Dr. Julie Overbaugh mines decades-old samples to find new clues to effective immune responses to HIV
When it comes to building an HIV vaccine, important lessons can come from unexpected sources. Take babies.
In the early 1990s, Dr. Julie Overbaugh, an HIV researcher in Fred Hutch’s Human Biology Division, was one of the few laboratory scientists who built collaborations with clinicians and epidemiologists to examine HIV transmission in areas hardest hit by the pathogen. As part of the nascent Kenya Research Program, she teamed up with other researchers to examine whether breast feeding could transmit HIV from infected mothers to their uninfected infants.
In the days before broad use of antiretroviral drugs, the group demonstrated that HIV could indeed jump from mother to child via breast milk. Their findings, showing that infants exposed to breast milk had almost double the risk of infection, helped inform prevention efforts.
Now, samples taken decades ago from these infant studies are revealing new insights into what may constitute an effective immune response against HIV — and, perhaps, giving hints as to how to create an effective vaccine.
Natural vaccine mimics
Antibodies, proteins produced by our immune systems that protect against infection, are thought to be the key to an effective vaccine. Researchers developing HIV vaccines are hoping to generate the right kind of antibody that protects against HIV infection. And infants, it turns out, mimic vaccination. The antibodies that babies receive from their mothers in utero circulate in their blood for months after they are born, similar to the antibodies a vaccine might promote.
For those infants who are HIV-negative at birth, “their [HIV-positive] mothers have antibodies they passively transfer, so it’s kind of like the infants are vaccinated,” explained Overbaugh.
During the period before antiretroviral drugs existed, infants breast-fed by HIV-positive mothers didn’t always contract the virus. Overbaugh decided to see what qualities of maternal antibodies correlated with a longer time before transmission and a less intense infection when it did occur.
When they looked at samples of breast milk and blood drawn more than 20 years ago, the researchers found that children whose mothers produced a specific type of cell-killing antibody were less likely to die of HIV infection. These antibodies help kill infected cells through what’s known as antibody-dependent cellular cytotoxicity, or ADCC.
“To my knowledge, the study is the first in humans to show that cell-killing antibodies, when present at exposure, have a protective effect against HIV,” said Overbaugh. Notably, the only HIV vaccine trial that’s so far shown any protection against the virus, known as the Thai trial, also triggered ADCC.
Jump-starting broadly neutralizing antibodies
Broadly neutralizing antibodies are the holy grail of HIV vaccine design. HIV is endlessly mutating and changing the structures that antibodies bind. Antibodies that can only bind and block a few strains of the virus won’t be very effective against infection. Broadly neutralizing antibodies are capable of warding off a wide range of HIV variants. A vaccine that generates broadly neutralizing antibodies will theoretically protect better against HIV infection than one that generates antibodies that block only a few HIV variants.
Adults infected with HIV can produce broadly neutralizing antibodies — eventually. It requires a several years–long maturation process to sufficiently hone antibodies so that they block a slew of HIV variants.
“As we currently understand the process in adults, you might have to vaccinate, vaccinate, vaccinate — for years” to achieve broadly protective antibodies, said Overbaugh.
But vaccines need to produce protective antibodies within months, not years. Enter the infant immune system. Overbaugh and her team found that indeed, infants could produce broadly neutralizing antibodies against HIV. They also saw that the HIV-blocking proteins arose within the first year of infection and needed much less honing than adult antibodies.
“We could 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,” said Overbaugh.
Decades after helping save babies born to HIV-infected moms, the Kenyan research samples may offer clues to developing a vaccine that, alone or in combination with other candidate vaccines now in development, could help prevent infection across all age groups or even help reduce the severity of HIV in those already infected. That’s a giant impact from the tiniest of research volunteers.
By Sabrina Richards