Researchers Determine Two-Dose Regimen Could Make HIV Vaccines More Effective

One of the main reasons it has been difficult to develop an effective vaccine against HIV is that the virus mutates very quickly, allowing it to evade the antibody response generated by vaccines.

A few years ago, MIT researchers showed that giving a series of escalating doses of an HIV vaccine over a two-week period could help overcome some of this challenge by generating 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 found they could get a similar immune response with just two doses, given a week apart. The much smaller first dose primes the immune system to respond more powerfully to the larger second dose.

This study, done by combining computer modeling and experiments on mice, used an HIV envelope protein as a vaccine. A single-dose version of this vaccine is currently in clinical trials, and the researchers hope to establish another study group that will receive the vaccine in a two-dose schedule.

“By bringing together the physical sciences and the life sciences, we have illuminated some fundamental immunological questions that have helped develop this two-dose regimen to mimic the multiple-dose regimen,” says Arup Chakraborty, MIT’s John M. Deutch Institute Professor and a member of the MIT Institute of Medical Engineering and Science and the Ragon Institute of MIT, MGH, and Harvard University.

This approach could also be generalized to vaccines against 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 the study’s senior authors.

The research results are published in Sciences ImmunologyThe paper’s lead authors are Sachin Bhagchandani Ph.D. ’23 and Leerang Yang Ph.D. ’24.

Neutralizing antibodies

Every year, HIV infects more than a million people worldwide, some of whom do not have access to antiviral drugs. An effective vaccine could prevent many of these infections.

One promising vaccine currently in clinical trials is made up of an HIV protein called an envelope trimer, along with a nanoparticle called SMNP. The nanoparticle, developed by the Irvine lab, acts as an adjuvant that helps elicit a stronger B-cell response to the vaccine.

In clinical trials, this and other investigational vaccines were given as a single dose. However, increasing evidence suggests that a series of doses is more effective in generating broadly neutralizing antibodies.

The seven-dose regimen works well, the researchers say, 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 looked at whether they could achieve the same effect using a smaller number of vaccine doses.

“Giving seven doses is simply not feasible in a mass vaccination setting,” Bhagchandani says. “We wanted to identify some of the critical elements needed to successfully scale up doses and see if that knowledge could help us 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 found that while three or more doses generated strong antibody responses, two doses did not.

However, by changing 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 as good a response as the seven-dose regimen.

“It was clear that understanding the mechanisms behind this phenomenon would be crucial for future clinical application,” Yang says. “Although the ideal dosage and timing of administration may differ for humans, the underlying mechanistic principles are likely to remain the same.”

Using a computer model, the researchers studied what happened in each of these dosing scenarios. Their work showed that when the entire vaccine is given in a single dose, most of the antigen is broken up before it reaches the lymph nodes. It is in the lymph nodes that B cells become activated to target a particular antigen, in structures called germinal centers.

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

However, very few B cells form and produce antibodies targeting the intact antigen. So 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 be broken 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 first doses generate small amounts of antibodies, which are enough to bind to the vaccine from the later doses, protect it and direct it to the lymph node. That’s how we realized we don’t need to give seven doses,” Bhagchandani says.

“A small initial dose will generate that antibody, and then when you give the larger dose, it can be protected again because that antibody will bind to it and circulate it to the lymph node.”

Stimulation of T lymphocytes

These antigens can remain in the 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 along, even more dendritic cells are stimulated, further strengthening the T-cell response.

Overall, the two-dose regimen resulted in a five-fold improvement in T-cell response and a sixty-fold improvement in antibody response, compared to a single dose of vaccine.

“Reducing the ‘ascending dose’ strategy to two injections makes it much more practical for clinical implementation. Additionally, a number of technologies are being developed that could mimic the two-dose exposure in a single injection, which could become ideal for mass vaccination campaigns,” Irvine says.

Researchers are currently studying this vaccine strategy in a non-human primate model. They are also working on specialized materials that can deliver the second dose over an extended period of time, which could further enhance the immune response.

This article is republished with kind permission from MIT News (web.mit.edu/newsoffice/), a popular site covering the latest research, innovation, and teaching at MIT.