ImmYOUnology

More than just vaccines


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Outbreak or not, vaccine immunology is still exciting

The recent US measles outbreak ended just over a week ago. But with an even larger outbreak ongoing in Sudan, and rising concerns over the possibility of one in Nepal, measles vaccination is still a hot topic globally. (Though for me, viruses and vaccines are always hot topics).

I saw a graph a couple of months ago that shows a huge plunge in measles cases and deaths in the few years leading up to the 1968 licensure of the measles vaccine. The graph actually comes up quickly if you do an image search for “measles graph.” I’ve seen it used to support the argument that the measles vaccine just doesn’t work and is therefore not worth the trouble.

I dug up the primary data used for this graph and made my own (below). It shows that measles cases dropped before introduction of the 1968 vaccine (measles deaths follows the same pattern). But you’ll also see that this plunge occurred two years after the first version of the measles vaccine was licensed in 1963.  I am not a public health expert, but it’s pretty clear that the drop in cases and deaths from measles came after licensure of the initial measles vaccine.

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I did this research to both appease my curiosity and demonstrate that the question of whether the vaccine works on a population scale has been settled for a long time.  That doesn’t mean that on an individual level it’s impossible to get sick even if being vaccinated against measles.

There are many potential reasons one may not respond to a vaccine. These range from very basic reasons, like the vaccine being stored at the wrong temperature or being injected incorrectly, to complex biological reasons that are active areas of ongoing research.  For example, we know that mothers’ antibodies (or immunoglobulins) circulate in newborns for about 12 months. Although these antibodies can protect a newborn from pretty much anything its mom is immune to, they also prevent the child’s own immune system from generating memory responses to the same diseases. Mom’s antibodies can actually cover up viruses and bacteria and hide them from baby’s immune cells. They can also form complexes with bits of virus or bacteria that bind a receptor that shuts down B cells, the cell responsible for making new antibodies. This receptor, called FcγRIIb, is part of a negative feedback system that tells B cells when they’ve made enough antibodies.

All of these possibilities are part of why the CDC recommends two shots separated by at least a month; statistically, getting two shots means you’re covered because the chance that your immune system would miss out twice in a row is very low. Still, the only way to be 100% sure an individual responded to the vaccine is to measure the level of antibodies in the blood that can bind to and neutralize the measles virus. For different viruses, there are different thresholds for the concentration of antibodies needed to protect a person from getting sick. When a vaccine is first tested, antibody levels are monitored to make sure it actually works. After that, it would be too expensive and unnecessary to measure antibodies in every person who receives the vaccine. So, even though two shots should do the trick statistically, there’s always a remote chance the vaccine just didn’t induce a good immune response, and most of the time, no one would be the wiser.

There was such case in New York City back in 2011, in which a woman who had gotten both requisite vaccinations still managed to get sick. The researchers who did this study measured measles-neutralizing antibodies in the woman’s blood and found that she was making a kind of antibody that the body mainly produces the very first time it sees a pathogen. That kind of antibody is called immunoglobulin M (IgM), and it’s a sort of knee-jerk, immature antibody response that keeps the virus at bay as the immune system generates the more mature, “stickier” IgG. So her body was acting as though it had never seen the measles before, even though she was vaccinated twice.  This is not a huge surprise; even after two shots, the failure rate for the measles vaccine is 3%.

What was unique was that she also ended up spreading measles to 4 other people who were also vaccinated (that’s 4 out of a total of 88 contacts).  All of these people made strong IgG responses and none of them spread the virus to anyone else. And, unlike the first case, none of them were hospitalized—even one who was on immunosuppressive drugs. So this study shows that yes, it is possible to get measles and even spread it to others if you’ve been fully vaccinated. It’s an anomaly, but it’s possible. In fact, that’s what made this case so interesting—the fact that it was so unlikely.

With all the variables of human life, it’s a wonder that the measles vaccine works 97% of the time. This study shows that even when it doesn’t work, the measles virus can’t go far if enough people are vaccinated. The strong secondary immune responses of those 4 cases made their illness less severe and reduced their chances of spreading the disease any further.

Sources

Committee to Review Adverse Effects of Vaccines; Institute of Medicine; Stratton K, Ford A, Rusch E, et al., editors. Adverse Effects of Vaccines: Evidence and Causality. Washington (DC): National Academies Press (US); 2011 Aug 25. 4, Measles, Mumps, and Rubella Vaccine. Available from: http://www.ncbi.nlm.nih.gov/books/NBK190025/

Niewiesk S. (2014). Maternal Antibodies: Clinical Significance, Mechanism of Interference with Immune Responses, and Possible Vaccination Strategies, Frontiers in Immunology, 5 DOI: http://dx.doi.org/10.3389/fimmu.2014.00446

Rosen J.B., C. J. Hickman, S. B. Sowers, S. Mercader, P. A. Rota, W. J. Bellini, A. J. Huang, M. K. Doll, J. R. Zucker & C. M. Zimmerman & (2014). Outbreak of Measles Among Persons With Prior Evidence of Immunity, New York City, 2011, Clinical Infectious Diseases, 58 (9) 1205-1210. DOI: http://dx.doi.org/10.1093/cid/ciu105


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A risk worth taking–And one your immune system is prepared to take.

