Leading the way for an HIV vaccine

Los Alamos National Laboratory scientists are using computational analysis and modeling to examine and predict how HIV spreads — and create a first-in-class preventive HIV vaccine now being tested for efficacy in humans.

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HIV prevention is making progress. And a breakthrough vaccine appears within reach

With a large-scale clinical trial launching this fall and several others already underway, scientists say they are cautiously optimistic that they’ll soon have a way to fight HIV long before a person is ever exposed.

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Johnson & Johnson is about to test an experimental vaccine on thousands of people

HuffPost logoJ&J’s vaccine targets multiple strains of HIV. Harvard’s Dan Barouch and Lab scientist Bette Korber designed an optimized set of “mosaic” proteins to go in the vaccine that would raise immune defenses against a wide variety of strains.

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Computational Biologist, HIV Researcher Bette Korber Named 2018 Scientist of the Year

Since joining Los Alamos in 1991, Bette Korber has managed and build up the lab’s HIV Database and Analysis Project, which features over 840,000 sequences of the HIV virus from around the world. She then built an innovative vaccine  created to overcome the extreme diversity of the HIV virus.

Computational Biologist, HIV Researcher Bette Korber Named 2018 Scientist of the Year





Bette Korber, PhD, has certainly had an impressive career.


Since joining Los Alamos National Laboratory (LANL) in 1991 she has managed and build up the lab’s HIV Database and Analysis Project, which today features over 840,000 sequences of the HIV virus from around the world.


Utilizing that same database, she then built an innovative vaccine design known as “mosaic,” created to overcome the extreme diversity of the HIV virus. It combines sets of proteins—assembled from fragments of natural sequences via a computational optimization method— to maximize vaccine coverage in the most efficient way possible.


Today, her mosaic design is the key element of a first-in-class preventative HIV vaccine now being tested for efficacy in humans in a Phase II clinical trial, a milestone few HIV vaccines have reached.


Despite these achievements, Korber—R&D Magazine’s 2018 Scientist of the Year—has not had an especially easy path to success.


In the 1980s during her time as an undergraduate at California State University, Long Beach and as a graduate student at the California Institute of Technology (Caltech), Korber was discouraged from following her passion for computational biology.


“As an undergraduate my skills were more in programing and math, but I kind of got pushed into the direction of experimental biology, I think because I was a woman at that time,” said Korber, in an exclusive interview with R&D Magazine. “Mentors pushed me in that direction, but I always really wanted to do computational work.”


Despite her interest, ultimately, Korber—one of only a handful of women at Caltech at the time—listened to her mentors and focused on bench work, receiving her PhD in immunology and chemistry in 1988.


Looking back she regrets letting others discourage her from her true passion and hopes that women today who are interested in male-dominated fields don’t make the same mistake.


“I was shy and young and in a man’s world and I didn’t stand up for myself,” she said. “Although I don’t think what happened to me happens as often now, women still need to encourage each other and men need to take women seriously, not just brush off their ideas, or worse, take their ideas, which still happens all the time. We have to fight back, we have to stand up for ourselves and each other.”

Finding her path


Although she started on a different path than she initially intended, Korber’s early work in immunology ended up shaping the trajectory of her career. During the time she was working on her PhD and studying the intricacies of the immune system, her close friend and roommate became one of the earliest people to be diagnosed with HIV.


“I was a basic immunologist working on mouse immunology like everyone does, but because of him contracting HIV and there being absolutely no way to cure it at that time, I got very interested in it,” explained Korber. “When I did a post-doc at Harvard I started working in the HIV field.”


Following her post-doc, Korber—along with her husband, fellow Caltech alumni and scientist James Theiler, PhD—moved to New Mexico and joined LANL in 1991. It was there that she was truly able to combine her interest fighting HIV with her passion for computing.


She quickly connected with Gerry Myers, PhD, the LANL researcher who had founded the lab’s HIV Database—the first-ever pathogen database—which at the time had just a few hundred sequences.


“I was really excited when I got the opportunity to come to Los Alamos and sort of leave bench work behind and sit full-time at the computer,” said Korber. “Gerry was really open to letting me re-learn and re-awaken the kinds of skills that I was more interested in, which were more analytical skills.”


Myers—who passed away in 2011—started the HIV Database in 1986 with the goal to collect, curate, and annotate HIV genetic material, and then provide the data to scientists in an open-access environment to encourage collaboration within the field. The initial data came from an earlier LANL effort called GenBank, a public database set up in 1982 to store laboratory samples of previously sequenced organisms.


Shortly after Korber began working with Myers she founded the sister HIV Molecular Immunology Database, the first immunology database. The two databases were then coupled, giving the researchers the ability to study the relationship between an immune response and the HIV sequences.


“It’s an integrated database where we pull together the HIV immunology data and all the HIV sequence data, and we make computational tools to go between the two of them,” said Korber. “I think there are other immunology databases now and there are other pathogen databases now, but this is still kind of unique with the cross fertilization that it has.”


The database—which quickly expanded—became the basis for Korber’s research.


“When Gerry and I were first working on it had just a few hundred sequences and then we got a few hundred more and then thousands,” said Korber.

A novel approach


As the database grew, so did its ability to inform Korber’s research. It was through the database that she first began to understand the potential of a mosaic vaccine design in the early 2000s.


“My vaccine work grew out of gathering all of that global data and feeding it back to the community, and then having my own research be part of using that global data,” explained Korber.


Looking at the data, Korber also began to understand why other HIV vaccines had failed.


“HIV is incredibly variable, and I think that is the main reason we haven’t had a working vaccine to date,” she said. “It evolves differently in every single infected person during the course of his or her infection. It evolves in different ways; not just by base mutation but by insertion and deletion, recombination, glycosylation patterns can change. It’s just extraordinarily variable.”


Typically, vaccines are designed to stimulate an immune response using one antigen or virus that is specifically targeted. However, because HIV is so variable between different individuals, the immune response the vaccine triggers must be able to interact with many different viruses.


Korber and her team worked to design the database to identity epitopes—bits of the virus that the immune system can recognize—and evaluate the evidence for the strength of each epitope. Through this work, Korber discovered that HIV is packed with epitopes, a finding that directly led to the creation of the mosaic vaccine approach.


“The mosaic was inspired by pulling together the database and just looking at the variability virtually every day and looking at how densely packed it was with little bits that the immune system could see; it was just that you’ve got to get an immune response that is cross reactive and see all the variance,” said Korber.


To achieve this, Korber and her team looked at virus sequences from all over the world, and using computer optimization, determined which few sequences would provide the optimal coverage of global HIV viruses. The computer then created synthetic antigens that are approximations of those sequences.


“What the mosaic does is it evolves sequences in a computer to solve a problem on how to—with just a couple of sequences—give the best immunological coverage you can,” explained Korber. “Instead of putting in two natural strains, you make two computationally designed strains that are kind of central and complement one another to really get the best coverage you can with just a couple of strains.”


Because no natural proteins were involved in this approach—contrary to typical vaccine design—Korber’s idea was not initially well received. In fact, she was denied for several of the first grants she applied for.


“There was extreme pushback, no one thought it had a chance,” she said. “These were constructed proteins that were evolved on a computer. People just didn’t think that they would fold, that they would make good immune responses, that they would be stable. But I followed the principles of the way that HIV evolved. Even after we showed that people still remained skeptical that it would work. It takes a little while for a field to get used to an idea.”


Eventually, she was able to secure funding to pay for the computational support she needed to create the mosaic via an internal LANL grant. She then reached out to several experimentalist colleagues to help with the project, including Barton Haynes, MD from Duke University and Dan Barouch, MD, PhD from Harvard University.


