Vaccine-induced T cell responses control Orthoflavivirus challenge infection without neutralizing antibodies in humans
Shirin Kalimuddin, C Tham, Yvonne Fu Zi Chan, Shou Kit Hang, Kamini Kunasegaran, Adeline Chia, Candice Yuen Yue Chan, Dorothy Hui Lin Ng, Jean Xiang Ying 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
Abstract
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 . The authors demonstrate the effectiveness of T cells in controlling acute viral infections, without neutralizing antibodies, by conducting an Orthoflavivirus vaccination and challenge study in humans.