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Measles and immune memory

memoryThere’s more than one reason to immunize your kids.

Even if just not getting measles was all you got for your immunization, it would still be worth it. But through some unknown mechanism, getting measles seems to erase prior immunological memory, by depleting B and T lymphocytes (so, we know the cause, but not how this happens).

Below, is a visualization of individuals’ lymphocyte numbers pre and post measles:

F1.large

Apparently, naive cells are either not impacted, or only minimally so. Whereas all specific lymphocytes are completely depleted. Following resolution of the infection, the only antigen-specific lymphocytes that remain afterwards are those specific to measles. That is, you now have the immune system of a toddler, with the sole exception of having immunity to measles. Recovering that lost immunity takes approximately 2-3 years of being exposed to and contracting infection after infection to rebuild memory.

One of the reasons that investigators knew that there was something to investigate was that once measles vaccine became available, not only did deaths associated with measles decrease, but so did deaths associated with a number of other infections.

 
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Posted by on June 3, 2015 in Uncategorized

 

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UPenn Webinar – ‘Mickey’s Got Measles’

mickey-mouse-and-measles

Poor Mickey

Today, I attended the webinar, Mickey’s Got Measles, through the Live Faculty Lecture Series offered at the University of Pennsylvania. Today’s lecture focussed on the epidemiology of Measles, Herd Immunity, and Trends in Immunization was presented by Alison Buttenheim. Given the recent outbreak of Measles that puts 2015 well ahead of year-to-date infection numbers, it was very timely and an excellent lecture. If you have 50 minutes, I highly recommend that you check it out here.

 
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Posted by on February 27, 2015 in Uncategorized

 

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Mickey’s got Measles

A webinar from UPenn

I think this webinar is free and available to anyone.

http://www.alumni.upenn.edu/s/1587/gid2/index_notitle.aspx?sid=1587&gid=2&pgid=5051&cid=11472&ecid=11472&crid=0&calpgid=411&calcid=4027

 
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Posted by on February 15, 2015 in Uncategorized

 

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Congressional hearing on Vaccination

schuchatIn the wake of several months of nation wide fear of ebola,  a new outbreak strikes home. One can only wonder whether the timing of these events will have a lasting effect on the country.

as a side note, it’s interesting to hear Dr Schuchat, the Director of the National Center for Immunization and Respiratory Diseases at the CDC, bring up the number of annual deaths attributed to influenza in the US as between 5-30,000. Because of the way deaths are reported, it is actually tricky to get a very accurate number for this, but a CDC study attempting to do so sets the range as falling between two recent extremes of  “3,349 in 1986–87 to 48,614 in 2003–04.”  For perspective, the 2014 / 15 outbreak of ebola in Africa has claimed just over 9,000 lives.

Despite the high annual mortality of flu, only about 40% of American adults get vaccinated each year.

Screen Shot 2015-02-11 at 1.10.13 PM

Measles has a track record of much higher mortality rates than flu, and is much more contagious. The WHO warns, “[t]he highly contagious virus is spread by coughing and sneezing, close personal contact or direct contact with infected nasal or throat secretions.

The virus remains active and contagious in the air or on infected surfaces for up to 2 hours.”

In 2004, Perry and Halsey summarized what we, as a population have forgotten, “Before the introduction of measles vaccines, measles virus infected 95%–98% of children by age 18 years, and measles was considered an inevitable rite of passage.”

Measles is associated with a number of complications, including pneumonia (either directly as a result of measles or from another agent) which is associated with the majority of deaths attributed to the disease. Over the years, as medical interventions have improved, the number of measles-associated fatalities has dropped from “One hundred years ago in Scotland, the measles case-fatality rate was 30–40 deaths per 1000 cases. In the United States, mortality from measles decreased from 25 per 1000 reported cases in 1912 to 1 per 1000 reported cases in 1962.”(see figure below) Nevertheless, it remains a dangerous disease capable of causing a number of complications and death. (all those deaths from flu mentioned above, flu kills only about 1.4 to 16.7 deaths per 100,000 persons.)

Screen Shot 2015-02-11 at 1.30.17 PM

Perry and Halsey conclude:

Measles vaccination is one of the most cost-effective health interventions ever developed. Without the vaccine, 5 million children would die each year from measles-assuming an estimated case-fatality rate of 2%–3%. Without measles vaccination, the costs of caring for those with measles in the United States would be ~$2.2 billion annually, and the indirect costs would be an additional $1.6 billion. Each dollar spent on measles vaccine saves $12–$ 17 in direct and indirect costs.

