Understanding Sequential Immunization Strategies

How are researchers using a step-wise approach to try to train the immune system to fend off HIV?

By Kristen Jill Kresge

Antibodies are one of the main ways the body fights off infection. These powerful proteins are also the key to the protection afforded by most, if not all, vaccines. So it is not surprising that HIV vaccine researchers have set their sights on antibodies. However, HIV presents some extraordinary challenges.

One of the challenges is that HIV is constantly changing or mutating in an effort to evade the immune responses the body mounts against it. Many people who are infected with HIV develop antibodies against the virus, but because the virus mutates so quickly, these antibodies are typically ineffective at controlling HIV infection. HIV’s furious mutation also results in the numerous different strains of the virus that are in circulation around a globe. Ideally, a vaccine would be able to protect against the majority of these strains, which is another challenge for vaccine researchers. It takes a special type of antibody to block most HIV strains. Researchers refer to these antibodies as broadly neutralizing because they are capable of inactivating or “neutralizing” diverse strains of HIV.

In recent years, researchers have identified scores of broadly neutralizing antibodies (bNAbs) from HIV-infected individuals. The immune systems of a small percentage of HIV-infected individuals make these antibodies after years of infection. These antibodies have been shown to neutralize most HIV strains in laboratory tests. Scientists are studying these antibodies extensively to learn how and why they develop, and what makes them able to neutralize HIV so well. They also have tested these bNAbs in animals and shown that they can protect against infection. This suggests that a vaccine that induces such antibodies might protect against HIV. Inducing these antibodies through vaccination, however, is a difficult task.

Now, thanks to new technologies and a clearer picture of how these antibodies bind to and interact with the heavily armored and notoriously unstable outer surface of HIV, researchers are developing multiple vaccine components and testing them in sequence to see if they can guide the immune system to make these highly specialized antibodies. Researchers have tested this sequential vaccination strategy in mice and have shown that this step-wise approach can induce antibodies that are able to neutralize some strains of HIV. Although these antibodies are not as broadly neutralizing as the antibodies isolated from naturally infected people, researchers think these studies in mice provide proof that a sequential immunization strategy can induce bNAbs and that this approach should be further optimized and eventually studied in human trials.

Why is sequential immunization necessary?

There are many reasons why bNAbs may be difficult to induce through vaccination. These antibodies only rarely develop in natural HIV infection because the immune cells that give rise to them aren’t that common. And when bNAbs do develop naturally, it usually only occurs after a couple of years of infection. Also, all of the bNAbs that researchers have isolated to date are unusual. These antibodies have many characteristics that make them more sophisticated than normal antibodies.

One of their unique characteristics of these antibodies has to do with their structure. The bNAbs against HIV that researchers have isolated and studied so far have all accrued many changes in their structure that occurred in response to constant exposure to the ever-mutating virus. The changes in the structure of the antibodies make them better able to bind to and neutralize HIV. The more times that the antibody changes or mutates, the more “mature” the antibody becomes, and the better it is at neutralizing HIV.

The process of maturation, through which an antibody mutates and becomes better at neutralizing HIV, is critical to the design of vaccines. Many scientists have hypothesized that multiple different vaccine components (the active ingredients of vaccines that are known as immunogens) would likely be required to guide the human immune system to make such “mature” antibodies. To test this, researchers from several different institutions have developed a series of vaccine immunogens and tested them in mice engineered to have more human-like immune systems. The first immunogens are intended to activate the appropriate immune cells, and the subsequent immunogens are meant to guide the antibodies produced by these cells to undergo the changes that will make them better at neutralizing HIV.

A batch of recently published studies shows that this sequential immunization approach did encourage the antibodies induced by the vaccine candidates to undergo the process of maturation. This approach led to the development of antibodies that were similar to, but not as good at neutralizing HIV as the bNAbs that were isolated from HIV-infected volunteers. Although this was only tested in mice so far, researchers are calling these studies a “significant milestone” in HIV vaccine development.

Of mice and men

Now that researchers have shown that a sequential immunization approach can be used to shepherd the development of bNAbs, they are eager to further refine and optimize this approach. First, researchers want to optimize the vaccine immunogens so that they can induce antibodies capable of neutralizing even more HIV strains. Second, they need to take into consideration that humans have a much more diverse and complex immune system than humanized mice, and so even an approach that is successful in animals may not work as well in humans.

Eventually, researchers hope to advance some of these sequential immunization strategies into early-stage human trials.