The project became a multidisciplinary endeavor with Korber and her LANL colleagues determining the design of the mosaic using computing techniques, and Haynes and Barouch building the synthetic antigens in their laboratories and testing them on small animals. She also recruited computational experts including now former LANL scientist Simon Perkins, PhD who wrote much of the mosaic codes for the vaccine. Korber’s husband Theiler, a mathematician and physicist, also collaborated with her on the project.


“The interdisciplinary aspect is really what made it fly,” said Korber. “I couldn’t have coded something this deep without Simon, but he could not have framed the question or figured out what to code without me working with him.”


The team published their first paper on the concept in 2007, a challenge in itself among a scientific community that still had its doubts about what they were doing.


“When you have an idea for designing a protein that is very different than anyone has tried before, selling that is very difficult,” said Korber. “It was very challenging trying to convince someone that this actually could work.”

Seeing results


It was Barouch—who serves as a professor of medicine at Harvard Medical School and the director of Center for Virology and Vaccine Research at Harvard—who helped Korber move her concept into the clinic. He designed a vaccine that used a strain of a common-cold virus— engineered so that it does not cause illness— to deliver the mosaic antigens Korber had computationally designed.


The vaccine was first tested on monkeys, where it showed promise.


“We found that, indeed, these proteins that we had designed were stable and they were really immunogenic,” said Korber. “When they were put into monkeys, the monkeys made really good immune responses and the immune responses that the monkeys made tended to be more cross reactive. They did what we wanted them to do in vaccinated animals.”


Preclinical studies with the mosaic-based vaccine regimen confirmed this, demonstrating that they were effective in protecting monkeys against infection with an HIV-like virus. Then two early-stage human clinical trials suggested that these vaccines are well-tolerated and can generate anti-HIV immune responses in healthy adult volunteers.


As a result, the National Institutes of Health (NIH) launched a large clinical trial in November 2017 to assess whether the mosaic HIV vaccine regimen is safe and able to prevent HIV infection in humans. The study is sponsored by Janssen Vaccines & Prevention, B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, with co-funding from two primary partners, the Bill & Melinda Gates Foundation and NIH’s National Institute of Allergy and Infectious Diseases. The new Phase IIb proof-of-concept study, called Imbokodo, aims to enroll 2,600 HIV-negative women in sub-Saharan Africa. The first Imbokodo participants received vaccinations at clinical research sites in South Africa, followed by participants in Malawi, Mozambique, Zambia, and Zimbabwe. Participants will be followed for at least two years.


Although Korber herself has stepped away from the clinical trial portion of this research, she is still closely watching its progress. She serves as an advisor for the project for both Barouch and Janseen.


“It is really exciting for me to know that this is getting taken forward and getting to witness it and helping out a little bit with the thinking, as the standard statistician doesn’t always think about sequence variation and all of that. I am glad I am able to help from that point of view,” said Korber.

Looking ahead


Although this particular HIV mosaic vaccine is the innovation Korber has that is furthest along in the pipeline, it is far from her only project.


She continues to work mainly in HIV vaccine optimization, focusing on approaches both related and unrelated to the mosaic concept. She has been working a mosaic vaccine that focuses just on conserved regions with colleagues at Oxford. Over the past few years, she has published papers on a second-generation algorithm she designed in collaboration with her husband called an Epigraph. This is an efficient graph-based algorithm for designing vaccine antigens to optimize potential epitope coverage (an epitope is a small part of a pathogen protein that the immune system can see). Epigraph vaccine antigens are functionally similar to mosaic vaccines, but in contrast to the mosaic algorithm, the epigraph code is much faster, and in some cases, provides a mathematically optimal solution.


In addition, Korber is working with experimentalist colleagues at Duke and Harvard on two other projects that they have not yet published research on. One is called a Signature-informed Epitope Targeting, or SET vaccine.


“It’s an idea where you look at the evolution of the viruses, and how that impacts how sensitive viruses are to antibodies, and then you design vaccines based on antibody activity and resistance patterns,” said Korber. “It is a quite different approach where you use a statistical measure to study the impact of diversity on antibody sensitivity, and to design vaccines. SET vaccines have shown some promise in guinea pigs so far, but we haven’t taken it further than that.”


Another approach she is working on, known as “structural mosaic,” takes into account the three-dimensional structure of a viral protein, as well as the sequence of the protein, explained Korber. This approach is also currently being tested in guinea pigs. Both strategies have yet to be tested for protection from infection, but Korber is optimistic about their potential.


Korber doesn’t know if the mosaic vaccine that is being tested in the Imbokodo trial— or any of her other ongoing projects— will result in a successful HIV vaccine, but she is hopeful either way. For Korber, even a failed idea is a worthwhile experience.


“If it does work that is wonderful, especially if it works to a level where it is actually useful enough to make it as a product,” said Korber. “If this doesn’t work we will learn from the trial anyway and we will learn why it didn’t work, maybe, and be able to do better the next trial. And meanwhile, both my laboratory and my colleague’s laboratories have other horses in the race. Either way it’s exciting.”


This article was originally published on RDmag.com

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R&D Magazine Announces 2018 Scientist of the Year

Bette Korber’s innovative HIV “mosaic” vaccine design is assembled from fragments of natural sequences via a computational optimization method. The vaccine is now being tested for efficacy in humans with support from the NIH and the Bill & Melinda Gates Foundation, a milestone few others have reached.

R&D Magazine Announces 2018 Scientist of the Year


R&D Magazine is proud to announce Los Alamos National Laboratory (LANL) theoretical biologist Bette Korber, PhD, as the 2018 Scientist of the Year.


Korber’s innovative HIV “mosaic” vaccine design—assembled from fragments of natural sequences via a computational optimization method—led to a first-in-class preventative HIV vaccine now being tested for efficacy in humans with support from the NIH and the Bill & Melinda Gates Foundation, a milestone few others have reached.


This year marks the 53rd annual Scientist of the Year Award, which recognizes career accomplishments in scientific research and technology spanning nearly all disciplines from physics to medicine to chemistry.


Korber will receive the award at the 2018 R&D 100 Awards black-tie ceremony on Nov. 16, 2018, at the Waldorf Astoria Orlando. The same event will also recognize the 2018 R&D 100 Award winners as well as R&D Magazine’s 2018 Innovator of the Year.


The R&D 100 Awards have served as the most prestigious innovation awards program for the past 55 years, honoring great R&D pioneers and their revolutionary ideas in science and technology. A full feature on Korber’s accomplishments will be featured in the October 2018 issue of R&D Magazine.


“We selected Bette as our 2018 Scientist of the Year to recognize not only her groundbreaking contribution to the mosaic vaccine and the fight against HIV, but also for her continued commitment to trying new and innovative scientific approaches,” said Bea Riemschneider, Editorial Director, R&D Magazine. “As both an expert in computational biology and immunology, Bette is also uniquely positioned to try truly interdisciplinary approaches, and with her work she encourages others to do so, something to be celebrated in R&D.”


Korber is responsible for managing and building LANL’s HIV Database, which today has over 800,000 sequences of the HIV virus from around the world.


Shortly after she joined LANL in 1991, Korber founded the companion HIV Molecular Immunology Database, and the two databases were coupled, giving researchers the ability to study the relationship between an immune response and HIV.It was through those databases that Korber first began to understand the potential of a mosaic vaccine design.


Typically, vaccines are designed to stimulate an immune response using one antigen or virus that is specifically targeted. However, because HIV is so variable between different individuals, the immune response the vaccine triggers must be able to interact with many different viruses.


Korber and her team worked to design the database to identity epitopes—bits of the virus that the immune system can recognize—and evaluate the evidence for the strength of each epitope. Through this work, Korber discovered that HIV is packed with epitopes, a finding that directly led to the creation of the mosaic vaccine approach.


Korber and her team looked at virus sequences from all over the world, and using computer optimization, determined which few sequences would provide the optimal coverage of global Hd approximations of those sequences.


