What’s behind a resurgence of mumps in the United States?

{***Pause/Music***}
{***Amie***}

What’s behind a resurgence of mumps in the United States?

{***Yonatan Grad Soundbite***}
(What caught my eye was that these were cases in a highly vaccinated population. As opposed to measles outbreaks over the past few years which have been predominantly in populations where there has been insufficient vaccination to provide herd immunity. These mumps outbreaks were taking place in highly vaccinated groups.)

In this week’s episode: new research shows that effectiveness of the mumps vaccine appears to wane over time. We’ll speak with one of the study’s authors about the findings, and why it may be necessary to consider changes to vaccination schedules.

{***Pause/Music***}
{***Amie***}

Hello and welcome to Harvard Chan: This Week in Health. It’s Thursday, June 14, 2018. I’m Amie Montemurro.

{***Noah***}

And I’m Noah Leavitt.

{***Amie***}

In this week’s episode we’re focusing on mumps: a highly contagious, viral disease that is often spread through infected saliva.

{***Noah***}

For most of the 20th century mumps was widespread in the United States—with an estimated 186,000 cases reported each year.

But in 1967, the U.S. launched a vaccination program, which led to a more than 99-percent decrease in mumps cases across the country.

{***Amie***}

Eventually, the mumps vaccine was combined with those for measles and rubella to form the well-known measles, mumps, and rubella—or “MMR” vaccine.

{***Noah***}
After recommendations for children to receive a second vaccine dose were issued in 1989, sustained reductions in mumps cases led to optimism that vaccination could eventually eliminate the disease.

{***Amie***}

But since 2006, there has been a resurgence of mumps in the United States—including several outbreaks on college campuses.

{***Noah***}

What makes these outbreaks notable is that they’ve occurred among vaccinated young adults.

And now new Harvard Chan research is shedding light on why we may be seeing more cases of mumps.

{***Amie***}

The research, from Yonatan Grad, assistant professor of immunology and infectious diseases at Harvard Chan School, and Joseph Lewnard, postdoctoral research fellow at Harvard Chan School’s Center for Communicable Disease Dynamics, finds that the effectiveness of the mumps vaccine appears to wane over time.

{***Noah***}

The findings suggest that, in addition to the currently recommended two doses of mumps vaccine in childhood, a third dose at age 18 or booster shots may help sustain protection among adults.

I spoke to Grad about the findings, and how this research may affect vaccination policy moving forward.

We also touched on a separate study led by Grad, which showed that a person’s immune history with the flu can impact the effectiveness of that vaccine.

But first, I began our conversation by asking him to explain a little more about the history of mumps in America.

{***Yonatan Grad Interview***}

YONATAN GRAD: Prior to the introduction of the vaccine in the late 1960s, early 1970s, mumps was basically a rite of passage of childhood. The vast majority of people were infected, with the age of infection usually between 5 and 9. Once the vaccine was introduced, there’s a huge drop in infections– over 99%.

And there was a little bit of a bump in the late 1980s, early 1990s. After that bump, there was the introduction of a second dose of the mumps vaccine, which was packaged together with measles and rubella in what we call MMR. With the two doses of MMR, the first given between the age 12 to 15 months, and the second between the ages of 4 and 6 years before entering elementary school, the incidence of mumps dropped to just a couple hundred of cases reported to the CDC each year from the US.

Then, starting in 2006, we saw an outbreak in colleges and universities. The incidence then dropped again, and we saw a resurgence over the past few years. The cases reported to the CDC in 2016 exceeded 6,000 cases. And we’re around 5,600 cases in 2017.

That’s really when we saw the resurgence that got me interested in the question of what’s going on. And for me, that was really driven by reports of outbreaks at Harvard, where what caught my eye was that these were cases in a highly-vaccinated population. As opposed to measles outbreaks over the past few years, which have been predominantly in populations where there has been insufficient vaccination to provide herd immunity, these mumps outbreaks were taking place in highly-vaccinated groups, like at Harvard College and University.

