Enhanced antigen exposure overcomes age-associated loss of malaria vaccine efficacy in mice: Transcriptomic analysis.
Vaccine efficacy can vary substantially with age, underscoring the need to identify strategies that sustain protective immunity across the lifespan. Malaria whole-sporozoite vaccines employ attenuated sporozoites, the liver-infective forms of Plasmodium parasites, to induce high levels of protection. Here, we show that immunization with radiation-attenuated sporozoites (RAS) confers robust sterile protection in young mice but fails to protect older adult mice. This age-associated loss of efficacy in older mice is associated with a blunted hepatic transcriptional response to RAS immunization and reduced expansion of hepatic CD8? T cell populations, including liver-resident memory CD8? T cells. These defects are not explained by an intrinsic inability of CD8? T cells from older animals to acquire a tissue-resident phenotype, suggesting that, instead, the observed age-associated changes in the hepatic immune environment constrain RAS-induced protection. Importantly, immunization with late-arresting genetically attenuated parasites (LA-GAP), which broaden and prolong exposure to liver-stage antigens, restores vaccine efficacy in older mice and confers durable sterile immunity.   As a part of study that aimed to understand relationship between age and different immunisation regimes we:  (i) characterized transcriptional responses linked to RAS immunization in young mice and older mice. RNA samples isolated from full livers of young and older immunized/non-immunised mice were sequenced.  (ii) We characterized transcriptomes of hapatic CD8+ TRM cells isolated from older mice immunized with either RAS or LA-GAP to characterise difference in immune response.
Vaccine efficacy can vary substantially with age, underscoring the need to identify strategies that sustain protective immunity across the lifespan. Malaria whole-sporozoite vaccines employ attenuated sporozoites, the liver-infective forms of Plasmodium parasites, to induce high levels of protection. Here, we show that immunization with radiation-attenuated sporozoites (RAS) confers robust sterile protection in young mice but fails to protect older adult mice. This age-associated loss of efficacy in older mice is associated with a blunted hepatic transcriptional response to RAS immunization and reduced expansion of hepatic CD8? T cell populations, including liver-resident memory CD8? T cells. These defects are not explained by an intrinsic inability of CD8? T cells from older animals to acquire a tissue-resident phenotype, suggesting that, instead, the observed age-associated changes in the hepatic immune environment constrain RAS-induced protection. Importantly, immunization with late-arresting genetically attenuated parasites (LA-GAP), which broaden and prolong exposure to liver-stage antigens, restores vaccine efficacy in older mice and confers durable sterile immunity.   As a part of study that aimed to understand relationship between age and different immunisation regimes we:  (i) characterized transcriptional responses linked to RAS immunization in young mice and older mice. RNA samples isolated from full livers of young and older immunized/non-immunised mice were sequenced.  (ii) We characterized transcriptomes of hapatic CD8+ TRM cells isolated from older mice immunized with either RAS or LA-GAP to characterise difference in immune response.