The hunt for HIV correlates of protection with Nicole Frahm

Vaccine and Infectious Disease Division

The hunt for HIV correlates of protection with Nicole Frahm

Nicole Frahm

Nicole Frahm, PhD is originally from Germany and grew up in Brazil, and is therefore a self-described ‘multicultural.’ In addition to being fluent in German and English, she speaks Portuguese (although she says it is a bit rusty) and can get by with Spanish and Italian. She has been at VIDD for 6 years and refers to this as her “dream job.”

The importance of developing an effective HIV vaccine cannot be overstated. The statistics are sobering: over 35 million are infected worldwide; approximately 2 million people are infected each year; the estimated death toll from the virus thus far is 36 million; around 1.5 million died from HIV/AIDS in 2012; over 700 children become HIV infected each day (

While antiviral medications, prevention education and behavioral interventions have provided help in mitigating HIV progression to AIDS, a vaccine is the Holy Grail. VIDD Associate Member Dr. Nicole Frahm, housed at the HIV Vaccine Trials Network (HVTN), studies people’s immune responses to HIV in order to inform vaccine design.

“We are trying to find an HIV vaccine,” Frahm said. “It is the best tool for halting the HIV pandemic.”

Frahm oversees the HVTN’s laboratory program here in Seattle, which focuses on the cellular immune response to HIV infection. The difficulty in vaccine research from the laboratory perspective is that the field really doesn’t have a good handle on what to look for. A major focus of the lab program is to identify correlates of protection (CoP), which are immune markers that indicate protection from infection. RV144, the first HIV vaccine trial to show protection, allowed the ability to propose CoPs.

“Trying to pinpoint what immune responses were responsible for that partial protection is a big part of what we do,” Frahm explained. “We were partially successful with RV144 by identifying a few immune responses that seemed to be associated with a decreased risk of infection.” 

HIV virion

But because the efficacy wasn’t very strong and the associations with these immune responses weren’t very strong, those data are more hypothesis generating than really confirming definitive CoPs. What the field needs now is another trial that shows protection to confirm that the same immune responses from RV144 can be protective, thereby translating to other vaccines. 

One theory is that the human population may have a universal CoP; inducing a certain type of immune response that protects irrespective of which vaccine induced it. There are other theories postulating that different vaccines may work by different mechanisms, so that each vaccine would have its own correlate. But until another trial shows protection, it is going to be nearly impossible to ascertain the answer. 

Frahm is currently investigating whether the RV144 CoPs turn up in the HVTN’s most recent efficacy trial, called HVTN 505, which failed to show a protective effect from vaccination. The idea is to measure the correlates identified in RV144 in HVTN 505. If they’re not present, it would be consistent with the notion that these immune responses relate to protection from HIV infection. However, if these correlates are present in 505 then the conclusion is they were associated with protection in RV144 but not 505.

Gag epitopes recognized by T cells

The number of Gag epitopes the vaccine recipient’s T-cell response targets are grouped into three bins: 0 epitopes (i.e., no T-cell response to Gag); 1-2 epitopes; and 3 or more epitopes. HIV viral load (y-axis) is plotted for 3 time points after vaccination (x-axis) for vaccine recipients who became infected within 1 year. Subjects who were infected with HIV within 1 year post-vaccination (red triangles) had significantly different viral loads depending on the number of Gag epitopes their immune system responded to. Subjects that made T-cell responses to 3 or more Gag epitopes had lower viral loads than those subjects that responded to 2 or less. Red dashed lines.

Adapted from Janes, et al. J Infect Dis. 2013;208(8):1231-9.

To move the field forward, vaccines need to go through the pipeline faster and more efficiently. Efficacy trials have been infrequent and conducted in a manner that has often led to a prolonged time period from study initiation to completion. While RV144 is a landmark study for the HIV vaccine field, it took six years between the initiation of the trial (mid 2003) and the communication of the final results (late 2009).

“We are now in limbo waiting for another trial that shows protection. If the field focuses too much on just the proposed CoPs we already have, they might miss some correlates that are truly important.” Frahm continues, “Because other immune responses might work though a different mechanism, we don’t want to box ourselves in too much.”

In a recent study, Frahm and VIDD colleagues analyzed data from the Step trial, which, like 505, did not show protection from either infection or progression. These post-hoc analyses can determine if the vaccine-induced immune responses present prior to infection were associated with viral load outcomes after infection. Interestingly, they found that certain immune responses were significantly associated with disease outcome; specifically, the breadth of these responses to the HIV protein Gag. HIV has different genes, some genes contain more diverse and some contain more conserved regions that are called epitopes. The ideal situation is that a vaccine will induce HIV specific T-cell responses to more conserved epitopes. In this case, there is a greater likelihood of protection against any circulating strain. The authors found a correlation between responses to multiple Gag epitopes and reduced disease progression, i.e., lower viral loads (Figure). Persons who had no T-cell responses to Gag epitopes had higher viral loads. This is noteworthy because it shows a vaccine-induced immune response can benefit the person even if they get infected. The multiple Gag epitope response didn’t prevent against infection, but slowed disease progression post HIV acquisition.