Surprisingly, Korber’s idea was not initially well received. In fact, she was denied several of the first grants she applied for because the approach was so different than what had been done before.


Eventually, she was able to secure funding to pay for the computational support she needed to create the mosaic via an internal LANL grant. She then reached out to several experimentalist colleagues to help turn the concept into an actual vaccine that used a strain of a common cold virus— engineered so that it does not cause illness—to deliver the mosaic antigens Korber had computationally designed.


The National Institutes of Health (NIH) launched a large clinical trial in November 2017 to assess whether the mosaic HIV vaccine regimen is safe and able to prevent HIV infection in humans. The study is sponsored by Janssen Vaccines & Prevention, B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, with co-funding from two primary partners, the Bill & Melinda Gates Foundation and NIH’s National Institute of Allergy and Infectious Diseases.


The new Phase IIb proof-of-concept study, called Imbokodo, aims to enroll 2,600 HIV-negative women in sub-Saharan Africa. The first Imbokodo participants received vaccinations at clinical research sites in South Africa, followed by participants in Malawi, Mozambique, Zambia, and Zimbabwe. Participants will be followed for at least two years.


Although Korber herself has stepped away from the clinical trial portion of this research, she is still closely watching its progress and serves as an advisor for the project. She continues to work mainly in HIV vaccine optimization, focusing on approaches both related and unrelated to the mosaic concept.


This article was first published on RDmag.com

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Computer simulations predict the spread of HIV

Researchers at Los Alamos National Laboratory have shown that computer simulations can accurately predict the transmission of HIV across populations, which could aid in preventing the disease. The simulations were consistent with actual DNA obtained from a global public HIV database.

Los Alamos National Laboratory

Computer simulations predict the spread of HIV


In a recently published study in the journal Nature Microbiology, researchers at Los Alamos National Laboratory show that computer simulations can accurately predict the transmission of HIV across populations, which could aid in preventing the disease.


The simulations were consistent with actual DNA data obtained from a global public HIV database, developed and maintained by Los Alamos. The archive has more than 840,000 published HIV sequences for scientific research.


“We looked for special genetic patterns that we had seen in the simulations, and we can confirm that these patterns also hold for real data covering the entire epidemic,” said Thomas Leitner, a computational biologist at Los Alamos and lead author of the study.


HIV is particularly interesting to study in this manner, Leitner noted, as the virus mutates rapidly and constantly within each infected individual. The changing “genetic signatures” of its code provide a path that researchers can follow in determining the origin and time frame of an infection, and the computer simulations are now proven to be successful in tracking and predicting the virus’s movements through populations.


The rapid mutational capability of the virus is useful for the epidemiological sleuthing, but also is one of the features that makes it so difficult to tackle with a vaccine.


Leitner and Ethan Romero-Severson, the study’s co-author and a Los Alamos theoretical biologist, used phylogenetic methods, examining evolutionary relationships in the virus’s genetic code to evaluate how HIV is transmitted. They found that certain phylogenetic “family tree” patterns correlated to the DNA data from 955 pairs of people, in which the transmitter and recipient of the virus were known.


“These HIV transmissions had known linkage based on epidemiological information such as partner studies, mother-to-child transmission, pairs identified by contact tracing and criminal cases,” the authors write.


The robust results from the study have led to a collaboration with Colorado and Michigan state health agencies. The researchers plan to develop public health computational tools to help the agencies to track the disease and allocate resources for targeted prevention campaigns. “We hope these tools will help to hinder new infections in the future,” said Leitner.


Leitner said the cutting-edge modeling tools can also be used to predict the patterns of other rapidly evolving infectious diseases.


Los Alamos has a strong history in genetic data analysis, having been the site of the original GenBank project in 1979, known at the time as the Los Alamos Sequence Database and established by Walter Goad of the Theoretical Biology and Biophysics Group.


Publication: Phylogenetic patterns recover known HIV epidemiological relationships and reveal common transmission of multiple variants, in Nature Microbiology.


Authors: Thomas K. Leitner and Ethan Romero-Severson.


Funding: The National Institutes of Health (NIH) funded the study.


This release originally appeared on the Los Alamos National Laboratory website

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Los Alamos research fundamental to first efficacy study for mosaic HIV-1 preventive vaccine

The HIV-1 mosaic vaccine in the trial was originally designed at Los Alamos National Laboratory by theoretical biologist Bette Korber and her team. The goal of the mosaic vaccine is to elicit immune responses that can protect a vaccinated person from the world of HIV diversity that they might encounter.

Los Alamos National Laboratory

Los Alamos research fundamental to first efficacy study for mosaic HIV-1 preventive vaccine


Just in time for World AIDS Day (Dec. 1) international partners are announcing the first efficacy study for an investigational HIV-1-preventive “mosaic” vaccine. Janssen Pharmaceutical Companies of Johnson & Johnson are joining forces with The Bill & Melinda Gates Foundation and National Institutes of Health on this study, and they have enlisted the aid of top researchers worldwide to conduct the trial.


The HIV-1 mosaic vaccine in the trial was originally designed at Los Alamos National Laboratory by theoretical biologist Bette Korber and her team. “My life’s work has been devoted to developing strategies to create a global HIV vaccine; mosaics were a realization of one such strategy,” said Korber. “It was initially very difficult to convince biologists that mosaic proteins, designed by evolving sequences in a computer, could ever lead to a viable vaccine approach. It is hugely rewarding to see this progress being made.”


Historically, the search for an HIV vaccine has been challenging due in part to the virus’s extraordinary diversity. HIV-1 has an ability to mutate rapidly, which results in great global genetic diversity with multiple strains and subtypes prevalent in different parts of the world. Understanding the history, structure and complexity of the viral foe has been key to developing the mosaic vaccine antigens, assembled from natural sequences, which are optimized to achieve coverage of the many different versions of HIV proteins that are circulating. The goal of the mosaic vaccine is to elicit immune responses that can protect a vaccinated person from the world of HIV diversity that they might encounter.

A radical but reasoned approach


Korber noted, “Thanks to experimentalist colleagues who were willing to give this radical but reasoned approach a try, mosaics have come a long way, and they have shown enough promise in monkey trials to merit further testing in people. Now we have to settle in for few more years of suspense as the human trial unfolds. I’m delighted, relieved and a bit astonished that the mosaic concept has come this far,” she said.


The new study, HVTN 705/HPX2008, is known as “Imbokodo,” the Zulu word for “rock,” from a South African saying that refers to the strength of women and their importance in the community. The study will evaluate whether the investigational vaccine regimen is safe and able to reduce the incidence of HIV infection among 2,600 sexually active women in sub-Saharan Africa.


The initiation of the Imbokodo study means that, for the first time in over a decade, two vaccine efficacy studies are taking place at the same time. Another study, HVTN 702, is currently underway in South Africa to evaluate a different vaccine candidate. The new study will be conducted at clinical sites affiliated with the NIAID-funded HIV Vaccine Trials Network.

HIV’s challenging diversity demanded a database


The mosaic design was based on input that included thousands of HIV sequences kept at the Los Alamos HIV Database, a publicly available international resource funded through the National Institutes of Health. The HIV database holds sequences gathered from scientists all over the world; it currently houses over 800,000 HIV sequences. Mosaic vaccines are computationally designed from protein sequence data that were extracted from this wealth of sequences, and the computer code used to design them was inspired by the way HIV-1 itself naturally evolves. The problem the mosaic code sets out to solve is to design just a couple of sequences that in combination will best capture the global diversity of the virus.

The path to human testing


The path from a vaccine concept to human testing is long. The original mosaic concept was first published in 2007 (Fischer et al. Nat Med. 1:100-6 2007). From there, the computational designs had to be taken from the computer screen into the physical world, being synthesized and tested at the lab bench. Then small animals were immunized to make sure mosaics raised good immune responses. Next monkeys were immunized to see if the vaccine protected them from infection (Barouch et al., Cell. 2013 Oct 24;155(3):531-9) and if the immune responses to mosaic vaccines elicited responses that could cross-react with highly diverse HIV strains.