When was the last time you made an important decision with 100% certainty?

Most, if not all, decisions in life come with risks, consequences or trade-offs. Healthcare is no different from anything else. Every surgery, pill, shot, even every new diet or exercise routine has its risks. And vaccines are not exempt. It’s true, vaccines have risks (probably the most common one for most vaccines is soreness at the injection site). And it’s no secret either—check out this list on the Center for Disease Control’s (CDC) website. They even list extremely rare reported events that they can’t prove were related to vaccination, but occurred around the same time.

Early recipients of vaccines understood side effects all too well. In the 1700’s, vaccination against smallpox, which entailed rubbing pus from an afflicted person into a small cut, was known to cause a mild form of disease, and in 1-2% of cases, death. But to those who saw what real smallpox could do firsthand, the risk was worth it, because even if they didn’t yet know how it worked, they knew that vaccination saved lives.

These days, vaccines are far safer, but the fear of potential side effects often overshadows the fear of disease. Perhaps the most notorious of these fears is the alleged and debunked link between autism and the measles, mumps and rubella (MMR) vaccine.  Many researchers have taken an honest and thorough look at this and the question has been settled from a scientific standpoint.

As is the case with everything, though, people factor things besides scientific evidence into their decisions. For example, a sense of social responsibility may influence your decision to get the flu shot each year. You may also factor in anecdotes about a co-worker’s friend getting the flu after being vaccinated. Though rejecting one piece of information and blindly accepting another is everyone’s right, making an informed decision requires consideration of all types of information.

Many take the reasonable route of deferring to their doctors who have hopefully kept abreast of the scientific evidence and have likely seen the anecdotal evidence first hand. A doctor may defer to the recommendations of an organization like the Advisory Committee on Immunization Practices (ACIP), a rotating group of doctors and scientists who painstakingly study the science and side effects of every vaccine that goes onto the market. You can learn more about ACIP here and even attend their meetings if you want.

Then there are some who would like to have a couple of questions answered and to feel more involved and informed about their own, or their children’s health care. And then some who are just plain scared of the potential side effects. These lingering questions and fears surrounding vaccination are worth addressing (not to mention scientifically fascinating). For a thorough list of such questions, I recommend this site (and of course, it’s always wise to speak with a trusted healthcare professional about your concerns). Over the next couple of posts, I plan to explore some recent research that sheds light on a just couple of these questions:

First, can a vaccine make you sick? And second, why do vaccinated people still catch disease?

One way to explore the first question is look at the differences between the altered form of a virus found in a vaccine and the real deal. For something like the flu shot, which contains dead virus, the difference is obvious. If the virus is not alive, it can’t get into cells and replicate. It can, and should, activate immune cells, which could bring along soreness or a headache.


You may have heard about people getting the flu, or flu symptoms from the flu shot itself. There is some evidence that the act of getting the flu shot can put you at risk for the flu. One study published last year concluded that just going to the doctor slightly increased the probability of experiencing flu-like symptoms within the following two weeks (read this for more). If you get the vaccine at a clinic or doctor’s office, you could increase your chance of contact with people who have the flu or surfaces they have recently touched. It takes about a week for your body to generate antibodies good enough to protect you from the virus, so it’s definitely possible to get sick just after being vaccinated. For more flu myths, check out this list.


For some diseases, like measles, the immune system really needs to see a live vaccine to generate long-term immunity. The reason for this is not completely clear, but we do know that it takes a while for our bodies to generate the “best and brightest” long-lived immune cells and a dead vaccine may be cleared too quickly for this to happen. So, we’re stuck with live vaccines, at least until researchers come up with something better.

Do live vaccines have more risks than dead ones? Well, for some people, yes. There are a handful of case reports of kids with rare genetic immunodeficiency disorders getting polio from the vaccine, and live vaccines could make someone with uncontrolled AIDs sick. However, there have been very few reports of HIV+ people getting sick after receiving a live viral vaccine (Summarized here).  And just to be safe, the CDC recommends pregnant women and those on immune-depleting chemotherapy avoid most live vaccines, though there is not a lot of data for or against them in those cases.

Measles pneumonia - Histopathology

Lung cells fusing together into one, measles-infected “giant cell.”

