Hope For a Vaccine
October 07, 2013 05:04 PM
Day One: AIDS Vaccine 2013
So the AIDS Vaccine conference in Barcelona started up today. And Day One went well, despite the forced absence of some leading scientists, owing to the shutdown of the US government over a budget impasse. Anthony Fauci, Director of the US National Institute of Allergy and Infectious Disease, participated via pre-recorded video, and spoke to journalists live.
Much of the focus this year, as last year, is on antibodies. Not just the broadly neutralizing antibodies (bNAbs) that have become all the rage in the field lately, but the non-neutralizing variety as well—the sort that appear to have played central role in the modest protection observed from a candidate HIV vaccine tested in the RV 144 trial in Thailand a few years ago.
Still, it was bNAbs (or, rather, their target protein) that stole the show in the afternoon satellite sessions before the official inauguration of the conference. That was the session on the characterization and structural analysis of a protein complex named BG505-SOSIP.664, designed to be an immunogenic mimic of the so-called native trimer—or spike—that HIV uses to latch onto cells and initiate infection.
Creating such a protein is not easy. The HIV trimer, a notoriously finicky, variable and structurally dynamic protein, is the sole target on the surface of HIV available to antibodies. Isolating a stable trimer or mimic thereof would do much to advance AIDS vaccine development. As Dennis Burton, who chaired the session and directs both IAVI’s Neutralizing Antibody Consortium and one of the CHAVI-IDs, pointed out: “The trimer has been a Holy Grail of HIV vaccine research for more years than any of us like to remember.”
And, indeed, the room set aside for satellite sessions was packed. Burton invited people to sit on the floor (which they did) saying, “but it’s good to see so many people here.”
All attempts to capture or create analogues of the trimer for vaccine design have so far failed. John Moore of Weill Cornell Medical College, whose laboratory led the curent effort, called the ones hitherto used in experiments, “Trimers in name only" or "TINOs".
This one, apparently, is no TINO. Named BG505-SOSIP.664 (BG505 from here on), it is derived from a subtype A “founder” virus isolated from an infant in Kenya--the word “founder” indicates that the virus in question was the variant that caused the infection in the child.
Moore and his colleagues engineered the gene encoding the trimer's components in that virus to make it soluble and improve its formation and stability. The product of their labors, BG505, assembles spontaneously in solution from the engineered subunits. But it lacks the part of the gp41 molecule that traverses the membrane, as well as the portion just outside, known as the membrane proximal external region (MPER). This latter region is an important target for some potent bNAbs, so its deletion is not insignificant.
Rogier Sanders of the University of Amsterdam and Weill Cornell Medical College reported in today’s session a series of studies examining the antigenic properties of BG505. Sanders and his colleagues found that BG505 specifically binds every single kind of bNAb it has so far been tested against, including the varieties that bind quarternary epitopes. These are complex, three dimensional molecular surfaces formed by the association of distant parts of a large protein that have been folded into proximity.
Such epitopes are notoriously difficult to recreate, and the fact that BG505 binds bNAbs that ordinarily bind such epitopes suggests that it is structured very much like the native trimer. Conversely, and as significantly, BG505 did not bind antibodies that fail to neutralize HIV, which researchers suspect are induced by malformed and partial trimers scattered over the surface of the virus.
Two other speakers provided evidence from different kinds of studies supporting that contention. Andrew Ward of The Scripps Research Institute shared data from cryo-electron microscopy studies that the structure of BG505, when bound to the business end of an antibody, very closely matches that of the best images we have of the native trimer in such a state. Given recent controversy about the veracity of these cryo-EM structures, Ward said, his team took great pains to validate their methods and analysis.
Ian Wilson of The Scripps Research Institute shared findings about the structure of BG505 compiled using X-ray crystallography. He said his laboratory tried more than 100,000 different experimental conditions to obtain BG505 crystals and assessed more than a thousand of the crystals obtained before finding one that suited their needs for crystalography. Elements of the native trimer structure that could be compared to BG505 were similarly identical.
Finally, Moore himself reported that initial experiments assessing the immunogenicity of BG505 showed that it induced antibodies in rabbits that neutralize the parent virus from which it is derived. This is a tier two virus, which is usually difficult to neutralize in laboratory studies of this kind. On the other hand, the researchers could not induce neutralization against other tier two HIV variants. (In science speak, it is capable of inducing autologous neutralization, but not heterologous neutralization.) BG505 is, in other words, far from ready for prime time as an immunogen.
Moore is not surprised. “We didn’t just stick something in a bunny and expect to get a homerun,” he told the audience. Work to improve BG505’s immunogenic properties continues in collaboration with Sanders and other researchers.
