ImmYOUnology

More than just vaccines

Measles_pneumonia_-_Histopathology


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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

prevent-norovirus


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Norovirus! (AKA the 24 hour stomach bug) Can it be avoided?

The other day I found myself in the break room near my lab eyeing a container of chocolate-covered nuts left over from the Christmas holiday.  Someone left them out as a treat for foraging graduate students and post-docs.  I stood for a moment holding a single piece in my fingers and as I was about to put it into my mouth, I remembered—Norovirus!

I had no reason to think the nuts could be a reservoir of norovirus, but I did have good reason to avoid shared uncooked food with an unknown history.   A good chunk of my family had just had their holiday ruined by the virus, sometimes known as the 24-hour bug or stomach flu.  It causes gastroenteritis, or inflammation of the gut, complete with diarrhea, vomiting and overall exhaustion.  It can only be transmitted via stool or vomit, and though there was certainly none of that visible in the bin of delicious looking nuts, I began to think of all the hands that may have been inside. If it came from a family holiday party, some of those hands may have belonged to kids who haven’t yet learned to wash them for a full 30 seconds after using the bathroom. I threw the candy away, closed the container and left the break room.

I may have avoided norovirus that day by a judicious food choice, but not everyone has that moment of doubt before sharing a drink, holding a child’s hand or ordering a deli sandwich.  It is sometimes just unavoidable, especially because it’s contagious for up to two weeks after the first horrible 24 hours. The center for disease control estimates that 19-21 million people are infected with norovirus each year and it’s actually responsible for somewhere between 600 and 800 deaths per year. Those most vulnerable are either over 65 or under 5 years old.

These figures are driving researchers to search for a vaccine, even if just for those most vulnerable or during outbreaks.  But norovirus, or I should say noroviruses are particularly complicated. They are split into 5 groups (I-V) based on how similar their DNA sequences are. Those groups, called genogroups, are split into anywhere between 8 and 30 genotypes and those can be further divided into variants.  The classification is complicated enough to require the use of a software program that compares genome sequences.

Only three of the genotypes can infect humans and the strain GII.4 has been the most common cause of outbreaks since the early 2000s.  For decades before that, a different strain dominated, and the power structure may shift again.  The abundance of genotypes and variants and their changing frequencies in communities make vaccine design a daunting task.  On top of that, researchers are still discovering new genotypes and variants.  In 2012 a strain called GII.4-Sydney was identified in Australia and made its way to the UK and the US within a year.

Norovirus 4

Up close scanning electron microscopic image of norovirus particles

There is evidence that infection with norovirus can generate immunity in some people, meaning that once they get infected, they are protected from re-infection for some weeks or months. However, no one knows how all of the viral subgroups and variants might affect immunity and vaccine design. In a study published in September, researchers from the University of Florida infected mice with one of two closely related norovirus strains and found major differences in the immune responses.

One of the two strains was much better at activating a class of immune cells called antigen presenting cells. These include dendritic cells and macrophages, and they are experts at displaying pieces of virus and training B and T cells to respond to the infection and turn into memory cells. As a result of the enhanced response, infected mice were protected from a reinfection six weeks later.

{Researchers determine “protection” by measuring how much virus shows up in an animal’s organs after infection. In this case, they measured norovirus in the small and large intestines and in the lymph nodes attached to the intestines.}

Oddly enough, the researchers narrowed down the cause of these changes down to a group of structural proteins whose sequences only varied by about 10% between the two strains.

A key finding in this study was that the protective norovirus strain protected mice from re-infection with both strains.  This is important since any vaccine against norovirus would have to protect against several strains and genotypes. It also points out specific characteristics of the immune response that make all the difference between becoming immune or getting re-infected, for example, robust antigen presentation and B and T cell memory.  A vaccine that could foster those characteristics could potentially protect people from several norovirus strains.  It may take a while to get there. In the meantime I will keep my hands clean and out of community candy dishes.

prevent-norovirus

*A reader noted that the poster above says norovirus is contagious for 2-3 days, whereas I wrote above that it can be contagious for 2 weeks.  To clarify, the virus is most contagious for 2-3 days, but it can continue to be shed in stool for 2 weeks. See http://www.cdc.gov/norovirus/preventing-infection.html for more.

