Monthly Archives: April 2011

Immunology, Vaccines

Can adenovirus be used to help cure a cocaine addiction?

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Contributed by guest blogger: Jessica Hughes ’11

It is well known that drug addiction is a worldwide problem, and so finding a therapy or cure for this issue would be extremely valuable. Scientists have been trying to create a vaccine for people with drug addictions that would allow them to be rid of their chemical dependence, but there are several challenges they face in trying to do so. First, addictive drugs are small molecules that do not cause an immune response on their own. Furthermore, because of the extremely high level of drugs often found in the blood of a systemic drug user, there needs to be a way to create high-titer, high-affinity antidrug antibodies to address that extremely high drug concentration. This second challenge has limited the effectiveness of many attempts at anti-addiction active immunization strategies.

In a 2010 study, researchers looked at creating an anticocaine vaccine with the help of adenovirus. With the knowledge that inhaled cocaine could not reach its target receptors in the brain when exposed to anticocaine antibodies, researchers looked into the possibility that cocaine addiction could possibly be reversed with an anticocaine vaccine. Here’s where adenovirus came in. Researchers knew that adenovirus gene transfer vectors act as potent immunogens, which provoke adaptive immune responses. They predicted that if they coupled the adenovirus with a cocaine analog, they could elicit high-titer antibodies against cocaine and successfully prevent this drug’s access to the brain. Specifically, they used a disrupted E1-E3- adenovirus gene transfer vector, which means they were able to avoid viral gene products that would pose a risk of infection to the vaccine receiver but still have the benefit of the immunogenic property of the vectors. E1-E3- has been used many times in gene transfer applications, proving to be very safe.

In their experiment, once they created the vaccine (called dAd5GNC), they used mice to test its effects. Both naïve mice and vaccinated mice were given cocaine intravenously, and subsequently their locomotor activity was observed. The administration of cocaine caused hyperlocomotor activity in mice. These effects were completely and consistently reversed for the vaccinated mice. This is a promising result, and further studies obviously need to be done to continue looking into the possibility of using anti-addictive drug vaccines. Some questions to think about: Would an anticocaine vaccine work in the real-life scenario of preventing an addict from relapsing? Could there be dangers with taking these vaccines, such as accidental overdoses of someone trying to obtain the feeling he/she is used to getting from the drug?

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Vaccines

Dear Hudson Valley Parent Magazine

11 Comments

Updated April 20

A local parenting magazine just published a story by Robert Lachman on vaccines and autism perpetuating the false link between them. An online version is available, which is slightly different from the paper version. In the past, Ive ignored these kinds of articles because I just get so frustrated. But I recently decided that if someone like me doesn’t speak up and start contributing accurate information to the public, who will?

As such, I am drafting a letter to the magazine and am seeking your editorial input. I want to write a clear, strong letter but also dont want to scare readers away with too much “science-y” stuff. The target audience is parents with, most likely, no science background. Please read what I have written and let me know what you think.

The article also refers to a study presented at a 2010 Pediatrics Academic Society Conference in Vancouver which he claims confirms the link. Thanks to a reader, we may have found the studies to which he refers, which do not support his claim (see comments section).

Anyway, here is a draft of my letter:

“Dear Hudson Valley Parent Magazine:

In your most recent issue, a story titled “Vaccines and Autism: The Controversy Continues” was published. The only thing that is continuing the controversy is continued publication of articles such as these that present misleading information. Scientifically, the issue is settled: there is no link between autism and vaccines.

The story downplays the fraud committed by Andrew Wakefield. It is clear that Wakefield falsified his data. He has been stripped of his positions, degrees, and license to practice. Brian Deer, the reporter who uncovered the fraud, is now under attack. Shooting the messenger is just a last ditch attempt to save a movement based on falsehoods. All you have to do is look at the data and the findings, the large body of independent scientific research that clearly shows there is no link.

It is also clear that he had financial interests in seeing the MMR vaccine discredited, since he had developed his own vaccine. Interestingly, the anti-vaccine movement is quick to blame vaccine manufacturers as being influenced by profit motive or finding conspiracy in discrediting Wakefield’s findings, but Wakefiled’s clear financial conflict of interest is conveniently overlooked.

However, I realize that evidence of fraud and financial conflict of interest isn’t going to resonate with many in the anti-vacccine movement. The fact is, scientifically, it doesn’t really matter that his data was fraudulent. The Wakefiled study involved only 12 children, a sample size much too small to draw strong conclusions. Further, the study was poorly designed: to connect vaccines to autism, the study depended entirely on parental or physician recall of events in the past, a method known to be highly ineffective. In fact, it’s not much different from anecdotal data. Since Wakefield’s study, there have been many subsequent studies involving larger number of participants that have been rigorously designed and appropriately controlled and NONE have supported a link between vaccines and autism. The reason the scientific method works, and the reason humanity has gained great knowledge and understanding of the natural world around us is that the scientific method is self-correcting. Any finding must be verified independently, by other researchers, using a combination of different approaches. Only after a significant body of work is developed can a strong conclusion be made. Wakefield’s study triggered such a body of research, which has consistently shown that that there is no link between vaccines and autism. That is to say, Wakefield’s conclusions have not withstood the test of the scientific method. The fact that his data was fraudulent only confirms what scientist already knew: vaccines do not cause autism.

