Halloween seems like a good time to resurrect old blog posts that haven’t seen the sunlight for several years. Creeping out of the tomb is my first blog post about Genes, DNA, Memes, and GMO foods. Rather than post it here, I decided to post it over on my Medium site to see if it can catch some new eyes.
Take a look: Linked Memes
Buy this poster print at: http://fictionalnape.deviantart.com/art/ReAnimator-Poster-359280577
I’ve had a question about Ebola posted on the StackExchange Biology page for some time without getting any answers. Basically, I was wondering about how antibody responses to Ebola can drive either sterilizing immunity (the goal) or actually improve the virus’s entry into host cells (a big problem). The idea that Ebola antibodies may be detrimental to the host was first raised by Baize et al, and my question is how this has impacted efforts to develop an effective vaccine. For background, I’ve written about this topic previously.
If anyone knows what the current thinking is in this area, please point them my way.
Too bad Terry Bradshaw didn’t pop in for a visit at the Royal’s clubhouse, he seems to be pretty aware of the pain and disability associated with Chicken Pox and Shingles.
Kansas City is a lock for the postseason – that’s KC topping out at 100% probability:
What’s one thing that could completely undermine the Royal’s season? How about getting blindsided by a completely vaccine-preventable illness* with a long incubation time that could lead to numerous infections?
Relief pitcher Kelvin Herrera, left, and outfielder Alex Rios, right
Completely preventable? The vaccine is about as likely to prevent infection by varicella as the Royals are likely to get in the playoffs
Data from CDC
With an incubation time of 10-21 days, varicella infection may not show up for some time after exposure, meaning that any previously unimmunized players may still come down with the pox. Fortunately, vaccination may still be done and be effective in preventing illness up to 5 days after infection, so intervention may be successful. Cross your fingers Royals fans. We can only hope that the management for the Royals as well as other teams are now up to speed on having their players fully vaccinated.
Oh – and for those of us who have had Chicken Pox at some time in our lives, here’s Terry to talk to you about getting vaccinated to prevent Shingles…
A second installment in questions referring to Paul Offit’s book, Autism’s False Prophets. These questions mark the last of those we will cover for this book.
Autism’s False Prophets Name:
Chapter 11 Questions
A Place for Autism
Most flu shots are administered I.M. (intra muscularly), therefore, at a 90 degree angle relative to the skin.
Bob and Sally go to get their annual Flu vaccine at the public clinic. Every year, the two go together and neither have contracted Influenza since they began five years ago.
This time, while he was getting his shot, he says to his nurse, “These shots are great. I haven’t been infected with the Flu for years, despite at least some of my co-workers getting sick every year.”
His nurse finishes his injection and then says, “Well, you might have gotten infected, but you’ve didn’t get sick.”
“What do you mean? Isn’t that the same thing?”
“Actually,” says the nurse, ” it’s not.”
Explain what the nurse means by ‘infection’ and ‘getting sick’ being different things. Include, in your explanation, why it is that a vaccine might not prevent organisms from getting into your body and even into your cells, but that they can still fail to make you ill. What cells and molecules are involved in protecting you in this way?
Viral Hepatitis comes in a number of flavors, named HAV, HBV, HCV, HDV, and HEV (not to mention any subtypes). HCV, identified as recently as 1990, is a serious form of Hepatitis causing cirrhosis of the liver, chronic infection, and often hepatocellular cancer. Prior to 1990, the most common way to become infected was through transfusion with contaminated blood. However, after identifying the virus, tests became available to prevent this form of passage, leaving the primary mode of transmission being sharing of needles between IV drug users and sexual contact.
Unlike other viruses (HAV), few people ever clear HCV and, instead, become chronically ill. This may, in part, be due to the inability of the body to generate protective, neutralizing antibodies. Those antibodies that are produced are mostly usable only as markers of disease. Symptoms of disease include fatigue, nausea, vomiting, loss of appetite, abdominal pain, jaundice, dark urine, and clay colored feces. The CDC definition of a case is: (sorry this isn’t clearer)
Serum alanine aminotransferase (ALT) levels greater than 400 IU/L indicate hepatocellular damage. This enzyme is normally found only in
liver cells, but is released into the blood when these cells are injured. Normal ALT should not exceed 60 IU/L, providing a fairly clear 
measure of cell injury.This can be seen clearly below as serum levels of ALT spike with symptoms of disease and then return (however not down to normal, ‘healthy’ amounts) to lower levels following resolution of symptoms.
