Around the world, approximately 38 million people are infected with HIV. And around two thirds of them live in Africa, which leaves the remaining over 12 million people to be dispersed over the rest of the globe. Now in the United States alone, there are just over 1.2 million people living with HIV. And as of 2019, there are just under 35,000 new infections per year. Now, HIV infection is no longer a death sentence as it was in decades past. And there are many ways to now treat HIV. But could there be a way to stop HIV from infecting people in the first place?
Hi folks, my name is Cole and I have a Master’s of Immunology. Today on Investigate Explore Discover, we’re going to be looking at a mosaic antigen HIV vaccine safety trial. So hang around with me throughout this whole video to get all of the relevant background information, so that way we can dive into some exciting experimental results.
HIV is a sexually transmitted disease, and can also be spread from mother to baby or by sharing used needles. So it is very unlikely that you will be in danger of contracting it by going about your day. Throughout the course of HIV infection, besides an initial spike when first infected, HIV slowly increases in the body over time and kills CD4 T-cells. When there are very low levels of CD4 T-cells in the body, this is when HIV progresses into AIDS. Getting AIDS is fatal, as it causes individuals to succumb to opportunistic infections. This is because the CD4 T-cells in your bodies are required for mounting a robust and effective immune response to help keep you healthy.
Now the HIV virus is made up of many components, which include envelope proteins, matrix related gag proteins, viral polymerases, and of course, the positive ssRNA genome that defines HIV. These are all essential for the virus to carry out its life cycle. Based on the composition of these viral parts, which are distinctly genetically defined, HIV can be further subcategorized into groups and clades, or subtypes. Group M is the strain of HIV that is responsible for the global epidemic, and has even further sub groupings labeled A through K and circulating recombinant forms. Now, these subgroups are spread all over the world in an unequal fashion. This results in each region of the world being primarily affected by a few major subtypes. This has to be considered when trying to create a vaccine that will work for everyone.
Now, there are many different viral components that can be used for vaccine targets. But the strategy that we’re focusing on today utilizes recombinant or synthetic derivatives of specific viral parts that can be used that will allow the immune system to recognize HIV. By using specific viral components like envelope, gag or polymerase proteins, it can teach the immune system to recognize and kill HIV on site. However, if only one stimuli is used, it leads to a one-sided protection that only works on a narrow range of viral variants. By effectively using multiple components that are computationally designed to broaden immune responses, we can create heterotypic stimuli that expose the immune system to a range of viral components, allowing for greater detection of a broader range of viral variants, making the vaccines more effective. Now as a proof of this concept, it has been previously shown that bivalent and trivalent mosaic inserts broaden immune responses in non-human primate models.
When vaccines are effective, they stimulate many different immune cells in our bodies, like Macrophages, Dendritic cells, T cells, and B cells, which then go on to create antibodies. These cells confer protection through antibody dependent cellular cytotoxicity, cytokine release, antibody binding and neutralization, and other cell dependent responses. Now, to determine the safety and efficacy of vaccines, they go through a rigorous testing procedure that involves many stages.
The first thing that vaccines have to pass is the preclinical research phase. This is where the proof of concept experiments are performed in animals. Once the proof of concept is laid out, this enables movement to clinical trials, which are done in a double blinded fashion so that no one can sway the results. This enables enrollment on phase 1 clinical trials. Phase 1 clinical trials use a small population of people to determine the safety effects that the vaccine may induce by itself and identifies how the vaccine works in the body by measuring adverse events. The adverse events that are observed in people are broken up onto a scale. This scale goes from grades 1 through 5 with grade 1 events typically described as asymptomatic or mild, and the events increase as severity as the grade goes up. Grade 3 events are typically severe or medically significant, but not life threatening, and grade 5 indicates that the treatment caused death. Now these events are always tested against a placebo because sometimes belief in a treatment may be enough to change the course of a person’s physical illness. Now, it’s a weird thing that people do but it has to be accounted for.
