New two-dose HIV vaccine strategy shows promise for stronger immune response

A major reason why it has been difficult to develop an effective vaccine for HIV is that the virus mutates very quickly, allowing it to evade the antibody response generated by vaccines.

Several years ago, MIT researchers showed that giving a series of escalating doses of an HIV vaccine over two weeks could help overcome some of this challenge by creating larger amounts of neutralizing antibodies. However, a multiple-dose vaccine regimen given over a short period of time is not practical for mass vaccination campaigns.

In a new study, researchers have now found that they can achieve a similar immune response with just two doses, one week apart. The first dose, which is much smaller, prepares the immune system to respond more strongly to the second, larger dose.

This study, which was conducted by combining computational models and experiments in mice, used an HIV envelope protein as a vaccine. A one-dose version of this vaccine is now in clinical trials, and researchers hope to create another study group that will receive the vaccine in a two-dose schedule.

By bringing together the physical and life sciences, we shed light on some key immunological questions that helped develop this two-dose schedule to mimic the multi-dose regimen.”

Arup Chakraborty, John M. Deutch Institute Professor at MIT 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, notes Chakraborty.

Chakraborty and Darrell Irvine, formerly a 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 the senior authors of the study. , appearing in Science Immunology. The paper’s lead authors are Sachin Bhagchandani PhD ’23 and Leerang Yang PhD ’24.

Neutralizing antibodies

Every year, HIV infects more than 1 million people around the world, and some of them do not have access to antiviral drugs. An effective vaccine could prevent many of these infections. A promising vaccine now in clinical trials consists of an HIV protein called an envelope trimer, along with a nanoparticle called SMNP. The nanoparticle, developed by Irvine’s 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 as a single dose. However, there is increasing evidence that a range of doses is more effective in generating broadly neutralizing antibodies. The seven-dose regimen, researchers believe, 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, accumulate in the body.

In the new study, the MIT team investigated how this response develops and investigated whether they could achieve the same effect using a smaller number of vaccine doses.

“Giving seven doses is just not feasible for mass vaccination,” says Bhagchandani. “We wanted to identify some of the critical elements necessary for this dose scaling to be successful and investigate whether this knowledge might 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 first found that while three or more doses generated strong antibody responses, two doses did not. However, by altering the dose intervals and ratios, the researchers found that giving 20% ​​of the vaccine in the first dose and 80% in a second dose seven days later achieved just as good a response as the seven-dose schedule.

“It was clear that understanding the mechanisms behind this phenomenon would be crucial for future clinical translation,” says Yang. “Even though the ideal dosing ratio and timing may differ for people, the underlying mechanistic principles will likely remain the same.”

Using a computational model, the researchers investigated what happened in each of these dosing scenarios. This work showed that when the whole vaccine is given as a single dose, most of the antigen is broken down into fragments before it reaches the lymph nodes. Lymph nodes are where B cells are activated to target a specific antigen, within structures known as germinal centers.

When only a minimal amount of the intact antigen reaches these germinal centers, the B cells cannot mount a strong response against that antigen.

However, a very small number of B cells arise that produce antibodies that target the intact antigen. Thus, giving a small amount in the first dose does not “waste” much antigen but allows some B cells and antibodies to develop. If a second, larger dose is given a week later, these antibodies bind to the antigen before it can break down and accompany it to the lymph node. This allows more B cells to be exposed to that antigen and ultimately leads to a large population of B cells that can target it.

“The early doses produce some small amounts of antibodies, and that’s enough to bind to the vaccine in the later doses, protect it and target it to the lymph node. So we figured out that we don’t need to give seven doses,” Bhagchandani says. small initial dose will create that antibody, and then when you give the higher dose, it can be protected again because that antibody will bind to it and take it to the lymph node.”

T-cell enhancement

These antigens may remain in the germinal centers for weeks or longer, allowing more B cells to enter and be exposed to them, making it more likely that different types of antibodies will develop.

The researchers also found that the two-dose schedule elicited a stronger T-cell response. The first dose activates dendritic cells, which promote inflammation and T-cell activation. Then, when the second dose arrives, even more dendritic cells are stimulated, further boosting the T-cell response.

Overall, the two-dose regimen led to 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 ‘escalating dose’ strategy to two doses makes it much more practical for clinical application. Additionally, various technologies are being developed that could mimic two-dose exposure in a single vaccine, which could become ideal for mass vaccination campaigns,” says Irvine.

The researchers are now studying this vaccine strategy in a nonhuman primate model. They are also working on specialized materials that can deliver the second dose over an extended period of time, which could further boost the immune response.

The research was funded by a Koch Support (core) grant from the National Cancer Institute, the National Institutes of Health, and the Ragon Institute of MIT, MGH, and Harvard.