With this in mind, here is the full video broadcast of CSPAN’s coverage of the the hearing on childhood vaccination:

http://www.c-span.org/video/?324253-1/hearing-childhood-vaccination

 
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Posted by on February 11, 2015 in Uncategorized

 

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The New Measles

leadApropos of class discussion about vaccine compliance and public policy, check out Adrienne LaFrance’s article from The Atlantic on how Measles is re-emerging in many countries – including the United States –  that have considered it eradicated for decades.

Click here to visit the article

The numbers in recent years are nothing like the devastation that Measles used to visit in the US, however, it is the trend that is disturbing. Prior to the introduction of the vaccine, cases numbered in the hundreds of thousands per year in the US. Globally, in 2013, there were 145 700 measles deaths compared to an estimated 2.6 million deaths each year prior to widespread immunization. (data from the WHO)

Measles cases in the US prior to and after the introduction of vaccine

Measles cases in the US prior to and after the introduction of vaccine Langmuir AD. Medical importance of measles. Am J Dis Child 1962;103:54-56

Some Data

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Measles Cases in the US 2001 – 2014

 
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Posted by on January 24, 2015 in Uncategorized

 

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Little Red

As always, my Microbiology class is reading Paul Offit’s Vaccinated this year. Recently, we have started into the chapters concerning Hilleman’s involvement in making vaccines against Measles, Mumps, and Rubella, each taking a chapter in the book.

 Rubella is often overlooked as an unimportant disease with milder symptoms than other vaccine-preventable illnesses such as Measles, Smallpox, or Polio. However, Rubella represents a different threat, less visible during the acute phase of infection.

From the Latin, Rubor, meaning red. Rubella (little red) was initially identified by its similarity to measles, resulting in a shorter-duration (aka 3-Day Measles) episode of red spots. Because of the similarity to Measles and being first described by a number of German scientists, Rubella took a third name, German Measles.

Although Rubella is not typically a dangerous disease for older children, it can be difficult for babies and is particularly destructive when contracted by women in the first trimester of pregnancy. Early in the pregnancy rubella infection can lead to serious problems in approximately 50% of babies. So common are these outcomes that they bear their own name, Congenital Rubella Syndrome (CRS). Effects include blindness, deafness, congenital heart disease, and intellectual disabilities.

During the course of the 1963-65 epidemic, “In the United States alone, about 11,000 babies died and 20,000 babies developed birth defects from rubella.” CDC

Following this epidemic, a vaccine against Rubella was approved for use in the US in 1969 and was followed by an abrupt decline in the number of cases as seen in this graph illustrating the number of rubella cases occurring in the US from 1966-1993. (taken from Centers for Disease Control and Prevention Summary of notifable diseases—United States, 1993 Published October 21, 1994 for Morbidity and Mortality Weekly Report 1993) Although not depicted in this graph, the resulting CRS incidence followed a similar pattern.

Rubella-us-1966-93-cdc

Until recently, the most common mechanism for vaccinating against Rubella was the Measles/Mumps/Rubella (MMR) combination vaccine. However, in 2004 a MMRV combination containing varicella (chickenpox virus) was approved adding additional protection to the single shot. Currently, the MMR/MMRV vaccine is recommended at age 12-14 months, with a booster at age 4-6.

 When the MMR vaccine came under suspicion following the 1998 publication of Andrew Wakefield’s notorious (and now retracted) article suggesting a link between vaccination and autism, Measles cases began to re-emerge.

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Concurrently, Rubella cases have also rebounded in countries that had previously nearly eliminated the disease (see data below from Poland).

 Ultimately, the future for these viruses depends on how we, the public choose to use the information available to us – and where we choose to get that information, from talk show hosts and celebrities, or from the agencies we have built to protect the health of the country.

Stefanoff-fig1

 
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Posted by on September 29, 2014 in Uncategorized

 

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An Epidemiological Method: Using RFLP to Identify Strains of Pathogens

An excellent classroom resource for a case study in epidemiology is presented by the CDC. This study walks students through an outbreak of E. coli O157:H7 in Michigan.

The purpose of this study is to provide student investigators with the opportunity to walk through the procedures and rationale behind investigating the etiology and to develop experiments testing hypotheses generated by the students.

I am using this exercise as an end-of-semester project for my microbiology students to work through collaboratively now that we have completed our discussion of Paul Offit’s Vaccinated.

The study begins:

PART I – OUTBREAK DETECTION

 

Escherichia coli O157:H7 was first identified as a human pathogen in 1982 in the United States of America, following an outbreak of bloody diarrhea associated with contaminated hamburger meat. Sporadic infections and outbreaks have since been reported from many parts of the world, including North America, Western Europe, Australia, Asia, and Africa. Although other animals are capable of carrying and transmitting the infection, cattle are the primary reservoir for E. coli O157:H7. Implicated foods are typically those derived from cattle (e.g., beef, hamburger, raw milk); however, the infection has also been transmitted through contact with infected persons, contaminated water, and other contaminated food products.

