Findings from a new National Institutes of Health study may have important implications for flu vaccine development.
Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) recently studied the way our immune systems naturally produce influenza-fighting antibodies, with findings that may help in the development of a novel flu vaccine.
The flu vaccine is designed to trigger the immune system to produce antibodies to fight antigens, or surface proteins, of the influenza virus. Hemagglutinin and neuraminidase are the two surface proteins of the virus targeted by the flu vaccine, and antibodies bind to antigenic sites to neutralize the virus and stop the spread of infection. The Centers for Disease Control and Prevention (CDC) notes that the challenge in creating an effective seasonal flu vaccine is that the virus is prone to antigenic shift and drift—gradual and sudden changes to the hemagglutinin and neuraminidase—which effectively make influenza a moving target. Antibodies effective against one kind of flu virus do not recognize the new antigens, and so, a vaccine that works one season may not work the next.
In a new study published in the journal mBio, researchers at the NIAID — a division of the National Institutes of Health – investigated the antibodies produced not just against the head region of hemagglutinin, but also its stem. The surface protein’s shape is comparable to a lollipop, and current vaccines target the top or head. While the head is the region that sees antigenic shifts, scientists have observed less change at the stem, and so, targeting that part of the virus has been a focus for researchers looking to create a vaccine that offers broader protection across more flu seasons. Individuals naturally produce stem-targeting antibodies when infected with the flu, but also have pre-existing levels of these antibodies.
The new study investigated how pre-existing and infection-fighting antibodies work against a flu infection. In a trial, 65 healthy volunteers between the ages of 18 and 50 were infected with a 2009 H1N1 influenza virus and studied while they stayed in an isolation and infection control unit. Researchers found that all individuals in the study had baseline levels of anti-stem antibodies at varying levels; 64% of the volunteers had increased levels of the antibodies following flu infection, however, those with higher levels at baseline saw a smaller increase of the antibodies. Volunteers with higher levels of anti-stem antibodies had less viral shedding when they get the flu, though they did not have fewer or less severe signs of illness.
These findings could potentially be used to inform efforts to develop a more effective, universal flu vaccine. The lead of the study, NIAID’s Matthew J. Memoli, MD, spoke with Contagion ® about the study and its implications:
Contagion ®: How do your findings move the needle on the development of a new, and even “universal”, flu vaccine?
Dr. Memoli: If you look at a number of the products in the pipeline in terms of universal vaccines, the things people are working on and have been publishing about over the last few years, you will note that many of them target inducing what are called stalk or stem antibodies, which are antibodies to the hemagglutinin protein in a different region than what we normally target. Our current vaccines target the generation of antibodies to the head, which is the part that we say shifts and drifts and changes, and this newer strategy is to target the stem.
The idea is that this stem is conserved across many different subtypes and strains of influenza, so that if you’re able to generate antibodies against that stem, that they would be protective against many or most strains or subtypes of influenza. This strategy has been pursued very heavily, and quite a number of universal vaccine work has gone into doing this. What hasn’t really been investigated well up to this point is, do human beings make these antibodies naturally? And if they do, what function do they play in immunity to flu?
Previous to this study that we’ve published, there were a few small studies showing that people do make some of these antibodies, but they were all one-off studies, so you’ll see papers with maybe 10 or 15 people where they see the antibodies, but they aren’t really able to investigate what role they’re playing in immunity.
I had a unique opportunity in that I’ve been doing these influenza healthy volunteer challenges or exposure studies, where we take healthy individuals and we give them flu to learn more about how flu works and immunity against flu. We had a unique opportunity to look at this question, so we took one of the studies that we had completed previously and we went back and looked at their antibody titers against the stem, and because we have this controlled environment we were able to look at their antibody titer against the stem before exposure to flu, what it was after exposure to flu, and what actually happened to them when we exposed them to flu. That’s what this paper is about, is trying to understand what role these antibodies play in protection or reducing the impact of influenza on a person.
We think this gives us a lot of new information to help us understand stem antibodies a little better, and what I’m hoping is that those who are working on these stem antibody strategies will take this information and think about the issues that may arise with these vaccines. What we saw in this study is that there does seem to be a limit to how high a human being can develop titers against the stem, and that may impact how efficacious a vaccine like this would be, so that would be something to try to overcome. It may be that a vaccine can induce higher levels of antibodies than an infection, but it’s something that has to be considered.
At least in this study, we did not see a strong correlation with reduction of clinical illness when these antibodies were present. We saw a reduction in shedding, in the detection of virus, but not a reduction in clinical illness, and it looked very similar to what we see with people with high head antibody titers generated with current vaccines. So it’s possible that a stem antibody vaccine may have similar efficacy to a head antibody vaccine, although I can’t say that for sure. Preexisting, naturally-occurring neck antibodies seem to play a role in protection similar to that of the head. It’s something to think about, that just targeting stem alone may not be enough for a universal vaccine. We really may have to include multiple targets and involve multiple parts of the immune system to protect against flu universally, rather than just focusing on one very specific piece.
C: So, targeting the stem won’t bring us a flu vaccine that’s 100% effective?
M: Yes, and I think part of the problem with current vaccines is that we are just targeting one thing, and so coming up with another vaccine that only targets one thing may not solve the problem. We need to include different parts of immunity to flight flu because flu immunity is complex, so we need to think about that when we design these vaccines. It’s not that the stem antibodies won’t play a role in a universal vaccine, it’s that they probably won’t play a role alone in a universal vaccine. They’ll need to be part of an overall strategy.
What we don’t know right now about the stem is if we do start introducing a vaccine that targets the stem, will the stem start to drift like the head? It’s possible that it might, and we don’t know the answer to that question yet, and there are some studies that may be coming out in the future that might help answer this.
C: If people with more stem antibodies have less viral shedding, is targeting the stem a good public health strategy in terms of creating a vaccine that makes sick people less contagious?
M: It’s hard to say. That may be true, and while stem could play a role as part of a vaccine but it doesn’t solve the problem. If I look at preexisting head antibody, that also reduces shedding, so what we’re doing now with current vaccines probably already is reducing shedding to some degree though it doesn’t completely protect against illness. There is this public health aspect of trying to reduce contagiousness, but the overall cost of flu — healthcare costs or the social cost of how people feel – is the clinical illness. Those are the things that we need to impact.
We need to keep people alive and from landing in the hospital, so to me the ultimate goal of the universal vaccine is it needs to prevent illness or reduce the illness to a level that is reasonable. If we could make all influenza infections like the cold, that would be a lot better than having thousands of people die each year from the flu.