Once passing phase 1, the vaccine undergoes general metabolism and safety testing in phase 2, which can be further broken up into phases 2a and b. Phase 2a can address issues such as dosing and safety, while phase 2b studies are generally many phase 3 studies that provide data on efficacy.
Phase 3 trials test the efficacy and safety in a large group of people. And pivotal phase 3 trials or registration trials provide the key data on efficacy in submissions for regulatory approval.
Now, once a vaccine is proven to be safe and efficacious, it is approved by a regulatory body and allowed to be given to the public. From there, phase 4 studies have been undertaken after a drug has been licensed to gather further safety efficacy or effectiveness data in routine clinical use.
And the vaccine that we’re talking about today uses an Adenovirus 26 vector to deliver the antigens to the cells to prime the immune response. This vector is used because it has been previously shown to be well tolerated and elicits humoral, cellular, mucosal and immune responses that are augmented by sequential vaccinations. The antigens used in this study, use the mosaic concept to develop a vaccine to achieve more optimal coverage of circulating HIV strains using HIV gag polymerase and envelope proteins. The authors also boosted their vaccines with trimeric GP140, which are the full envelope proteins to improve the immunity that they generate. The components in this vaccine are Mosaic antigens 1 and 2 for Gag-Pol and Envelope proteins co-formulated in a 1:1:1:1 ratio. Now, Mosaic 2 envelope has the highest coverage of Clade C strains, and is designed to complement the coverage of Mosaic 1 envelope, which highly covers Clade B and CRF_01AE strains.
Now, I want to take a moment and really highlight why HIV vaccine research is so important. First and foremost, this information is important because 36.3 million people have died from HIV since the beginning of the epidemic in the 1980s. And last year alone, 1.5 million new people were infected with HIV while 680,000 died from it. Thus, there is a need for an effective prophylactic vaccine against HIV to prevent continued infections.
This brings us to the paper that we’re focusing on today. This paper is called: Safety and Immunogenicity of Two Heterologous HIV Vaccine Regimens in Healthy HIV Uninfected Adults (TRAVERSE): A Randomized Parallel-Group, Placebo-Controlled, Double-Blind Phase 1/2a Study by Baden and Stieh et al. from multiple groups throughout the world. And in this paper, the authors observed the safety and immunogenicity of a trivalent versus a tetravalent Mosaic antigen HIV vaccine in people worldwide.
In their study, the author screened 379 people and applied exclusion criteria to ensure that the participants did not have HIV or other chronic viral infections, and were not pregnant, among other things. Thus, 201 people passed the acceptance criteria and were enrolled in this study. The authors then randomly split the participants into three groups that underwent a series of four injections. 27 out of 34 people received the full regimen for the placebo, 45 out of 55 received the full regimen of the trivalent vaccine and 94 out of 112 received the full regimen of the tetravalent vaccine. Now there were a host of reasons why some people did not complete the full vaccine regimen, which included people being lost to follow up, withdrawing from the study, getting pregnant, or having adverse effects. For this study, people were recruited from the United States and Rwanda. And the demographic characteristics of people who received at least one dose were similar across treatment groups, with the exception that proportionately more women were enrolled in the placebo group. Also important to note, the participants of this study were predominantly white.
Now these shots were administered by intramuscular injection into the deltoid muscle, and the schedule looked a little something like this. On day 0, participants received a first injection of either the tetravalent vaccine Ad26.Mos4 HIV, the trivalent vaccine Ad26.Mos HIV or the placebo, and those injections were repeated in 12 week intervals. At week 24, when receiving their third dose, the vaccine recipients were also administered a Clade C gp140 booster, which again is the viral envelope, of which this dose was repeated again at 48 weeks. Samples were taken for analysis the day of injection, after injecting, and throughout the following four weeks.
