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mRNA HIV Vaccine Trials Begin-Moderna
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Update on clinical development of HIV vaccine candidates (mRNA-1644 & mRNA-1574)
mRNA-1644 is a novel approach to HIV vaccine strategy in humans designed to elicit broadly neutralizing HIV-1 antibodies (bNAbs) and is being developed in collaboration with the International AIDS Vaccine Initiative (IAVI) and the Bill and Melinda Gates Foundation (BMGF). A Phase 1 study for mRNA-1644 will use iterative human testing to validate the approach and antigens and multiple novel antigens will be used for germline-targeting and immuno-focusing.
A second approach, mRNA-1574, is being evaluated in collaboration with the National Institutes of Health (NIH) and includes multiple native-like trimer antigens. The Company expects to begin phase 1 clinical trials for both mRNA-1644 and mRNA-1574 in 2021.
Dr. William Schief is presenting new data from the Phase 1 study of the IAVI G001 HIV vaccine candidate, which established the proof-of-principle for germline-targeting vaccine design in humans. This Phase 1 study confirms that vaccines can induce broadly neutralizing antibodies, a necessary strategy to develop an HIV vaccine. The development is expected to require multiple iterative human clinical trials. Moderna's mRNA technology may have promise in HIV vaccine development. Three Phase 1 trials studying HIV vaccine concepts delivered by Moderna mRNA are expected to launch in 2021. The speed and cost advantages of Moderna's mRNA vaccine technology have enabled Moderna's collaborators to develop these trials rapidly.
https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-clinical-progress-its-industry-leading-mrna
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Moderna's Experimental HIV Vaccine Could Begin Human Trials as Soon as This Week
FIONA MACDONALD
18 AUGUST 2021
Moderna will start trialling its experimental mRNA-based HIV vaccine as early as tomorrow (19 August), according to a new submission to the US National Institutes of Health Clinical Trial registry.
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A Phase 1 Study to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer mRNA Vaccine (mRNA-1644) and Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2-Core)
https://clinicaltrials.gov/ct2/show/NCT05001373
Detailed Description:
A Phase 1, Randomized, First-in-human, Open-label Study to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer mRNA Vaccine (mRNA-1644) and Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2-Core) in HIV-1 Uninfected Adults in Good General Health. The hypothesis is that sequential vaccination by a germline-targeting prime followed by directional boost immunogens can induce specific classes of B-cell responses and guide their early maturation toward broadly neutralizing antibody (bnAb) development through an mRNA platform. Fifty-six participants. Adults 18 to 50 years of age who meet all protocol inclusion criteria, who do not meet any protocol exclusion criteria, who understand the study (as demonstrated by the Assessment of [Informed Consent] Understanding [AOU]), and who can provide written informed consent. Randomization allocation is 16:16:16:8 for Groups 1-4 respectively.
There is no blinding in this study. Site and study staff will not be blinded to the IP.
Study Design
Go to
Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 56 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open
Primary Purpose: Prevention
Official Title: A Phase 1, Randomized, First-in-human, Open-label Study to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer mRNA Vaccine (mRNA-1644) and Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2-Core) in HIV-1 Uninfected Adults in Good General Health
Estimated Study Start Date : September 19, 2021
Estimated Primary Completion Date : April 1, 2023
Estimated Study Completion Date : May 1, 2023
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The Phase 1 trial will reportedly involve 56 healthy adults aged 18 to 50 who do not have HIV, and will test the safety of the vaccine as well as look for a basic immune response. The vaccine candidate is functionally similar to the mRNA system that's been so successful in Moderna's COVID-19 vaccine.
For years, researchers have been investigating the potential of mRNA vaccines, but the Pfizer and Moderna COVID-19 vaccines are the first to have been used in humans, and both have been shown to be safe and broadly successful at preventing and reducing severity of SARS-CoV-2 infection.
Moderna will be trialling two versions of its new vaccine candidate, officially called mRNA-1644 (the variant is known as mRNA-1644v2-Core). This is the first mRNA vaccine against HIV to be trialled in humans.
There will be four groups as part of the trial – two receiving a mix of the vaccine versions, and two receiving one or the other.
At this early stage, the trial isn't 'blind', which means everyone who receives the vaccine will know what they're getting. That's because right now the researchers aren't trying to work out how well the vaccine works. This first phase will last approximately 10 months, and they just want to make sure it's safe and that it mounts a basic immune response.
If the vaccine passes this phase, they will still need to go through phase 2 and phase 3 trials to determine how well they work at preventing HIV infection in the broader population.
So how do mRNA vaccines work? Unlike traditional vaccines, which usually contain some part of a weakened or inactivated virus, mRNA vaccines contain an 'instruction booklet' that's passed into our cells and tells them how to make fragments of specific proteins that sit on the outside of the target virus.
For a short period of time (usually 24 to 48 hours), our cells start to make these proteins, and our bodies mark them as foreign and mount an immune response. Hopefully that means when you're exposed to the actual virus, your body will recognize the spike proteins and be quick enough to fight it off before infection becomes too severe.
According to the Moderna clinical trial submission about its HIV vaccine candidate: "The hypothesis is that sequential vaccination by a germline-targeting prime followed by directional boost immunogens can induce specific classes of B-cell responses and guide their early maturation toward broadly neutralizing antibody (bnAb) development through an mRNA platform."
That's a bit wordy, but stimulating those broadly neutralizing antibodies (bnAbs) is important when it comes to HIV.
We're already very good at using antivirals to treat HIV and reduce the risk of someone exposed getting infected.
But making a vaccine against the virus has proved difficult because of how rapidly it infects our DNA and is able to readily mutate its structure.
