An HIV vaccine based on how the adult immune system responds to the virus could take a long time to build protection, say researchers, who after looking at how HIV affects infants, suggest mimicking their immune response may offer a better model.
In the journal Cell, researchers led by a team from the Fred Hutchinson Cancer Research Center, Seattle, WA, describe how broadly neutralizing antibodies to HIV can arise in infants within a year after infection – much more quickly than in adults.
Even though scientists have accumulated mountains of information on HIV, the prospect of a protective vaccine remains elusive. For a vaccine to be effective, it must act relatively quickly to trigger an immune response with the right mix of antibodies to eliminate the virus.
Moreover, an effective HIV immune response also adapts to the virus during the infection, and it tweaks its initial antibody response by adding antibodies that have undergone “somatic hypermutation.”
Somatic hypermutated antibodies have enhanced ability to bind to and block the pathogen and form an essential component of a broadly neutralizing response.
In the adult immune system, this process can take years – even decades – to produce an effective, broad immune response that is capable of protection against HIV.
A vaccine that mimics the adult immune response would, therefore, take too long to provide protection.
In their study, the team examined samples taken from infants in Nairobi born to HIV-positive mothers in the years before antiretroviral drugs were developed.
They found that the infant immune system can produce broadly neutralizing antibodies against many HIV variants within a year after infection – and with less fine-tuning than previously thought.
Senior author Dr. Julie Overbaugh leads a lab at the Fred Hutchinson Cancer Research Center that investigates mechanisms of HIV transmission and disease development. She says that in contrast to studies of HIV in adults, this study enabled them to “document a case in infants where a broadly neutralizing antibody developed in a time frame and in a way that is something that we could consider mimicking with a vaccine.”
When HIV infects a human, their body cannot control the virus – “it’s too late,” explains Dr. Overbaugh. Thus, broadly neutralizing antibodies “are really a response to the replicating virus and the evolution of the virus.”
However, to be practical, an HIV vaccine needs to trigger an effective immune response within months – not years.
The new study builds on previous findings that unexpectedly found broadly neutralizing antibodies can be generated early in life.
In that study, the team used blood samples from infants who, with their mothers, took part in a breast-feeding study in the Kenya Research Program. The samples were collected before antiretrovirals were available that can protect infants from becoming HIV-infected through breast milk.
In the new study, the team took a closer look at the antibodies in the infants’ blood. They examined the antibody response of one baby in particular – the child was HIV-negative at birth but was infected by the age of 4 months.
The researchers found the infant’s blood contained evidence of what is called a “polyclonal response.”
Dr. Overbaugh explains that all adults studied so far have produced immune responses that are dominated by a single, specific antibody. Polyclonal responses are much harder for viruses to elude and much more likely to protect against a wider range of variants.
The team also found that broadly neutralizing antibodies in the infant samples had gained their HIV-blocking abilities without exhaustive rounds of somatic hypermutation, which – in theory – shortens the time it takes to produce a broadly neutralizing response.
In another part of the study, the team found that the infant broadly neutralizing antibodies target a different site on HIV to that targeted by adult antibodies – again suggesting a different path from infection to protection.
These results suggest broadly neutralizing antibodies from infants could lead to a fast-acting, effective HIV vaccine. However, the roadmap still needs to be charted, and many questions remain.
For example, do infant antibodies differ because of differences in the types of HIV variants they are exposed to, or because of unique features in the infant immune system?
Dr. Overbaugh suggests perhaps infants are exposed to a different spectrum of HIV variants than adults because those viruses have already been exposed to their mothers’ immune systems, so the ones that pass into breast milk are shaped by the mothers’ antibodies.
However, if it turns out that infant immune systems have a unique ability to make broadly neutralizing antibodies against HIV quickly, then perhaps vaccinating babies is the way to early protection.
The researchers are already doing further research to confirm their findings in blood samples taken from another baby whose HIV variants have led to many studies of the structure of the virus.
They are also taking a closer look at the process of HIV antibody fine-tuning, and hope to deploy any new findings into developing preclinical models of infection that may also produce fast, protective responses.