Sources:

The CDC

Zhu S., Regev D., Watanabe M., Hickman D., Moussatche N., Jesus D.M., Kahan S.M., Napthine S., Brierley I. & Hunter R.N. & (2013). Identification of Immune and Viral Correlates of Norovirus Protective Immunity through Comparative Study of Intra-Cluster Norovirus Strains, PLoS Pathogens, 9 (9) e1003592. DOI:

Hoa Tran T.N., Trainor E., Nakagomi T., Cunliffe N.A. & Nakagomi O. (2013). Molecular epidemiology of noroviruses associated with acute sporadic gastroenteritis in children: Global distribution of genogroups, genotypes and GII.4 variants, Journal of Clinical Virology, 56 (3) 269-277. DOI:


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Training the immune system to kill cancer

Have you ever heard the term “cancer vaccine?”  Are there really vaccines to prevent cancer, and do they really work? The truth is, it’s kind of a misnomer. The vaccine against herpes papilloma virus (HPV) is often called a cancer vaccine, but it’s actually a vaccine to prevent an infection that can lead to cancer.  In other cases, the term “cancer vaccine” describes a treatment that trains immune cells to attack cancer cells.  There is one FDA-approved vaccine treatment for prostate cancer, but there are ongoing clinical trials for many other types of cancers. 

One recent clinical trial for patients with glioblastoma found that a cancer vaccine approach significantly extended the patients’ lives. Glioblastoma is the most common and most aggressive type of tumor that originates in the brain, and the average survival after treatment is about a year. This vaccine approach tested at Cedars-Sinai Medical Center in LA was so significant is because it gave half of the patients about five years.  The results of the study were reported at a meeting, but the details of the trial and initial findings were published in January.

Researchers collected large numbers of white blood cells (immune cells) from the volunteers through a process called leukapheresis, which separates immune cells and returns red blood cells and other blood components back to the donor.  They were after a rare cell type called monocytes that can morph into different cell types depending on their environment. Monocytes originally come from the bone marrow and remain round and smooth as they roll through the blood. Given the right signals, they can leave the blood for other tissues and change into macrophages or dendritic cells, both rugged spindly cells that poke out tiny arms to sense their environment.  

If you put white blood cells in a culture dish, as the scientists at Cedars-Sinai did,  the monocytes will stick to the bottom of the dish in just a couple of hours. Then you can wash away all of the other cells and keep just the monocytes. After about a week, they will morph on their own into macrophages—cells that eat up pathogens or other dead cells.  But if you add a couple of signaling proteins called cytokines, the monocytes will become dendritic cells.

Dendritic cells also eat up foreign material, but they are somewhat more refined at it. They break down everything that they eat and then present little pieces of it to educate other immune cells about what is going on in the body. T cells are their main pupils, and have receptors that sense what the dendritic cells are displaying.  Then both types of cells can make proteins to attack the foreign material (bacteria, cancer cells, infected cells) and signal other cells to start a cascading immune response.

Our bodies use this process to fight infection and to prevent cancers from developing. But once a tumor is formed, tumor cells are very effective at re-educating T cells and other immune cells.  Tumor cells can make proteins that lull and calm immune cells so that they can’t respond or don’t recognize the tumor cells as foreign. Technically, cancer cells aren’t foreign, but mutated and rebellious.  Proteins displayed on cancer cells can be distorted or can be made in excess, distinguishing them from normal cells.

File:Dendritic cell therapy.png

By Simon Caulton. This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

The idea behind cancer vaccines is to prepare dendritic cells outside of the body and put them back in where they can push immune system toward actively attacking tumors. The researchers at Cedars-Sinai coaxed monocytes into becoming active dendritic cells in culture. Then they gave the cells peptides, or pieces of proteins, that resembled the ones made in high abundance on glioblastoma cells.  Years of research went into simply identifying exactly which proteins were overproduced by these cancer cells and which would best activate the dendritic cells.  This study used six peptides to activate and train the dendritic cells.  Then the cells were sent back into the patients near their lymph nodes, which are full of T cells awaiting instructions.

Variations on this method are being tested for breast cancer, melanoma, leukemia and many other cancers. The outcomes will depend on which peptides are used, which peptides are made by each person’s tumor, how well one’s cells grow in culture and respond to activation and other variables. It’s a simple idea—to use the body’s own defenses to fight cancer—but there is a lot more to learn about this fascinating and promising treatment.

Sources:

The National Cancer Institute 

Vaccine promises longer survival for brain tumor patients, Belinda Weber Medical News Today, Nov 2013

Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma, Phuphanich S, Wheeler CJ, et al. Cancer Immunol Immunother. Jan 2013