The most promising approach we have is stimulating those broadly neutralizing antibodies, which some people naturally develop against HIV – but which we haven't been able to trigger with a vaccine so far.
However, an mRNA approach may be different. Earlier this year, research from the International AIDS Vaccine Initiative and Scripps Research tested a component of the mRNA vaccine candidate – the immunogen – but using a non-mRNA system.
While the vaccine candidate didn't mount the full immune response needed, 97 percent of participants developed the desired immune response – the early stimulation of B cells.
"We and others postulated many years ago that in order to induce bnAbs, you must start the process by triggering the right B cells – cells that have special properties giving them potential to develop into bnAb-secreting cells," said immunologist William Schief who led the Scripps Research team back in February.
"In this trial, the targeted cells were only about one in a million of all naïve B cells. To get the right antibody response, we first need to prime the right B cells. The data from this trial affirms the ability of the vaccine immunogen to do this."
This same immunogen will now be used in this new trial in conjunction with Moderna's mRNA system, which has been so useful against SARS-CoV-2.
The hope is that the combination will result in broadly neutralizing antibodies that are capable of fighting off HIV infection in the first place – and may also be effective against a range of other viruses in the future, such as the 'next pandemic'. The new trial is run in partnership with the Bill and Melinda Gates Foundation.
In an announcement to shareholders in April, Moderna said it's also developing another HIV vaccine candidate in addition to mRNA-1644, called mRNA-1574. And mRNA vaccines are also being investigated to prevent a variety of other viruses, such as the herpes simplex virus and influenza.
While the COVID-19 pandemic continues to rage around the world, it's promising to see that some of the technology we've developed to fight it could also help us to prevent other devastating viruses in the future.
You can read more about Moderna's Phase 1 trial here.
https://www.sciencealert.com/moderna-s-experimental-hiv-vaccine-could-begin-human-trials-as-soon-as-this-week
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Targeting B-cell responses
mRNA-1644 is designed to stimulate B cells of the immune system to generate broadly neutralizing antibodies (bnAbs) against the virus.
In 2009 previously undescribed potent bnAbs from large groups of HIV-infected individuals were first identified. It was the isolation of these antibodies that renewed activity in HIV vaccine development.
By investigating how these antibodies interact with the virus and neutralise it in lab tests, scientists were able to underpin numerous spots of vulnerability on the HIV virus, which they used to design vaccine immunogens.
The first of these engineered immunogens is eOD-GT8 60mer, developed by IAVI and partners. In a Phase I trial scientists tested whether this approach would stimulate the human immune system to initiate the generation of bnAbs.
An additional development that ignited interest in the design of immunogens to induce bnAbs was the gaining of a clearer understanding of HIV's outermost protein – the HIV Envelope glycoprotein, which is the target of all bnAbs
"For decades scientists were hindered by their inability to capture the precise structure of this notoriously unstable trimeric protein," IAVI has noted. "But recent advances have allowed them to both stabilize and understand HIV Envelope in unprecedented detail."
Now, the Moderna trial will explore how to deliver the eOD-GT8 60mer immunogen with Moderna's mRNA technology and investigate how to use mRNA to direct cells to make proteins that will elicit immune responses against HIV.
The holy grail for HIV on the horizon?
A highly stigmatised virus, HIV is no longer a death sentence but it is responsible for acquired immunodeficiency syndrome (AIDS), a lifelong, progressive disease with no effective cure.
According to Moderna, approximately 38 million people worldwide are currently living with HIV with 1.2 million in the US. Approximately two million new infections of HIV are acquired worldwide every year and around 690,000 people die annually due to complications from HIV/AIDS.
The most common routes of transmission are sexual intercourse and IV drug use, meaning that younger people are at the highest risk of infection.
HIV represents a significant economic burden – from 2000 to 2015, a total of $562.6 billion globally was spent on care, treatment and prevention of HIV.
The first vaccine for this devastating disease is considered a holy grail in pharma.
There have been multiple attempts before now but many were found to be unsafe and most failed to demonstrate a hint of effectiveness – two studies evaluating adenovirus type-5 vectored vaccines for HIV (Ad5) in the 2000s were found to actually increase the risk of HIV infection.
Other vaccines for various infectious diseases including Covid use an inactive form of the virus they aim to generate an immune response for – in some cases 'live' viruses are used.
mRNA vaccines however don't contain any parts of a virus meaning that they should be safer.
With this type of vaccine, a piece of messenger RNA that codes for a part of the virus, in this case HIV, is enfolded into a vector. Once injected, the mRNA travels inside cells, where the cells' genetic machinery produces the virus protein. Based on that protein, the immune system is then trained to recognise the virus so that when it encounters it, it rallies to attack it.
Over the years, HIV has mutated into numerous variants. Another possible benefit of the mRNA approach is that it is viewed as easily modifiable, meaning it could have an edge over other vaccine techniques.
Moderna noted the Phase I trial, to be conducted with US academic partners including the University of Texas at San Antonio, George Washington University, Fred Hutchinson Cancer Research Center and Emory University, is expected to be completed by May 2023.
If the vaccine is found to be safe and shows signs of generating an immune response, it will progress to more advanced trials and spur hopes that a comprehensive solution to one of the world's most devastating pandemics is on the way.
As IAVI president Mark Feinberg wrote in June at the 40th anniversary of the HIV epidemic: "The only real hope we have of ending the HIV/AIDS pandemic is through the deployment of an effective HIV vaccine, one that is achieved through the work of partners, advocates, and community members joining hands to do together what no one individual or group can do on its own."
https://www.clinicaltrialsarena.com/news/moderna-hiv-vaccine/
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