This seemed to me a really interesting question. It suggested one of two possibilities. One, that there is a new strain of mumps virus that’s circulating that escapes from the pressure provided by the vaccine. Or that there is waning vaccine-induced immunity. And so those were the two hypotheses that we set out to address.

NOAH LEAVITT: And so, what this paper found is that indeed, the immunity of the vaccine appears to wane over time. So, can you kind of explain what your findings were in that regard? And then maybe why this other hypothesis about new strains of mumps maybe didn’t pan out.

YONATAN GRAD: What we did was to look at a bunch of studies from the literature and use a meta-regression model to estimate the rate of waning. And what we saw was that it looked like there was a duration of immunity conferred by the vaccine.

So, we often think of vaccines as conferring lifelong, sterilizing immunity, that once you get your vaccine, you’re protected, and you’re protected forever. But that’s not what we saw. And we saw that it seems like there is protection, but that it actually decreases over time with a rate such that around 25% of people will lose their protection after 8 years and 50% after about 19 years.

And that tempo, when we used a model to look at the epidemiology, is actually consistent with what we’re observing, both with the outbreaks in the late 1980s, early 1990s, when there was just one dose of the vaccine, and then also consistent with what we see with the outbreaks in the college-age populations subsequently after the introduction of two doses.

When we looked at what would happen if there were, in fact, a new strain of mumps, we saw that the epidemiology is not really consistent with that for a couple of reasons. If it were to look like mumps used to look in the pre-vaccine era, which is what you’d imagine if there was a strain that had escaped from the vaccine pressure, then you’d expect many more cases, and you’d also expect to see them in younger populations. Again, with a circulation that’s more consistent with what mumps used to be like.

NOAH LEAVITT: Do we have a sense of why that immunity tends to wane over time? Is that just the fact of vaccines, and this is how the mumps vaccine tends to work?

YONATAN GRAD: It is a great question, and one that I’m really interested in. It seems as though some vaccines, like measles vaccine, confer a stronger and longer-lasting immunity. Why do some vaccines last a long time and some vaccines a short time? I think this is a super interesting question that I don’t know the answer to. I’m not sure that anyone does. But it is one question that I think is very interesting from the basic biology and immunology.

There are some vaccines where we’re used to getting boosters. Things like tetanus, where you’re supposed to get a booster every 10 years, suggesting that there’s a protection that wanes over time. And then there are others, again, like measles, where you get your first couple of doses as an infant or in early childhood, and then that seems to last for a while.

There are interesting factors there that we don’t totally understand. Sometimes vaccines are given with adjuvants in order to help boost the immune response and the duration. Why those work, I think, is also a little bit of a mystery. So, this gets into an area of active and extremely fascinating research.

NOAH LEAVITT: I believe it was that on average, the immunity tends to wane after about 27 years. Is that 27 years important at all? And does that maybe offer any clues to research going forward?

YONATAN GRAD: It’s important, at least in the sense that it sets the tempo and helps explain the observations of why we’re seeing the outbreaks in the populations that we’re seeing them currently. And I think that that helps to direct us to think about the next question, which is, how do we respond to these outbreaks? Does it warrant reconsideration of the vaccine schedule?

Currently, the Advisory Committee on Immunization Practices, or the ACIP, recommends that a third dose of MMR, or Measles, Mumps, Rubella, be delivered in the context of high-risk populations in outbreaks or in outbreak settings. And whether we should be thinking about doing a general booster prior to college or other types of alterations to the schedule, I think, is up for debate.

Certainly, this is something that warrants further investigation. We don’t know, for instance, whether the immunity conferred by vaccination in young adulthood would have the same tempo of waning immunity as the vaccine confers from doses in early childhood. It could be that getting a dose of MMR as an 18-year-old lasts a much shorter time. It could be that it lasts a much longer time.

