A vaccine is a substance intended to stimulate the body's own immune defences against a micro-organism. While preventative vaccines are designed to protect the recipient against initial infection, therapeutic vaccines are designed for people who are already infected with the micro-organism, with the aim of boosting or expanding their immune response against it.

There are two main kinds of immune response. The first is the humoral immune response, which relies mainly on antibodies. In the case of HIV infection, the body produces antibodies which recognise and lock onto gp120, the viral protein on the surface of HIV particles and HIV-infected cells. By locking onto gp120, these antibodies may prevent the virus from binding onto human cells. They may also 'mark' the viral particles and infected cells for destruction by other elements of the immune system.

The other type of immune response is the cellular immune response, which relies mainly on the stimulation of T-cells which recognise HIV-infected cells and kill them. In the case of viral infections other than HIV, these cytotoxic CD8 T-cells are the most effective means of eliminating virally infected cells.

When the immune system is activated to respond to an antigen, some of the immune cells become 'memory' cells. The next time an individual comes into contact with that same antigen, the existence of memory cells means that the immune system is primed to destroy it quickly, before it can establish a new infection in the body. This is why people who have recovered from an illness, such as measles or mumps, tend not to be susceptible to the same illness again.

Vaccines contain either non-infectious fragments of micro-organisms or whole micro-organisms which have been killed or weakened so that they cannot cause disease. By introducing these into the body, the humoral or cellular immune responses are triggered and memory cells are produced.

The theory of therapeutic vaccination for HIV

HIV therapeutic vaccines consist of either whole, killed HIV particles, or genetically engineered fragments of the virus. Trials have focused on the following HIV antigens:

• gp160, the large protein which essentially forms the outer surface of HIV particles. See gp160 vaccines in Drugs used by people with HIV: Therapeutic vaccines.

• gp120, the protein which forms part of the surface of the virus, with which HIV binds to the CD4 receptor on human cells. See gp120 vaccines in Drugs used by people with HIV: Therapeutic vaccines.

• p24, a protein from the core of the virus

• p17, another core protein.

• Vector vaccine, where small portions of HIV are grafted onto harmless viruses e.g. canarypox.

Unlike some other immune boosting treatments, therapeutic vaccines aim selectively to activate the immune system against specific HIV proteins alone. Although individuals infected with HIV will already have viral proteins in their bodies as a result of infection, the theory is that by presenting them to the immune system in a different way, the specific immune responses may be augmented. For example, people bitten by rabid animals can be protected from developing rabies by subsequent vaccination with parts of rabies virus shortly afterwards. A number of animal and test-tube studies have provided encouraging evidence that therapeutic immunisation may lower viral load, particularly during the early stages of HIV infection.

There are a number of different ways of preparing the vaccine product and of delivering it into the body. For example, different gp120 vaccines have been prepared from different strains of HIV. However, it is unclear whether it would be most effective to try to match therapeutic vaccine treatment to the strain with which an individual is infected, or to use a different strain to try to stimulate broader immune responses. The genetically engineered proteins used in these products are mass-produced by growing them in yeast, insect or mammalian cells, which affects the form of the final vaccine. The different preparations also use various adjuvants, which are substances intended to increase the vaccine's effect, and may use various different vectors, which are other inactivated organisms such as vaccinia virus, canarypox or adenovirus which are used to transport the HIV fragments into the body.

Trial results

Therapeutic vaccine trials in animals and humans have generally resulted in increased levels of antibodies and CD4 T-cells as intended. Several vaccine products have been tested in human trials:

• MVA-BN-nef vaccine.

• Tat toxoid vaccine.

• pTHr.HIVA.

• ALVAC-HIV vCP1433.

• VIR201.

• MicroGeneSys, a gp160-based product.

• p24-VLP.

• Remune.

• vCP1452.

• Vacc-4x.

• Neutralising antibodies 2F5 and 2G12.

For details of these vaccines, see gp160 vaccines and gp120 vaccines in Drugs used by people with HIV: Therapeutic vaccines.

Some encouraging results so far have come from French researchers using the ALVAC vCP1433 therapeutic vaccine in conjunction with Lipo-6T. A randomised study of 70 HIV-infected people on antiretroviral therapy with CD4 cell counts above 350 cells/mm³ and viral load below 50 copies/ml was conducted. Those randomised to vCP1433 and interleukin-2 (IL-2) were significantly less likely to experience virological failure after stopping antiretroviral treatment (Levy 2003). The ability of vCP1433 to help control viral replication suggests that therapeutic vaccination may provide clinical benefit.

Many other studies have found that therapeutic immunisation can stimulate HIV-specific immune responses.

Two studies of gp120 vaccines found that HIV-specific lymphocyte responses were most likely to occur in vaccine recipients with CD4 cell counts above 350 cells/mm³ and undetectable viral load at the time of vaccination. The responses also tended to be specific to the strain of HIV used in the preparation of the vaccine (Schooley 2000).