Infection with E. coli O157:H7 is diagnosed by detecting the bacterium in the stool. Most laboratories that culture stool do not routinely test for E. coli O157:H7, but require a special request from the health care provider. Only recently has E. coli O157:H7 infection become nationally notifiable in the U.S. Outside the U.S., reporting is limited to a few but increasing number of countries.

In the last week of June 1997, the Michigan Department of Community Health (MDCH) noticed an increase in laboratory reports of E. coli O157:H7 infection. Fifty-two infections had been reported that month, compared with 18 in June of 1996. In preliminary investigations, no obvious epidemiologic linkages between the patients were found.   The increase in cases continued into July.

Students are then asked a number of introductory questions and then presented with the following problem:

Compare the DNA fingerprints in Figure 2 from seven of the Michigan E. coli O157:H7 cases. Each isolate has its own vertical lane (i.e., column). Controls appear in lanes #1, 5, and 10. Which Michigan isolates appear similar?

This question requires some background in DNA Fingerprinting (aka Restriction Fragment Length Polymorphisms, or RFLPs), which I want to take some time to explain.

As the source material states, The purpose of this test is to identify common strains of organisms through their DNA banding pattern. “Different DNA composition will result in different PFGE banding patterns. Bacteria descended from the same original parent will have virtually identical DNA and their DNA fingerprints will be indistinguishable. Identification of a cluster of isolates with the same PFGE pattern suggests that they arose from the same parent and could be from the same source. “ (emphasis mine).

The method involves two core techniques. First, DNA from the target organism must be isolated and cut with one or more restriction enzyme(s). This will create a number of DNA fragments, where the precise number and size of fragments is determined by the sequence of that organism’s DNA.

As an example, let’s imagine a 10,000 base pair (bp) chromosome that we intend to cut with the restriction enzyme, EcoRI. EcoRI recognizes and cuts double stranded DNA at a specific sequence of 6 bases.

Image

Figure: DNA cut by the Restriction Enzyme, EcoRI. A. DNA sequence with EcoRI recognition site highlighted and cut pattern illustrated. B. Enzyme binds to DNA at the recognition site. C. DNA has been cleaved.

On average, this enzyme will cut a random sequence of DNA every 4096 bases (this can be estimated by 4 raised to the power of n, where n = the number of bases in the enzyme’s recognition sequence , or 46 = 4096 in this case.) In our example, this suggests that a 10,000 bp chromosome will have two EcoRI sites by random chance.

The circular chromosome should be cut twice by this enzyme, resulting in two fragments of DNA (see note #2, below). Let’s say the two bands are 4000 bp and 6000 bp.

We can see these two fragments by running them through agarose, which works as a molecular sieve, to separate the two fragments by size

How does this work?

DNA is a negatively charged molecule with that charge spread uniformly across the length of the fragment. Therefore, there is no difference in charge between our two fragments, except in proportion to their length. This means that as they run through the sieve, the only difference between the molecules comes from their lengths. As any sieve, smaller objects go through easier, while larger ones are held up.

ImageThe result is that the two fragments will appear as distinct bands on a gel, with the smaller fragment running farther through the agarose that the larger. (here, the smaller band at the bottom of the gel has migrated farther toward the positive electrode)

If someone new were to become infected with this bacteria, we could isolate it from them, digest the DNA and get the same banding pattern. A closely related bacteria may have one additional EcoRI site. This would result in one of the two bands being cut into two smaller fragments, meaning that the two strains could be easily distinguished.

Back to the question posed above…

Given this, examine the following compilation of samples. Controls appear in lanes #1, 5, and 10. Which of the remaining isolates appear similar?

Image

Definitions:

  1. Restriction Enzyme or Restriction Endonuclease– an enzyme that can recognize and cut DNA.
  2. Recognition Sequence – the sequence of bases that a restriction enzyme recognizes and binds to.

 

Notes:

  1. In my example, we are using the restriction enzyme, EcoRI, to cut DNA from E. coli. As the name suggests, EcoRI actually derives from E.coli, where it functions as a defence against invading DNA, i.e. a virus. In order to do this successfully, E. coli will either not have any EcoRI restriction sites in its own DNA, or it will protect them by methylation so that the enzyme does not destroy the host’s own DNA. I am ignoring the possibility that the DNA we are dealing with in our experiment may not be cleavable with this enzyme.
  2. Also note, that bacterial chromosomes are circular, rather than linear – interestingly, this means that they are not actually ‘chromosomes’ at all. Again, let’s ignore this.
 
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Posted by on April 18, 2014 in Uncategorized

 

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