IAVI Report - September / November 2000
Richard Jefferys

The apparent contradictions among the results obtained by the Ensoli, Pauza and Shiver studies (see main article) continue to be a source of some controversy in the vaccine research community. Shortly after the Gallo meeting, Shiver's data showing a lack of protection with Merck's Tat protein vaccine was presented by Tong-ming Fu from Merck Research Laboratories at the "18th Annual Symposium on Nonhuman Primate Models for AIDS," held in Madison, Wisconsin on 4-7 October 2000.

The conflicting results could be at least partly due to the different study designs. Firstly, the immunization protocols were very different, with Ensoli's team using 8 immunizations over 32 weeks plus a booster containing immune-stimulating complexes (ISCOMs) at week 36. In contrast, Shiver immunized his rhesus macaques 3 times, at 0, 8 and 24 weeks using RIBI with aluminum salts as the adjuvant. The Pauza study used up to 5 vaccinations over 10 weeks, in the adjuvants IFA or polyphosphazene.

These varying regimens clearly generated different immune responses: high titers of anti-Tat antibodies and no CTLs in the Shiver work, compared with Tat-specific tumor necrosis factor a production and CTL activity reported in Ensoli's study. Tat-specific antibodies were detected in Ensoli's native Tat study, but not with their tat-DNA. Most of the animals in the Pauza study also generated anti-Tat antibodies, but CTL responses were not observed.

Ensoli maintains that CTLs are needed for protection by tat-based vaccines, so the lack of this response in Shiver's animals (which she thinks could be due to the shorter immunization schedule) would explain the absence of protection. As further support for the key role of CTLs, she points to a recent study on SIV-infected monkeys by Todd Allen and colleagues, who showed that Tat-specific CTLs helped reduce viral load (see article on p.13). She also cites reports that fully biologically active Tat can gain access to the MHC class I pathway of antigen presentation, which is necessary for CTL induction (e.g. Kim et al, J Immunol 1997 Aug 15;159(4):1666-8). Subtle differences in the biological activity of the protein may also influence presentation to CTL and thus affect vaccination outcome, she says, and therefore her team routinely verifies that the Tat protein is fully active prior to each use.

John Shiver, however, believes that his protocol was a reasonable approach to inducing both anti-Tat antibody and CTL responses, based on past experience. While these results suggest that the ability to induce CTLs may not be a consistent property of Tat protein, his team is continuing to work with tat in the hope of clarifying this question.

Another potentially crucial difference between these studies is in the challenge. The Shiver study used a higher challenge dose of 50 m.i.d. 50 (50x the minimum dose required to infect half the animals exposed) compared to Ensoli's 10 m.i.d. 50. There is currently no consensus on what type of challenge most closely mirrors a typical human exposure. It is also unclear whether Ensoli's challenge virus is as highly pathogenic as Shiver's, although her team has just published evidence of high viral loads, CD4 T-cell decline and 70% mortality in challenged cynomolgus macaques that may address this issue (J Med Primatol 2000 Aug;29(3-4):193-208). Each study also used a different dose of Tat protein (Ensoli gave 10 µg, Shiver 20 µg and Pauza used 3 doses of 10, 20 and 40 µg).

With the Shiver/Letvin paper now submitted for publication, the debate about the merits of tat in vaccines is likely to continue. Also unresolved by these studies, which all examined vaccines based on tat alone, is the question of whether tat can contribute to protection in a multi-antigen vaccine.

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©2000. The IAVI Report.

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