But there is some data to suggest that at least the antibody titers decrease rather quickly. We need to figure that out and see whether, in fact, the protection is sufficient to carry you through the high-risk times in colleges and universities and use those data to help guide recommendations for immunization.

NOAH LEAVITT: Would the next step be something like running a study where you give a population a booster shot before they go to college? I mean, so what would be the next step from a research perspective?

YONATAN GRAD: Yeah, so I think that there are a couple of steps. One is to look at the immune responses in this population over time. And the other is to think about what kinds of trials could we put together to estimate the effectiveness of the vaccine in this population, and in protecting against mumps outbreaks?

NOAH LEAVITT: For people maybe who aren’t familiar, they’ve just heard of mumps, but the fact of why students in college are so much more likely to see an outbreak of mumps, I mean, what is it about the disease?

YONATAN GRAD: So, mumps virus is transmitted through respiratory droplets. And we think that the close proximity of students in colleges helps to promote its spread. So often, in college and university outbreaks, we see it in teams, sports teams, or in dormitories, suggesting that the transmission really is promoted by close contact.

There have also been outbreaks in other populations. So, in 2009, 2010, there’s an outbreak in an adolescent boys in yeshivas in Brooklyn, where, again, there is close contact, suggesting something about the nature of transmission. And similarly, recently, in Arkansas, there was an outbreak in a population from the Marshall Islands. And there, as well, it’s a community that is very tightly-knit. And again, suggests that close contact, cohabitation, and so on promotes the transmission of mumps virus.

NOAH LEAVITT: And I think it’s probably important to clarify– I like to do this whenever vaccines come up. But I mean, this research isn’t showing that the mumps vaccine is unsafe in any way. It’s still recommended to get your mumps vaccine. It’s just looking at the effectiveness over the long term.

YONATAN GRAD: Oh, absolutely. And in fact, the mumps vaccine has been extraordinarily effective in reducing mumps incidence over time. It’s absolutely a success story. And this is not an indication at all about it being a dangerous vaccine. Far from it, it’s incredibly safe. These are studies that explain why we’ve been seeing a little bit of a resurgence of mumps.

NOAH LEAVITT: Another study you recently did with the University of Chicago looked at the flu vaccine. So, it’s interesting to me that– I mean, is this kind of an emerging area of research, I guess, looking more critically at the way vaccines are administered, and maybe their effectiveness? Is there a reason why we’re seeing more research in this area?

YONATAN GRAD: I think there has been a lot of research in this area, even going back decades to the time when these vaccines were first being developed. We now have more tools with which to study them, and with which to understand why they work and when they don’t work that will facilitate, I think, putting together the next generation of vaccines and vaccine administration strategies, that will, I hope, promote even greater effectiveness than what we’ve seen. I think it’s through these kinds of studies that we really will be able to advance the field.

NOAH LEAVITT: Looking down the line, based on the research you and other people are doing, what would a future vaccine strategy look like that’s maybe informed by this kind of research? How might what we’re used to now change in the future?

YONATAN GRAD: One possibility, as we’ve talked about, is the notion of a booster shot. Another possibility is to explore, are there alternatives to the timing for the two doses of MMR that we’re using currently? Would 12 to 15 months plus another shot maybe instead of between ages 4 to 6, then moving it, perhaps, to around age 11, what impacts would that have? So, there are a variety of different possibilities that we can imagine for altering the vaccine schedule.

Another possibility, of course, is coming up with a new vaccine. Are there ways to develop vaccines for mumps that are longer-lasting in the immunity that they confer. That is, I think, another interesting possibility. So, a next generation mumps vaccine.

Interestingly, one of the other vaccines tied together with mumps in its package, rubella, was replaced soon after the first MMR was introduced. So, the reason why it’s called MMR II is actually because the rubella vaccine that was initially packaged together was replaced by a second one.

