Scientists test new vaccine strategy to help body target HIV – ScienceDaily

Researchers at the La Jolla Institute of Immunology (LJI) have discovered how the immune system can turn into an antibody-making machine capable of neutralizing one of the most elusive viruses: HIV.

Researchers once believed that B cells (which make antibodies) spent just weeks perfecting their weapons against viral threats. LJI’s research now shows that a “slow-delivery, escalating dose” vaccination strategy can prompt B cells to spend months mutating and developing pathogen-fighting antibodies.

This result was published in temper natureis an important step towards developing effective and long-lasting vaccines against pathogens such as HIV, influenza, malaria and SARS-CoV-2.

“This shows that the immune system can do really extraordinary things if you give it the opportunity – and that patience in some vaccine contexts is a virtue,” says senior study author Professor Shane Crotty, PhD.

The development of immune cells inside you

Most pathogens seem foreign to the immune system. They are unwelcome visitors covered in unfamiliar proteins. When the body’s dendritic cells see these foreign proteins, they signal the “helper” T cells to start training the army.

B cells get a signal that an invader is approaching, and show them a molecular marker (called an antigen) from that invader. B cells want to make effective antibodies to neutralize the invader, so they head to a special place: the germinal centers.

Germinal centers are microscopic structures that form in special “lymph tissues” throughout the body. Germ centers are essential for fighting pathogens because they give B cells a place to mutate and test for their antibodies. Researchers call germinal centers “engines of antibody evolution.” B cells that do not mutate and improve their antibodies over time are eliminated. B cells with beneficial mutations are sent into the body to wage war.

“It’s really a development,” Crotty says. “This process can work very well and lead to antibodies that are a thousand times better at binding to the virus.”

Microbial centers live quickly, and die young

Germinal Centers are also the original pop-up stores. Once the threat is over, the germinal centers collapse. No one yet knows why the germinal centers have collapsed, but there must be some kind of molecular signal that points to the end.

For Crotty’s lab, the important question is how to keep the germinal centers open for longer. Timing is important because some pathogens can only be inactivated by rare, highly specialized antibodies.

HIV is one of the difficult clients. Covered in an invisible mantle of sugar molecules, HIV can change shape when it enters cells. This stealth and this shape-shifting power make it really difficult for immune cells to identify useful antigen targets on HIV.

As a result, the germinal centers begin to drive B cells that make “low-affinity” antibodies. These antibodies cannot bind and neutralize HIV in a very effective manner. Instead of throwing a wrench into the HIV mechanism, the body throws cotton balls.

The altered structure of HIV can also lead to ‘high-affinity’ antibodies that can bind tightly — to the wrong targets. Imagine shooters trying to stop a raging bull by shooting it in the tail.

Crotty thinks B cells just need more time to mutate. “It takes a long time, and many cell divisions, before you get lucky and one of the right mutations eventually occurs,” says Crotty. The idea is that the longer B cells can mutate and complete themselves in the germinal centers, the more likely the B cells will be fortunate to produce broadly neutralizing antibodies against HIV.

Slow and steady vaccine strategy

For years, Crotty and his collaborators at the LJI Center for Infectious Diseases and Vaccine Research and the research-led Scripps Consortium for HIV/AIDS Vaccine Development (CHAVI-ID), have worked to solve parts of the HIV vaccine puzzle. Crotty Lab co-led pivotal studies on the use of promising new vaccine ingredients and how to better activate B cells against HIV.

The new study highlights the importance of extending the period during which B cells can develop in germinal centers.

For the study, research collaborators at the Tulane National Primate Research Center vaccinated rhesus monkeys every other day for 12 days. The seven-shot series contained an “escalating dose” of HIV antigen (the protein on HIV they wanted the immune system to learn to target).

“This pattern mimics a natural infection more than just a single immunization,” explains LJI postdoctoral fellow Harry Sutton, who worked as co-first author on the new study with former LJI instructor Jeong Hyun Lee, PhD. . He is now a senior scientist in the IAVI Neutralising Antibody Center at Scripps Research.

