Experimental mRNA Vaccine Could Lead Fight Against HIV

More than four decades since the onset of the HIV/AIDS pandemic an effective vaccine for preventing HIV remains an elusive goal, despite sustained efforts by the global research community. 

The major hurdles responsible for this lack of success, include

1. high antigenic variability of the HIV-1 envelope (Env).
2. protected configuration of conserved neutralization epitopes due to extensive glycan shield and conformational masking.
3. the relative rarity of B-cells expressing precursors of broadly neutralizing antibodies (bNAbs). 
4. the autoreactivity of bNAbs directed against certain envelope (Env) sites

According to a recent study published in Nature Medicine, an experimental HIV vaccine based on mRNA shows promise in mice and non-human primates like Rhesus macaques. The research was led by Paolo Lusso, M.D., Ph.D., of NIAID’s Laboratory of Immunoregulation, in collaboration with other NIAID scientists, investigators from Moderna, Inc. and colleagues at other institutions.

“This experimental mRNA vaccine combines several features that may overcome shortcomings of other experimental HIV vaccines and thus represents a promising approach,” said NIAID Director Anthony S. Fauci, M.D., chief of the Laboratory and a co-author of the paper.

mRNA Vaccine Induces Virus-Like Particle (VLP) Formation, Elicits Immune Response 

The experimental vaccine works like the two highly effective mRNA COVID-19 vaccines. However, instead of carrying mRNA instructions for the coronavirus spike protein, the vaccine delivers coded instructions for co-expressing the membrane-anchored HIV-1 envelope (Env) and simian immunodeficiency virus (SIV) Gag proteins. Muscle cells in an inoculated animal assemble these two proteins to produce virus-like particles (VLPs) studded with numerous copies of Env on their surface. Although they cannot cause infection or disease because they lack the complete genetic code of HIV, these VLPs match whole, infectious HIV in terms of stimulating suitable immune responses.

Safety Profile of VLP mRNA Vaccine

The results from the study show that the novel vaccine is safe and prompted the desired antibody and cellular immune responses against an HIV-like virus. In their studies, the investigators report that in mice two injections of the VLP-forming mRNA vaccine-induced neutralizing antibodies in all animals. The Env proteins produced in the mice from the mRNA instructions closely resembled those in the whole virus, an improvement over previous experimental HIV vaccines. “The display of multiple copies of authentic HIV envelope protein on each VLP is one of the special features of our platform that closely mimics natural infection and may have played a role in eliciting the desired immune responses,” said Dr. Lusso.

The Env-Gag VLP mRNA vaccine was then tested in Rhesus macaques. The details of the vaccine regimen differed among subgroups of vaccinated animals but involved priming the immune system with a vaccine modified to optimize antibody creation. The prime was followed by multiple booster inoculations delivered over the course of a year. The boost vaccines contained Gag mRNA and Env mRNA from two HIV clades other than the one used in the prime vaccine.  The investigators used multiple virus variants to preferentially activate antibodies against the more conserved “shared” regions of the Env—the target of broadly neutralizing antibodies—rather than the more variable regions that differ in each virus strain.

Although the doses of mRNA delivered were high, the vaccine was well-tolerated and produced only mild, temporary adverse effects in the macaques, such as loss of appetite. By week 58, all vaccinated macaques had developed measurable levels of neutralizing antibodies directed against most strains in a test panel of 12 diverse HIV strains. In addition to neutralizing antibodies, the VLP mRNA vaccine also induced a robust helper T-cell response.

Beginning at week 60, immunized animals and a control group of unimmunized macaques were exposed weekly, via the rectal mucosa, to SHIV. Because non-human primates are not susceptible to HIV-1, scientists use a chimeric SHIV in experimental settings because that virus replicates in macaques. After 13 weekly inoculations, two out of seven immunized macaques remained uninfected. The other immunized animals had an overall delay in infection, which occurred, on average, after eight weeks. In contrast, unimmunized animals became infected on average after three weeks. 

Refinements to the Vaccine

A vaccination regimen encompassing seven or more sequential immunizations would be difficult to implement in humans however, refinements of the current protocol, including improvements in both the yield and quality of VLP generation, may increase the efficacy of immunization and thereby require fewer vaccine boosts. Specific modifications in the choice of Env immunogens and mRNA formulations are being evaluated., in parallel with the original protocol, in a second vaccine-challenge study in rhesus macaques that is currently underway.

Author

Arvind C. Shekhar