Under the oversight of Dan Barouch at Harvard, the mosaic vaccine being tested in the Imbokodo passed all of those hurdles. In parallel, the Barouch lab worked continuously on improving the vaccine delivery strategies. Janssen, Barouch and other global partners then took the lead in moving the vaccine into initial human testing to make sure it raised good immune responses and was safe in people. Now, a decade after the concept was first published, enrollment for the first HIV mosaic-based vaccine proof-of-concept study has finally begun; in a few years, researchers will know if a mosaic vaccine can lower the rate of HIV infection among individuals in sub-Saharan Africa.


Nearly two million people become infected with HIV every year, despite recent advances in both HIV treatment and prevention. According to UNAIDS, women and girls account for nearly 60 percent of people living with HIV in eastern and southern Africa.

Funding


Bette Korber’s initial funding to develop the concept at Los Alamos National Laboratory came from an internally directed research grant at Los Alamos, but continued over the years under various collaborative NIH grants with Duke and Harvard.


This release originally appeared on the Los Alamos National Laboratory website.

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Promising Los Alamos innovations take the spotlight

Bette Korber, a theoretical biologist, has drawn inspiration for her innovative vaccine designs from the decades of work pursued by a team she leads. That team built a global HIV database of over 840,000 published HIV sequences for scientific research.

Los Alamos National LaboratoryPromising Los Alamos innovations take the spotlight




Los Alamos scientist Bette Korber was recently honored with the 2018 Richard P. Feynman Innovation Prize for her ground-breaking HIV vaccine designs. Korber was recognized at a ceremony that celebrates the “Next Big Idea” – scientific breakthroughs that achieved exceptional innovation.


Los Alamos National Laboratory researchers Laura Lilley and Yuxiang Chen were also recognized for outstanding presentations at DisrupTech — an annual event hosted by Richard P. Feynman Center for Innovation at Los Alamos and New Mexico Angels — that offers scientists a platform to present their work to businesses and the community.


“At the Laboratory, our researchers develop technologies that can have tangible benefits to industry and the general public,” said Nancy Jo Nicholas, principal associate director of Global Security at Los Alamos National Laboratory, which oversees the Feynman Center. “DisrupTech is a unique opportunity to share those emerging technologies and begin exploring how they could be developed and brought to market.”


The Feynman Center also created the Innovation Honor Society and inducted 10 Los Alamos scientists for their outstanding contributions to scientific discovery, innovation and the transfer of technology to the commercial sector.


In 2017, principal investigators at Los Alamos National Laboratory filed 130 patent applications, 92 patents were issued and 43 copyright assertions took place.

2018 Richard P. Feynman Innovation Prize


Korber, a theoretical biologist, has drawn inspiration for her innovative vaccine designs from the decades of work pursued by a team she leads. That team built a global HIV database of over 840,000 published HIV sequences for scientific research.


“Without the work of my database team, the vaccines would not have been possible,” said Korber. “I am honored to represent their efforts that are reflected in this award.”


Several of Korber’s vaccine designs have transitioned to the commercial sector. Janssen, a subsidiary of Johnson & Johnson, is testing one of her designs, called “mosaic,” in a clinical trial called the Imbokodo Study, being conducted in South Africa. If successful, the vaccine could be one of the first to prevent the HIV infection.


Biotechnology company VIR is also testing another HIV vaccine design in monkeys that have the simian immunodeficiency virus (SIV), the counterpart to HIV.


Korber says the award is also significant because it reminds her of a tough phase in her career. As a new Caltech graduate student in the early 1980s, there were few women students and faculty. She took a class from Feynman, and then went on to become friends with him.


“At a time when kindness seemed rare, I really appreciated his generous spirit and encouragement,” said Korber. “I think he would have been pleased about this award.”

DisrupTech Winners


At the fourth annual DisrupTech showcase, attended by 125 people, three Los Alamos staff scientists and eight postdoctoral researchers presented pitches for 11 different technologies to judges encompassing industry experts and venture investors.


Chen, a postdoctoral researcher, won the “Most Fundable Technology” award for his presentation, “NanoCluster Beacons: Fast Testing for Food Safety.” The $25,000 funding award will help Chen improve his technology that quickly and accurately tests pathogens in food.


Among the Los Alamos postdoctoral researchers, Lilley received the “Best Pitch” award for her presentation, “Nuclear Antibiotics: Winning the War on Bugs.” Lilley developed a small molecule that nukes microbial agents.


DisrupTech was hosted by Los Alamos’ Richard P. Feynman Center for Innovation, the New Mexico Angels investor group and the New Mexico Start-Up Factory. Sponsors included title sponsor EY, as well as the State of New Mexico Economic Development Department, the New Mexico Manufacturing Extension Partnership, the Los Alamos Commerce and Development Corporation, TechNavigator and Emera Technologies.




This release originally appeared on the Los Alamos National Laboratory website.

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Analyzing genetic tree sheds new light on disease outbreaks

Los Alamos National Laboratory Scientists have a new tool for unraveling the mysteries of how diseases such as HIV move through a population, thanks to insights into phylogenetics, the creation of an organism’s genetic tree and evolutionary relationships.

Los Alamos National Laboratory


Analyzing genetic tree sheds new light on disease outbreaks






Computational modeling fills in potential gaps in transmission chains


Scientists have a new tool for unraveling the mysteries of how diseases such as HIV move through a population, thanks to insights into phylogenetics, the creation of an organism’s genetic tree and evolutionary relationships.


“It turns out that three different types of transmission histories are possible between two persons who might have infected each other,” said Thomas Leitner of Los Alamos National Laboratory, the corresponding author of a new paper out this week in the Proceedings of the National Academy of Sciences. “Using phylogenetic inference in the epidemiological investigations of HIV transmission, we’ve determined that between two sampled, potentially epidemiologically linked persons, we can now evaluate the possibility that an unsampled intermediary or common source existed, even without a sample from that individual.”


Like a detective inferring the existence of an unseen actor in a sequence of events, the Los Alamos team used computational phylogenetic analysis to examine how strains of HIV, both in computer modeling and compared with real-life case studies, would be transmitted.


The team’s research has broad implications. “The inference of donor-recipient relationships we describe here is not restricted to HIV transmissions; it applies to all situations when an original population seeds a new population with a restricted random draw (a bottleneck) of individuals. We use HIV transmission to illustrate the effects because it helps trace contacts among people and untangle investigations into outbreaks. Also, statistical guidelines are needed for interpreting phylogenetic results in court.”


Phylogenetic inference of who infected whom has great value in epidemiological investigations, the authors point out, because it should explain how transmission(s) occurred. Until now, however, there has not been a systematic evaluation of which phylogeny to expect from different transmission histories, and thus interpreting the meaning of an observed phylogeny has remained elusive.


“Previously it was thought that it would be impossible to say who infected whom and whether there were unsampled intermediary links in an alleged transmission, or if both persons were infected by an unsampled/unknown third party. We show that this is now possible in many cases,” Leitner said. “This will have large impact on future epidemiological investigations, including forensics and outbreak investigations."


In the paper, the team showed that certain types of phylogenies associate with different transmission histories, which may make it possible to exclude possible intermediary links or identify cases where a common source was likely but not sampled. “Our systematic classification and evaluation of expected topologies should make future interpretation of phylogenetic results in epidemiological investigations more objective and informative,” Leitner said.


The paper is titled “Phylogenetically resolving epidemiologic linkage,” by Ethan O. Romero-Severson, Ingo Bulla, and Thomas Leitner. The work was supported by National Institute of Allergy and Infectious Diseases/National Institutes of Health.


