Limits...
Distinct time effects of vaccination on long-term proliferative and IFN-gamma-producing T cell memory to smallpox in humans.

Combadiere B, Boissonnas A, Carcelain G, Lefranc E, Samri A, Bricaire F, Debre P, Autran B - J. Exp. Med. (2004)

Bottom Line: Only 20% of the vaccinees displayed both immediate IFN-gamma-producing effector-memory responses and proliferative memory responses at 6 d; 52.5% showed only proliferative responses; and 27.5% had no detectable vaccinia-specific responses at all.The number of recalls did not affect the persistence of residual effector-memory T cells.Programmed revaccination boosted both IFN-gamma and proliferative responses within 2 mo of recall, even in vaccinees with previously undetectable residual effector-memory cells.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire d'Immunologie Cellulaire, INSERM U543, Paris, France.

ABSTRACT
Residual immunity to the smallpox virus raises key questions about the persistence of long-term immune memory in the absence of antigen, since vaccination ended in 1980. IFN-gamma-producing effector-memory and proliferative memory T cells were compared in 79 vaccinees 13-25 yr after their last immunization and in unvaccinated individuals. Only 20% of the vaccinees displayed both immediate IFN-gamma-producing effector-memory responses and proliferative memory responses at 6 d; 52.5% showed only proliferative responses; and 27.5% had no detectable vaccinia-specific responses at all. Both responses were mediated by CD4 and CD8 T cells. The vaccinia-specific IFN-gamma-producing cells were composed mainly of CD4Pos CD45RANeg CD11aHi CD27Pos and CCR7Neg T cells. Their frequency was low but could be expanded in vitro within 7 d. Time since first immunization affected their persistence: they vanished 45 yr after priming, but proliferative responses remained detectable. The number of recalls did not affect the persistence of residual effector-memory T cells. Programmed revaccination boosted both IFN-gamma and proliferative responses within 2 mo of recall, even in vaccinees with previously undetectable residual effector-memory cells. Such long-term maintenance of vaccinia-specific immune memory in the absence of smallpox virus modifies our understanding of the mechanism of persistence of long-term memory to poxviruses and challenges vaccination strategies.

Show MeSH

Related in: MedlinePlus

Recent vaccinia recall allows a complete immune response recovery in vaccinees independently of the time since priming. (a) Reciprocal distributions of ELISpot and proliferation assays for 17 recently revaccinated individuals (age, 32–57 yr; median, 41) tested 2 mo after revaccination. Positive responses were defined according to the same criteria: a stimulation index ≥3 and a frequency of IFN-γ–producing cells ≥50 SFC/million PBMCs after subtraction of background (shown by dashed lines). (b and c) CD8-depleted PBMCs of recently revaccinated individuals (grey bars) compared with total PBMCs (black bars) were tested by ELISpot (b) and proliferation (c) assays. Graphs represent changes in IFN-γ production (d) and proliferative responses (e) of five representative recently revaccinated individuals: PRE (before revaccination, 1–2 mo) M1 and M2 (after revaccination).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211784&req=5

fig7: Recent vaccinia recall allows a complete immune response recovery in vaccinees independently of the time since priming. (a) Reciprocal distributions of ELISpot and proliferation assays for 17 recently revaccinated individuals (age, 32–57 yr; median, 41) tested 2 mo after revaccination. Positive responses were defined according to the same criteria: a stimulation index ≥3 and a frequency of IFN-γ–producing cells ≥50 SFC/million PBMCs after subtraction of background (shown by dashed lines). (b and c) CD8-depleted PBMCs of recently revaccinated individuals (grey bars) compared with total PBMCs (black bars) were tested by ELISpot (b) and proliferation (c) assays. Graphs represent changes in IFN-γ production (d) and proliferative responses (e) of five representative recently revaccinated individuals: PRE (before revaccination, 1–2 mo) M1 and M2 (after revaccination).

Mentions: The observations above—that neither the number of immunizations nor the delay since the last immunization influence persistence of long-term memory—raised two questions. Could effector–memory responses, when undetectable, be reinduced in vivo after revaccination? Would the discrepancy observed between effector–memory and proliferative responses in long-term vaccinees influence response after a recent antigen recall? Vaccinia-specific assays were performed 1 and 2 mo. after revaccination of 17 of the 79 vaccinees tested above. We found intense effector–memory and proliferative vaccinia-specific responses in all but one of them (median for positive responders, 154 SFCs/million PBMCs; range, 68–593) (Fig. 7 a). The median frequency of effector–memory T cells was twice as high in recently revaccinated individuals as in long-term vaccinees, 2 mo. after revaccination. CD8 depletion experiments showed that both CD4 and CD8 contributed to vaccinia-specific effector (Fig. 7 b) and proliferative (Fig. 7 c) responses in these recently revaccinated individuals. Furthermore, revaccination of those subjects who had no detectable IFN-γ–producing cells on initial testing induced potent effector–memory and proliferative responses within 2 mo. of antigen recall (Fig. 7, a, d, and e). This is in accordance with our finding that in vitro proliferation of virus-specific T cells led to the expansion of IFN-γ–producing cells, and it should be compared with a recent report that vaccinia-specific responses are detectable in all new vaccinees, 6 mo. after priming (26).