That second one, which was developed by Stanley Plotkin, showed that it was more immunogenic, meaning it could elicit more of an immune response, and that that immune response was no longer-lasting than the original rubella vaccine that was packed together as MMR. So, I think there’s a historical precedent for updating these vaccines with ones that are more able to elicit an immune response, and an immune response that lasts a longer time.

NOAH LEAVITT: I mean, it seems like you’re kind of saying is that the understanding that vaccines are kind of a dynamic thing. I think people– they’ll see in the news, oh, this year, the flu vaccine wasn’t very effective. But I think people need to understand, like you said, that there will always be evolution in vaccines and their effectiveness.

YONATAN GRAD: Absolutely. And on the topic of flu, people are extremely interested in coming up with next generation flu vaccines. One of the big targets is what we call a universal flu vaccine. Rather than having to update the flu vaccine every year, if we had a vaccine that could elicit protective antibodies or immunity against all flu strains, that would, of course, be much better.

And in the recent budget passed by Congress, there’s money allocated towards the research and development of a universal flu vaccine. So, this is now a topic that, I think, is gaining not only research interest, but now funding support, as well.

{***Noah***}

In addition to his work on mumps and flu, Yonatan Grad also studies gonorrhea and the growing threat of drug resistance.
I asked him to explain why this is an important area of focus for public health in the years ahead.

{***Yonatan Grad Soundbite***}

YONATAN GRAD: Gonorrhea is a major public health problem. There are over 400,000 cases reported each year in the US, with a true incidence that is estimated to be at least double that, in part because there is asymptomatic infection.

And gonorrhea has become progressively more antibiotic resistant. Recently, there was a report of an outbreak in England of gonorrhea that has high level of resistance to azithromycin, which is one of the two drugs that is part of the dual treatment for gonorrhea. And it’s really a last-line therapy. So, as we see resistance, we’ve got a pretty big problem.

There was a report last year from a vaccine trial for Neisseria meningitidis type B– this is a meningococcus which can cause meningococcal meningitis. And it showed that it appeared to have some protective effect against gonorrhea infection. And so now, the vaccine manufacturers for the MenB vaccine are interested in exploring the possibility of doing a vaccine trial to see if it does, in fact, protect against gonorrhea, as well, or to what extent does it protect. So, I think that is going to be one really interesting area.

A last point on that– the notion there is that a vaccine against gonorrhea infection may also be helpful for antibiotic resistance in gonorrhea. More broadly, people are really interested in the impact of vaccines on issues of antibiotic resistance.

You can imagine that for influenza, for example, when you’re vaccinated and you don’t get flu, that protects you not only against influenza, but also against the possibility of being inappropriately prescribed antibiotics when you get sick. And so, these vaccines have a dual effect. They both protect you against the viruses and against inappropriate antibiotic prescribing that could promote antibiotic resistance generally.

So, there’s also now a lot of interest in the use of vaccines as approaches to help prevent the problem of antibiotic resistance. And I think that’s an area of increasing research and interest, as well.

NOAH LEAVITT: That’s really interesting. So basically, using vaccines, as you said, kind of prevent, well, maybe overall about use, but also the incorrect use of antibiotic.

YONATAN GRAD: Correct. People are also interested in using vaccines to target antibiotic-resistant bacteria. So, there are a few different strategies that are starting to link two areas that I’m interested in, which is both vaccines and also antibiotic resistance.

{***Noah***}

Thank you to Yonatan Grad for taking the time to chat with us about his research into mumps, the flu, and gonorrhea.

{***Amie***}

That’s all for this week’s episode.

Coming up next week: Banning trans fats.

{***Noah***}

On June 18, all American food manufacturers will have to eliminate trans fats from their products.

We’ll examine how these harmful fats become so ubiquitous in our food, and the decades-long battle to remove them from our food supply.

{***Amie***}

In the meantime, a reminder that you can always find our old episodes on Soundcloud, iTunes, Spotify, or wherever else you get your podcasts.