The article describes the personal experience of specific parents who believe their children are autistic as a result of vaccination. Anecdotal data can be used to support any position. Where are the interviews with parents of vaccinated children who don’t have autism? The anecdotal data doesn’t sand up when you consider the many anecdotes I have about parents who vaccinated and don’t have autistic kids. Whose anecdotes should we believe? The only information we should consider is from well designed and controlled studies.

The article also describes a study presented at the Pediatrics Academic Society conference in Vancouver in 2010, which he claims confirms the link between autism and vaccines. I, and others, have carefully searched the abstracts of the work presented at the conference and found no such study. Two abstracts addressed gastrointestinal symptoms associated with autism, the closest I could find to the topic. However, the issue of vaccination is not addressed in these studies. It would be appreciated if the author provided a specific citation so that readers can look at the study themselves. It is concerning to me that either Mr. Lachman completely misunderstood the research or is being intentionally misleading. In fact, in the article, he writes that Wakefield’s study connecting vaccines to autism has been vindicated, and in support states that the PAS study links gastrointestinal disease in autistic children. The issue in question is not regarding a connection between gastrointestinal symptoms in autism but a connection between vaccines and autism. There appears to be a vast leap, making conclusions that simply can not be made from the data. Implying that these studies support a link to vaccination is entirely misleading.

Finally, Wakefield’s study, the actions of the anti-vaccine movement and the perpetuation of misleading information is troubling on a very deep level. Children are dying from preventable diseases, directly attributable to decreased vaccination rates. It is a crime that this should happen. The other victims in this whole scandal are kids with autism. Rather than focusing on finding the actual cause of autism, the distraction of the vaccine link has driven the focus away from valuable research that needs to be done. With so much data to support the absence of a link between vaccines and autism, and so much reason to find the real cause (or causes) of autism, I seriously wonder whether the driving force behind this movement is now the desire to be right, rather than the desire to protect our kids.

Sincerely,
David Esteban
Assistant Professor of Virology and Microbiology
Vassar College

Im adding some links:
Here is Wakefield’s paper. You might find it hard to read due to the big red RETRACTED written over each page.
One of the articles in BMJ regarding the fraud.
An Editorial from BMJ

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Epidemics, Guest Blogger, Immunology, Vaccines

A possible new HIV vaccine target?

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Contributed by guest blogger: Lydia Mendoza ’11

In 2009, it was estimated that 33.3 million people in the world were living with HIV/AIDS. Since the discovery of HIV, more than two decades ago, money has poured into research in the hopes that an effective vaccine might be developed. As of yet a vaccine remains elusive. One reason why it is so difficult to create a vaccine is because HIV is highly mutable and genetically diverse subtypes, or clades, have evolved. A vaccine needs to be able to offer protection from a range of HIV clades.

Normally viral vaccines are based upon neutralizing antibodies, which prevent infection of the host cell. The first attempts to develop neutralizing antibodies against HIV targeted gp120, which is known to play a role in HIV’s ability to enter and infect CD4 t-cells. These attempts have not been successful as of yet because of the gene’s high rate of mutations. However a recent paper has shown that the V3 loop of gp120 is a potential vaccine target.

The strand of protein known as the V3 loop was never thought to be an attractive vaccine target because it is not highly conserved. However, it appears to have conserved structural elements that are involved in interactions with coreceptors. To study whether V3 was a viable vaccine target, a human monoclonal antibody, HGN194 was used. HGN194 was isolated from memory B cells of a person infected with HIV-1 clade AG circulating recombianant form (CRF). HGN194 targets the V3 loop and has been previously shown to neutralize a broad range of neutralization-sensitive and resistant strains of HIV.

The study evaluated whether HGN194 was able to protect rhesus monkeys from an HIV model system. One group of monkeys was injected with HGN194 then they were challenged with a high dose of a clade C SHIV, which is a chimeric simian-human imunodeficiency virus encoding HIV envelope genes in a SIV backbone. The second group of monkeys was also given a high dose of SHIV but was not given the HGN194. The monkeys given the antibody were protected from SHIV infection, and those not given the antibody were infected. The researchers concluded that HGN194, isolated from an HIV-positive individual harboring a clade AG CFR, was able to confer complete cross-clade protection against clade C SHIV.

The antibody apparently latches onto the virus’s V3 loop and prevents the virus from invading cells. This does not mean that this antibody treatment technique is a vaccine for HIV. It does not create long-term protection because the antibodies do not remain active in the body for very long. This is only a first step. A vaccine target has been identified but now scientists must create an antigen that induces formation of an antibody similar in structure to HGN194. There is a lot of work left to be done but this finding hopefully brings researchers much closer to the development of a vaccine.