This story originally appeared on the Los Alamos National Laboratory website.

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How it Began: HIV Before the Age of AIDS

Using samples of HIV-infected tissue harvested over the last three decades, virologist Dr. Bette Korber of Los Alamos National Laboratory has calculated that an ancestral form of HIV started spreading, slowly at first, in humans about 75 years ago.


How it Began: HIV Before the Age of AIDS


As soon as HIV was identified in 1983, scientists started trying to understand where it had come from, when it had arisen, and why it had spread. Were they too late? To answer most of their questions, they would have had to witness the virus's evolution. Scientists can track new pathogens such as SARS and avian flu because they produce obvious symptoms almost immediately. But HIV is a stealth virus that takes as many as 10 years to present symptoms; by the time researchers knew enough to wonder about its origins, those origins were in the distant past.


For the last 23 years, scientists have been trying to peer into that past. Jon Cohen, a correspondent for Science who has written extensively about the virus, compares the work to fossil hunting, using a few precious shreds of evidence to construct a possible history. "Everybody's always looking for certainty. It doesn't exist [in this field]," he says. "In a sense it's all theory."


Nonetheless, the theory rests on facts, and at least a few of them are undisputed -- including, most significantly, HIV's family tree. There are two species of the virus, HIV-1 and HIV-2. The first evolved from a simian immunodeficiency virus (SIV) found in chimpanzees, while the second came from an SIV in a type of monkey called the sooty mangabey.


HIV-1, which is responsible for the vast majority of AIDS cases worldwide, is divided into three groups -- the "major" group M, and the much rarer "outlier" group O and "new" group N -- that have diverged over years of mutation and evolution. Within the M group -- which makes up 90 percent of all infections worldwide -- there are at least nine strains, known as "clades," of HIV-1 that are constantly mutating and merging with each other, creating yet more new varieties. "The M group epidemiologically has overwhelmed what else is out there," says Dr. Beatrice Hahn of the University of Alabama-Birmingham, who has conducted much of the research into HIV's origin. HIV-2, on the other hand, is not as virulent and largely confined to West Africa, where it originated.


In May 2006, an international group of researchers led by Hahn answered two major questions about the origin of HIV-1 M, the deadliest and most widespread form of the virus: Where was its cradle, and what kind of chimp did it come from? Answering the questions was literally messy work -- researchers collected 599 waste samples from wild chimpanzees and analyzed the viral particles they contained -- but the results were immaculate. Three populations of Pan troglodytes troglodytes living in southern Cameroon provided the crucial data. Two of those populations currently carry SIVs that are molecular dead ringers for HIV-1 M, while many chimps in the third group are infected with an SIV remarkably similar to HIV-1 N. Group O's simian sibling is probably lurking in other chimp populations in West Central Africa, says Hahn, adding that she has "a pretty good idea where it's going to be … and we're going to find it."


The research puts to rest decades of speculation about the birthplace of most types of HIV and their animal "reservoir" in the wild. But there are still many questions that haven't yet been definitively settled -- questions such as:

When did HIV-1 first start spreading in humans?


HIV-1 is surprisingly old, and it probably "debuted" in humans at least three separate times -- one for each subtype, M, N, and O. Scientists' best guess is that the precursor of the most common "M" virus jumped from the Cameroon chimps to humans sometime before 1931. Using samples of HIV-infected tissue harvested over the last three decades, virologist Dr. Bette Korber of Los Alamos National Laboratory has calculated that an ancestral form of HIV started spreading, slowly at first, in humans about 75 years ago. The actual jump from chimps to humans probably occurred shortly before that, says Hahn: "There's no reason to believe this was just lingering around in people."


Korber's model estimates a virus' age based on how extensively different strains have mutated. HIV is an unusual virus; it changes its DNA by both mutation and, more often, recombination, when two strains merge within the body and exchange genetic material. Some scientists refer to this process as "viral sex," and it may partially explain why it is so hard for scientists to make a treatment or vaccine. Korber's model does not take recombination into account, but given a virus' DNA configuration, it can roughly predict the age of that strain. Korber has tested the oldest known HIV sample, taken in 1959, and derived the 1931 estimate.

Why do scientists look at recent samples of HIV to determine the virus' overall age? Wouldn't it be better to use older samples that haven't had as much time to mutate?


It would, but scientists don't have that luxury. Other than the 1959 sample, there are very few preserved specimens of HIV-infected tissue that predate the early '80s, when the virus was first recognized by health authorities. Researchers still hope there are forgotten samples in African freezers. "There has to be some serum or plasma somewhere, and given modern technology we could fish out the virus," says Dr. David Ho, director of the Aaron Diamond AIDS Research Center and one of the world's leading authorities on HIV.


But even if those samples are found someday, they won't necessarily yield definite answers about the virus' age, says Korber: "Often, you can't get anything out of samples like that." Most African samples are made of blood serum, and serum samples contain viral RNA, which degrades much faster than the DNA found in tissue samples. In fact, says Ho, the 1959 sample, which was sequenced by his laboratory, was kept in a freezer but still didn't survive the ravages of time. "It was completely dried up," he says. "We were only able to get small pieces [of genetic material], and we had to stitch them together."

So scientists have estimated when and where the most deadly type of HIV started infecting humans -- but how did it do that?


Most AIDS researchers believe that the "bushmeat trade" allowed the HIV-1 virus, and separately HIV-2, to enter the human bloodstream several times. Hunters who kill and butcher chimps and monkeys are regularly exposed to animal blood teeming with SIVs. If the hunters have cuts, bites, or scratches -- and given the nature of their work they almost always do -- they can catch the viruses from their prey. Hunters going after chimps in Cameroon could have caught the first strains of HIV-1. Sooty mangabeys, hunted and kept as pets in West Africa, could have transmitted HIV-2 to humans.


Africans have hunted chimps and monkeys and kept them as pets for centuries; they've presumably been exposed to SIVs during most of that time. But the conditions needed for HIV to spread widely weren't in place until after the continent was colonized and urbanized. The first victims would have found it easier to unwittingly spread the virus to sexual partners far and wide as roads and vehicles started connecting previously isolated villages and cities. Hospitals may have played a role, too. Strapped for cash, some of them probably re-used dirty needles, unknowingly infecting patients in the process.

Are there other theories about how the virus could have gotten into humans?


There are several competing theories, ranging from implausible conspiracies to arguments grounded in extensive research. The best-known of the latter, the "OPV/AIDS" theory, was exhaustively detailed in the 1999 book The River, by author Edward Hooper. As many as a million Africans were given oral polio vaccines (OPV) between 1957 and 1960. Hooper says witnesses have told him that a few batches of those vaccines were "grown" in chimp cells at a lab in Kisangani, a city in the Democratic Republic of the Congo -- and that the chimp cells, and thus the vaccines, could have contained SIVs that jumped into humans. "There are highly significant correlations between the places where this vaccine was administered and the places where … AIDS first appeared on the planet four to 20 years later," Hooper says.


The majority of HIV researchers subscribe to the bushmeat theory and raise several arguments against the OPV theory. Hahn's recent research confirming that HIV-1 M and N arose from Pan troglodytes troglodytes chimps in Cameroon presents one problem: The Kisangani lab is in the Democratic Republic of the Congo, and it's home to a different subspecies of chimp than the one that was the source of HIV-1 M and N. However, it is possible that the chimps used in the Kisangani experiments were not from the area. In the spring of 2006, Hooper found a paper indicating that at least one of eight chimps at the Kisangani lab was a Pan troglodytes troglodytes.


The 1959 sample also presents a problem for the OPV theory. Judging by how fast the virus mutates, it had already diverged significantly from its SIV ancestors by the time doctors extracted it from a patient. However, the African polio vaccination program had begun only two years earlier, so under the OPV theory, the virus would have had only those two years in which to evolve. Dr. Ho, who sequenced the sample, says it looks like the virus has been around a lot longer than that.


