Study: HIV Vaccines in Early Human Trials Undermined by Off-Target Antibodies

Analyzing how off-target antibodies may be undermining HIV vaccine prototypes allows for design improvements.

A new study by Scripps Research suggests that some of the HIV vaccines in early human trials generate antibodies that actively delay protection by degrading the vaccine’s payload.

According to the study’s lead author Andrew Ward, PhD, analyzing how off-target antibodies may be undermining HIV vaccine prototypes allows for design improvements.

“Our study provides critical insights for further improvement of HIV subunit trimer vaccines for future rounds of the iterative vaccine design process,” Ward said in a press release.

HIV is known to hide itself in a protective coat of sugar molecules stolen from its host to appear safe, in addition to developing mutated versions at a rapid rate and staying ahead of people’s immune responses.

“The HIV surface spike is a sugar-coated, shape-shifting nightmare for antibodies to latch onto and provide protection” said co-author Dennis Burton, PhD, in the press release. “HIV exists in literally hundreds of thousands of different variants of concern compared to the handful for coronavirus.”

There have been techniques developed to engineer vaccine particles intended to create formation of antibodies that broadly neutralize many subtypes of HIV, according to the researchers. The prototypes consist of a fragment of the actual virus, known as the envelope glycoprotein (Env), which is found on the virus exterior.

Using molecular staples and other protein engineering tricks, the vaccine has been stabilizing the spike proteins in their pre-fusion trimer state, according to the researchers. In the new study, the team used single particle electron microscopy to evaluate a wide range of samples from animals immunized with collaborating scientists’ experimental HIV vaccines.

“Here we observed that immunization with these highly stable Env spike trimers elicited a certain class of off-target antibodies that induced the trimers to fall apart. These degraded components then elicited an additional wave of off-target responses,” said first author Hannah Turner in the press release.

She added that the research team is already engineering improved HIV vaccine spikes designed to prevent off-target, base-binding antibodies.

Electron microscopy polyclonal epitope mapping, or EMPEM, takes thousands of images of immune complexes and classifies them into the many molecular structures that appear in a global immune response. This technique is helping other viral diseases, including HIV, and their vaccine design, according to the researchers.

“The more in-depth analysis you can do to understand what happens in terms of antibodies elicited and the antigens’ fate in vivo, the more opportunities you have to redesign and engage the immune system in a more productive manner,” Ward said in the press release.

He added that with protein subunits based on viral spikes coming to the forefront of vaccine efforts for different viruses, it is important to prevent these unintended responses.

“It will take more iterations and more technology to find the design principles to steer the immune system to where we want it to go for HIV,” Ward said in the press release. “Our study provides yet another piece of the puzzle, and once again demonstrates the power of electron microscopy for analyzing immune responses.”

REFERENCE

Off-target antibodies undermine HIV vaccine efforts. Scripps Research. July 28, 2021. Accessed July 29, 2021. https://www.scripps.edu/news-and-events/press-room/2021/20210728-turner-burton-ward-hiv-vaccines.html