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Tag Archives: immunity

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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Virus, Vaccine and Passive Antibody Therapy

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

mapEbola 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:

Eboal5Ebola 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

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.

 
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Posted by on November 5, 2014 in Uncategorized

 

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Herd Immunity

In MicroBiology class we’re still a long way from our immunology unit, but we have started talking about some basic principles of the immunity and vaccination, including the idea of ‘herd immunity’. This is the notion that even incomplete vaccination may be sufficient to prevent the spread of an infection through an entire population.

In this video, Scientific American’s Dina Fine Maron explains Herd Immunity very simply.

http://link.brightcove.com/services/player/bcpid910142956001?bckey=AQ~~,AAAAAFNl7zk~,OmXvgxJOvrGd04F7pX4DjTcq0KXtMvCb&bctid=2632175457001

Interestingly, as I started writing this, I stumbled upon the old crap movie, Outbreak – I’ll also be calling this film crap on my film blog, 100FilmIn100Days.

 
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Posted by on August 31, 2013 in Uncategorized

 

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The ethics of vaccination

ImageI recently came across an interesting article on vaccination. The article, written by Dr. Stemwedel of San Jose State University, addresses the ethics of non-vaccination with respect to the social contract.

Although this aspect of the argument may be mentioned in other articles, it is seldom given such thorough treatment.

What I find most comical is that parents can bypass the social contract and decline to vaccinate their children but still send them into public school (etc.). Apparently (although I may be wrong here), all you have to do is express an ethical opposition to vaccination and that’s acceptable.

Are all obligations of the social contract as easily dispensed with while still keeping the benefits?

Can I send my son to school with a pack of Marlboros because we don’t agree about the dangers of secondhand smoke? After all, it’s just my one son who will be smoking in class. -I know this is an absurd argument, but don’t we forbid smoking in class for the same reason we insist on vaccination? And I would be pretty disappointed if my son started smoking – he is only 8.

What other elements of the social contract can be ethically declined?

Must I pay taxes even when the guy I voted for lost?

Can I be the one guy who declines to be burdened by speeding laws?

 

By the way, last year saw an outbreak of Measles in Wales that has been attributed to declining vaccination rates over recent years.

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Posted by on July 7, 2013 in Uncategorized

 

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Cancer and the immune system (briefly)

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Macrophage engulfing bacteria

 What a breath of fresh air! A good old friend of mine, who I met while in graduate school and is now living in Mexico city has been working on a couple of papers that he is submitting to some English language journals. I’ve only read one of them so far – it’s an interesting review of work that suggests that tumors actively co-opt processes of the immune system to their own advantage. His spoken English is quite good, but it’s another thing altogether to write well for a scientific publication. Lucky for me, I guess, because it gives me a way to be involved.

It is well established that the immune system functions to prevent tumor formation known as immunosurveillance. This is pretty consistent with the basic role of defending the self against any non-self target it encounters. If you’re unfamiliar with immunology and want one thing to learn, that’s it: The immune system is there to recognize a black and white world of self vs non-self. The details are complicated, but it’s fairly well worked out that through a series of positive and negative selection events you can train your immune cells to be tolerant of you (self), but reactive against anything new (non-self).

With respect to cancer, it’s important to recognize that these cells start out as self and are ignored by the immune system, but they change in a way that they are not acting the way they should. The problem for the immune system is that these changes typically just mean that the cells are acting abnormally, but they don’t necessarily look foreign. Despite this, we know that animals that lack a functional immune system will succumb to tumors at higher frequency earlier in life than those with competent immunity.

My friend’s article extends this relationship beyond immunosurvellience and suggests that the tumor cells undergo a selection process by the immune system that will eliminate weaker cells, leaving only cells that either escape the notice of the immune system entirely or are extraordinarily resistant to attacks. Further, he describes that the remaining cells will often co-opt signals of the immune system to advance their own function and survival. 

I look forward to finishing up this paper and hope to be able to point you toward a journal that it is published in sometime in the near future. Until then, it’s so refreshing to think about immunology again. I miss it.

 

 
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Posted by on November 3, 2012 in Uncategorized

 

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