Hope against AIDS: A first mRNA vaccine against AIDS has shown promise in tests with mice and monkeys. The vaccination with the gene codes of two virus proteins produced a strong antibody response against several variants of the HI virus. In macaques, multiple vaccinations reduced the risk of infection by 79 percent. This raises hope that the mRNA technology that is successful against the coronavirus could also help in the fight against HIV.
While vaccine development against the Coronavirus took less than a year, researchers have been looking for a suitable vaccination strategy for AIDS for 40 years – so far largely in vain. All attempts to boost the immune system through live vaccines, or protein vaccines gene-based vaccines Arming against the HIV virus has produced disappointing results. The best approach to date achieved a protective effect of only around 30 percent in clinical studies – and even that could not be reproduced.
Why vaccine development against HIV is so difficult
The problem: The envelope protein (Env) of the HI virus is highly variable and changes easily. In addition, important identifying features of the viral protein envelope are hidden by sugar attachments. In the HIV virus, these glycans form an almost area-wide “Camouflage coat“. The result: “Generating neutralizing antibodies through a vaccination has proven to be extremely difficult and even after a natural infection only a fraction of those affected develop such antibodies,” explains Peng Zhang from the US National Institute of Allergy and Infectious Diseases (NIAID) and his colleagues.
But the mRNA technology now offers new opportunities to overcome these problems. This is because the gene codes for certain viral proteins and protein parts can be combined in a vaccine and tailored for optimal effect. “Our experimental vaccine combines several features that compensate for the deficits of previous HIV vaccine candidates,” explains senior author Anthony Fauci from NIAID.
Building instructions for two virus proteins combined
Specifically, the new HIV vaccine consists on the one hand of RNA with the instructions for the viral envelope protein Env. In the variant administered for the first vaccination doses, this envelope protein lacks some sugar attachments, which means that they can be better recognized by the immune system. The vaccine for the booster doses, on the other hand, contains the code for the complete protein of several HIV-1 mutants. “This is supposed to strengthen the B-cell response to common antibody attachments of these variants,” explains the team.
Another decisive factor: the mRNA vaccine contains the gene code for a second virus protein (Gag). The combination of these two proteins is sufficient to stimulate the formation of virus-like particles in the body – small structures that resemble the surface of natural HI viruses. In initial tests with mice, this led to all vaccinated animals developing neutralizing antibodies, as reported by Zhang and his colleagues.
Antibodies and T cells against HIV
The researchers used 14 macaques to investigate how well this mRNA vaccine protects against HI infection. Half of the monkeys received a dose of the different vaccine variants every two to three weeks, the others remained unvaccinated. As the team found, the vaccine was well tolerated and the animals developed
The result: after the first booster dose, the titre of the neutralizing antibodies rose significantly in the vaccinated monkeys, but fell again relatively quickly. Only after the third vaccination did the antibodies remain stable at a high level, as reported by Zhang and his colleagues. The cellular immune response also reacted to the vaccine: after six months, both T killer cells and T helper cells against HIV were detectable, and after a year their activity had increased significantly again due to the booster vaccinations.
Risk of infection reduced by 79 percent
Then the decisive test followed: a good year after the first vaccination, all animals received a diluted solution of HI viruses injected into the anus once a week. In the unvaccinated monkeys, this led to an infection on average after the third contact with the virus. “In contrast, two of the seven immunized animals showed no signs of infection even after 13 weeks,” the scientists report. The remaining five monkeys only became infected after a considerable delay, on average only after the eighth virus contact.
The vaccinated animals therefore had a 79 percent lower risk of contracting the HIV virus in the event of unprotected contact. This immune protection also worked against twelve different variants of the pathogen. “Such an mRNA platform represents a very promising approach for the development of a vaccine against AIDS,” states the research team.
Further optimization is necessary
As a next step, the scientists are now planning to further optimize the vaccine candidate so that fewer booster vaccinations are required. Because a vaccination regime consisting of seven or more doses would hardly be accepted by people and would also be difficult to implement in many poorer countries. “We are therefore adapting our vaccination protocol in order to increase the quality and quantity of the virus-like particles generated,” explains Paolo Lusso, head of the study from NIAID.
If the optimized vaccine variants then also prove to be successful and safe in animal experiments, a first phase 1 clinical study should follow. The vaccine is first given to healthy volunteers to check whether it is tolerated by humans. (Nature Medicine, 2021; doi: 10.1038 / s41591-021-01574-5)
Source: NIH / National Institute of Allergy and Infectious Diseases