Unique structure of bovine bNAbs may inform HIV vaccine, therapeutics design.
Scientists supported by the National Institutes of Health have achieved a significant step forward, eliciting broadly neutralizing antibodies (bNAbs) to HIV by immunizing calves. The findings offer insights for HIV vaccine design, and support further study of modified bovine antibodies as HIV therapeutics or prevention tools in humans, scientists reported in a paper published online in the journal Nature.

Researchers have observed that about 10 to 20 percent of people living with HIV naturally develop bNAbs to the virus, but usually only after about two years of infection. These bNAbs have been shown in the laboratory to stop most HIV strains from infecting human cells, and to protect animal models from infection. However, scientists have so far been unsuccessful in prompting the human immune system to produce bNAbs through immunization. Further, while bNAbs isolated from people with HIV infection have demonstrated promise in primate studies and have entered human studies for HIV prevention and treatment, questions remain about whether effective antibodies could be produced rapidly and at a scale suitable for widespread distribution.

In their study, the researchers injected HIV immunogens into the flanks of four calves and waited for their immune systems to respond. All four cows developed bNAbs to HIV in their blood as rapidly as 35 to 50 days following two injections. This immunogen – a BG505 SOSIP trimer – can elicit HIV bNAb responses consistently and rapidly.

While bovine bNAbs are not likely suitable for clinical use in humans in their current form, exploring this rapid production may help answer important research questions.

The TRSI investigators isolated specific antibodies from the immunized calves to study their properties. One of these antibodies is particularly potent, and binds to a key site that HIV uses to attach to and infect immune cells. Called NC–Cow 1, it neutralized about two–thirds of a panel of diverse HIV isolates. This activity is somewhat similar to bNAbs isolated from humans, such as VRC01, an agent currently in clinical trials as an HIV prevention tool that neutralizes 90 percent of HIV strains but is less potent.

“A minority of people living with HIV produce bNAbs, but only after a significant period of infection, at which point virus in their body has already evolved to resist these defenses,” said Dennis R. Burton, PhD, a lead author on the study, director of the NIH’s Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery and scientific director of the IAVI Neutralizing Antibody Consortium at TSRI. “The potent responses in this study are remarkable because cattle seem to produce bNAbs in a relatively short amount of time. Unlike human antibodies, cattle antibodies are more likely to bear unique features and gain an edge over complicated HIV immunogens.”

HIV researchers previously discovered that bNAbs isolated from people living with HIV for many years tend to have longer versions of a looped region called HCDR3. These extended loops help to penetrate sugar molecules on the surface of HIV, enabling the high performing antibodies to reach and recognize concealed regions of HIV proteins and neutralize the virus. The researchers note that a promising approach to HIV vaccine development may be to promote the human immune system’s development of long HCDR3 loops.

Researchers may also explore mimicking or modifying the potent isolated bNAb or those like it to develop experimental antibody–based HIV therapeutics and prevention tools, as well as treatments for other pathogens that have evolved to avoid human antibody responses.