p24.VLP is a therapeutic vaccine preparation based on genetically engineered forms of HIV's core proteins, p24 and p17. These are assembled into a `virus-like particle' (VLP). In people with HIV, antibodies to p24 tend to decline or disappear at around the same time that they progress to AIDS. By giving injections of p24, it was hoped that the immune response to the protein would be augmented and sustained for longer, perhaps delaying disease progression.

p24.VLP was manufactured by the Oxford-based company British Biotech Pharmaceuticals Ltd.

Current use

p24.VLP is an unlicensed, experimental drug. A study in uninfected people showed that it can successfully cause the production of anti-p24 antibodies in people, but clinical trials have found no evidence of any immunological benefits such as an increase in CD4 cell count, and no effects on disease progression. Development has now been abandoned.

Further developments

As well as studying the vaccine in a conventional adjuvanted formulation (using aluminium hydroxide), researchers tested an unadjuvanted form of p24.VLP to determine whether a cytotoxic T-lymphocyte (CTL) response could be induced. A study in the United States was designed to study whether oral doses of p24.VLP followed by rectal booster doses could stimulate antibodies in the body's mucosal membranes.

Key research

British Biotechnology developed a novel means of producing particulate antigens in yeast. Genetic engineering of an HIV p17/p24 fusion gene produces an expression plasmid containing 25% of p17 and 79% of p24. The plasmid is introduced into yeast cells which are grown to high cell density in a medium containing glucose. Expression of the fusion protein is then induced, producing high yields of p24.VLPs. p24.VLPs are particles of approximately 80 nm in diameter. The p24 antigen component of the hybrid has been demonstrated to be on the surface of the particles by gold immunolabelling techniques.

During the late stages of HIV infection, p24 antibody wanes and up to 18 months after the loss of antibody p24 antigenaemia reappears in up to 47% of individuals. De Wolf and Pedersen demonstrated that the risk of developing AIDS is greatly increased in individuals exhibiting undetectable or falling titres of p24 antibody and in those exhibiting the secondary p24 antigenaemia. Moreover, Cheingsong-Popov showed that an initially low titre p24 antibody response following HIV infection in haemophiliacs was associated with a significantly faster progression to AIDS than a high titre response. These data suggest, indirectly, that high titres of p24 antibody may be important in maintaining a disease-free state. It was theorized that vaccination of seropositive individuals with core protein (p24) attached to virus-like particles (VLPs) may enhance p24 antibody and cellular responses and prolong the disease-free state in HIV infection.

Lindenburg reported long-term follow-up of 56 people enrolled in a placebo-controlled study of p24VLP in 1993. Exposure to the vaccine did not affect progression to a CD4 count below 200, AIDS or death after controlling for antiretroviral therapy.

Veenstra enrolled 74 asymptomatic HIV-positive people with CD4 counts greater than 350 in a placebo-controlled study of p24.VLP (100, 500 or 1000 µg) via intramuscular injection at study weeks 0, 4, 8, 12, 16 and 20. 63 participants completed the course and were assessed up to week 48. There was no difference in the proportion of people in the placebo and treatment groups who experienced four-fold increases in anti-p24 antibody at any time during follow-up (5/19 placebo recipients versus 2/18 at 100 µ, 4/19 at 500 µg and 5/18 at 1000 µg of p24.VLP). There were also no differences in the proportions experiencing four-fold increases in anti-p17 antibodies (4/19, 10/18, 7/19 and 3/18 respectively). Ty antibodies appeared in 17/18 recipients of p24.VLP at the 1000 µ dose, but no placebo participants. There was no significant difference in viral load changes between the groups.

Peters enrolled 15 asymptomatic HIV-positive people with CD4 counts above 350 in a placebo-controlled phase II study of p24.VLP (25µg 0r 100µg at weeks 0 and 4 intramuscularly). No serious adverse events were observed. Treated participants experienced CD4 count increases, with a mean rise of 100 in the 100 µg after the second immunisation, although these changes were not statistically significant. There were no significant changes in CD8 count, p24 antigen or antibody levels or quantitative plasma viraemia.

Smith enrolled 310 people with CD4 counts below 300 to receive p24-VLP vaccine (500 or 1000 µg) or placebo at months 0,1,2,3,4 and 5. After six months and one year CD4 counts did not significantly differ between the arms. 61 participants experienced clinical disease progression, with no significant differences between the arms. No significant adverse reactions were observed.

Kelleher enrolled 61 people with CD4 counts above 400 in a study comparing AZT monotherapy, p24-VLP monotherapy (500 µg monthly for six months) and the combination. At the end of one year there was no significant difference between the arms in antibody responses to p24, CD4 or CD8 counts, viral load, T-cell responses to p24, p17, recall antigen or mitogen, or markers of immune activation. No adverse effects of vaccination were observed.

Clarkson randomised 36 asymptomatic people with CD4 counts greater than 400 to receive six month's therapy with p24-VLP (500 µg) plus AZT (200 three times daily), alum adjuvant plus AZT, or p24-VLP plus placebo. Nine participants who received p24-VLP and AZT had an augmentation and/or a broadening of their CTL response compared to baseline. Eight participants who received p24-VLP and seven participants who received AZT also had an increase or broadening of CTL activity, but this was not statistically significant. There was no statistical difference between the arms.

References

Cheingsong-Popov R et al. Relation between humoral responses to HIV gag and env proteins at seroconversion and clinical outcome of HIV infection. British Medical Journal 302:23-26, 1991.

Clarkson J et al. Therapeutic vaccination with p24-VLP and AZT augments HIV specific CTL activity in HIV infected individuals. Fifth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 83, 1998.

De Wolf F et al. Risk of AIDS related complex and AIDS in homosexual men with persistent HIV antigenaemia. British Medical Journal 295:569-572, 1987.

Kelleher AD et al. Safety and immunogenicity of a candidate therapeutic vaccine, p24 virus-like particle, combined with zidovudine, in asymptomatic subjects. AIDS 12(2):175-182, 1998.

Lindenburg CE et al. Long-term follow-up: no effect of therapeutic vaccination with HIV-1 p17/p24:Ty virus-like particles on HIV-1 disease progression. Vaccine 20(17-18):2343-2347, 2002.

Pedersen C et al. Temporal relation of antigenaemia and loss of antibodies to core antigens to development of clinical disease in HIV infection. British Medical Journal 295:567-569, 1987.

Peters BS et al. A pilot phase II study of the tolerance and safety of HIV p17/p24:Ty-VLP (p24-VLP) in asymptomatic HIV seropositive subjects. Second International Congress on Drug Therapy in HIV Infection, Glasgow, abstract 15.4, 1994.

Smith DE et al. Therapeutic vaccination (p24-VLP) of patients with advanced HIV-1 infection does not alter CD4 decline. Third International Congress on Drug Therapy in HIV Infection, Birmingham, abstract OP6.5, 1996.

Veenstra J et al. Immunization with recombinant p17/p24:Ty virus-like particles in human immunodeficiency virus-infected persons. Journal of Infectious Diseases 174:862-866, 1996.