Distinct time effects of vaccination on long-term proliferative and IFN-gamma-producing T cell memory to smallpox in humans.

Combadiere B, Boissonnas A, Carcelain G, Lefranc E, Samri A, Bricaire F, Debre P, Autran B - J. Exp. Med. (2004)

Recent vaccinia recall allows a complete immune response recovery in vaccinees independently of the time since priming. (a) Reciprocal distributions of ELISpot and proliferation assays for 17 recently revaccinated individuals (age, 32–57 yr; median, 41) tested 2 mo after revaccination. Positive responses were defined according to the same criteria: a stimulation index ≥3 and a frequency of IFN-γ–producing cells ≥50 SFC/million PBMCs after subtraction of background (shown by dashed lines). (b and c) CD8-depleted PBMCs of recently revaccinated individuals (grey bars) compared with total PBMCs (black bars) were tested by ELISpot (b) and proliferation (c) assays. Graphs represent changes in IFN-γ production (d) and proliferative responses (e) of five representative recently revaccinated individuals: PRE (before revaccination, 1–2 mo) M1 and M2 (after revaccination).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211784&req=5

fig7: Recent vaccinia recall allows a complete immune response recovery in vaccinees independently of the time since priming. (a) Reciprocal distributions of ELISpot and proliferation assays for 17 recently revaccinated individuals (age, 32–57 yr; median, 41) tested 2 mo after revaccination. Positive responses were defined according to the same criteria: a stimulation index ≥3 and a frequency of IFN-γ–producing cells ≥50 SFC/million PBMCs after subtraction of background (shown by dashed lines). (b and c) CD8-depleted PBMCs of recently revaccinated individuals (grey bars) compared with total PBMCs (black bars) were tested by ELISpot (b) and proliferation (c) assays. Graphs represent changes in IFN-γ production (d) and proliferative responses (e) of five representative recently revaccinated individuals: PRE (before revaccination, 1–2 mo) M1 and M2 (after revaccination).
Mentions: The observations above—that neither the number of immunizations nor the delay since the last immunization influence persistence of long-term memory—raised two questions. Could effector–memory responses, when undetectable, be reinduced in vivo after revaccination? Would the discrepancy observed between effector–memory and proliferative responses in long-term vaccinees influence response after a recent antigen recall? Vaccinia-specific assays were performed 1 and 2 mo. after revaccination of 17 of the 79 vaccinees tested above. We found intense effector–memory and proliferative vaccinia-specific responses in all but one of them (median for positive responders, 154 SFCs/million PBMCs; range, 68–593) (Fig. 7 a). The median frequency of effector–memory T cells was twice as high in recently revaccinated individuals as in long-term vaccinees, 2 mo. after revaccination. CD8 depletion experiments showed that both CD4 and CD8 contributed to vaccinia-specific effector (Fig. 7 b) and proliferative (Fig. 7 c) responses in these recently revaccinated individuals. Furthermore, revaccination of those subjects who had no detectable IFN-γ–producing cells on initial testing induced potent effector–memory and proliferative responses within 2 mo. of antigen recall (Fig. 7, a, d, and e). This is in accordance with our finding that in vitro proliferation of virus-specific T cells led to the expansion of IFN-γ–producing cells, and it should be compared with a recent report that vaccinia-specific responses are detectable in all new vaccinees, 6 mo. after priming (26).

Bottom Line: Only 20% of the vaccinees displayed both immediate IFN-gamma-producing effector-memory responses and proliferative memory responses at 6 d; 52.5% showed only proliferative responses; and 27.5% had no detectable vaccinia-specific responses at all.The number of recalls did not affect the persistence of residual effector-memory T cells.Programmed revaccination boosted both IFN-gamma and proliferative responses within 2 mo of recall, even in vaccinees with previously undetectable residual effector-memory cells.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire d'Immunologie Cellulaire, INSERM U543, Paris, France.

ABSTRACT
Residual immunity to the smallpox virus raises key questions about the persistence of long-term immune memory in the absence of antigen, since vaccination ended in 1980. IFN-gamma-producing effector-memory and proliferative memory T cells were compared in 79 vaccinees 13-25 yr after their last immunization and in unvaccinated individuals. Only 20% of the vaccinees displayed both immediate IFN-gamma-producing effector-memory responses and proliferative memory responses at 6 d; 52.5% showed only proliferative responses; and 27.5% had no detectable vaccinia-specific responses at all. Both responses were mediated by CD4 and CD8 T cells. The vaccinia-specific IFN-gamma-producing cells were composed mainly of CD4Pos CD45RANeg CD11aHi CD27Pos and CCR7Neg T cells. Their frequency was low but could be expanded in vitro within 7 d. Time since first immunization affected their persistence: they vanished 45 yr after priming, but proliferative responses remained detectable. The number of recalls did not affect the persistence of residual effector-memory T cells. Programmed revaccination boosted both IFN-gamma and proliferative responses within 2 mo of recall, even in vaccinees with previously undetectable residual effector-memory cells. Such long-term maintenance of vaccinia-specific immune memory in the absence of smallpox virus modifies our understanding of the mechanism of persistence of long-term memory to poxviruses and challenges vaccination strategies.

Show MeSH
Related in: MedlinePlus