Another of the issues raised by the Merck HIV vaccine trial results relates to an ongoing – and sometimes heated – debate among immunologists regarding what type of T cell response such a vaccine should ideally induce.
The aim of any T cell-based vaccine is to induce what are called “memory” T cells (see this prior blog post for a description of how memory T cells develop) from the two major T cell subsets: CD4 T cells, also called helper cells, and CD8 T cells, which are also called killer T cells due to their ability to recognize and kill virus-infected T cells. There is now a substantial literature showing that virus-specific memory CD4 and CD8 T cells work in tandem and that CD8 T cells become dysfunctional when deprived of their CD4 T cell partners. Preliminary studies of Merck’s adenovirus-based HIV vaccine clearly showed it has the ability to induce HIV-specific memory CD4 and CD8 T cell responses in the majority of recipients; this is the primary reason many people hoped the vaccine would show some evidence of efficacy.
But there is a further wrinkle to the memory T cell story. Memory T cells (both CD4 and CD8) can be further subdivided into two broad subsets: “effector memory” T cells, also designated Tem, and “central memory” T cells (Tcm). Effector memory T cells are so designated because they are in an activated state, expressing markers associated with trafficking to body tissues and mainly producing the cytokine interferon-gamma. Effector memory cells do not proliferate (make copies of themselves) very well. Central memory T cells, on the other hand, are in a resting, non-activated state. They express markers associated with circulation through the lymphatic tissues and can typically produce multiple cytokines, including IL-2. Central memory T cells are renowned for their ability to proliferate vigorously when they encounter the antigen they recognize, and this proliferation generates a wave of newly-made, activated effector memory T cells.
Some immunologists have argued that the presence of effector memory T cells is critical to obtaining the best protection with T cell-based vaccines. Others have countered that the data suggests that central memory T cells are more important and that vaccines which bias toward effector memory T cells may be less effective than those that induce more central memory T cells. Up until now, the data underpinning these battling viewpoints has largely been drawn from studies in mice. The Merck trial now presents an opportunity to explore whether the issue may have had a real-world impact in humans.
The manufacturer of another HIV vaccine candidate, GeoVax, has already issued a commentary on the Merck results which cites the possible importance of central memory T cells, noting that their construct biases toward this type of response. They point out that adenovirus, on the other hand, may primarily induce effector memory T cells, perhaps because adenovirus-based vaccines seem to express their protein payload more persistently (restimulating memory T cells rather than allowing them to return to a resting central memory state). There have recently been a number of studies and a review addressing this aspect of adenovirus vaccines in animal models (see cites, below), but human data on the persistence of antigen expression and the phenotypes of vaccine-induced T cells is currently lacking. It would seem counter-intuitive that persistent antigen expression could be harmful given the success of live attenuated vaccines in animal models, but these will be important questions to explore as the Merck results are dissected in more detail.
Note: when reading the GeoVax release, it should be borne in mind that all the macaque challenge experiments mentioned involved SHIV89.6P (see previous posting on vaccine challenge viruses).
T-cell immunity generated by recombinant adenovirus vaccines.
Expert Rev Vaccines. 2007 Jun;6(3):347-56.
Yang TC, Millar JB, Grinshtein N, Bassett J, Finn J, Bramson JL.
Adenoviral vectors persist in vivo and maintain activated CD8+ T cells: implications for their use as vaccines.
Blood. 2007 Sep 15;110(6):1916-23. Epub 2007 May 1
Tatsis N, Fitzgerald JC, Reyes-Sandoval A, Harris-McCoy KC, Hensley SE,
Zhou D, Lin SW, Bian A, Xiang ZQ, Iparraguirre A, Lopez-Camacho C,
Wherry EJ, Ertl HC.
The CD8+ T cell population elicited by recombinant adenovirus displays a novel partially exhausted phenotype associated with prolonged antigen presentation that nonetheless provides long-term immunity. (free access)
J Immunol. 2006 Jan 1;176(1):200-10.
Yang TC, Millar J, Groves T, Grinshtein N, Parsons R, Takenaka S, Wan Y, Bramson JL.
T cell vaccines for microbial infections (free access)
Nature Medicine 11, S25 - S32 (2005)
Harriet L Robinson & Rama Rao Amara (note: Harriet Robinson developed the GeoVax DNA/MVA HIV vaccine candidate).
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