A major impediment in trying to develop vaccine candidates that can induce potent and broadly neutralizing antibodies is time. While all antibodies mature to some degree, the bNAbs uncovered from HIV-infected individuals in the chronic stages of disease take much longer to develop and follow much more convoluted developmental pathways. It takes several years of continuous stimulation by the infecting virus to drive mutations or changes in the bNAbs so that they can bind tightly to their targets, a process scientists refer to as affinity maturation (see VAX Jan. 2011 Primer on Understanding Advances in the Search for Antibodies against HIV). These bNAbs also typically have a long heavy chain complementary determining region 3 (HCDR3) that allow the antibodies to bind more strongly and to target more epitopes on the surface of HIV.
Until recently, many scientists were convinced that antibodies capable of preventing HIV infection could not be elicited through vaccination. But the discovery of dozens of potent broadly neutralizing antibodies (bNAbs) and the elucidation of some of their structural targets on HIV’s surface protein—the Envelope glycoprotein trimer that all bNAbs target—have revealed weaknesses that researchers believe can be exploited for both drug and vaccine development.
Scientists still do not know how the prime-boost regimen used in the R144 trial worked, but an ongoing analysis of nearly 1,000 genetic sequences from 110 HIV-infected recipients across the vaccine and placebo arms of the trial strengthen the theory that the candidate is applying selective pressure against a vulnerable region of HIV’s Envelope protein known as the V1/V2 region.
It’s been almost three years to the day that the surprisingly upbeat results from the RV144 trial in Thailand, which demonstrated the first and thus far only evidence of vaccine-induced protection, hit the newsstands and airwaves and re-energized the field. Yet a series of ambitious efforts set forth not long after to try and improve upon the modest 31.2% efficacy seen in the trial of 16,000 at-risk men and women from Thailand—and perhaps see a candidate to market—have been tempered by the realities of the ground war.