There is no vaccine against HCV, so the best way to avoid it is to avoid contact with blood or other bodily fluids that may be contaminated.
Don’t forget to check out my comments on the novel ‘Rosemary’s Baby’ on my other blog. I highly recommend this book to anyone who enjoys thrillers / light horror (a la Stephen King).
Amongst the many interesting topics that Paul Offit’s Autism’s False Prophets brings up are how science is perceived in the media, received by the public, and judged in the courtroom.
For reference, Offit brings up the fiasco of the 1990s lawsuits against the makers of silicone implants.
Kristin E. Schleiter writes an excellent paper about the history of silicone implants and the litigation that followed them in Silicone Breast Implant Litigation in the AMA Journal of Ethics.
Breast implants, she says, were first introduced in the 1960s. In 1976, the FDA was granted the power to regulate them as medical devices, but did not specifically do so until 1988. Prior to that, in 1984, Maria Stern won [the first case against an implant manufacturer totaling] “$211,000 in compensatory damages and $1.5 million in punitive damages from silicone breast implant manufacturer Dow Corning after claiming that her breast implants caused autoimmune disease.” This was the first, but not last case to bring implants to court. In the 1990s public opinion was against the makers of breast implants and thousands of suits were filed against their makers.
A natural progression
-Schleiter’s paper goes through a list of important individual and class action cases that I don’t feel the need to repeat here, however it is a fascinating read.
In the midst of these lawsuits, the attorney, “John O’Connor, relied on PR and sympathy to win [his case representing client, Pamela Johnson]. O’Connor hired a public relations firm that gave interviews to Phil Donahue and 60 Minutes, and the trial was broadcast in its entirety on Court TV. At trial, O’Connor set up a rebuttable presumption, asking the jury to hold MEC liable unless the company could prove that they knew their implants were safe at the time they marketed them. “
That is, it doesn’t matter whether the implants caused damage, but instead, whether the company, MEC, could prove them to be safe.
In the wake of litigation, studies began appearing showing the lack of any connection between breast implants and negative health outcomes.
Schleiter provides a list of papers reviewing the safety or danger linked to implants consolidated here:
However, billions of dollars had already been awarded or settled upon and Dow Corning was forced into Bankruptcy.
With respect to Offit’s book, the question arises, “How should science be settled in court?” It’s tempting to say that the cases should prompt investigations that statistically determine the culpability of, in this case, breast implant manufacturers. But that leads directly to one of the core problems that raised the specter of a MMR / Autism connection. Andrew Wakefield’s paper was intended to do just that – provide scientific evidence to help determine a case. In that case, the British government provided $30M to a law firm in order to fund their investigation. But that’s not proper either. To begin with an outcome in mind, i.e. “MMR shots cause autism” and then try to uncover evidence to support that idea is putting the cart in front of the horse. It’s OK to ask, “Does MMR vaccination cause autism?” and then look for the answer, but starting with the answer in mind – No.
For those in my Pathophysiology class, consider, as you read these next chapters, how these questions should be answered. If you were in the position to outline how cases involving questions of science / healthcare should be handled in court, how would you do it? Are these questions any different from the other questions that courts have to address?
In 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.
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.)
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
The immune system is a many-layered construction that protects the body through barrier defences, additional non-specific responses including phagocytosis and chemokines, an antibody-mediated humoral response capable of neutralizing viral particles, and a cellular response for eliminating infected cells.
Ebola: Disease and Response
Ebola is a viral disease first identified during a first appeared in 1976 in two simultaneous outbreaks, one in Nzara, Sudan, and the other in Yambuku, Democratic Republic of Congo. It is reasonable to suspect that Ebola has infected humans prior to this time without being identified specifically. This is a reasonable assertion because, like the first, all subsequent outbreaks have occurred in remote areas of Western African countries that are largely isolated. Although infamous for its lethality, this remoteness has proved self-limiting in terms spread.
