Therapeutic HIV vaccines

A vaccine is a substance intended to stimulate the body's own immune defences against a disease-causing agent. There are two types: preventive vaccines are designed to protect against a new infection taking hold in the body, while therapeutic vaccines are designed to boost immune responses against an existing infection.

Therapeutic vaccines have been studied as a means of restoring immunity in people with HIV. There are two main kinds of immune response. The first, humoral immunity, relies primarily on antibodies. The second, cellular or cell-mediated immunity, relies mainly on CD4 and CD8 T-cells that recognise and fight disease-causing agents and destroy infected cells. These are explained further in How the immune system works.

Vaccines work by introducing a disease-causing agent into the body in order to stimulate the immune system to recognise and respond to the invader. While vaccines for some diseases contain whole pathogens (live, killed or inactivated), in the case of HIV, specific antigens or pieces of the virus are usually used instead.

Modern ‘recombinant’ vaccines are genetically engineered in the laboratory. Typically another virus, called a vector, is altered so it carries HIV antigens. Canarypox, vaccinia and adenovirus are commonly used in experimental HIV vaccines. Vaccine preparations also may contain adjuvants, substances intended to increase the vaccine's effect.

HIV vaccine research is hampered by several barriers. The body’s normal immune responses usually cannot control the virus, so it is unclear whether boosting these responses can have much benefit. In part, this is because HIV mutates, or changes rapidly, as it replicates, so the immune system must constantly contend with slightly different viruses. In addition, HIV can lie hidden in inactive cells, where the immune system cannot recognise it. Finally, the virus attacks the very cells – CD4 T-cells – that direct the body’s immune response.

Researchers have tested many HIV vaccine candidates.¹ Several early vaccines were designed to stimulate an antibody response against single specific HIV antigens, for example the core protein p24 or the gp120 or gp160 proteins on viral envelopes. While such vaccines often stimulated production of neutralising antibodies, this did not lead to control of HIV.

Other vaccine candidates are intended to stimulate cell-mediated responses by CD4 or CD8 T-cells (killer T-cells) against HIV.

The Remune vaccine (also known as the Salk vaccine) contains whole inactivated HIV with a full set of genes, but altered so they do not express the gp120 protein necessary for infection of cells. In various studies, Remune appeared to stimulate HIV-specific CD4 T-cell responses and was associated with delayed viral rebound in patients on highly active antiretroviral therapy (HAART). However, in a trial of more than 2500 patients, it did not lower viral load, increase CD4 cell counts significantly or reduce disease progression or death.²

A more recent technique involves engineered virus vectors that carry DNA ‘plasmids’, or loops of genetic material containing specific HIV genes that express proteins such as Gag, Pol or Nef.

Several ALVAC canarypox vaccines have been tested in clinical trials. French researchers studied ALVAC vCP1433, containing HIV Gag and Env proteins, plus interleukin-2 in patients on HAART with suppressed viral load. They found that treated patients were less likely to experience viral rebound after stopping antiretroviral therapy than those receiving a placebo vaccine.³

More recently, an ongoing phase III trial in Thailand found that a canarypox primer vaccine called ALVAC vCP1521, which contains Gag and gp120 envelope proteins from subtype B HIV, followed by a booster containing either gp120 or gp160, did not produce significantly greater CD8 T-cell responses compared with placebo, although it did produce neutralising antibody responses in most participants.⁴

Looking at a different strategy, German researchers tested a vaccine using the modified vaccinia virus Ankara (MVA) engineered to express the Nef protein. After three doses of the vaccine, recipients interrupted antiretroviral treatment. All experienced viral rebound, but viral load stayed below pre-treatment levels and HIV-specific CD4 and CD8 T-cells responses were detected.[ref

Swedish researchers recently reported that a series of DNA primer vaccines followed by a booster vaccine consisting of a MVA vector expressing Env, Gag and Pol from subtype A and E HIV produced strong T-cell responses in more than 90% of vaccinated participants in a small pilot study.⁵

Two HIV vaccine candidates using adenovirus vectors are being tested in ongoing trials. One, being developed by Merck, contains gag, pol and nef genes from subtype B HIV.⁶ One study of this vaccine was halted in 2007 after it failed to control viral load in people who became infected. The other vaccine contains gag, pol and nef from subtype B plus env from subtypes A, B, and C.⁷ Both were shown to stimulate CD8 T-cell responses in a majority of volunteers.

In summary, in more than 50 vaccine trials to date, safety results have been good and several candidates have shown some degree of efficacy – that is, they produce signs of enhanced immune responses against HIV. But so far, none has proven effective at controlling the virus or slowing disease progression.