A team of researchers from the La Jolla Institute of Immunology (LJI) in California has discovered how the immune system becomes an antibody-making machine, capable of neutralizing one of the most elusive viruses that exist: HIV.
Researchers thought that B cells (which make antibodies) spent weeks perfecting their weapons against viral threats, but the new research shows that a strategy of vaccination of "slow delivery and increasing dose" it can cause these cells to spend months mutating and improving their antibodies against the pathogen.
This finding, published this Wednesday in the journal Nature, is an important step towards the development of effective and long-lasting vaccines against pathogens such as HIV, influenza, malaria and SARS-CoV-2.
"This shows that the immune system can do truly extraordinary things given the chance, and that in some contexts, patience really is a virtue."stresses the study’s lead author, Shane Crotty of LJI.
pathogens that attack the body are covered in unknown proteins and when the body’s dendritic cells see them, they signal the T cells to start building an army.
The B cells receive the warning that an invader is nearby and the molecular marker (or antigen) to recognize it, and they start making antibodies in structures called "germinal centers"where B lymphocytes mutate and test their antibodies.
Those that do not mutate over time and do not improve their antibodies are eliminated and B cells with useful mutations are sent to the body for war.
When the threat has passed, the germinal centers collapse – it is not known why – but many scientists like Crotty try to make these centers last longer, because some pathogens can only be neutralized by rare and highly specialized antibodies, but that takes time.
HIV is one of them. His ability to shapeshift makes it very difficult to detect for immune cells.
The new study highlights the importance of lengthening the period in which B cells can evolve in the germinal centers.
For the research, collaborators at the Tulane National Primate Research Center vaccinated rhesus monkeys every other day for 12 days with a series of seven injections containing a "increasing dose" of the HIV antigen (the protein they wanted the immune system to learn to attack).
One group of monkeys was not vaccinated again, but two other groups received a booster shot at 10 weeks, and the researchers then followed the monkeys’ immune responses.
The team also monitored the development of B cells in individual germinal centers. The work revealed that germinal centers remained active and B cells continued to evolve six months after the initial series of seven injections.
But, how did highly evolved B cells behave? The authors performed gene sequencing analysis to analyze immune cell memory and antibody binding capacity.
They found that monkeys given the series of seven injections and not given a booster dose had a stable and long-lasting population of HIV antibodies six months after treatment.
These animals also had more immune cells (helper T cells) ready to recognize the HIV antigen and launch B cells into battle, while the boosted animals had a second "peak" in the number of antibodies after their booster shot, but they didn’t end up with the same high-quality antibodies.
The strategy of slow administration and staggered dosing had paid off.
The team is now studying whether they can achieve the same quality of antibodies with two vaccines versus seven, and also whether they can design an mRNA vaccine that causes the same evolution of B cells by slowly producing antigen over time.
