AIDS Vaccine Research: Better By Design?
Posted on by Dr. Francis Collins
A while ago, I highlighted a promising new approach for designing a vaccine against the human immunodeficiency virus (HIV), the cause of AIDS. This strategy would “take the immune system to school” and teach it a series of lessons using several vaccine injections—each consisting of a different HIV proteins designed to push the immune system, step by step, toward the production of protective antibodies capable of fending off virtually all HIV strains. But a big unanswered question was whether most people actually possess the specific type of precursor immune cells that that can be taught to produce antibodies that kill HIV.
Now, we may have the answer . In a study published in the journal Science, a research team, partly supported by NIH, found that the majority of people do indeed have these precursor cells. While the total number of these cells in each person may be low, this may be all that’s needed for the immune system to recognize a vaccine. Based in part on these findings, researchers plan to launch a Phase 1 clinical trial in human volunteers to see if their latest engineered protein can find these precursor cells and begin coaxing them through the complicated process of producing protective antibodies.
The new work, led by William Schief of the Scripps Research Institute, La Jolla, CA, and Shane Crotty of the La Jolla Institute for Allergy and Immunology, is rooted in basic research discoveries showing that some people infected with HIV eventually do develop a strong immune response that is characterized by broadly neutralizing antibodies (bnAbs) that can kill HIV . The response, though, appears only after years of attack and counterattack between HIV and their immune systems. Since the initial discoveries more than a decade ago, vaccine researchers have been intensively studying how to channel this natural effect in a swifter and more reliable manner that would enable uninfected people to produce bnAbs that could ward off HIV infection.
What makes bnAbs special are their unusual features, which allow them to bind to certain “conserved” parts of proteins on the surface, or envelope, of HIV. Since these conserved regions rarely change, they are considered to be ideal targets for vaccines that provide broad, sustained protection.
However, a major challenge for HIV vaccine development is the genes for antibodies in the human genome doesn’t directly code for bnAbs that can bind the virus at its most conserved—and vulnerable—locations. Their development hinges upon the ability of genes in certain immune cells called B cells, to go through a series of DNA rearrangements and mutations, producing precursor proteins that gradually adapt and change over time into bnAbs capable of neutralizing HIV in its many forms.
In their latest work, Schief and colleagues conducted sophisticated modeling experiments to analyze whether it’s possible to take a protein engineered to mimic the HIV envelope protein and present it in a way that activates those crucial precursor cells and starts them down the path toward eventual production of bnAbs. The team then used this information to engineer and test an optimized protein, called eOD-GT8, which was designed like an irresistible siren song to inspire precursors in human blood to pay attention and get to work.
To gauge the frequency of precursor activation, the team sorted through millions of B cells in blood donated by 15 healthy, HIV-negative volunteers. The results? Approximately one precursor per 2.4 million B cells. Given that most humans have about 100 billion B cells, the researchers estimate that most potential vaccine recipients would have anywhere from 2,700 to 31,000 of these critical precursors—including about a dozen or so located in each of many lymph nodes, a location where they should be targetable by a vaccine.
In their proposed Phase 1 clinical trial, Schief and colleagues plan to fuse their eOD-GT8 protein to a nanoparticle and administer the protein to healthy, HIV-negative volunteers to see if it elicits the desired anti-HIV immune response involving those special precursor B cells. However, even if eOD-GT8 works well, Schief cautions that it would be just the first of a series of steps towards developing an effective HIV vaccine. He thinks additional shots of various natural HIV proteins will also likely be needed to mount an eventual immune response that would provide effective, long-lasting protection against the virus that still annually infects an estimated 2 million people worldwide.
 HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen. Jardine JG, Kulp DW, Havenar-Daughton C, Sarkar A, Briney B, Sok D, Sesterhenn F, Ereño-Orbea J, Kalyuzhniy O, Deresa I, Hu X, Spencer S, Jones M, Georgeson E, Adachi Y, Kubitz M, deCamp AC, Julien JP, Wilson IA, Burton DR1, Crotty S, Schief WR. Science. 2016 Mar 25;351(6280):1458-1463.
 The modern era of HIV-1 vaccine development. Mascola JR. Science 2015 Jul 10;349(6244):139-140.
Fact Sheet 2015, UNAIDS (The Joint United Nations Programme on HIV/AIDS/Geneva, Switzerland)
HIV Vaccine Research (National Institute of Allergy and Infectious Diseases/NIH)
IAVI’s Neutralizing Antibody Center (The Scripps Research Institute, La Jolla, CA)
Shane Crotty (La Jolla Institute for Allergy and Immunology, La Jolla, CA)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences