Robert Hood / Fred Hutch News Service
Anyone who has been around a baby knows that while tiny in size, an infant has a giant impact. Now, babies may be making their strong influence known in a surprising way – by providing clues on how to create a better HIV vaccine.
Researchers know that a key piece of the puzzle on how to create an effective HIV vaccine will be antibodies, proteins made by the immune system that recognize pathogens like HIV and help ward off infection. But antibodies come in different flavors, and which flavor will be most protective remains an open question.
Dr. Julie Overbaugh, an HIV researcher in Fred Hutch’s Human Biology Division, and her team wanted to identify which ones will be the most effective in warding off HIV. To do so, they decided to turn to a natural vaccine mimic: infants.
During the first few months of life, infants receive maternal antibodies passed in utero and through breast milk. For those infants who are HIV-negative at birth, “their [HIV-positive] mothers have antibodies, so it’s kind of like [the infants] are vaccinated,” explained Overbaugh.
She and her team knew that they could look at the antibodies in infants of HIV-positive mothers who are HIV-negative at birth but continue to be exposed to HIV through breastfeeding. They could compare which antibody types correlated with resistance to infection or better survival after infection. Their work, published Wednesday in Cell Host & Microbe, reveals that a specific type of cell-killing antibody helps curtail HIV infection and could be a critical component to a protective vaccine.
“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.
Most HIV vaccine research has focused on so-called neutralizing antibodies, which prevent infection entirely by blocking HIV’s entry into its target cells. The type of cell-killing antibody that the Overbaugh lab focused on in their study is a bit different. In a process known as antibody-dependent cellular cytotoxicity, or ADCC, these antibodies instead bind HIV-infected cells and trigger the immune system to destroy them. ADCC appears to have contributed to the partial protection seen in the Thai trial, so far the only HIV vaccine to show any protective effect against the insidious virus.
An effective vaccine would elicit the right antibodies to be produced and linger in case a person encounters HIV. Though data from preclinical models suggest that it’s likely “neutralizing antibodies are important, so far there’s no direct evidence in humans showing this,” noted Overbaugh.
The right antibody for the job
Previous work by Overbaugh’s team had looked at ADCC activity in breast milk, and shown that infants who ingested milk with higher levels of ADCC were better protected against HIV.
“But no one had looked at the infant side,” explained Caitlin Milligan, an M.D./Ph.D. student in Overbaugh’s lab and the study’s first author. When Milligan looked at the different levels of ADCC in the blood of breastfed infants who contracted HIV after birth, she saw that babies with higher levels of ADCC survived significantly better than those with lower levels, suggesting that ADCC helped lessen the severity of HIV infection.
Though higher levels of ADCC also tended to protect against infection itself, Overbaugh and Milligan noted that there weren’t enough samples to definitely show a link. The team is hoping to test samples from a second cohort of mothers and infants to see whether they show a similar protective trend. If so, their results will support the conclusion that HIV-directed ADCC may well protect against HIV infection as well as curtail it.
Teaching old data new tricks
Such an experiment could only be done in a world without antiretroviral therapy, and it was. Nowadays, maternal transmission of HIV is nearly nonexistent for those mothers lucky enough to have access to antiretroviral drugs, but 20 years ago researchers were still struggling to design the tools to detect infection let alone ameliorate it. The samples that Milligan and Overbaugh examined were collected in the early 1990s as part of an effort to determine whether breastfeeding raised HIV transmission risk. The far-sighted team running the study was the Kenya Research Program.
Overbaugh had joined the KRP in 1993 as a young faculty member, collaborating with Joan Kreiss at University of Washington and tasked with designing methods to detect HIV infection. KRP scientist Dr. Ruth Nduati, a professor of Pediatrics at University of Nairobi who also collaborated with Overbaugh on the current study, designed a clinical trial to determine whether breastfeeding, compared to formula feeding, raised the risk of HIV transmission to HIV-free infants born to HIV-positive mothers. At the time, no treatment or preventive measures existed and the World Health Organization recommended that HIV-positive mothers breastfeed.
The KRP team not only answered their initial question — yes, breastfeeding transmitted HIV infection, especially during infants’ first few months — but had the foresight to collect samples that would allow them to probe the question more deeply. The generous participation of the Kenyan women more than 20 years ago is still providing new insights that could save even more lives in the future. Because the study cannot be repeated, its results are exceptionally precious.
In the intervening years, technology has advanced far beyond what Nduati and her colleagues originally dreamed and allow today’s scientists to ask even more questions. “We’re cloning antibodies from 20-year-old B cells,” the type of immune cell that produces antibodies, Overbaugh said. Studies of ADCC antibodies from adults hint at what kind of structure the antibodies bind, but Overbaugh’s samples from infants will show whether antibodies in adults and infants focuses on the same structures on HIV. Their team hopes that this will enable scientists to find new ways to design a vaccine mimic.
An eye on vaccines
Overbaugh and Milligan hope the findings provide insights for designing a better preventive HIV vaccine, though it remains to be seen how best to elicit ADCC or create a vaccine that could produce both ADCC and neutralizing antibodies against HIV.
It’s possible that the findings could also contribute to a therapeutic vaccine that helps reduce the severity of HIV’s effects in those already infected, said Overbaugh. She is teaming up with Fred Hutch colleagues Dr. Dan Stone and Dr. Keith Jerome to investigate this possibility. Using a preclinical model of HIV, they plan to see whether ADCC can curtail an active HIV infection by killing the reservoir of infected cells, and removing HIV’s breeding ground.
In developing a vaccine “we’re trying to do better than natural immunity,” said Overbaugh.