The failure of antiretroviral therapy alone to eradicate HIV from the body has led researchers to study therapeutic vaccines in combination with antiretroviral therapy. Researchers have aimed to stimulate HIV-specific T-helper responses, which are a feature of the immune responses of long-term non-progressors in several cohorts.

Studies with the experimental vaccine Remune, administered with antiretroviral therapy, have found that people treated with Remune developed strong HIV-specific CD4 T-cell responses similar to those seen in long-term non-progressors. However, this does not prove that such responses are beneficial or that they can control HIV in the absence of antiretroviral therapy.

Nevertheless, the data on Remune plus antiretrovirals continue to be interesting, and have encouraged its developers to persist despite the setback of a major clinical trial which some investigators believed showed no efficacy. A Spanish study showed that randomisation to the Remune arm was associated with delayed virologic failure (Fernandez-Cruz 2002). See Remune in Drugs used by people with HIV: Therapeutic vaccines for further details.

It has been proposed that priming the immune system with IL-2 might improve the effect of therapeutic vaccination, but attempts to use IL-2 to boost responses to subsequent immunisation with Remune have not proved successful. The study ACTG 328 randomised people on antiretroviral therapy to receive IL-2 or not. The 38 individuals with viral loads below 2000 copies/ml after 60 weeks in the study received a cycle of three Remune immunisations two months apart and two tetanus toxoid immunisations two months apart. IL-2 cycles continued every eight weeks during this schedule. Those receiving IL-2 had significantly higher CD4 cell counts at the beginning of the immunisation schedule, but showed no difference after 24 weeks in antibody responses to HIV or tetanus (Valdez 2002).

Combination of IL-2 with a different vaccine and treatment interruptions was tested by French researchers in a randomised, placebo-controlled trial called ANRS 093 (Levy 2005). This trial gave patients either placebo or four immunisations of the ALVAC 1433 vaccine containing Gag and Env proteins in a canarypox vector spaced four weeks apart. Patients also received a HIV lipopeptide, which consists of HIV Gag protein fragments attached to a fatty lipid tail. Patients then had three cycles of IL-2 or placebo, again spaced four weeks apart.

Eight weeks after the last IL-2 cycle patients stopped antiretroviral therapy and remained off unless their viral load went above 50,000 copies/ml on one measurement or more than 10,000 copies/ml on two occasions. Statistically significant decreases in the viral load set points were reached with lower levels in vaccinated patients than controls. By the third treatment interruption, viral load set points in the vaccinated patients were almost 1 log₁₀ lower than in control patients. Vaccinated patients spent 42% of the time in treatment interruptions compared to control patients who spent 27% of the time in treatment interruptions.

A research team from Aaron Diamond AIDS Research Center in collaboration with the Rockfeller University and Aventis tested a vaccine cocktail including a gp160 vaccine and a canarypox vector vCP1452 vaccine. Fourteen people recently infected with HIV were given antiretroviral therapy plus the vaccine cocktail on days 0, 30, 90 and 180. While some recipients had antibody responses and transient CD4 T-cell responses, there was no protection against HIV replication when antiretroviral therapy was ceased (Markowitz 2002).

The Vacc-4x targeting p24 has been tested for safety in eleven HIV-infected people. Immunisation induced antibody responses in two individuals (Asjo 2002).

Intravenous infusions of the HIV antibodies 2F5 and 2G12 produced transient reductions in viral load in five of seven treated persons (Stiegler 2002). Infusion triggered a transient increase in cellular immune activity.

Another approach has been to use a plasmid DNA vaccine which can be delivered through the skin, rather than by injection, in the hope that it will be taken up by 'Langerhans cells' and presented to the immune system more efficiently. A product called DermaVir has been tested in ten monkeys with simian AIDS, treated with antiretroviral therapy with or without structured treatment interruptions. After six cycles of three weeks on and three weeks off therapy, the monkeys were exposed to DermaVir during four further treatment interruptions. After nine months of follow-up, all but one of the monkeys on antiretroviral therapy had died, whilst three out of four monkeys that had received DermaVir remained alive, with reductions in viral load peaks during successive treatment interruptions. By the fourth interruption, the median viral load was less than 200 copies/ml, compared with a median of greater than 4,000,000 copies/ml during the first interruption. Viral control was similar to that seen in monkeys treated during acute infection, and corresponded to strong simian immunodeficiency virus (SIV)-specific T-cell responses (Lisziewicz 2002).

NYVAC, a poxvirus vector-based vaccine expressing a range of HIV proteins, has been tested in macaques and found to contain viral rebound when administered prior to therapy interruption (Tryniszewska 2002).

Both DermaVir and Remune treatment have been associated with a slower rate of viral rebound in vaccinated individuals when compared to control groups (Bucy 2002).

German researchers tested a vaccine using the modified vaccinia virus Ankara (MVA) which is a poxvirus that is related to the small pox vaccine virus (Harrer 2005). This virus was engineered to express HIV's Nef protein. Fourteen HIV infected patients with CD4 cell counts above 400 cells/mm³ on antiretroviral therapy received vaccinations at weeks 0, 4 and 16 followed by a treatment interruption at week 18. All patients experienced viral load rebounds, although after 36 weeks levels of virus remained below pre-treatment levels. CD4 cell counts were also higher than pre-treatment levels. Six patients were able to remain of treatment for a median time of 64 weeks. New HIV-specific CD4 and CD8 T-cells responses were detected.