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Evolution, Guest Blogger

The strangest family reunions

Contributed by guest blogger: Amelia McKitterick ’11

Next time you are sick from a viral infection, you should ask yourself if you’re just hosting a visit from distant relatives. Although “relative” might not seem like the most appropriate term for a virus, there has been evidence of a history viral influences and insertions into animal genomes, including that of humans!

A crucial step in the replication of RNA retroviruses is the integration of the viral genome into the host genome. Fragments of a viral genome in the genome of a non-viral cell are called endogenous viral elements (EVEs), and they can either be phased-out of the host genome or be passed on to become fixed within a population. A recent study examined genomes of a variety of mammals, birds, and insects for EVEs with matching amino acid sequences to extant, non RNA retroviruses. The genomes of 44 animals were converted into amino acid sequences and checked via tBLASTn (a BLAST that matches amino acid sequences with nucleotide sequences) for alignment with a library of currently known mammalian viruses with genomes larger than 100 kb in length. Matches were found to viruses with all types of RNA genomes (ss/ds, +/-, segmented, un-segmented) in all three of the major phyla tested, matches to DNA genomes (ss/ds, rt) were only found in mammals and birds, and even unclassifiable viral proteins were found in mammals that could represent extinct or undiscovered lineages.

But what is the use of all this new information? First, the data can be used to determine the minimum evolutionary divergence dates of different viral families based on host divergence dates. This study of paleovirology estimated the minimum ages of virus fossils Parvo-, Circo-, Filo- and Bornaviridae within the mammalian samples and found the oldest (Borna-) to be about 93 million years old, where it was originally infecting the distant relatives of the Afrotheria clade (Elephants, hyrax, tenrec, etc. For reference, the common ancestor of the primates evolved about 85 million years ago). A second use of the data is to illustrate the variety of viruses, and to give a better indication of the types of viruses that infect different hosts. The presence of the EVEs in a host genome can provide new insight about the replication process of non-reverse transcription viruses, and show patterns of host vulnerability. Similarly, new viruses, such as the unclassifiable EVE in mammals, could lead to new routes of investigation into the types of viruses and cures to infections.

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Immunology, Molecular Virology, Vaccines

Can miRNAs help further attenuate influenza A vaccines?

Contributed by Guest Blogger: Brittany Sider ’11

MicroRNA (miRNA) molecules, first characterized in the early 1990s, have been implicated in a variety of different biological mechanisms. It took almost a decade for researchers to detect and understand the role of miRNAs in regulation of translation. Since then, research has focused on how we can scientifically manipulate these regulating molecules to our advantage in order to further understand biological underpinnings of certain diseases, as well as potential miRNA-based therapies.

The ability of the influenza virus to undergo frequent and substantial genomic mutations forces us to continually monitor its prevalence, and modify yearly vaccines to target the prevailing viral strains. Recently, live attenuated influenza vaccines (LAIVs, e.g. FluMist) have been proven effective, and have been distributed to a large portion of the eligible population to combat the seasonal flu. These vaccines are manipulated to become much more temperature-sensitive, and therefore are only capable of replicating in temperatures found in the nose. The inability of these attenuated viruses to replicate in the respiratory tract (due to higher temperatures) allows the vaccinated individual to produce antibodies to the influenza strains in the vaccine from the infection in the nasal passage. Therefore, the individual can produce the correct immune response without the virus spreading to the respiratory tract and causing symptoms.

In 2009, a group of researchers from Mount Sinai School of Medicine found that using microRNA response elements (MREs) can supplement the effectiveness of LAIVs. In the study, the MREs for the miR-124 (neural tissue-specific) and miR-93 (a ubiquitous miRNA) were inserted into open reading frames of influenza A nucleoprotein coding regions. The investigators vaccinated mice with miR-93-seeded strains, and then inoculated them with a lethal dose of influenza A/PR/8/34 H1N1 21 days later. This resulted in 100% survival of the subjects, as well as a robust immune response. In an attempt to attribute these results to other influenza strains, the same experiment was done with H5N1 (MREs were inserted into the vaccine specific for H5N1, and methods were repeated). Subjects who had received mock vaccinations 21 days prior to being inoculated with H5N1 displayed rapid weight loss, as well as 100% mortality. On the other hand, mice that had received the MRE-containing H5N1 strain did not display any signs of disease. Furthermore, serum from these subjects exhibited neutralizing activity against the wild-type H5N1, and a wide array of antibody responses (high levels of IgM, IgG1, IgG2a and IgG2b).

The results from this study lead the researchers to believe that MRE-containing LAIVs can be used, and potentially be even more effective than currently available LAIVs in protecting against influenza A outbreaks. In addition, this technology provides the potential to control for the degree of attenuation of the vaccine by manipulating the number of MREs/miRNAs. Lastly, FluMist – although proven to be equally as effective as injected vaccines – has some age exclusions. Perhaps the addition of MREs/miRNAs could expand the target demographic of this method of vaccination.

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