In the aftermath of the Merck HIV vaccine trial results, I wrote a little about the scientific debates regarding whether T cell-based vaccines should induce an activated "effector memory" T cell response or a resting "central memory" T cell response. Underlying this debate is the question of how long a vaccine should ideally express its antigen payload after immunization (an antigen is a part of a pathogen that a vaccine is trying to trigger an immune response against, e.g. in the case of the Merck vaccine, the antigens were the HIV proteins Gag, Pol & Nef).
Following up on the prior post, two recently published papers suggest that prolonged antigen expression by vaccines can lead to the induction of CD8 T cell responses which are functionally impaired. One study, in the December 15th issue of the Journal of Immunology, used a technology called GeneSwitch to control the duration of antigen expression in mice immunized with a DNA vaccine. Even though prolonged antigen expression induced higher numbers of antigen-specific memory CD8 T cells compared to a short burst of antigen expression, the CD8 T cell responses created by the latter approach expanded (proliferated) far more robustly when re-exposed to antigen 60 days later (35-fold, compared to 4-fold for the CD8 T cell responses induced by prolonged antigen expression). In discussing their results, the authors state:
"An important goal of vaccination is to generate memory T cells with the capacity to undergo vigorous expansion in response to secondary Ag challenge. Compatible with this aim, memory CD8+ T cells elicited via transient rather than sustained expression of a DNA-encoded Ag exhibited the greater proliferative potential. Why this should be remains to be determined but may reflect the poor recall response potential of exhausted T cells. Alternatively, limiting the duration of Ag expression may speed the conversion of effector to central memory T cells. The latter subset, originally described by Sallusto et al., has greater proliferative capacity upon Ag re-encounter compared with effector-memory T cells. To distinguish between these possibilities, additional experiments will be performed to characterize the memory phenotype, activation status, and effector functions of the T cell populations generated by the GeneSwitch plasmids. We also intend to determine whether shortening Ag expression after DNA vaccination impacts on memory CD4+ T cell development."
In the second paper, in the December issue of the Journal of Investigation, Shih-Wen Lin and colleagues report similar findings with an Adeno-Associated Virus (AAV) vector encoding the HIV Gag protein in mice. Their study found that persistent antigen expression by the AAV vector led to the induction of Gag-specific CD8 T cells which were unable to expand upon rechallenge with the Gag antigen.
Although somewhat less recent, another DNA vaccine study from the October issue of Microbes & Infection offers the potentially related observation that lengthening the time between immunizations in the Plasmodium yoelii murine model of malaria improved both the magnitude of vaccine-induced CD4 and CD8 T cell responses and their protective efficacy against a sporozoite challenge. The authors note that the finding is consistent with data (from Rafi Ahmed's group among others) on the kinetics of memory CD8 T cell differentiation. This study highlights the little-discussed empirical nature of many vaccine immunization schedules; as an example, the Merck vaccine trial began with two immunizations a month apart, seemingly only because such schedules have been commonly used in the past. Although the differentiation of vaccine-induced T cell responses can now be studied in exquisite detail using technologies such as microarrays to track changes in gene expression associated with memory development (and detrimental changes in gene expression associated with T cell exhaustion), to my knowledge no one has yet used this type of approach to rationally select the ideal immunization schedule for a T cell-based vaccine in humans.
The Journal of Immunology, 2007, 179: 8313-8321.
Joanna N. Radcliffe, Joanne S. Roddick, Freda K. Stevenson and Stephen M. Thirdborough
Cancer Sciences Division, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom
After priming, naive T cells undergo a program of expansion, contraction, and memory formation. Numerous studies have indicated that only a brief period of antigenic stimulation is required to fully commit CD8+ T cells to this program. Nonetheless, the persistence of Ag may modulate the eventual fate of CD8+ T cells. Using DNA delivery, we showed previously that direct presentation primes high levels of effector CD8+ T cells as compared with cross-presentation. One explanation now revealed is that prolonged cross-presentation limits effector cell expansion and function. To analyze this, we used a drug-responsive system to regulate Ag expression after DNA injection. Reducing expression to a single burst expanded greater numbers of peptide-specific effector CD8+ T cells than sustained Ag. Consequences for memory development were assessed after boosting and showed that, although persistent Ag maintained higher numbers of tetramer-positive CD8+ T cells, these expanded less (~4-fold) than those induced by transient Ag expression (~35-fold). Transient expression at priming therefore led to a net higher secondary response. In terms of vaccine design, we propose that the most effective DNA-based CD8+ T cell vaccines will be those that deliver a short burst of Ag.
J. Clin. Invest. 117:3958-3970 (2007). doi:10.1172/JCI33138. (free access to full text)
Shih-Wen Lin1,2, Scott E. Hensley1,2, Nia Tatsis2, Marcio O. Lasaro2 and Hildegund C.J. Ertl2
1University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 2The Wistar Institute, Philadelphia, Pennsylvania, USA.
Recombinant adeno-associated virus (rAAV) vectors were used in human trials as carriers of vaccines for HIV-1 after encouraging preclinical results. However, the clinical trials yielded disappointing results. Here we demonstrated that in mice, rAAV vectors expressing the gene encoding HIV-1 gag stimulated gag-specific CD8+ T cells, but these T cells failed to expand after a booster immunization with a replication-defective adenoviral (Ad) vector also expressing gag. We tested rAAV vectors of different serotypes expressing HIV-1 gag for induction of transgene product–specific CD8+ T cells and found that the immunoinhibitory effect of rAAV priming observed with different AAV serotypes was transgene product specific, was independent of the interval between prime and boost, and extended to boosts with vaccine modalities other than Ad vectors. rAAV vector–induced CD8+ T cells proliferated poorly, produced low levels of IFN-{gamma} in response to gag stimulation, and upregulated immunoinhibitory molecules. These T cells did not protect efficiently against challenge with a surrogate pathogen. Finally, we showed that the impaired proliferative capacity of the T cells was caused by persistence of the antigen-encoding rAAV vectors and could be reversed by placing the CD8+ T cells in an antigen-free environment. Our data suggest that rAAV vectors induce functionally impaired T cells and could dampen the immune response to a natural infection.
Microbes Infect. 2007 Oct;9(12-13):1439-46. Epub 2007 Aug 3.
Brice GT, Dobaño C, Sedegah M, Stefaniak M, Graber NL, Campo JJ, Carucci DJ, Doolan DL.
Malaria Program, Naval Medical Research Center, Silver Spring, MD 20910-7500, USA.
Effective vaccines against infectious diseases and biological warfare agents remain an urgent public health priority. Studies have characterized the differentiation of effector and memory T cells and identified a subset of T cells capable of conferring enhanced protective immunity against pathogen challenge. We hypothesized that the kinetics of T cell differentiation influences the immunogenicity and protective efficacy of plasmid DNA vaccines, and tested this hypothesis in the Plasmodium yoelii murine model of malaria. We found that increasing the interval between immunizations significantly enhanced the frequency and magnitude of CD8+ and CD4+ T cell responses as well as protective immunity against sporozoite challenge. Moreover, the interval between immunizations was more important than the total number of immunizations. Immunization interval had a significantly greater impact on T cell responses and protective immunity than on antibody responses. With prolonged immunization intervals, T cell responses induced by homologous DNA only regimens achieved levels similar to those induced by heterologous DNA prime/ virus boost immunization at standard intervals. Our studies establish that the dosing interval significantly impacts the immunogenicity and protective efficacy of plasmid DNA vaccines.
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