Spanish researchers have tested a therapeutic vaccination method that uses a patient's monocyte-derived dendritic cells, pulsed with inactivated HIV, that are then vaccinated at six weekly intervals over six months. In this phase I study, twelve patients underwent the vaccination schedule and then stopped antiretroviral therapy for six months. They were compared with a control group of six antiretroviral therapy recipients. Viral load changes after therapeutic vaccination were compared with changes during a treatment interruption prior to vaccination. Viral load doubling time increased significantly in vaccinated patients, and one-third had viral set points more than 0.5 log₁₀ lower in the second treatment interruption. However, cytotoxic T-lymphocyte responses decreased significantly after vaccination, but were restored to pre-vaccination levels after treatment interruption (Lejeune 2003).

A similar approach was investigated by a Brazilian / French collaborative team in which monocyte-derived dendritic cells were produced from 18 untreated people with stable CD4 cell counts (and viral loads (Lu 2004). Using the patients own viruses the researchers pulsed the dendritic cells with inactivated HIV in order to prime them to express antigens from the patients own strains of virus. In eight of the 18 patients viral loads fell by more than 1 log₁₀ after one year. CD4 cell counts were stable or rising. The remaining ten patients also had falling viral loads, but these were unsustained. Looking at all the patients there was a statistically significant reduction in viral load and increase in CD4 cell counts of about 100 cells/mm³, although after one year this returned to baseline levels. These changes were associated with HIV-specific CD4 and CD8 T-cell responses.

Of all the therapeutic vaccine studies to date, this has demonstrated the most dramatic effect on viral loads and CD4 cell counts, although it lacked a control group for comparison. However, the technique involved in the preparation of this type of vaccine is complex and expensive, and would not be easy to scale up for mass use.

References

Asjo B et al. Phase I trial of a therapeutic HIV type 1 vaccine, Vacc-4x, in HIV type 1-infected individuals with or without antiretroviral therapy. AIDS Res Hum Retroviruses 8: 1357-1365, 2002.

Bucy RP et al. Therapeutic immunization with Remune alters kinetics of viral rebound after analytical therapy interruption. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 314, 2002.

Fernandez-Cruz E et al. 3 year evaluation of a therapeutic vaccine (HIV-1 immunogen) administered with antiretrovirals versus antiretroviral therapy alone in patients with HIV chronic infection. XIV International AIDS Conference, Barcelona, abstract ThOrA1482, 2002.

Harrer E et al. Therapeutic vaccination of HIV-1-infected patients on HAART with a recombinant HIV-nef-expressing MVA: safety, immunogenicity and influence on viral load during treatment interruption. Antivir Ther 10: 285-300, 2005.

Lejeune M et al. Therapeutic vaccination using autologous monocyte-derived dendritic cells (MD-DC) loaded with inactivated autologous virus in patients with chronic HIV infection and nadir of CD4 T cells above 400mm3. A phase 1 study. Second International AIDS Society Conference on HIV Treatment and Pathogenesis, Paris, abstract LB30, 2003.

Levy Y et al. Immunological and virological efficacy of ALVAC-VIH 1433 and HIV lipopeptides (Lipo-6T) combined with SC IL-2 in chronically HIV-infected patients - results of the ANRS 093 randomized study. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 62, 2003.

Levy Y et al. Sustained control of viremia following therapeutic immunisation in chronically HIV-1 infected individuals: long-term follow-up of the ANRS 093 trial. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston. Abstract 133LB, 2005.

Lisziewicz J et al. Control of viral load rebound during treatment interruptions in macaques with AIDS induced by a novel topical DNA immunization (DermaVir). Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 312, 2002.

Lu W et al. Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nat Med 10: 1359-1365, 2004.

Markowitz M et al. Discontinuation of antiretroviral therapy commenced early during the course of human immunodeficiency virus type 1 infection, with or without adjunctive vaccination. J Infect Dis 186: 634-643, 2002.

Schooley R et al. Two double blind randomized comparative trials of 4 human immunodeficiency virus type 1 (HIV-1) envelope vaccines in HIV-1 infected individuals across a spectrum of disease severity: AIDS Clinical Trials Groups 209 and 214. J Infect Dis 182: 1357-1364, 2000.

Steiger G et al. Antiviral activity of the neutralizing antibodies 2F5 and 2G12 in asymptomatic HIV-1-infected humans: a phase I evaluation. AIDS 16: 2019-2025, 2002.

Tryniszewska E et al. Vaccination of macaques with long-standing SIVmac251 infection lowers the viral set point after cessation of antiretroviral therapy. J Immunol 169: 5347-5357, 2002.

Valdez H et al. Interleukin-2 increases CD4+ lymphocyte numbers but does not enhance responses to immunization: results of A5046s. J Infect Dis 187: 320-325, 2003.