Bette Korber

Phylogenetic tree showing HIV compared to SIV

Korber oversees the HIV Database and Analysis Project at Los Alamos.[13] She and her team have built a global HIV database of more than 840,000 sequences from publications of the viral genome.[5] In addition, the database focuses on the small regions (called epitopes) within the virus that can be recognized by antibodies, and evaluates the evidence for the strength of each epitope in eliciting immune responses. There is also data on the immunological profiles of individuals resistant to HIV.[13] Korber and many other researchers have applied the data to devise possible treatments and vaccines against HIV.[5] Her work has resulted in design of vaccines now being tested in clinical trials.[4][5]

Creating a vaccine against HIV has been challenging because the virus mutates rapidly, creating multiple variants that may not be recognized by immune system components specific to the original infecting virus.[2] The most variable region is the surface of the virus, but there is also some variation of the internal proteins involved in virus replication, which may be attacked by the cellular immunity system or T cell responses.[14] A recent approach that Korber and collaborators have taken is to design mosaic antigens.[2] Korber developed a novel mosaic HIV vaccine that may slow or prevent HIV infection; this is currently in human testing in Africa.[2] The goal of the mosaic antigen vaccine is to protect the vaccinated person against the great variety of HIV variants encountered.[2]

Since the proteins of HIV vary so greatly, mosaic test proteins are designed to represent the most common forms of HIV-1 virus that can be recognized by antibodies or cellular immune responses (epitopes).[15] In 2009, Korber described the process: "I create sort of little Frankenstein proteins that look and feel like HIV proteins but they don't exist in nature."[16]

Several of the major variations are included in each molecule of protein, thus producing a variant protein antigen that probably does not exist in the wild virus population but should cross-react with variants that do exist.[15] Korber has taken two different approaches to designing such antigens. Her group has developed a computer algorithm to choose epitopes to combine into a mosaic molecule for the mosaic antigens.[17] In 2009, she described a designed mosaic protein this way: "People didn't know if it would fold properly, if it would be antigenic, or if it would have the same sites that recognized by killer T cells". They found that the newly designed antigens did fold properly and acted as a strong antigen, and were recognized by the cytotoxic T cells (killer cells).[16] Also, Korber and her collaborators have developed a graphical analysis called Epigraph that can generate promising antigens with a mixture of epitopes.[17] Korber explains that the approach of designing a protein via computer, combining bits of known proteins that provoke immune responses, had never been tried. She says, "Even after it worked, it was hard to convince people that this novel thing could be a vaccine because it hadn't been done before".[2]

In collaboration with Dan Barouch, a professor at Harvard Medical School, some of these antigens have been tested in monkeys as possible vaccines. With one series of tests, Barouch checked a number of possible ways to deliver the virus genes and chose to use the common cold virus as a vehicle.[2] The tested mosaic vaccine routinely slowed monkey infection with the closely related Simian Immunodeficiency Virus (SIV), and for 66 percent of monkeys exposed multiple times, no infection resulted.[2] Next, in collaboration with the National Institutes of Health, Janssen Pharmaceutical Companies (a division of Johnson & Johnson), and the Bill and Melinda Gates Foundation, the researchers tested a mosaic vaccine for safety in human subjects; it passed that test too.[2] In 2017, the group of collaborators announced a human efficiency test with that same mosaic protein preparation, vaccinating 2,600 women in Sub Saharan Africa, who will be examined for several years to show how efficiently, if at all, the virus interferes with infection.[2] Korber cautioned that effectiveness of this strategy in monkeys is not a guarantee that a human vaccine will work.[2]

In recognition of her research, Korber received the 2018 Feynman Award for Innovation, the first woman at Los Alamos National Laboratory to receive one.[18] She recalled that at Caltech when few women were there, she took a class with physicist Richard Feynman and became friends with him. She said, "At a time when kindness seemed rare, I really appreciated his generous spirit and encouragement. I think he would have been pleased about this award".[5]

In the history of HIV/AIDS virus with regard to when and where HIV originated, Edward Hooper had postulated in a best-selling book called The River: A Journey to the Source of HIV and AIDS in 1999[19] that HIV could have jumped from chimpanzees to humans because of an accidental contamination by chimpanzee SIV of the oral polio vaccine (CHAT) used in Africa in the 1950s.[20] Korber and her colleagues employed the Los Alamos National Laboratory database's genomic data to calculate when the HIV sequence evolution began, using a model of evolution based on the mutation rate of HIV strains and assuming that variable was the same on all branches of the evolutionary tree. In 2000 they published an estimate of approximately 1930 for the origin of the human immunodeficiency virus.[21] Their research was covered widely as establishing a new date for the origin of the human virus, discrediting the oral polio virus theory, and therefore refuting concerns about using oral polio vaccine (OPV).[22][23][24][25][26] These two concepts of the origin of this virus plus other related theories continued to compete for scientific credibility.[20][21][27]

In 2008, Worobey and collaborators used a computer modeling approach similar to Korber's but with a relaxed evolutionary model and two older samples, collected earlier than any genomes included in Korber's study, and found an origin date for HIV of approximately 1900.[28]

As the COVID-19 pandemic unfolded, Korber and her Los Alamos colleagues devised computational strategies that look for evolutionary changes in genes that encode the Spike proteins that stud the SARS-CoV-2 coronavirus and give it its crown-like appearance.[29] Her strategies can examine millions of global genomes stored by GISAID, and it flags mutations that vary from the original Wuhan sequence by at least a minimum specified threshold amount.[30] Using this strategy, she and colleagues identified a particular Spike mutation, Aspartic acid (Asp) to Glycine (Gly) at position 614 (D614G), that was gaining prevalence across the globe since February 2020.[31] This finding, which was controversial at first,[32] was validated by multiple other groups who showed that the D614G mutation was shown to improve the efficiency of replication and transmission of SARS-CoV-2,[33] and this mutation, as of June 2020, has become part of all globally prevalent SARS-CoV-2 strains. As of September 28, 2021, she and her group continue to analyze GISAID data for novel variants,[34][29] and she continues to be an active member of the NIH TRACE Working Group,[35] whose objective is to "provide actionable intelligence on SARS-CoV-2 variants through genomic surveillance, data sharing and curation, and standardized in vitro assessments of therapeutics against novel strains."