Researchers have demonstrated the ability to generate a strong immune response against HIV through two doses of a vaccine administered one week apart.
The rapid mutation of the HIV virus has made it particularly challenging to create a successful vaccine, as it can easily avoid the antibody responses triggered by vaccinations.
In past studies, MIT researchers found that giving multiple escalating doses of an HIV vaccine over a span of two weeks could potentially address this issue by eliciting greater amounts of neutralizing antibodies. Nonetheless, this method is not suitable for widespread vaccination efforts due to its complexity.
In a recent study, the same researchers discovered that a comparable immune response can be achieved with only two doses, the first being significantly smaller to prepare the immune system for a stronger reaction to the larger second dose.
This research, involving computational modeling alongside experiments in mice, utilized an HIV envelope protein as the vaccine. A single-dose version of this vaccine is currently undergoing clinical trials, and the team hopes to create another trial group to receive the vaccine using the two-dose strategy.
“By integrating physical and life sciences, we illuminate fundamental immunological questions that guided the development of this two-dose schedule, emulating the effects of a multiple-dose regimen,” says Arup Chakraborty, the John M. Deutch Institute Professor at MIT and a member of both MIT’s Institute for Medical Engineering and Science and the Ragon Institute of MIT, MGH and Harvard University.
According to Chakraborty, this technique may also be applicable to vaccines for other diseases.
Chakraborty and Darrell Irvine, a former MIT professor now at the Scripps Research Institute, serve as senior authors of the study, which is published in Science Immunology. The leading authors are Sachin Bhagchandani PhD ’23 and Leerang Yang PhD ’24.
Neutralizing antibodies
HIV infects over 1 million individuals each year globally, with many lacking access to antiviral treatments. An effective vaccine could significantly reduce the number of infections. One promising candidate currently in clinical trials features an HIV protein known as an envelope trimer, coupled with a nanoparticle called SMNP. Developed in Irvine’s lab, SMNP acts as an adjuvant, intensifying the B cell response to the vaccine.
So far, this vaccine and others in testing have only been administered as a single dose. However, increasing evidence suggests that a series of doses is more effective in generating broadly neutralizing antibodies. Researchers believe that the seven-dose regimen is effective because it simulates the body’s immune response to a virus, as the immune system strengthens when more viral proteins or antigens are encountered.
In the recent study, the MIT team examined the development of this immune response and whether the same effect could be achieved with fewer doses.
<p”Administering seven doses is impractical for mass vaccination,” Bhagchandani notes. “We aimed to identify essential factors for the success of the escalating dose strategy and explore if we could reduce the number of doses while maintaining efficacy.”
The research team began experimenting with one to seven doses delivered over a 12-day timeframe. They initially saw strong antibody responses with three or more doses, but not with just two. By adjusting the intervals and dose ratios, they found that administering 20% of the vaccine in the first dose and 80% in the second dose, one week later, achieved an immune response comparable to the seven-dose regimen.
“Understanding the mechanisms behind this phenomenon is crucial for future clinical applications,” Yang states. “While the ideal dosing ratio and timing may vary for humans, the fundamental mechanisms are likely to remain consistent.”
The researchers utilized a computational model to analyze what occurred in each dosing scenario. This investigation indicated that when the vaccine is delivered in a single dose, most of the antigen is fragmented before reaching the lymph nodes, where B cells get activated to target specific antigens within structures known as germinal centers.
If only a minuscule amount of the whole antigen arrives at these germinal centers, B cells are unable to generate a robust response against that antigen.
Nevertheless, a limited number of B cells can produce antibodies against the intact antigen. Thus, administering a smaller first dose doesn’t waste much antigen; it enables the development of some B cells and antibodies. When a larger second dose is provided a week later, the antibodies connect to the antigen before breakdown occurs, guiding it into the lymph node. This exposure allows more B cells to interact with that antigen and ultimately leads to a larger population of B cells capable of targeting it.
“The initial doses produce a small amount of antibody, sufficient to bind to the vaccine of the subsequent doses, protecting it and directing it to the lymph nodes. That’s how we realized seven doses are unnecessary,” Bhagchandani explains. “An initial smaller dose triggers this antibody production, and a larger dose later can be protected as the antibody binds to it and facilitates its movement to the lymph node.”
T-cell boost
These antigens might reside in the germinal centers for several weeks or even longer, allowing more B cells to be exposed to them, which enhances the chances of developing a diverse array of antibodies.
The researchers also noted that the two-dose schedule prompts a more robust T-cell response. The first dose activates dendritic cells that induce inflammation and T-cell activation. When the second dose is introduced, even more dendritic cells are activated, further enhancing the T-cell response.
As a result, the two-dose regimen produced a fivefold increase in T-cell responses and a 60-fold increase in antibody responses compared to a single dose.
“Reducing the ‘escalating dose’ method to just two injections makes it far more feasible for clinical use. Moreover, numerous technologies are being developed that could replicate the two-dose effect in a single shot, which would be ideal for large-scale vaccination efforts,” Irvine adds.
The researchers are currently evaluating this vaccine strategy in a nonhuman primate model and exploring specialized materials that can deliver the second dose over an extended period, potentially improving the immune response.
This research received funding from the Koch Institute Support (core) Grant from the National Cancer Institute, the National Institutes of Health, and the Ragon Institute of MIT, MGH, and Harvard.