Limitations aside, BG505 impressed the audience. As one wag in attendance put it at the end of the session, gathering his things as the crowd streamed out of the room: “There, we can go home now.”
Much of the focus this year, as last year, is on antibodies. Not just the broadly neutralizing antibodies (bNAbs) that have become all the rage in the field lately, but the non-neutralizing variety as well—the sort that appear to have played central role in the modest protection observed from a candidate HIV vaccine tested in the RV 144 trial in Thailand a few years ago.
Still, it was bNAbs (or, rather, their target protein) that stole the show in the afternoon satellite sessions before the official inauguration of the conference. That was the session on the characterization and structural analysis of a protein complex named BG505-SOSIP.664, designed to be an immunogenic mimic of the so-called native trimer—or spike—that HIV uses to latch onto cells and initiate infection.
Creating such a protein is not easy. The HIV trimer, a notoriously finicky, variable and structurally dynamic protein, is the sole target on the surface of HIV available to antibodies. Isolating a stable trimer or mimic thereof would do much to advance AIDS vaccine development. As Dennis Burton, who chaired the session and directs both IAVI’s Neutralizing Antibody Consortium and one of the CHAVI-IDs, pointed out: “The trimer has been a Holy Grail of HIV vaccine research for more years than any of us like to remember.”
And, indeed, the room set aside for satellite sessions was packed. Burton invited people to sit on the floor (which they did) saying, “but it’s good to see so many people here.”
All attempts to capture or create analogues of the trimer for vaccine design have so far failed. John Moore of Weill Cornell Medical College, whose laboratory led the curent effort, called the ones hitherto used in experiments, “Trimers in name only" or "TINOs".
This one, apparently, is no TINO. Named BG505-SOSIP.664 (BG505 from here on), it is derived from a subtype A “founder” virus isolated from an infant in Kenya--the word “founder” indicates that the virus in question was the variant that caused the infection in the child.
Moore and his colleagues engineered the gene encoding the trimer's components in that virus to make it soluble and improve its formation and stability. The product of their labors, BG505, assembles spontaneously in solution from the engineered subunits. But it lacks the part of the gp41 molecule that traverses the membrane, as well as the portion just outside, known as the membrane proximal external region (MPER). This latter region is an important target for some potent bNAbs, so its deletion is not insignificant.
Rogier Sanders of the University of Amsterdam and Weill Cornell Medical College reported in today’s session a series of studies examining the antigenic properties of BG505. Sanders and his colleagues found that BG505 specifically binds every single kind of bNAb it has so far been tested against, including the varieties that bind quarternary epitopes. These are complex, three dimensional molecular surfaces formed by the association of distant parts of a large protein that have been folded into proximity.
Such epitopes are notoriously difficult to recreate, and the fact that BG505 binds bNAbs that ordinarily bind such epitopes suggests that it is structured very much like the native trimer. Conversely, and as significantly, BG505 did not bind antibodies that fail to neutralize HIV, which researchers suspect are induced by malformed and partial trimers scattered over the surface of the virus.
Two other speakers provided evidence from different kinds of studies supporting that contention. Andrew Ward of The Scripps Research Institute shared data from cryo-electron microscopy studies that the structure of BG505, when bound to the business end of an antibody, very closely matches that of the best images we have of the native trimer in such a state. Given recent controversy about the veracity of these cryo-EM structures, Ward said, his team took great pains to validate their methods and analysis.
Ian Wilson of The Scripps Research Institute shared findings about the structure of BG505 compiled using X-ray crystallography. He said his laboratory tried more than 100,000 different experimental conditions to obtain BG505 crystals and assessed more than a thousand of the crystals obtained before finding one that suited their needs for crystalography. Elements of the native trimer structure that could be compared to BG505 were similarly identical.
Finally, Moore himself reported that initial experiments assessing the immunogenicity of BG505 showed that it induced antibodies in rabbits that neutralize the parent virus from which it is derived. This is a tier two virus, which is usually difficult to neutralize in laboratory studies of this kind. On the other hand, the researchers could not induce neutralization against other tier two HIV variants. (In science speak, it is capable of inducing autologous neutralization, but not heterologous neutralization.) BG505 is, in other words, far from ready for prime time as an immunogen.
Moore is not surprised. “We didn’t just stick something in a bunny and expect to get a homerun,” he told the audience. Work to improve BG505’s immunogenic properties continues in collaboration with Sanders and other researchers.
Limitations aside, BG505 impressed the audience. As one wag in attendance put it at the end of the session, gathering his things as the crowd streamed out of the room: “There, we can go home now.”
Comments
Post a Comment