One group of monkeys was not vaccinated again, but two other groups received a booster vaccine 10 weeks later.

The researchers then tracked immune responses by examining the monkeys’ lymph nodes. The team also monitored the development of B cells in individual germinal centers. Their work revealed that the germinal centers remained active and that B cells continued to develop for six months after the initial seven-shot series. As Sutton points out, the study was due to end after six months, but the germinal centers may have lasted longer if the research continued.

So, how were highly developed B cells measured? The researchers performed genetic sequencing analysis to analyze immune cells’ memory and antibody binding abilities.

They found that monkeys who were given a series of seven shots but were never boosted had a stable and durable set of HIV antibodies after six months. These unenhanced animals also had more immune cells (follicular helper T cells) ready to recognize HIV antigen and release B cells into battle. The booster animals had a second ‘peak’ in antibody numbers after the booster shot, but did not end up with the same high-quality antibody.

The strategy of slow delivery and escalating dose has paid off. It is possible that the large dose of antigen gave the immune system enough of a ‘bait’ of the virus that the germinal centers were ready to stay open and the B cells were induced to develop as long as possible to counter the perceived threat.

Next Steps for Better Vaccines

When it comes to HIV vaccination, timing really seems to be the key to long-term protection. Giving the booster vaccine too soon may interrupt an already effective process. “You want to kick-start the immune response, and then let it do its work,” Crotty says. “Let her try and undergo as much antibody development as possible before she comes back with a booster.”

Of course, a 12 day, 7 shot regimen would be impractical for most people. “If you want to give the HIV vaccine to people in an area where they are severely affected by the virus, which is primarily in sub-Saharan Africa, you cannot expect people to come every other day to get a vaccine for two weeks,” Sutton says. “How can we recreate these results with fewer vaccines?”

The team is now looking into whether they can achieve the same antibody quality with two vaccines, versus seven. They are also studying whether they can design an mRNA vaccine that sparks the same evolution of B cells by slowly producing an antigen over time. This follow-up work is supported by significant funding from the Bill & Melinda Gates Foundation.

Long-lived germ centers may also be important in the fight against COVID-19. As Crotty explains, the original COVID-19 vaccines did an excellent job of getting the body to rapidly make high-affinity antibodies against the primary variants of SARS-CoV-2. Research from Crotty Lab indicates that B cells against SARS-CoV-2 continue to develop for at least four months, giving them the opportunity to become more effective.

Unfortunately, there is reduced antibody protection against newer SARS-CoV-2 variants, such as Omicron and Omicron BA.1. Crotty is very interested in investigating the usefulness of a long method of vaccine delivery.

“Our new study suggests that if you want to have good antibodies against variants, these long germinal centers are likely the way to do that.”

Additional authors of the study, “Long-term germ center responses to primary immunization with persistent spread and somatic mutation,” include Christopher A. , Sarah T. Ritchie, Jonathan L. Torres, Wayne Hsien Lee, Eric Georgeson, Michael Kobitz, Sam Hodges, Tina Marie Mullen, Yumiko Adachi, Kimberly M. Cirelli, Amitiender Kaur, Carolina Allers-Hernandez, Marisa Fahlberg, Brooke F. Grasperge, Jason P. Dufour, Faith Schiro, Pyone P. Aye, Diane G. Carnathan, Guido Silvestri, Xiaoying Shen, David C. Montefiori, Ronald S. Veazey, Andrew B. Ward, Lars Hangartner, Dennis R. Burton, and Daryl J. Irvine, and William R.

This study was supported by the National Institutes of Allergy and Infectious Diseases of the National Institutes of Health (CHAVD-ID UM1AI100663, CHAVD UM1AI144462, R01 AI125068, R01 AI136621, P01AI048240 and NIH NIAID SVEU Contract No. Collaboration on AIDS Vaccine Discovery (CAVD; OVPP1115782/OPP1115782/OPP1115782). -002916).

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