Trials and tribulations for creating HIV vaccines

Research published in Retrovirology tells of promising results from a phase II trial of a new vaccine that has been created, the HIV-1 Tat vaccine.

There is currently no cure for HIV infection, and so research into producing and trialling potential treatments is vital to prevent the number of infected individuals from increasing. Here, we ask co-authors of an article published in Retrovirology, Barbara Ensoli and Aurellio Cafaro from the National AIDS Center, Istituto Superiore di Sanità, Italy, more about producing an HIV vaccine.

Why has creating an effective vaccine against HIV been difficult for researchers in the past?

There are many reasons. Historically, HIV/AIDS vaccines were designed to prevent infection and therefore the Envelope (Env) molecules present on the virus surface represented the most obvious antigens to target. However, it turned out that HIV-1 Env is very variable as it is largely composed of glycans which shield the proteic portion targeted by most antibodies. The neutralization sensitive domains are often hard to reach, and are also displayed too shortly and too late during cell infection to be effectively attacked by antibodies.

Furthermore, there is extensive molecular mimicry of Env with self-molecules that hampers the generation of protective antibodies. Virtually all Env-based preventative vaccine trials that have been conducted so far have used a monomeric form of Env as the vaccine. This differs antigenically from the functional form displayed on the virus membrane, which is oligomeric.

In addition, vaccine candidates aimed at eliciting cytotoxic T cell responses capable of killing HIV infected cells soon after virus transmission have been similarly unsuccessful, mostly due to the inherent ability of the virus to rapidly mutate without loosing infectivity and fitness. This renders it difficult to design a vaccine covering the majority of the circulating virus strains, and even if an effective vaccine is created, there is no guarantee that the virus will not mutate and escape immune control.

What is the most recent progress on finding an HIV vaccine?

Historically the HIV vaccine development has followed two main streams: the induction of antibodies or the induction of cellular responses to protect from infection. To date, only one HIV-1 Env based preventative vaccine, aimed at inducing protecting antibodies, has shown some level of protection from infection in a low risk population (the RV144 ‘Thai trial’).

In this trial, protection from infection was a promising 61% in the first year but declined to 32% after two years and continued to decline thereafter. However, this was enough to revitalize the field of Env-based vaccines.

HIV vaccine development has followed two main streams: the induction of antibodies or the induction of cellular responses to protect from infection

Enormous progresses have been made in the identification and characterization of potent broadly neutralizing anti-Env antibodies naturally occurring in chronically HIV-infected people. However, these antibodies appear too late (after two or more years since infection), in too few individuals (about 25%) and are very peculiar under many respects.

It is the ability to design an immunogen capable of eliciting them very quickly and in most subjects that is the formidable challenge researchers’ face at present. Several approaches have been undertaken to tackle it, which are still in the preclinical stage of development.

Strategies aimed to provoke protective cell-mediated immune responses, rather than antibodies, represent the second main stream in the HIV vaccine field. Here the challenge is represented by the well-known ability of HIV to mutate and escape T cell recognition. To overcome this problem, several strategies taking advantage of bioinformatics or the unique ability of certain viral vector to elicit a peculiar type of CTL response are being developed and are in preclinical or early clinical development.

What is different about the immunotherapy that you and your colleagues have applied?

First of all we target a molecule that, until recently, was considered not to be present in the virion or on its surface. This molecule is known as Tat, the HIV-1 transactivator of transcription. Tat was thought to be expressed transiently and mostly only at the very beginning of the infection, to be strictly intracellular and therefore not attackable by antibodies.

In contrast, Tat is actually released extracellularly and plays important roles throughout the different phases of infection, including reactivation in chronically infected individuals on successful combined anti-retroviral therapy (cART). We have recently demonstrated that extracellular Tat binds Env spikes present on virus particles forming a virus entry complex that favors infection of dendritic cells and transmission to T cells, while shielding Env from anti-HIV antibodies, thus inhibiting virus neutralization. Strikingly, anti-Tat antibodies restore and further increase virus neutralization.

Notably, unlike all the other HIV-1 proteins, Tat is infrequently targeted by specific antibodies in the course of the natural infection, but when this occurs the infection progresses at a very slow pace, if at all. This strongly supports the notion that anti-Tat antibodies exert a protective role against progression of disease.

We have used a recombinant biologically active Tat protein to retain the antigenicity of the natural counterpart and to exploit its inherent immunogenicity, which permitted us to avoid the use of adjuvants in the vaccine. This was clearly a contrarian approach, since in the scientific community, the assumption that the biologically active HIV-1 Tat is harmful and should be inactivated to be used as a vaccine prevails.

To date, the biologically active Tat vaccine has been administered to 314 people, and our data clearly indicate that this vaccination is absolutely safe, both in healthy individuals and in HIV-1 infected subjects, whether on cART or not.

You followed up with patients after a period of three years, why was this important to do?

HIV-1 infection slowly disables the immune system, leading, on average after ten years in untreated individuals, to the severe immune deficiency that defines AIDS. Thus, we reasoned that the immune restoration upon cART intensification by the Tat vaccine would have proceeded at a similar pace.

Indeed, while some changes were clearly occurring soon after immunization, changes in the CD4 T cell subsets and especially in the CD8 T-cell and natural killer cell compartments became apparent only from the second year onward, somewhat mirroring, at the reverse, the kinetics of the damage provoked by the virus.

According to the data we are gathering, this has proven to be an extremely good decision.

But there were other important questions to address with a prolonged follow-up; how long will the Tat vaccine be effective? Will a boost be required to keep it working? Will the vaccine effects progressively increase over time or plateau at a certain time? Will cART intensification by the Tat vaccine affect the size of the virus reservoir?

The three-year follow up clearly demonstrated that within this time interval the vaccine efficacy does not decline. The promising results prompted us to initiate an observational roll-over study, in which we were able to enrol 93 out of the 168 vaccinees from the experiment, to further extend the follow up for an additional two and half years to see what happens in the long term. According to the data we are gathering, this has proven to be an extremely good decision.

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