Antibody News

In the last two years, several research groups have reported the isolation of a slew of new broadly neutralizing antibodies (bNAbs) that are more potent than the handful of such antibodies that had been known until then. Among them was VRC01, a bNAb isolated by researchers at the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases, which can neutralize over 90% of currently circulating HIV-1 strains (see Raft of Results Energizes Researchers, IAVI Report, Sep.-Oct. 2009). VRC01 and other HIV-specific bNAbs also have an unusually high degree of affinity maturation, which means that they are quite different from the germline version of the antibody that they are derived from (see Vaccines to Antibodies: Grow Up!, IAVI Report, July-Aug. 2010). 

Researchers are now interested in finding antibodies similar to VRC01 from additional HIV-infected volunteers to see how common such antibodies are and how they develop. This work could help researchers understand how to be able to elicit such antibodies with a vaccine. Today, Peter Kwong, chief of the structural biology section at the VRC, described a new way to isolate VRC01-like antibodies by sequencing the antibody genes in millions of B cells per person using 454 next generation sequencing. “From 10 milliliters of blood from any person you have about one million B cells, so you potentially have one million new sequences from 10 milliliters of blood,” Kwong said. The trick, he said, was to find a way to sort the sequences and narrow them down to the relevant ones (for example, ones that show a high degree of affinity maturation), and to then combine the heavy and light chain sequences to generate a functional antibody which can be tested to see if it too is broadly neutralizing. 

This has already resulted in the identification of additional VRC01-like antibodies, showing that the approach works, and will make the identification of such antibodies much less expensive than previous methods that involved isolation of antibodies that bound to a probe. 

While bNAs like VRC01 are very potent, they may not always provide the best protection from HIV if they are used in isolation. At least that was the message from a talk today by Shannon Allen from Tom Hope's group at Northwestern University. She reported that adding the VRC01 bNAb to vaginal mucus from uninfected women inhibited the movement of HIV particles in the mucus; however, in vaginal mucus taken from HIV-infected women, the movement of HIV was even more inhibited (in fact, the HIV particles were not moving anymore at all). 

Hope believes that the stronger HIV movement inhibition observed in the mucus from HIV-infected women may be due to a combination of many different antibodies in the mucus. “Antibodies don’t work as monoclonals,” Hope said. “Antibodies work as swarms.” 

If this turns out to be true, it could mean that a vaccine may have to induce a combination of many different antibodies that don’t necessarily have to be broadly neutralizing. Hope said the candidate vaccine regimen in the RV144 trial may have actually showed a modest protection from HIV infection in part because the RV144 vaccine regimen may have induced a combination of many different antibodies in the mucus. Consistent with this possibility, he added, it appears that the regimen tested in RV144 mostly protected women from heterosexual transmission. 

Still, even if a vaccine could be developed that induces such a combination of antibodies in vaginal mucus, there is one quite obvious limitation. “This will only protect women,” Hope says. “[Men] don’t have any mucus.”