With RNA technology, the hope of an AIDS vaccine? By Prof. Gilles Pialoux

Why do we still not have a vaccine against the AIDS virus, when it took barely fifteen months to develop anti-Covid injections? The question comes up regularly in this health crisis. Let’s correct one point right away: if the arrival of messenger RNA vaccines from Pfizer and Moderna was very rapid, their technology is the result of fifteen years of research. Moderna, for example, initially targeted many diseases, from the Zika virus to certain cancers or orphan diseases. But not HIV.

This quest for the AIDS vaccine represents, on a personal level, a subject full of memories. On a certain day in May 1992, in the former hospital of the Institut Pasteur, I in fact performed the injection on the first volunteer selected by the National Agency for AIDS Research, in the ANRS VAC- 01. Media arrived from everywhere, a bit like today with the Covid.

This was a phase 1 trial, with a double vaccine product using the canarypox virus as a vector, and a recombinant protein (Gp120), resulting from the work of Pasteur Mérieux serums and vaccines. He was not selected, but several volunteers still have antibodies in their blood that he induced, sufficient to give a false positive to HIV screening tests, but not enough to protect them from the virus.

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HIV can have hundreds of mutations

Where are we in February 2022? Only one trial, Thai (the RV144 study, dating from 2009), showed partial preventive efficacy, with a 31% reduction in the risk of infection, during a phase 3 trial. The vaccine strategy used was already that which currently enjoys a consensus: a prime-boost with two injections of different vaccines. The first prepares the vaccine response, the second boosts it. Unfortunately, more recent phase 2b/3 trials conducted in Africa failed to confirm the results obtained in Thailand. The causes of this failure are currently being analysed.

Why so many difficulties? First, because of the complexity of the AIDS virus. Like all retroviruses, it has an enzyme that allows it to transform its RNA into DNA and integrate into our own genome, from where it can no longer be dislodged. It also presents a phenomenal variability. Where the Omicron variant displays 32 mutations on its spike protein, which is already a record, HIV can present hundreds.

Even more, it varies from one continent to another, from one individual to another, but also in the body of the same individual over time. We know, for example, that homozygous twins contaminated in utero or during childbirth by the same maternal virus will no longer have, from mutation to mutation, no longer a virus similar to that of their mother, but also different viruses. the other. Furthermore, the preferential target of neutralizing antibodies, the envelope protein, is the most variable part of HIV.

Finally, it is not “only” a question of protecting against the serious forms of the disease but of blocking the transmission, in particular by the mucous membranes. Future HIV vaccines will therefore need to induce both neutralizing antibodies and cellular and mucosal responses.

The main challenge: characterizing the right antigens

Unlike that of the anti-Covid vaccine, the challenge of the anti-HIV vaccine therefore relates less to the question of the choice of the vaccine model than to the characterization of the vaccine antigens to be targeted. All current strategies aim to induce broad-spectrum neutralizing antibodies, the only way to ensure significant protection at the individual level. It is necessary to be able to block the infection of more than 90% to 95% of viral strains, which is the case in only 1% of individuals infected with HIV-1.

A hopeful lead is that followed by Moderna. The laboratory chose to combine mRNA vaccines encoding eOD-GT8 60mer proteins (germline) 27 to others encoding Core-g28v2 60mer proteins (boost), as recently announced in the press. The selected antigens have already proven themselves with other vaccine vectors. But the development of an anti-HIV vaccine remains a complex research strewn with hopes and disappointments. Remember that we are still only in phase 1 trials. As in 1992.

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Professor Gilles Pialoux is head of the infectious diseases department at the Tenon hospital (AP-HP), in Paris, member of the health center of Terra Nova and vice-president of the French Society for the Fight against AIDS. He just published Like a slight tremor (Editions Mialet/Barrault).