But what about in the average healthy person? What happens after a live virus vaccine enters your body, and how is it different from a live, natural, infectious virus? Let’s take a closer look at the recently popular measles vaccine. The virus used in for measles vaccine is “weakened” because it’s been grown, harvested, and grown again and again in human or chicken cells in culture dishes. The virus adapted to its environment in a culture dish, and lost its potency in the human body. On a molecular scale, scientists are still collecting information about exactly how this “weakening” happens. One thing they know is that the vaccine version of the virus infects different kinds of cells than the natural version of the virus does.

One researcher working toward a better understanding of this question is W. Paul Duprex, at the Boston University School of Medicine. His lab engineered measles viruses to glow by giving them the gene for the jellyfish green fluorescent protein (GFP). Then they infected macaques monkeys with either the infectious natural measles virus or the vaccine strain and looked for the glowing viruses in different parts of the animals’ bodies. When they looked for the virus in blood or throat swabs, they found much less—orders of magnitudes less—of the vaccine strain compared to how much natural virus was growing in the monkeys. The researchers also examined slices of lymph nodes with a microscope and measured GFP in immune cells using a laser and detected very little, if any, of the vaccine virus strain inside immune cells. The infectious version, on the other hand, seemed to love infecting and dividing inside of immune cells.

Both viruses were able to infect one type of innate immune cell, but only in the lungs. And, it’s important to note that the scientists delivered both types of virus straight into the animals’ airways, so both strains had ample opportunity to infect. Just this month, though they published a study that mimicked the actual vaccine route, which is an injection into a muscle, and saw that the vaccine virus also only infected innate immune cells in the muscle. To see pictures of Duprex’s “glowing” virus infecting these cells, check out this recent National Geographic blog post.

When these innate immune cells, called dendritic cells and macrophages, get infected, they display little bits of the virus to other immune cells in nearby lymph nodes. For this reason, they are called professional antigen presenting cells. Other immune cells in the lymph nodes will generate a response, clear the present virus, and remember it well enough to prevent infection with the natural version in the future.

If innate immune cells brought the natural virus to the lymph nodes, cells in the lymph node would become infected and the virus would continue to spread throughout the body. This research is just getting started, but so far it looks like the vaccine version of the virus is well contained by dendritic cells and macrophages. They are professionals after all, and they do this kind of thing all day every day.

So, should you fear live viral vaccines? Well, do you fear the live bacteria, viruses and fungi living all over your body? Your immune system has done a good job at keeping them in check so far. If you’re generally healthy, a live viral vaccine is like a blip on your immune system’s radar.

I think of it like going on a roller coaster. You can stand in line and mull over all of the things that have a one in a million chances of going wrong, or consider the actual data–the hundreds of people who rode it without any incident just during the time you were in line.

In the case of live vaccines, millions of people have had them with no incident just in the past year. And unlike a roller coaster ride, the marginal risks of measles vaccination are exchanged for a major, life-long benefit.

Please note:

I am not a medical professional and the opinions within this blog are not intended to be used as medical advice.

Sources:

Gerber J. (2009). Vaccines and Autism: A Tale of Shifting Hypotheses, Clinical Infectious Diseases, 48 (4) 456-461. DOI: http://dx.doi.org/10.1086/596476

Simmering J.E., Joseph E. Cavanaugh & Philip M. Polgreen (2014). Are Well-Child Visits a Risk Factor for Subsequent Influenza-Like Illness Visits?, Infection Control and Hospital Epidemiology, 35 (3) 251-256. DOI: http://dx.doi.org/10.1086/675281

Angel J. (1998). Vaccine-Associated Measles Pneumonitis in an Adult with AIDS, Annals of Internal Medicine, 129 (2) 104-106. DOI: 10.7326/0003-4819-129-2-199807150-00007

de Vries R.D., Lemon K., Ludlow M., McQuaid S., Yüksel S., van Amerongen G., Rennick L.J., Rima B.K., Osterhaus A.D.M.E. & de Swart R.L. & (2010). In vivo tropism of attenuated and pathogenic measles virus expressing green fluorescent protein in macaques., Journal of virology, PMID: http://www.ncbi.nlm.nih.gov/pubmed/20181691

Rennick L.J., Thomas J. Carsillo, Ken Lemon, Geert van Amerongen, Martin Ludlow, D. Tien Nguyen, Selma Yüksel, R. Joyce Verburgh, Paula Haddock & Stephen McQuaid & (2014). Live-Attenuated Measles Virus Vaccine Targets Dendritic Cells and Macrophages in Muscle of Nonhuman Primates, Journal of Virology, 89 (4) 2192-2200. DOI: http://dx.doi.org/10.1128/jvi.02924-14