The current epidemic has defied these rules resulting in escape from the remote areas of West African villages to larger population centers, and for the first time ever, even resulting in at least one case presenting in the United States. (citation)
In general, although viral infections are not treatable by classical antibiotics, vaccines against these types of organisms have been largely successful. Although it is impossible to know exactly why a specific vaccine works, it is reasonable to assume that a humoral response (i.e. mediated by antibodies) is involved in most cases as antibody titer correlates well with protection.
I the case of Ebola, there is data regarding the type of immune responses mounted by patients who have survived the disease compared to those who have not. Baize et al report that “early and increasing levels of IgG, directed mainly against the nucleoprotein and the 40-kDa viral protein, were followed by clearance of circulating viral antigen and activation of cytotoxic T cells” in survivors of disease. While “fatal infection was characterized by impaired humoral responses, with absent specific IgG and barely detectable IgM.” Again, this supports the idea that an effective humoral response is key to protection.
More evidence of the centrality of the humoral response comes from data published by Villinger, et al (citation) showing that “IL-6 levels are unusually low among fatal cases.” They suggest that this points to a deficiency of the endothelial cells that produce this cytokine leading to failure to protect. An alternative explanation may be that macrophages, which are key targets of ebola infection – and are producers of IL-6, are also failing to respond appropriately due to their involvement as targets. This leads to an obvious defect in immune response as IL-6 supports the growth of B cells and is antagonistic to regulatory responses (i.e. regulatory T cells).
If antibodies are so important to response, what are the targets of these antibodies and what issues are there related to this response?
Ebola Virus:
Ebola has only one known surface protein found on virions and infected cells. It is presumed that this protein, a ‘sugar-coated’ glycoprotein (GP), is what enables virions to adhere to target cells, a vital first step in the infection of host cells by animal viruses. As neutralizing immunity against viruses is presumed to be a result of the opsinization of viral particles by antibody, the Ebola GP is the obvious target of these antibodies. However, there are still a number of epitopes (regions of the protein to which immune reactions develop) on the GP protein to which antibodies bind. And, furthermore, two versions of GP are made, one in the viral envelope (membrane) and one that is secreted from infected cells. Together, this means that there are a lot of different spots for antibodies to bind, and some spots may be better for protective immunity, while others have no protective effect at all.
Vaccines against ebola are currently being developed with the hope of bringing these to affected areas to either prevent – or at least control- outbreaks at their source. The benefits of developing an effective vaccine include actively inducing life-long immunity.
A second method of fighting disease is to treat with previously generated antibodies in a way that the virus is neutralized, but life-long protection is not induced. One way of accomplishing this treatment is by harvesting serum from patients who were infected, but survived the disease. This has obvious limitations logistically and there is insufficient data on these treatments to know whether they were actually helpful in treating patients. Another way to transfer this sort of ‘passive’ immunity is by making large amounts of a single antibody in cell culture. These ‘monoclonal’ antibodies are highly standardized and can be produced in very large quantities.
A number of monoclonal antibodies targeting different epitopes on the Ebola GP have been developed and show protective effects when administered after viral exposure (i.e. therapeutically). One example of this kind of therapy is ZMapp from Mapp biopharmaceutical. In studies with animals, they found that “a combination of monoclonal antibodies (ZMapp), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge.”
Treatment of Ebola patients with Convalescent Serum
I’ve written before in this space about one of the challenges that antibody treatment against ebola. Because ebola infects macrophages as one of its targets, and because one of the jobs of macrophages is to clear opsonized (antibody-coated) particles, ebola appears to have co-opted this function as a mechanism for penetrating and infecting cells. This characteristic is termed Antibody-Dependent Enhancement (ADE) of infection and has been shown to increase the infectivity of the embryonic kidney cell line, HEK-293, in vitro (Takeda et al 2003). Reportedly, the mechanism for this enhancement is via the complement protein, C1q, and receptors on the host cells.
Together, these data beg the question of whether antibody treatments, such as ZMapp, or vaccines leading to humoral responses will be helpful or harmful in the treatment and protection of patients.
“On 11 August, a group of experts convened by WHO reached consensus that the use of experimental medicines and vaccines under the exceptional circumstances of the Ebola epidemic is ethically acceptable.” So, we may find out the answers to these questions much sooner than we would otherwise expect.
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.
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.
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.
DownHouseSoftware 