A need for speed

Scientists look to natural infection to provide clues to optimize vaccine design — but it can take years, and much tweaking, before the immune system creates the kind of broadly neutralizing antibodies that could actually block HIV infection.

“When a human is already infected, they don’t control virus — it’s too late. And so [broadly neutralizing antibodies] are really a response to the replicating virus and the evolution of the virus,” said Overbaugh. In order to be practical, an HIV vaccine (like all the other vaccines currently available) needs to trigger an effective response within months, not years.

A vaccine hasn’t done its job if it just prompts the immune system to spit out antibodies. As the immune system becomes more acquainted with a virus, antibodies undergo a tweaking process known as somatic hypermutation that enhances their ability to bind to, and ideally block, the pathogen.

Broadly neutralizing antibodies from adults “have extensive somatic hypermutation. And if you look at vaccines that have worked [against other viruses], no vaccine has ever elicited that level of hypermutation,” said Overbaugh. “As we currently understand the process in adults, you might have to vaccinate, vaccinate, vaccinate — for years.”

That’s one reason why the results from the infant samples are so exciting — not only do the broadly neutralizing antibodies arise quickly, but it didn’t take much tweaking to produce them. The results give hope that a relatively simple path to fast and effective vaccine response exists.

A different path

The current work builds on previous findings from Overbaugh’s group showing that, unexpectedly, broadly neutralizing antibodies could be generated early in life. The team drew on samples taken during a breastfeeding study conducted with the Kenya Research Program prior to the advent of antiretroviral drugs that could protect infants from being infected through breastmilk.

In the current study, Overbaugh and first author and graduate student Cassandra Simonich decided to look more closely at the broadly neutralizing antibodies produced by the infants. It wasn’t clear how structurally similar they were to adult-derived broadly neutralizing antibodies or even if infant antibodies latched onto the same areas of HIV.

Simonich examined the antibody responses from one infant in particular, who was HIV-negative at birth but infected by four months of age. She and the team found, importantly, that more than one antibody contributed to the HIV neutralizing activity of the infant’s blood plasma, in what’s known as a polyclonal response.

All the adults who have been studied so far have produced antibody reponses dominated by a single specific antibody, explained Overbaugh. Polyclonal antibody responses, in contrast, are harder for viruses to elude, making them more likely to protect against a wider range of variants. “I think for a vaccine we’ll do way better if we can elicit a polyclonal response,” she said.



Additionally, the team found that infant broadly neutralizing antibodies had gained their HIV-blocking abilities without exhaustive rounds of somatic hypermutation, which theoretically would shorten the time needed to generate a broadly neutralizing response.

Understanding where antibodies bind — and block — HIV provides clues to what the immune system is responding to during infection — and what a vaccine could mimic. When Simonich and Overbaugh zeroed in on a specific antibody from their sample, they found that, like many adult-produced broadly neutralizing antibodies, it locked on to a particular section of the envelope protein covering HIV. But studies in collaboration with Dr. Kelly Lee’s group at the University of Washington indicated that, unlike adult antibodies, the infant-generated antibody bound a little differently, again suggesting a different path from infection to protective response.

Charting next steps

While the broadly neutralizing antibodies produced by infants suggest that a fast-acting, effective HIV vaccine could be attainable, the path to that vaccine remains to be charted. It’s still not clear whether the infant antibodies differ due to differences in the types of HIV variants infants encounter or because of unique characteristics of infant immune systems.

“One of the things we knew from our earlier studies is that the viruses that got transmitted to infants had to go through this bottleneck that was shaped by the mom’s antibodies, because the virus that was transmitted had to escape the mom’s antibodies,” said Overbaugh. In this case, infants could be seeing a different spectrum of HIV variants than adults.

If it turns out that infant immune systems have a unique ability to produce broadly neutralizing antibodies within a short time frame, it may be that vaccinating in early childhood is the key to producing protection.

Overbaugh and her team are currently confirming these results in another infant, whose strain of HIV has become the foundation of many structural studies of HIV’s various components. Capitalizing on the fact that they have samples from infants prior to infection (a rare resource in adult studies), the team will also examine the process of antibody fine-tuning during the course of infection. This will give them the opportunity to compare the original antibody to its final, HIV-neutralizing form.

They are also parlaying these insights to develop preclinical models of HIV infection that may also produce a fast, protective response.