Vaccines

  • The development of an HIV vaccine is a slow and challenging process.

The promise of an effective HIV vaccine has always been just over the horizon, but more than 20 years after the identification of HIV, vaccines remain far from implementation.

Vaccine research has taken two appraoches: induction of neutralising antibodies, or stimulation of cell-mediated immunity.

Trials of vaccines designed to induce neutralising antibodies have produced disappointing results to date. Two VaxGen subunit vaccines (named AIDSVax), one composed of subtype B sequences, the other of subtypes E and B, have been tested in large studies in the Americas and Thailand1 respectively, and showed no protective effect. A NIAID phase III study of ALVAC vcp1521 (a CTL-inducing vaccine) and AIDSVAX B/E as a prime/boost regimen is currently underway in Thailand, is due to complete during 2009.

Efforts are underway to identify neutralising antibodies produced by individuals that react to viral proteins which vary little from one virus to another, on the assumption that stimulating the development of these antibodies will control the widest range of viral variants possible. It is also essential that these antibodies target viral proteins which undergo little evolution in response to the antibody.

Vaccines that induce cell-mediated immune responses have been regarded as a more promising avenue of research, and there has been much interest in developing a vaccine that stimulates strong HIV-sepcific T-cell responses. So-called T-cell vaccines have been conceptualised either as a means of providing complete protection against HIV infection, or as a means of limiting the harmful effect of HIV infection.

In September 2007 the STEP trial of Merck’s adenovirus-based vaccines containing sequences of HIV’s gag, pol and nef genes was halted based on a futility analysis. Subsequent analysis revealed a higher rate of infection in those who received the vaccine than in the placebo group. Subsequent analysis of vaccine recipients showed the highest risk of infection in individuals with the highest levels of pre-existing adenovirus immunity, while Ad5 seropositive men who were uncircumcised were at four times greater risk of infection if they received the vaccine compared to circumcised men in the placebo group.2 There was no evidence of an enhanced risk of infection in vaccinated male volunteers who were circumcised and Ad5 seronegative.

The termination of the Merck Ad5 vaccine study has been viewed as a huge setback for the T-cell vaccine approach, and the US National Institutes of Health has decided to return to basic research in order to gain a better understanding of HIV and the immune response to infection.3

References

  1. Pittisittithum P et al. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J Infect Dis 194(12):1661-71, 2006
  2. Robertson M et al. Efficacy results from the STEP Study (Merck V520 protocol 023/HVTN 502): a phase II test-of-concept trial of the MRKad5 HIV-1 gag/pol/nef trivalent vaccine. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 88LB, 2008
  3. Thongcharoen P et al. A phase 1/2 comparative vaccine trial of the safety: ALVAC-HIV (vCP1521) prime with oligomeric gp160 (92TH023/LAI-DID) or bivalent gp120 (CM235/SF2) Boost. J Acquir Immune Defic Syndr, 2007 [Epub ahead of print], 2007
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