For decades, scientists have pursued a central goal in HIV vaccine research: developing a vaccine that can teach the immune system to produce broadly neutralizing antibodies (bnAbs)—specialized antibodies capable of recognizing and blocking diverse strains of HIV. While a protective HIV vaccine remains elusive, researchers have made important progress toward this goal by learning how to stimulate rare B cell populations with the potential to mature into bnAb-producing cells.
But creating these antibodies is only part of the challenge. Like any evolving pathogen, HIV is constantly changing. As the virus mutates and accumulates genetic diversity, antibodies that can neutralize one generation of HIV strains may become less effective against newer variants. This creates a critical need for better tools to determine whether vaccine-induced antibody responses are truly developing the breadth needed to protect against the HIV strains circulating today.
In a new study in PLOS Pathogens, researchers from the Vaccine and Infectious Disease Division and collaborating institutions—including lead author Dr. Bette Korber of the New Mexico Consortium—developed updated HIV-1 envelope (Env) pseudovirus panels, in which non-pathogenic, non-replicating viruses are used to study viral infection, enabling safer research for dangerous pathogens. The collaborative effort brought together expertise in HIV sequencing, neutralization assays, and viral evolution from institutions including the New Mexico Consortium, Harvard University Center for AIDS Research, Duke University, the National Center for Infectious Diseases in Johannesburg, South Africa, the University of Cape Town, and the University of Washington.
The new panels were designed to more accurately measure whether vaccine-induced B cell responses are progressing toward broadly neutralizing activity. The work builds on insights from the Antibody Mediated Prevention (AMP) trials, which evaluated whether passive administration of the broadly neutralizing antibody VRC01 could prevent HIV infection by binding the virus's CD4 binding site—the region HIV uses to attach to and infect immune cells.
“The AMP trials established that passive infusion of the CD4 binding site broadly neutralizing antibody VRC01 can prevent acquisition of HIV viruses sensitive to this antibody,” said senior author Dr. Elena Giorgi, a Senior Staff Scientist in the Gilbert Group. “In addition to this landmark result, these trials also gave us an updated snapshot of the diversity of HIV circulating in Southern Africa and in the Americas.”
Although AMP demonstrated that bnAbs could provide protection against susceptible viruses, it also highlighted a persistent challenge: HIV is extraordinarily diverse. The virus’s rapid mutation and recombination rates have produced a vast array of circulating variants, making genetic diversity one of the greatest obstacles to HIV prevention.
Historically, many laboratory panels used to evaluate antibody activity relied on HIV strains collected more than two decades ago. While these panels have been invaluable for advancing the field, they may not fully represent the viruses people are exposed to today.
“Genetic variation is making the virus more resistant to broadly neutralizing antibodies, affecting the efficacy of bnAb prevention strategies, whether the bnAbs are passively administered or elicited through vaccination,” said Giorgi.
To address this challenge, the researchers analyzed envelope sequences from viruses collected from placebo participants in the AMP trials and compared their neutralization profiles with older HIV reference panels. Sequencing efforts were led by the Williamson laboratory at the University of Cape Town and the Mullins laboratory at the University of Washington, while neutralization data were generated through collaborations with Michael Seaman at the Harvard University Center for AIDS Research, the Montefiori laboratory at Duke University, and the Mkhize and Moore laboratories at the National Center for Infectious Diseases in Johannesburg, South Africa.
They then selected contemporary HIV strains to create three new pseudovirus panels: class-specific panels designed to detect antibodies targeting major HIV Env regions, a combined panel optimized for detecting low levels of bnAb activity across antibody classes, and a contemporary diversity panel representing the range of neutralization sensitivity found among current circulating viruses. These panels provide researchers with a more sensitive way to track whether vaccine-induced B cell lineages are moving in the right direction during the process of affinity maturation—the evolutionary process in which B cells refine their antibodies after repeated exposure to antigen.
“The next step is to discover and optimize vaccine strategies that will selectively induce such maturation,” the authors wrote in a summary description of their work. The new panels are designed to help researchers identify promising antibody responses earlier and determine whether experimental vaccines are generating antibodies with the potential to become broadly protective.
The study also highlights the importance of continued HIV surveillance and global sequencing efforts. As HIV continues to diversify, understanding the viruses circulating in different regions will be essential for developing prevention strategies that remain effective.
Giorgi emphasized that expanded surveillance is particularly important in regions that have historically been underrepresented in global HIV sequencing efforts. Before the AMP trials, for example, only a limited number of full HIV Env sequences from Peru were publicly available. Data generated through AMP and subsequent studies have revealed that viruses circulating in Peru can differ genetically and antigenically from those circulating elsewhere, even within the same HIV subtype.
“These findings are extremely important to inform the design and deployment of effective prevention strategies,” said Giorgi. “We need broad and ongoing sampling of circulating strains to minimize and prevent the emergence of escape.”
As HIV continues to evolve, researchers are adapting their approaches to keep pace. By creating more realistic tools to measure antibody responses, these new panels provide an important foundation for the next generation of HIV vaccine studies—and bring scientists closer to the goal of durable, broadly protective prevention.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. James Mullins contributed to this research.
The spotlighted research was funded by the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Gates Foundation.
Korber B, Seaman MS, Mkhize NN, Greene K, Gao H, Shen X, Domin E, Tang H, Theiler J, Wagh K, Moore PL, Williamson C, Mullins JI, Doria-Rose NA, Montefiori D, Giorgi EE. 2026. Contemporary HIV-1 envelope pseudovirus panels for detecting and assessing B cell lineages with broadly neutralizing antibody potential. PLOS Pathogens. https://doi.org/10.1371/journal.ppat.1013739.
Science Spotlight writer Jenny Waters is a postdoctoral research fellow in the Hsieh lab at Fred Hutch. She studies how mRNA translation coordinates bladder cancer transformation and metastasis by post-transcriptionally regulating expression of oncogenic proteins. Outside of the lab, Jenny enjoys spending time with her dogs, convincing her husband to join her on trail runs, and pretending every steep hill is just a "gentle incline."