The success of the COVID-19 mRNA vaccines from Pfizer/BioNTech and Moderna has sparked a possible preventative mRNA vaccine candidate to tackle HIV infections.
The human immunodeficiency virus (HIV) causes AIDS (Acquired Immune Deficiency Syndrome) where there is a complete shutdown of the host immune system, making the patient susceptible to other deadly diseases. AIDS has claimed around 36.3 million lives so far, with an estimated 37.7 million living with deadly virus at the end of 2020 according to the World Health Organization (WHO).
Like the coronavirus, HIV envelope glycoprotein uses protein spikes to attach to the host cells, in this case, the T-cells of the immune system. The membrane of the HIV virus then fuses with the host cell membrane and the virus injects its RNA along with reverse transcriptase genes. The reverse transcriptase enzyme converts the viral RNA to viral DNA which gets integrated into the host genome. The viral genome uses the host genome’s machinery to generate more viral copies. The newer viral particles then infiltrate the other cells of the immune system thus leading to a decrease in the number of T-cells causing severe immunodeficiency.
Over the years, the HIV virus has managed to escape the host immune system’s defence mechanisms. This is mainly due to the virus’s ability to rapidly mutate that helps to evade antibodies. The virus has also developed a way to camouflage its outer envelope with the same sugar chains found on human proteins, so that it remains hidden.
Roadblocks in developing the HIV vaccine
Despite knowing the ins and outs about the virus, there is still no clear cut cure and there is no vaccine. An ideal HIV vaccine will evoke both humoral and cell-based immunity. The humoral response mainly consists of broadly neutralising antibodies that neutralize the virus would provide the first layer of defense, preventing infection of host cells upon virus entry into the body. The HIV vaccine candidates that have been tested in people so far have been unsuccessful in producing these broadly neutralizing antibodies.
The challenges in HIV vaccine development is also due to the fact that the exact correlates of immune response have not been clearly identified. These correlates help to stimulate protection against HIV and the enormous diversity potential of the virus. Inducing broadly neutralising antibodies against HIV envelope protein and CD8 T cell responses has been the major focus.
A possible mRNA HIV vaccine
The US pharmaceutical and biotech company Moderna, which developed the world’s first Covid-19 vaccine, recently announced human trials for two HIV mRNA vaccines. IAVI (International AIDS vaccine initiative) and Scripps Research, along with Moderna have launched a phase I clinical study that assesses the ability of two vaccine candidates mRNA 1644 and mRNA 1644v2 to safely generate broadly neutralizing antibodies in healthy adults. This is the first mRNA vaccine against HIV to be trialled in humans.
This randomized, open label study examines HIV-1 uninfected adults in good general health. Adults between 18 to 50 years of age who have applied for the trial will be assigned into four groups randomly Then, depending upon their assigned group, trial participants will receive either or both of the experimental mRNA vaccines (mRNA- 1644 [eOD-GT8 60mer mRNA], mRNA- 1644v2-Core [Core-g28v2 60mer mRNA]) via intramuscular injection.
Safety and tolerability, the primary outcome measure, will be assessed by the proportion of participants with mild, moderate, or severe adverse effects at different times throughout the study. Investigators will also study immunogenicity, the secondary outcome measure, by means of presence and magnitude of relevant immune biomarkers at 10 months. A total of 56 participants enrolled for the study and is expected to be completed by May 1, 2023.
The process of stimulating immature B cells with specific properties (that mature into cells capable of generating multiple broadly neutralizing antibodies) is called “germline targeting”. Researchers are using this process to “prime” young B cells as part of a first step of an eventual multi-step vaccine strategy. The goal of the first study is to see how far down the path the initial immunogen goes and use the findings to define the steps needed to further refine the process of preparing broadly neutralizing antibodies against HIV.
There are several challenges ahead for developing the HIV mRNA vaccine. However, the durability of responses, ease of production, ability to encode complex protein designs and safety as immunogens makes mRNA an excellent molecule for HIV vaccine development