Proponents of each theory have acknowledged (albeit grudgingly) that the other is scientifically possible. In the last two years researchers have found that both "simian foamy viruses" and at least two types of retroviruses can and do jump from monkeys to humans via hunting and butchery. And no one doubts that a vaccine cultured in primate cells could be contaminated with a primate virus. Some early polio vaccines contained SV40, a simian virus discovered in 1960, and the RNA virus that causes Marburg hemorrhagic fever.


The question is not whether either scenario could have happened -- it's which one did. To truly disprove the OPV theory, Hahn says, researchers would have to find HIV-infected human tissue samples that predate the polio vaccine trials. To prove the OPV/AIDS theory, on the other hand, they'd have to find the ancestral SIV in batches of the vaccine that were made in Kisangani. Neither of those things has happened, and it's possible they never will.

Why do we care? Does all this research into how the virus got started tell us anything about how to stop it?


Research into the HIV's origins may eventually yield practical results. It could help scientists understand why HIV's viral ancestor, SIV, doesn't kill or even sicken chimps who carry it. With that knowledge, researchers might be able to make drugs with fewer side effects, or broad-spectrum vaccines that protect against all the strains of the disease that infect people today.


Korber suggests that in an era of emerging diseases, looking back on the virus' shadowy origins offers a "history lesson," or perhaps even a fable, with a moral attached. By the time doctors realized that HIV/AIDS existed, it had already taken up permanent residence in humans. They couldn't have known about it before then, but, Korber says, at least now they know to be wary as the virus continues its shape-shifting spread around the globe. "The fact that it could be with us for quite a long time before we even realized it was there is kind of eye-opening," she says. "I think it's something to keep us on our toes. It helps us understand that we can be surprised." And of course, HIV research may have a few surprises left for us, too.


This article originally appeared on Frontline.

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Study Pushes AIDS Origins Back to 1930s

The strain of virus responsible for nearly all cases of AIDS first appeared in the 1930s, say scientists who used a “molecular clock” to date the origin of HIV. The finding casts doubt on the controversial idea that contaminated polio vaccines seeded the AIDS pandemic in the late 1950s.

Study Pushes AIDS Origins Back to 1930s



The strain of virus responsible for nearly all cases of AIDS first appeared in the 1930s, say scientists who used a "molecular clock" to date the origin of HIV. The finding, reported in the 9 June issue of Science, casts doubt on the controversial idea that contaminated polio vaccines seeded the AIDS pandemic in the late 1950s.


The origin of AIDS is much clearer today than it was in the early 1980s, when the new disease blindsided the scientific establishment. Virologists have identified the chimpanzee virus that probably gave rise to HIV, while epidemiologists have rummaged through old samples and forgotten medical records to identify early cases. Still, the trail of direct evidence stops with an HIV-positive blood sample drawn in 1959 in what is now the Democratic Republic of Congo. How and when the chimpanzee virus entered humans remains uncertain.


To look farther into HIV's murky past, theoretical biologist Bette Korber of Los Alamos National Laboratory in New Mexico and her colleagues used a statistical model to clock the evolution of HIV's envelope gene, which codes for one of the spiky proteins jutting from the virus's surface. With help from a supercomputer, Korber's group compared 159 gene sequences from viruses in the so-called M group, which causes the majority of AIDS cases worldwide. Assuming that differences between genes accumulate at a constant rate, the researchers calculated that the common ancestor of all the M group viruses arose between 1915 and 1941--most likely in 1931. They believe the virus had already jumped to humans at this time; a later invasion would require that multiple viral strains entered people before spreading from person to person--a scenario Korber calls very unlikely.


The study impresses other scientists in the field. "It's the best analysis by a long way that's been carried out in this area," says molecular evolutionist Paul Sharp of the University of Nottingham in the United Kingdom. If confirmed, the early date would squash the hypothesis--described recently in a book called The River (Science, 12 November 1999, p. 1305)--that the AIDS pandemic was triggered by an oral polio vaccine inadvertently contaminated with the chimpanzee virus.

This article originally appeared on ScienceMag.com.

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Tracking HIV Evolution

At LANL, Bette Korber and her team of  multidisciplinary scientists track, with exquisite detail, the evolution of one of the most diverse and peripatetic viruses ever identified with a vast network of super-computer systems that can crunch data at speeds of up to 10 to the 15th power, roughly in the blink of an eye.

Tracking HIV evolution



Los Alamos, New Mexico, consists of a series of rust-colored mesas that form a picture-postcard setting: snow-capped Jemez Mountains in the distance and vast swathes of undisturbed wilderness that belie its history-making role in US defense.


Los Alamos is, of course, the place where 30 scientists gathered in 1943 to build the world’s first atomic bomb. Physicists recruited to work at the Los Alamos National Laboratory (LANL) with nuclear physicist J. Robert Oppenheimer, scientific director of the Manhattan Project, worked feverishly in the race to develop a nuclear weapon before the Germans. Their top-secret crusade transformed this bucolic southwest community and its acres of pine trees into a nerve center for US military weapons research.


Seven decades later, the LANL campus still looks a bit like a frontier outpost. Single-story modular units—like those found at construction sites—are laid out like a maze and are surrounded by acres of federally-owned forest that remain largely off-limits to the public.


It is here that theoretical biologist Bette Korber and her team of 13 multi-disciplinary scientists track, with exquisite detail, the evolution of one of the most diverse and peripatetic viruses ever identified. They do this with a vast network of super-computer systems—some occupying a space equivalent to half a football field—that can crunch data at speeds of up to 10 to the 15th power, or a quadrillion calculations per second, roughly in the blink of an eye.


The work of tracking HIV began in earnest in 1986 with the creation of the HIV Database and Analysis Project. The US National Institute of Allergy and Infectious Diseases (NIAID), which funds the project through an agreement with the Department of Energy, hoped the formation of the database would accelerate the development of better drugs, as well as a vaccine to protect against HIV/AIDS.


Since its inception, the main goal of the HIV database project has been to collect, curate, and annotate HIV genetic material, and provide the data to scientists in an open-access environment to try to encourage collaboration within the field. Relying on data from an earlier LANL effort called GenBank, a public database set up in 1982 to store laboratory samples of previously sequenced organisms, the HIV database took the effort to a new level.


To date, the HIV database contains published genetic sequences of DNA from 250,000 different viruses obtained from HIV-infected individuals around the world. Although not the only database of its kind—Stanford University also has a database of about 100,000 viral sequences that it uses to identify drug-resistant HIV mutations—it is by the far the largest and most utilized by HIV researchers. And the project’s scope and mission hasn’t ended there. LANL scientists have also cooked up dozens of software tools to assist scientists in their research, including programs that help identify the specific subtype or clade of the HIV sequence. More recently, researchers used the HIV database at LANL to engineer vaccine candidates designed to provide greater coverage against the diverse strains of HIV in circulation—which Korber hopes will finally provide sufficient breadth to cope with the problem of viral diversity in HIV vaccine development.


LANL researchers have also established three additional databases. A molecular immunology database provides a comprehensive listing of defined HIV epitopes, including epitope alignments, epitope maps, and reference information for cytotoxic T-cell (CTL) and helper T-cell epitopes, as well as antibody-binding sites. Another database tracks drug-resistant HIV mutations, while another tracks HIV vaccine trials being conducted in nonhuman primates (NHPs).


The HIV database, overseen by Korber, is an incredibly important tool for HIV scientists, judging by the number of citations and acknowledgements to LANL, as well as the numerous plaudits from leading AIDS researchers. “They have supported everyone’s research over the past 15-20 years and are the central repository not only for sequences but meticulous annotations of those sequences,” says Barton Haynes, director of the Duke Human Vaccine Institute and the Center for HIV/AIDS Vaccine Immunology (CHAVI) at Duke University in North Carolina, who has collaborated with LANL researchers on a number of vaccine-related projects.