Now, the authors next observed the adverse events from each of these treatments. They found that 89% of people in the trivalent and tetravalent groups and 64% of the placebo group reported grade 1 to 2 adverse events at the site of injection. These numbers were representative of all people over four shots. Now, 2%, 11% and 3% of people in the tetravalent, trivalent and placebo groups respectively, reported grade 3 local events. Now, when looking at the systemic adverse events, the authors did not list the percentage of people that reported grades 1 to 2, but they did report that almost a quarter of people given the tetravalent and trivalent vaccines reported grade 3 events, while 3% of people reported them in the placebo. Some of these systemic events that were specifically asked about were fatigue, headaches, myalgia or muscle pain or a fever. When people were asked to self-report other adverse events, the authors found that around 65% to 70% of all participants had mild adverse events, while 5% and 6% of tetravalent and trivalent vaccine recipients had grade 3 level events. Interestingly, none were reported at this stage for the placebo. Now, these adverse events included infection, rheumatoid arthritis, lymphedema, atrial fibrillation, ankle fracture, and syncope. Now it is particularly important to note that the authors determined that this vaccine was the cause of rheumatoid arthritis in one patient after four months, who had a medical history of eczema, depression, anxiety and multiple fractures. It was also noted that laboratory abnormalities were infrequent.
Now throughout this experiment when collecting samples, the authors were able to isolate cells from participants and analyze their immune responses. Both the tetravalent and trivalent vaccines were highly immunogenic throughout the study, and were enhanced with additional vaccine doses. But the tetravalent vaccines typically induced more immunogenicity, which was measured by identifying the IgG antibodies to envelope protein. On the other hand, placebo recipients did not show consistent responses. To get a greater handle on exactly how well the vaccine would work, the authors then tested multiple different parameters. They performed a slew of tests on the recovered cells that measured things like cytokine release, T and B cell activation, antibody concentrations, cross-clade reactivity and multiple antigen specificity. Now, through these tests the authors determined that this vaccine was effective against multiple HIV subtype antigens, and it caused the induction of antibody release, which helped mediate antibody dependent cellular cytotoxicity, T and B cell responses and stimulation of cytokine release.
Now, to quickly summarize everything altogether, the authors recruited 201 people from the United States and Rwanda, and split them into three experimental groups to test out the efficacy of a tetravalent or trivalent mosaic HIV antigen vaccine against a placebo. They found that these vaccines had a safety profile that was within acceptable limits. And across all the immune responses evaluated, the tetravalent vaccine induced greater immune responses than the trivalent, though both did mount immune responses.
Now, not only do I think these observations are exciting to investigate and learn about, they’re also significant in a broader context. This information is significant because this data shows that both the trivalent and tetravalent vaccines are generally safe and well tolerated. However, the tetravalent formulation elicits a stronger immune response than the trivalent mosaic vaccine. This indicates that the tetravalent vaccine is the best candidate to move forward in future clinical trials. All science is basically a stepping stone for new knowledge. And these steps are driven by questions. And I had a few questions myself after reviewing this information.
My first question revolves around places in the world that do not have Clade B or C as dominant HIV strains. Could these regions have an alternative vaccine developed for them using the ideas in this paper leading to development of region specific HIV vaccines? Now, the biggest question that I had about this, which is addressed by further clinical trials, is whether this vaccine will actually prevent HIV infection. I mean, this vaccine was effective in non-human primates and the immunogenicity was good, but only actual testing will be able to tell us how this will work in humans. Speaking of, there are two studies that have been launched as a result of the findings from this paper, one looks at the efficacy of preventing HIV in women of Sub-Saharan Africa, and the other looks at preventing HIV infection in cis-gender men and trans-gender individuals who have sex with other cis-men or trans-people in the Americas and Europe.
Another question that I had has to do with whether this could also be used for people who are chronically infected with HIV already? Would this vaccine give their immune system possibly a boost to prevent the progression from HIV into AIDS? I mean, I’m not sure that this will be tested but it’s an interesting thought.
As always, my final question revolves around you. What sort of ideas or questions popped into your head when hearing about this information? I would love to hear about them in the comment section below. Also, let me know if there are any topics that you’d like to hear about in the future. Ultimately, I hope that you learned something. But more importantly, I hope that you enjoyed your time doing so. So if you did, give this video a like and subscribe for more in the future. Well, that’s everything for today. Thank you for watching, and I’ll see you next time.
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