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<p>T cells have been identified as correlates of protection in viral infections. However, the level of vaccine-induced T cells needed and the extent to which they alone can control acute viral infection in humans remain uncertain. Here we conducted a double-blind, randomized controlled trial involving vaccination and challenge in 33 adult human volunteers, using the live–attenuated yellow fever (YF17D) and chimeric Japanese encephalitis–YF17D (JE/YF17D) vaccines. Both <i>Orthoflavivirus</i> vaccines share T cell epitopes but have different neutralizing antibody epitopes. The primary objective was to assess the extent to which vaccine-induced T cell responses, independent of neutralizing antibodies, were able to reduce post-challenge viral RNAaemia levels. Secondary objectives included an assessment of surrogate measures of viral control, including post-challenge antibody titres and symptomatic outcomes. YF17D vaccinees had reduced levels of JE/YF17D challenge viraemia, compared with those without previous YF17D vaccination (mean log<sub>10</sub>(area under the curve genome copies per ml): 2.23 versus 3.22; <i>P</i> = 0.039). Concomitantly, YF17D vaccinees had lower post-JE/YF17D challenge antibody titres that reduced JE virus plaque number by 50%, or PRNT<sub>50</sub> (mean log<sub>10</sub>(PRNT<sub>50</sub> titre): 1.87 versus 2.5; <i>P</i> &lt; 0.0001) and symptomatic rates (6% (<i>n</i> = 1/16) versus 53% (<i>n</i> = 9/17), <i>P</i> = 0.007). There were no unexpected safety events. Importantly, after challenge infection, several vaccinees had undetectable viraemia and no seroconversion, even in the absence of neutralizing antibodies. Indeed, high vaccine-induced T cell responses, specifically against the capsid protein, were associated with a level of viral control conventionally interpreted as sterilizing immunity. Our findings reveal the importance of T cells in controlling acute viral infection and suggests a potential correlate of protection against orthoflaviviral infections. ClinicalTrials.gov registration: <a href="https://clinicaltrials.gov/search?cond=NCT05568953">NCT05568953</a>.</p>

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Vaccine-induced T cell responses control Orthoflavivirus challenge infection without neutralizing antibodies in humans

  • 期刊论文

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  • 发表日期：

    2025年1月10日

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  • Shirin Kalimuddin,
  • Christine Y. L. Tham,
  • Yvonne F. Z. Chan,
  • Shou Kit Hang,
  • Kamini Kunasegaran,
  • Adeline Chia,
  • Candice Y. Y. Chan,
  • Dorothy H. L. Ng,
  • Jean X. Y. Sim,
  • Hwee-Cheng Tan,
  • Ayesa Syenina,
  • An Qi Ngoh,
  • Noor Zayanah Hamis,
  • Valerie Chew,
  • Yan Shan Leong,
  • Jia Xin Yee,
  • Jenny G. Low,
  • Kuan Rong Chan,
  • Eugenia Z. Ong,
  • Antonio Bertoletti,
  • Eng Eong Ooi

摘要

T cells have been identified as correlates of protection in viral infections. However, the level of vaccine-induced T cells needed and the extent to which they alone can control acute viral infection in humans remain uncertain. Here we conducted a double-blind, randomized controlled trial involving vaccination and challenge in 33 adult human volunteers, using the live–attenuated yellow fever (YF17D) and chimeric Japanese encephalitis–YF17D (JE/YF17D) vaccines. Both Orthoflavivirus vaccines share T cell epitopes but have different neutralizing antibody epitopes. The primary objective was to assess the extent to which vaccine-induced T cell responses, independent of neutralizing antibodies, were able to reduce post-challenge viral RNAaemia levels. Secondary objectives included an assessment of surrogate measures of viral control, including post-challenge antibody titres and symptomatic outcomes. YF17D vaccinees had reduced levels of JE/YF17D challenge viraemia, compared with those without previous YF17D vaccination (mean log10(area under the curve genome copies per ml): 2.23 versus 3.22; P = 0.039). Concomitantly, YF17D vaccinees had lower post-JE/YF17D challenge antibody titres that reduced JE virus plaque number by 50%, or PRNT50 (mean log10(PRNT50 titre): 1.87 versus 2.5; P < 0.0001) and symptomatic rates (6% (n = 1/16) versus 53% (n = 9/17), P = 0.007). There were no unexpected safety events. Importantly, after challenge infection, several vaccinees had undetectable viraemia and no seroconversion, even in the absence of neutralizing antibodies. Indeed, high vaccine-induced T cell responses, specifically against the capsid protein, were associated with a level of viral control conventionally interpreted as sterilizing immunity. Our findings reveal the importance of T cells in controlling acute viral infection and suggests a potential correlate of protection against orthoflaviviral infections. ClinicalTrials.gov registration: NCT05568953.