The spectrum of research studies that have benefited from the HIV databases has been huge, and ironic, given that its founder Gerald Myers, an LANL scientist, initially thought the HIV sequencing project would only last about a year. But from its inception, the project was flooded with database entries that reflected the incredible genetic variation of HIV strains circulating globally. Myers soon realized the tremendous challenges viral diversity posed in the development of an effective AIDS vaccine and pushed NIAID to escalate funding and expand its contract.


Much of the credit for the project’s credibility today goes to Korber, whose aversion to doing experiments—or as she phrases it, the tedious cycle of pipetting, pipetting, pipetting—drove her toward mathematics, and ultimately theoretical biology, when she was working toward her doctoral degree in immunology at the California Institute of Technology (Caltech) in the 1980s. “I like thinking and puzzling better. That also takes great care and hard work, but it’s just the nature of the work that I like better,” says Korber, when interviewed at her office on the eve of the annual Keystone Symposia on HIV Biology and Pathogenesis in Santa Fe, New Mexico.


As the largest repository of information about the mind-boggling diversity of HIV, it’s no surprise that over the years, the HIV database project, and Korber as well, has been drawn into thorny, sometimes contentious, debates about who discovered HIV, the origin of the virus, and even the widely publicized case of a Florida woman who claimed she had been infected with HIV by her dentist.


Using math to tackle HIV


Theoretical biologists use a variety of analytic tools, from mathematical and computational models to systems biology and bioinformatics, to better understand biological systems and predict how they will evolve. This partly explains why Korber accepted a position at LANL—with its nascent database project and access to some of the best computer hardware in the world—after completing a post-doctoral fellowship in molecular epidemiology of human retroviruses at Harvard University in 1990.


But there were also very deep, personal reasons why Korber decided to focus her attention on HIV. In the early 1980s, when Korber and her fiancé James Theiler were studying at Caltech, they became close friends and housemates with a physicist from the UK. The bond was so close that when Korber and Theiler decided to get married in 1988, their friend received training as a lay minister so he could marry them at a ceremony by a stream in the mountains above Pasadena, California. “He was just a wonderful, brilliant man,” Korber says of her housemate.


Their friend was also, unfortunately, one of the earliest reported individuals to be infected with HIV in Pasadena. His struggle with the virus had a profound effect on Korber’s life. It was still early days in the escalating epidemic, long before highly active antiretroviral therapy (HAART) began rescuing HIV-infected individuals from the brink of death. “We learned a lot about HIV while he was sick,” says Korber. “But there was no treatment for him and he died in 1991. I decided when I graduated from my PhD program that I wanted to work on HIV.”


Specifically, her friend’s battle with HIV propelled Korber to commit her life to finding an AIDS vaccine. “I hate HIV,” she says, her voice rising with emotion. “I lost a couple friends to it. HIV kills in horrible ways. I think of what the epidemic has done to Africa and it motivates me.”


Korber spent her first few months at LANL getting used to “playing” on the computer, a transition made easier, she says, because her mentor, Myers, was patient and gave her space. Eventually, Korber suggested to Myers that LANL add the Molecular Immunology Database, which like the HIV Sequence Database, was the first database of its kind dedicated to a single pathogen.


The goal of the immunology database was to provide a comprehensive listing of defined HIV and SIV epitopes associated with sequences previously published in scientific literature and submitted to the HIV database, and then make the searchable collection available to the general scientific community. Launched in 1995, it now contains more than 1,200 HIV epitopes, with at least 275 of them considered “A-list” because they have been characterized with a high degree of detail, according to HIV Molecular Immunology, which provides annual updates and reviews of the database. Over time, the development of large cohorts of individuals known as long-term nonprogressors, who have demonstrated an unusual ability to control HIV infection without treatment, and an evolving war chest of gene sequencing and data analysis tools has enabled researchers to assess different HIV epitopes for their potential role in controlling or preventing HIV infection, the authors of the compendium noted in its 2009 review.


“The HIV Database project took on the issue of the interface of the virus with the host, compiling not only viral sequences but immunological epitopes recognized by B cells, CD4+ and CD8+ T cells, and antibodies, then laid out the foundation for a relational database that they made available to the field. They emphasized the need for collaboration early on in the AIDS epidemic,” says Haynes.


In most cases, the information about each epitope includes the protein fragment’s published name, the specific protein that it is associated with, the location on the protein within a region of 21 amino acids or less, the viral subtype, and the host species.


A more in-depth search of each epitope will show the country where the circulating virus was identified, assays used to test the immune response, the major histocompatability complex/human leukocyte antigen (MHC/HLA) of the infected donor, and how many different epitopes are linked to the particular HIV sequence in question. Each epitope entry in the HIV Molecular Immunology Database also includes annotated footnotes that summarize information about the immune responses measured, such as cross-reactivity patterns, escape mutations, and antibody sequences that overlap with an epitope, as well as a link to studies measuring the epitope response in human and animal studies.


By documenting all the known epitopes of every DNA sequence published in the HIV literature, the HIV Immunology Database offers researchers an unprecedented way of studying HIV’s diversity. “What we did was really unique,” says Korber.


Bruce Walker, director of the Ragon Institute, first met Korber when she was doing her post-doc at Harvard and the two are now collaborators on various projects. Like many scientists in the field, he has found the LANL HIV database a uniquely valuable resource, and gives Korber high marks for her oversight of the project.


“I think she’s extremely careful, meticulous, and passionate about digging through to the truth behind the phenomenon we are observing,” says Walker. “She’s been a fantastic steward for this repository because she puts so much effort into making sure that what is in there is accurate. I can’t express that enough. A database is only as good as the data put into it. This is a resource you can completely count on and it has been an enormous benefit for the field.”


Korber, along with Myers, also helped shepherd in an at first controversial policy for journals in the early 1990s that ended the practice of allowing researchers to publish papers about viral sequences without submitting the sequences to the public repository. Sometimes researchers would not take the time to make the sequences public, closing the door on other researchers trying to replicate the findings and missing the opportunity to build on the collective body of sequencing information. “We had to fight for this,” says Korber reflecting on the new policy, which was eventually adopted by major scientific/medical journals. “It will be interesting to see how curation and data sharing unfold in the years ahead with the advent of new sequencing technologies.”


Her many passions


Korber’s work schedule is grueling. She usually rises at 4 a.m. and is often firing off emails to colleagues as the clock approaches midnight in her Los Alamos-area home. “I can vouch for that,” says Mark Muldoon, a long-time friend and colleague from the UK, who was visiting Korber’s lab while he was in Santa Fe for the January Keystone Conference.


But HIV research is not her sole passion. Korber and her husband, a physicist at LANL’s Space and Remote Sensing Sciences Division, both love to hike, and Korber holds a black belt in Tae Kwon Do. Korber also jams regularly with a Celtic band called Roaring Jelly, named for the blasting gelatin used more than a century ago for mining operations. Korber plays the bodhran, an Irish hand-held drum about twice the size of a tambourine, and the Irish whistle. Her 17-year-old son, Sky Korber, plays a “hot fiddle” in the band, says Korber, referring to her son’s musical prowess. Korber’s 21-year-old son, Max Theiler, attends the University of California in Santa Cruz.


Korber has also taken a keen interest in helping people and regions disproportionately impacted by the HIV pandemic. Four years ago, Korber used US$50,000 in prize winnings from the prestigious E.O. Lawrence Award—the Department of Energy’s highest honor for scientific achievement—to help establish, along with family and friends, an orphanage in South Africa for 500 AIDS orphans. The orphanage was created under the auspices of Nurturing Orphans of AIDS for Humanity (NOAH). Korber is also trying to help initiate use of portable, maintenance-free gardening systems known as Earth Boxes, which have been placed at various orphanages, clinics, and schools in Africa.


