The challenges of developing HIV vaccines

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In January this year, Johnson & Johnson broke disappointing news about its phase III HIV vaccine trial, known as the Mosaico study (or HPX3002/HVTN706). The vaccine regimen, composed of 3 HIV genes carried by an adenovirus vector followed by boosts with HIV proteins based on the predominant strain in different regions, was not effective in preventing HIV infection compared to the placebo. Due to the lack of efficacy, Johnson & Johnson decided to discontinue this trial, adding another failed attempt to several others in the past 40 years. Disappointed for sure, but you may wonder why it is so hard to develop an HIV vaccine that works. Here are the major hurdles to developing an HIV vaccine.

No case of self-clearance of HIV

For most infections, the immune system can successfully clear the pathogen or at least keep it at bay. By studying these convalescent cases, researchers learn what immune responses are most effective against the pathogen and then develop a vaccine based on the immune responses needed to be activated. For example, neutralizing antibodies are an effective weapon against COVID-19, so the titer of neutralizing antibodies is often used as an indicator of the efficacy of a COVID-19 vaccine. However, unlike most infections, there is so far no documented case of self-clearance of HIV without medical intervention. Without knowing what immune response is effective against HIV, if there is any, developing an HIV vaccine is like building a plane without a blueprint.

Extremely fast mutation rate

HIV belongs to a unique class of viruses known as retroviruses. Like other retroviruses, HIV particles carry the viral genome in RNA format. As soon as it enters the target cell, the first thing HIV does is use an enzyme called reverse transcriptase to make a DNA copy from its RNA genome — a process called reverse transcription. It’s a crucial process for HIV’s ability to infect the cell. Unlike most transcriptions in mammalian cells, where errors rarely happen due to the proofreading mechanism, reverse transcriptase is highly error-prone. During each round of replication, HIV’s reverse transcriptase introduces errors to its genome, which you may know as mutations. Due to this unique property of HIV’s reverse transcriptase, HIV mutates at an extreme speed, much faster than COVID-19 and flu viruses. Over time, just like the COVID-19 virus, many different strains of HIV emerge. Therefore, for an HIV vaccine to be protective, it must generate immunity to all the strains circulating in the human population.

Comparison of mutation rates in different viruses. Image obtained from PLoS Biology by José M. Cuevas et al.

Obstacles to inducing broadly neutralizing antibodies

By studying the antibodies in patients living with HIV, scientists now have some sense of what might be needed for an effective HIV vaccine. A unique class of antibodies can be found in 10-50% of people living with HIV after years without treatment. This class of antibodies known as broadly neutralizing antibodies (bnAbs) can neutralize most HIV strains by targeting the sites of the virus where mutations happen less frequently. However, it is still unclear how the immune system develops bnAbs over the years of infection. The time needed for bnAbs to develop after infection implies several doses of vaccine may be required to induce this type of antibody. And the fact that only a fraction of people living with HIV develop bnAbs suggests the generation of bnAbs may be not favored by the immune system. Ever since the discovery of bnAbs, vaccine researchers have taken on a mission to tackle the roadblocks to inducing bnAbs by different vaccine strategies. Despite some progress, all the attempts to induce bnAbs by vaccines have not been successful.