This month, the biotech company Moderna has begun human trials for a new HIV vaccine. This vaccine, unlike its predecessors, will be the first of its kind based upon the new messenger RNA (mRNA) vaccine platform developed for COVID-19.
HIV, or Human Immunodeficiency virus, is a retrovirus that is known for attacking the human immune system leading to increased susceptibility to opportunistic diseases. HIV has taken over 36.3 million lives so far, and 37.7 million are currently living with it as of 2020 according to the World Health Organization (WHO). (1) This virus is clever, utilizing its HIV envelope glycoprotein to mimic the same sugar chains found on human proteins, evading immune response. (2) Similar to COVID-19, it also utilizes protein spikes, hidden by the HIV envelope, which allows for quick attachment and infection of cells. (3) Consequently, a successful HIV vaccine candidate has eluded the scientific world for decades, remaining as a holy grail that has yet to be discovered.
The retrovirus acts rather quickly, inserting itself into the human genomes as quickly as 72 hours after transmission. (4) To prevent infection, the body must have high level of broadly neutralizing antibodies (bNAbs) at the time of transmission. These act by targeting the HIV envelope to keep them from entering cells. Unfortunately, only 10-20% of people with HIV have been observed to produce bNAbs on their own, most commonly after many years, so vaccine priming is mandatory. (5)
Traditionally, HIV vaccine trials have tried presenting inactive or weakened forms of the virus to the immune system. However, after 40 long-years, trials have seen little success in producing desirable immune responses. (6) In fact, a trial held during the early 2000s in Thailand had to be cancelled, as the developed vaccine resulted in increased susceptibility to HIV rather than prevention. (3) At present, HIV is thought to mutate too rapidly, evading the immune system in unique ways that cannot be targeted with traditional vaccine strategies.
Instead, Moderna with the support of the International AIDS Vaccine Initiative (IAVI) and the Bill and Melinda Gates Foundation (BMGF), seeks to solve this issue with an mRNA based vaccine. (7) Moderna has begun trials with two different mRNA vaccine candidates: mRNA-1644 and mRNA-1644v2. The clinical trials started on August 19 and is projected to end in spring of 2023. (3) Both candidates have passed their first round of safety tests in non-human subjects. 56 HIV-negative candidates have now been selected from ages 18-56. Four groups have been assigned, two receiving a combination, and two receiving only one of the vaccines. (4) The hope is to eventually combine this with vaccines previously developed by the IAVI, which will allow for efficient priming and stimulation of neutralizing antibody response.
In contrast to traditional methods, the mRNA platform behaves as a genetic blueprint, encoding the body’s cells for production of benign spike proteins, similar to those that are embedded into our cell’s surface upon infection of the retrovirus. (8) The cells then present these spike proteins on their surface, where the immune system can learn to recognize and build a remembered response. (3) This begins through the priming of immature B lymphocytes, which will be guided into the production of bNAbs that target the HIV envelope at what is known as the CD 4 binding site. (2)
Mechanism of the mRNA vaccine platform, which is similar between SArs-CoV-2 and HIV retrovirus.
One may ask why suddenly there is a sudden surge in trials for mRNA vaccines, and where they have all been hiding. The recent successes of mRNA based COVID-19 vaccines has undoubtedly signalled a breakthrough in early disease prevention technologies. Researchers have been studying mRNA vaccines for decades but have been limited in its use in human trials. (8) Accelerated approval by the FDA in response to COVID-19 has allowed for a loosening of these restraints, and a resurgence of interested research parties.
Moderna’s mRNA vaccines instill hope into a once thought to be lost cause. However, they still require extensive testing into their overall effectiveness, dosage, safety, and how the drug and body interact. If the vaccine proves successful past Phase III testing, Moderna will have the chance to bring these studies to the FDA for approval to enter Phase IV trials on a larger population. (3) This will require many years to perform, but if successful, these vaccines could help end an epidemic that has faced the human population for the last 40 years.
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