left upper arm), live oral typhoid vaccine (Ty21a; PaxVax, London, UK; one capsule per day taken for three alternate days), and quadrivalent virus-like particle human papillomavirus (HPV) vaccine (Merck, Rahway, NJ, USA; 0·5 mL intramuscularly, left upper arm) at week 4; and toxoid vaccines (tetanus-diphtheria; Serum Institute of India; 0·5 mL intramuscularly, left upper arm) and an HPV booster at week 28. An additional HPV vaccination at week 8 was provided to female participants older than 14 years who had not previously been vaccinated. The primary outcomes were yellow fever neutralising antibody titres at 4 weeks post-YF-17D vaccination, Salmonella enterica serovar Typhi (henceforth S Typhi) O-lipopolysaccharide (O:LPS)-specific IgG concentration at 4 weeks post-Ty21a vaccination, and HPV-16 and HPV-18 L1 protein-specific IgG concentration at 4 weeks post-HPV vaccination. Primary outcome assays were conducted at week 8, and at week 52 for tetanus-diphtheria. We conducted an intention-to-treat analysis comparing log-transformed outcomes between trial groups, with results back-transformed to geometric mean ratios (GMRs). The safety population comprised all randomly allocated participants. The trial was registered at the ISRCTN Registry (ISRCTN10482904) and is complete. FINDINGS Between Aug 31 and Oct 12, 2020, we screened 376 potential participants for eligibility. We enrolled and randomly allocated 300 participants to the two groups (151 [50%] to the BCG group and 149 [50%] to the no BCG group). 178 (59%) of 300 participants were male and 122 (41%) were female. 142 (91%) of 151 participants in the BCG group and 139 (93%) of 149 in the no BCG group completed follow-up. There was no effect of BCG revaccination, compared with no BCG revaccination, on the response observed for any vaccine. Yellow fever plaque reduction neutralising reference tests (PRNT50) titres (the reciprocal of the last plasma dilution that reduced by 50%) had a GMR of 0·95 (95% CI 0·75-1·19; p=0·62) and PRNT90 (reciprocal of the last plasma dilution that reduced by 90%) had a GMR of 0·94 (0·74-1·19; p=0·60); IgG to S Typhi O:LPS was 0·99 (0·80-1·23; p=0·94); IgG to HPV-16 was 0·97 (0·69-1·35; p=0·85) and to HPV-18 was 1·03 (0·76-1·40; p=0·83); and toxoid-specific IgG for tetanus was 1·13 (0·87-1·47; p=0·36) and was 1·00 (0·87-1·16; p=0·97) for diphtheria. There were no serious adverse events in either group. INTERPRETATION We found no evidence that BCG revaccination is an effective strategy to improve immunogenicity of other vaccines in this low-income, urban setting. FUNDING UK Medical Research Council. TRANSLATION For the Luganda translation of the abstract see Supplementary Materials section.

中文翻译：

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卡介苗再接种对乌干达城市青少年对无关疫苗反应的影响 （POPVAC C）：一项开放标签、随机对照试验。


背景 几种重要疫苗诱导的免疫反应因人群而异，与高收入和城市环境相比，低收入和农村地区的反应较低。卡介苗免疫可增强高收入人群对某些不相关疫苗的免疫反应。我们旨在检验 BCG 再接种可以增强乌干达学童对无关疫苗的反应的假设。方法 我们进行了一项开放标签、随机对照试验，以比较 BCG 再接种与不 BCG 再接种对 13-17 岁青少年后续无关疫苗免疫原性的影响，这些青少年是乌干达城市出生队列研究的参与者，其中记录了出生时接种 BCG 疫苗。如果参与者在 5 岁或以上时接受过任何试验疫苗或相关药物，则被排除在外。在 REDCap 中实现计算机生成的 1：1 随机化。如果参与者同时参加其他试验，则被排除在外;有临床意义的免疫缺陷病史，或严重的精神疾病或中度至重度急性疾病;正在服用免疫抑制药物;对疫苗成分过敏，易患瘢痕疙瘩;HIV 检测或妊娠试验阳性;是哺乳期的女性参与者;或者他们是否计划使用研究药物、疫苗、血液制品或其任何组合。分配到 BCG 再接种组的试验参与者在第 0 周接受了肠外活 BCG-Russia 疫苗（印度血清研究所，印度浦那;0·1 mL 皮内注射，右上臂）。 所有参与者都接种了黄热病疫苗 （YF-17D;Sanofi Pasteur，法国里昂;0·5 mL 肌肉注射，左上臂）、口服伤寒活疫苗（Ty21a;PaxVax，英国伦敦;每天一粒胶囊，隔天服用）和四价病毒样颗粒人瘤病毒 （HPV） 疫苗（默克，罗威，新泽西州，美国;0·5 mL，肌肉注射，左上臂）;和类毒素疫苗（破伤风-白喉;印度血清研究所;0·5 mL 肌肉注射，左上臂）和第 28 周时的 HPV 加强剂。在第 8 周时，向 14 岁以上且之前未接种过疫苗的女性参与者提供额外的 HPV 疫苗接种。主要结局是 YF-17D 疫苗接种后 4 周的黄热病中和抗体滴度，Ty21a 疫苗接种后 4 周的伤寒沙门氏菌血清型（以下简称伤寒沙门氏菌）O-脂多糖 （O：LPS） 特异性 IgG 浓度，以及 HPV 疫苗接种后 4 周的 HPV-16 和 HPV-18 L1 蛋白特异性 IgG 浓度。在第 8 周和第 52 周进行破伤风-白喉的主要结果分析。我们进行了一项意向性治疗分析，比较了试验组之间的对数转换结局，结果反向转换为几何平均比 （GMR）。安全人群包括所有随机分配的参与者。该试验已在 ISRCTN 注册处 （ISRCTN10482904） 注册并已完成。结果 在 2020 年 8 月 31 日至 10 月 12 日期间，我们筛选了 376 名潜在参与者的资格。我们招募并随机分配了 300 名参与者到两组（151 名 [50%] 给 BCG 组，149 名 [50%] 给无 BCG 组）。300 名参与者中有 178 名 （59%） 是男性，122 名 （41%） 是女性。 BCG 组的 151 名参与者中有 142 名 （91%） 和无 BCG 组的 149 名参与者中有 139 名 （93%） 完成了随访。与不接种 BCG 相比，再接种 BCG 对观察到的任何疫苗的反应都没有影响。黄热病斑块减少中和参考试验 （PRNT50） 滴度（最后一次血浆稀释度减少 50% 的倒数）的 GMR 为 0·95（95% CI 0·75-1·19;p=0·62），PRNT90（最后一次血浆稀释度减少 90% 的倒数）的 GMR 为 0·94（0·74-1·19;p=0·60）;伤寒沙门氏菌 O：LPS 的 IgG 为 0·99 （0·80-1·23;p=0·94）;HPV-16 的 IgG 为 0·97 （0·69-1·35;p=0·85），HPV-18 的 IgG 为 1·03 （0·76-1·40;p=0·83）;破伤风的类毒素特异性 IgG 为 1·13 （0·87-1·47;p=0·36） 和白喉的 1·00 （0·87-1·16;p=0·97）。两组均无严重不良事件。解释 我们没有发现证据表明在这种低收入城市环境中，卡介苗再接种是提高其他疫苗免疫原性的有效策略。资助英国医学研究委员会。翻译 关于摘要的卢干达语翻译，见补充材料部分。