In addition to leading an eclectic group of molecular biologists, sequence analysts, and computer technicians at LANL, Korber is also on the faculty of the Santa Fe Institute, a 26-year-old research and education non-profit organization that encourages collaboration among scientists across different disciplines to solve complex problems of the day. Her research portfolio also includes hepatitis and she recently received a $1.5 million grant to study the interactions between tuberculosis and HIV.


But Korber’s main research endeavor, from the start, has been driving toward the development of the elusive AIDS vaccine, and specifically, how a vaccine could overcome HIV’s diversity, one of the most potentially vexing obstacles to the development of a vaccine. Although recent findings from complete genome sequence analyses of transmitted founder viruses suggest a single viral variant usually initiates infection in heterosexual transmission cases, the infecting strains are still unique and distinctive.


Designing a vaccine capable of overcoming such genetic variation has been daunting. One approach being explored by Korber, along with collaborators at Beth Israel Deaconess Medical Center in Boston, the University of Manchester, NIAID’s Vaccine Research Center, the University of Alabama, and Duke University, is to use various computational methods to determine the most common amino acids in the Envelopes of multiple variants of HIV from different clades, and then develop antigens based on these Env proteins, which are referred to as consensus sequences.


When a vaccine candidate containing a computationally derived, global consensus Envelope sequence was evaluated in rhesus macaques, it generated cellular immune responses to three- to four-fold more HIV epitopes of Env proteins across clades A, C, and G than a clade B immunogen from a naturally occurring Envelope sequence from a single individual did against clades A, C, and G. Moreover, the T-cell responses stimulated by the consensus immunogen within clade B was comparable with those stimulated by the naturally occurring clade B immunogen (3).


More recently, Korber and her collaborators also created what are referred to as mosaic vaccine antigens, which are assembled from natural sequences and optimized to achieve coverage of the many different versions of HIV proteins that are circulating. These mosaic vaccine candidates triggered strong cross-reactive immune responses in rhesus macaques in two separate studies (4,5).


One study led by Norman Letvin, a professor of medicine at Beth Israel Deaconess Medical Center, showed that the CD8+ T-cell responses in rhesus macaques vaccinated with a prime-boost regimen of a DNA plasmid followed by a recombinant vaccinia virus vector were stronger if the vaccine constructs expressed mosaic immunogens compared to those expressing consensus immunogens (5). “This increased breadth and depth of epitope recognition could contribute to protection against infection by genetically diverse viruses and, in some instances, may block the emergence of common variant viruses,” the study’s authors noted.


A second animal study led by Dan Barouch, also of Beth Israel Deaconess Medical Center, evaluated mosaic Gag, Pol, and Env antigens expressed by recombinant, replication-incompetent adenovirus serotype 26 (rAd26) vectors. The team immunized 27 rhesus macaques with a single injection of the rAd26 vectors expressing mosaic antigens, consensus antigens, combined clade B and clade C antigens, or naturally occurring clade C Gag, Pol, and Env antigens. The Ad26 vector expressing mosaic antigens induced CD8+ T cells that recognized more epitopes, as well as more variants within an epitope, than Ad26 vectors expressing consensus or natural sequence antigens (4). Overall, mosaic antigens provided a four-fold improvement in the breadth of the immune response.


Taken together, these NHP studies suggest that mosaic antigens could both broaden the range of recognized epitopes and increase responses to high-frequency HIV variants, although it remains to be seen if this approach will work as well in humans. A Phase I trial to compare the safety and immunogenicity of mosaic Envelope antigens with antigens that express either a global consensus Env sequence or a natural env gene, is scheduled to begin later this year and will involve about 100 volunteers. The HIV Vaccine Trials Network is conducting the trial in collaboration with CHAVI, the European Vaccine Effort Against HIV/AIDS, and the Bill & Melinda Gates Foundation.


“I am really hopeful,” says Korber, who confesses she “thinks about sequences and HIV diversity all the time. We have to deal with the diversity issue. If we don’t, we will never have a vaccine that works.”

This article originally appeared in IAVI Report.

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Published Research

Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19)

By Bette Korber, et al
Abstract

More than 1.8 million new cases of HIV-1 infection were diagnosed worldwide in 2016. No licensed prophylactic HIV-1 vaccine exists. A major limitation to date has been the lack of direct comparability between clinical trials and preclinical studies. We aimed to evaluate mosaic adenovirus serotype 26 (Ad26)-based HIV-1 vaccine candidates in parallel studies in humans and rhesus monkeys to define the optimal vaccine regimen to advance into clinical efficacy trials.

READ MORE

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Graph-based optimization of epitope coverage for vaccine antigen design

By James Theiler and Bette Korber
Abstract

Epigraph is a recently developed algorithm that enables the computationally efficient design of single or multi-antigen vaccines to maximize the potential epitope coverage for a diverse pathogen population. Potential epitopes are defined as short contiguous stretches of proteins, comparable in length to T-cell epitopes. This optimal coverage problem can be formulated in terms of a directed graph, with candidate antigens represented as paths that traverse this graph. Epigraph protein sequences can also be used as the basis for designing peptides for experimental evaluation of immune responses in natural infections to highly variable proteins.

READ MORE

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Videos

 

HIV vaccine enters human efficacy trials
The HIV mosaic vaccine was originally designed at Los Alamos National Laboratory using a machine learning algorithm designed by Bette Korber and her team. It's the first computationally designed HIV vaccine. The study will evaluate whether the investigational vaccine regimen is safe and able to reduce the incidence of HIV infection among 2,600 sexually active women in sub-Saharan Africa.

 

Photos

    Bette Korber: Los Alamos National Laboratory

    Black download iconAt Los Alamos National Laboratory, Bette Korber combined her interest fighting HIV with her passion for computing.

    HIV-1 vaccine | Los Alamos National Laboratory

    Black download icon Novel viral analysis approach leads to potential “global vaccine.”


    Experts

    Bette Korber | Los Alamos National Laboratory

    Bette Korber

    Korber is a Laboratory Fellow and Scientist 6 at Los Alamos National Laboratory, in the Theoretical Biology and Biophysics group. Her professional career has been devoted to the study of pathogen evolution and the immune response, with the intent of contributing to the global efforts to make an HIV vaccine. Several of her designed HIV vaccines have shown promise in animal studies, and several human trials are ongoing; her mosaic design is being tested in a Phase 2b proof of concept study, HVTN 705 (it began Nov. 2017). Other vaccine design strategies are currently being tested in animals.

    She has also led the conceptual design of vaccines for Ebola and Hepatitis B and C, and evaluation of several versions of designs are  in animal or human trials. She has recently begun work in large collaborations that will attempt to use immune-based strategies  to cure or contain HIV infections. In addition, she has worked on the evolution of drug resistance for both HIV and TB, and in the field of molecular epidemiology.

    Thomas Leitner | Los Alamos National Laboratory

    Thomas Leitner

    Leitner is a computational biologist with interests in public health. His research mainly revolves around molecular evolution and how its trace can be used to understand pathogen-host interactions and infectious disease spread. He collaborates with experimental, clinical, and theoretical scientists and public health experts across the globe.

    His current research focuses on modeling HIV dynamics both on the within-host level and on the epidemic level, and especially on the connection between these levels.

    Elena Giorgi | Los Alamos National Laboratory

    Elena Giorgi

    Giorgi is a computational biologist, whose main research interest is developing statistical tools to analyze genetic and immunological data, with a particular interest in cancer and viral infections, and cancer associations. She holds a Ph.D. in applied mathematics and an M.S. in biostatistics.

     

    Contact

    Nancy Ambrosiano, (505) 667-0471,  nwa@lanl.gov

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