Shown is a flowchart that describes a mechanism called "Macaque CD4 Binding Site Broadly Neutralizing Antibody (BNab) Precursor Ininitiation and Affinity Maturation". This mechanism involves the immune response and the production of antibodies.
First, in the upper left corner there is a small animal (possibly a monkey) that has been injected with a vaccine or drug, which represents the process of immunostimulation of viruses or other pathogens.
Then there are two boxes at the bottom, the left is the gene sequence used by humans, and the right is the gene sequence used by macaques. These genes encode specific types of proteins, called the heavy chain variable segments VH1-46 and VH1-105, which bind to CD4 and create resistance.
This is followed by a series of schematics of cellular structures that show how antibodies at different stages have evolved to improve their ability to fight viruses.
In this process, some antibodies with high affinity are better able to recognize and attack the target virus, and can be further developed into more powerful broad-spectrum neutralizing antibodies. Finally, there is a chart in the bottom right corner showing two different antibodies: one from humans and one from macaques. Both antibodies target the same region, the CD4 binding site, but their shapes differ slightly, indicating that they have some functional similarities and differences. This section highlights how differences in genetic information between species may affect the functional properties of antibodies.
The pathway to successful HIV vaccination depends on the critical first step – activating specific immune cells and inducing a broad spectrum of neutralizing antibodies.
A team of researchers led by the Duke University's Human Vaccine Institute reported in the journal Cell on Jan. 4 that the necessary first steps have been taken in a study using monkeys. The next phase of this work will now move to human testing.
The study confirms that these antibodies are structurally and genetically similar to human antibodies, and we need to use them as the basis for a protective HIV vaccine,said Kevin O., first author of the study and associate director and associate professor in the Department of Surgery, Molecular Genetics and Microbiology, and the Department of Integrative Immunobiology, Duke University's Human Vaccine InstituteDr. Saunders said.
We are on the right track," he said. "From here, we just need to start putting together the other components of the vaccine.
In earlier work, the research team isolated naturally occurring broad-spectrum neutralizing antibodies from individuals and then traced all the changes experienced by the antibodies and viruses to reach the point of origin of the natural antibody and its binding site on the HIV envelope.
With these experiences, they devised a molecule that could elicit antibodies that mimic natural antibodies and their binding sites on the HIV envelope.
Four years ago, Saunders and colleagues published a study in the journal Science in which they determined that monkeys produced neutralizing antibodies when vaccinated with an engineered immunogen vaccine, but were not sure if these antibodies were like the broad-spectrum neutralizing antibodies required for human vaccines.
In the current study, researchers have created a new, more effective vaccine formulation and delivered it to monkeys. This time, their goal was to determine if the neutralizing antibodies produced in animals were structurally and genetically similar to those needed in humans. And they do.
We think we've been on the right path since 2019 and we now have atomic-level details to confirm these findings," Saunders said. "This is a significant step forward. ”
References. **
kevin o. saunders et al, vaccine induction of cd4-mimicking hiv-1 broadly neutralizing antibody precursors in macaques, cell (2024). doi: 10.1016/j.cell.2023.12.002