One of the main reasons it has been difficult to develop an effective HIV vaccine is that the virus mutates very rapidly, allowing it to evade the antibody response generated by vaccines.
Several years ago, MIT researchers showed that administering a series of escalating doses of an HIV vaccine over a two-week period could help overcome some of that challenge by generating greater amounts of neutralizing antibodies. However, a multi-dose vaccine regimen administered over a short period is not practical for mass vaccination campaigns.
In a new study, researchers have found that they can achieve a similar immune response with just two doses, given a week apart. The first dose, which is much smaller, primes the immune system to respond more strongly to the second, larger dose.
This study, which was carried out by combining computer modelling and experiments in mice, used an HIV envelope protein as a vaccine. A single-dose version of this vaccine is currently being tested in clinical trials and the researchers hope to establish another study group that will receive the vaccine in a two-dose regimen.
“By bridging the physical and biological sciences, we shed light on some basic immunological questions that helped develop this two-dose regimen to mimic the multi-dose regimen,” says Arup Chakraborty, an MIT John M. Deutch Institute Professor and a member of the MIT Institute for Medical Engineering and Science and the Ragon Institute of MIT, MGH, and Harvard University.
This approach can also be generalized to vaccines for other diseases, Chakraborty notes.
Chakraborty and Darrell Irvine, a former professor of biological engineering and materials science and engineering at MIT and a member of the Koch Institute for Integrative Cancer Research who is now a professor of immunology and microbiology at The Scripps Research Institute, are senior authors of the study, which appears in Science ImmunologyThe lead authors of the paper are Sachin Bhagchandani PhD ’23 and Leerang Yang PhD ’24.
Neutralizing antibodies
Each year, HIV infects more than a million people worldwide, and some of them do not have access to antiviral drugs. An effective vaccine could prevent many of those infections. One promising vaccine currently in clinical trials consists of an HIV protein called envelope trimer, along with a nanoparticle called SMNP. The nanoparticle, developed by the Irvine lab, acts as an adjuvant that helps recruit a stronger B-cell response to the vaccine.
In clinical trials, this vaccine and other experimental vaccines have been given in a single dose. However, there is growing evidence that a series of doses is more effective at generating broadly neutralizing antibodies. Researchers believe the seven-dose regimen works well because it mimics what happens when the body is exposed to a virus: The immune system mounts a strong response as more viral proteins, or antigens, build up in the body.
In the new study, the MIT team investigated how this response develops and explored whether they could achieve the same effect using fewer vaccine doses.
“It’s not possible to administer seven doses for mass vaccination,” Bhagchandani said. “We wanted to identify some of the critical elements needed for success in this escalating dose and explore whether that knowledge could allow us to reduce the number of doses.”
The researchers began by comparing the effects of one, two, three, four, five, six, or seven doses, all given over a 12-day period. They initially found that while three or more doses generated strong antibody responses, two doses did not. However, by adjusting the intervals and ratios of doses, the researchers found that giving 20 percent of the vaccine in the first dose and 80 percent in a second dose seven days later achieved a response as good as the seven-dose regimen.
“It was clear that understanding the mechanisms behind this phenomenon would be crucial for its clinical application in the future,” Yang says. “Although the ideal dose and timing of administration may differ for humans, the underlying mechanistic principles will likely remain the same.”
Using a computational model, the researchers explored what was happening in each of these dosing scenarios. This work showed that when the entire vaccine is given in a single dose, most of the antigen is cut into fragments before reaching the lymph nodes. Lymph nodes are where B cells are activated to attack a particular antigen, within structures known as germinal centers.
When only a small amount of intact antigen reaches these germinal centers, B cells cannot mount a strong response against that antigen.
However, a very small number of B cells are generated that produce antibodies directed against the intact antigen. So giving a small amount in the first dose doesn’t “waste” much antigen, but instead allows some B cells and antibodies to develop. If a second, larger dose is given a week later, those antibodies bind to the antigen before it can be broken down and escort it to the lymph node. This allows more B cells to be exposed to that antigen and eventually leads to a large population of B cells that can attack it.
“The first doses generate small amounts of antibodies, which are enough to bind to the vaccine in subsequent doses, protect it and direct it to the lymph node. So we realized that we don’t need to give seven doses,” Bhagchandani says. “A small initial dose will generate this antibody and then when you give the higher dose, you can be protected again because that antibody will bind to it and transport it to the lymph node.”
T cell booster
These antigens can remain in germinal centers for weeks or even longer, allowing more B cells to enter and be exposed to them, increasing the likelihood that various types of antibodies will develop.
The researchers also found that the two-dose regimen induced a stronger T-cell response. The first dose activates dendritic cells, which promote inflammation and T-cell activation. Then, when the second dose comes, even more dendritic cells are stimulated, further boosting the T-cell response.
Overall, the two-dose regimen resulted in a five-fold improvement in T cell response and a 60-fold improvement in antibody response, compared to a single dose of vaccine.
“Reducing the ‘stepping dose’ strategy to two injections makes it much more practical for clinical application. In addition, there are several technologies being developed that could mimic two-dose exposure in a single injection, which could be ideal for mass vaccination campaigns,” Irvine said.
Researchers are now studying this vaccination strategy in a non-human primate model. They are also working on specialized materials that can deliver the second dose over an extended period, which could further enhance the immune response.
The research was supported by a Koch Institute Core Support Grant from the National Cancer Institute, the National Institutes of Health, and the Ragon Institute of MIT, MGH, and Harvard.