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?
Contributed by Guest Blogger: M. Carraher ’14
A former leader of the Pentagon considers, “Mother Nature among the worst terrorists.” Throughout modern time, the threat of a virus pandemic has seemed more likely, and more deadly than a nuclear war. Swine flu, HIV, and SARS have all frightened average citizens and leading microbiologists into a frenzy. The biggest threats have been the viruses that were least expected. If you don’t see them coming, how can you protect against a deadly outbreak? The general strategy for antivirals is “one bug, one drug”. However, any small mutation of the virus might render the drug useless. Research is currently being poured into developments of a broader range of antivirals. The current hypothesis is that certain proteins inside cells are vital for virus replication. But what if those cellular proteins aren’t necessarily vital for host life? A promising target is the TSG101 protein, which is involved in the transport of viruses out of a cell. A small-molecule drug has been developed to inhibit that interaction between the protein and virus. Researchers have identified more than 30 viruses that rely on this protein, so the drug does protect over a broader range infections. One hundred percent of Ebola-infected mice survive if exposed to the drug, a day after infection. Eighty percent survive if treated two days post infection, and 40% live four days after infection. The early test results seem promising for a strong, broad ranged antiviral drug, that does not hurt the host.
The most promising broad spectrum antiviral targets the host instead of the virus. Healthy cell membranes express a substance called phosphatidylserine on their inner surfaces. When under stress from a viral infection, this substance ends up on the outer surface. All viral infections seem to exhibit this behavior, making it a key target for drugs. An antibody called bavituximab has been developed, which binds to the phosphatidylserine. Once bound, the immune system should clearly recognize the infected cell and destroy, thus limiting viral replication. This method was tested on guinea pigs exposed to a Pichinde virus. Half the animals treated with bavituximab survived, compared 100% death for the control group, not injected with the antibody.
The antibody is currently being tested for a broader range of viruses, such as HIV, hepatitis, and influenza. So far, all infected cells express this molecule on the outside of their membranes, as compared to healthy cells, which maintain the molecule within the cell. This antibody could potentially protect against all known viruses, and some unknown as well, considering all viruses are believed to exhibit this behavior. However, viruses do evolve. Could they evolve to become immune to the antibody at some point? Further testing with humans is also needed to determine any potential side-effects. But, this is one step closer to a universal antiviral.
Once a cell is infected, our immune system clears the infection not by targeting the virus, but by simply killing the infected cell. Antibodies are also an important part of our defense against viral infections, but their function is limited to targeting viruses floating around outside the cell. It is believed the once the virus enters the cell, it’s safe from antibodies. But a recent study suggests that this may not be true; it seems that antibodies can eliminate viruses from inside cells too. This is particularly groundbreaking because this may be a mechanism to cure infected cells, rather than just killing them.
Researchers identified a protein called TRIM21 that binds antibodies, but it was localized to the cell’s cytoplasm. Why would it be there, when antibodies are secreted? It seems that sometimes viruses can enter a cell with antibodies bound to it. While some antibodies are neutralizing, meaning that they prevent attachment to the receptor, others are not. If the virus is coated with these non-neutralizing antibodies, it can still enter, and it bring the antibodies in with it. TRIM21 recognizes these internalized antibodies, with virions attached to them, and then targets it for destruction in a cellular blender called the proteasome. In an appropriately named “fate of capsid” experiment, the researchers showed that antibody bound adenovirus capsid proteins were being degraded as soon as 2 hours after infection and that the degradation required both the proteasome and TRIM21. So the virus is being destroyed quickly, before it gets the chance to replicate.
As always, this study introduces many new questions. They used adenovirus, which causes mild respiratory infections, but does the mechanism extend to other non-enveloped viruses? Can this mechanism be used to improve existing vaccines or develop new ones? How important is this mechanism in the overall response to viral infection? Have viruses evolved mechanisms to block TRIM21?
The flu comes back year after year, and every season we get vaccinated (well, some of us anyway). Why do we need to keep getting a new shot for the flu while for others, like measles, we got way back in childhood and are done with it for the rest of our lives?
Our immune response to influenza involves production of antibodies, large proteins that specifically bind to the virus and help clear it out or neutralize it. It seems like the key to influenza immunity is neutralizing antibodies, antibodies that bind to the virion and prevent it from attaching to the host cell. You can imagine this large protein just being physically in the way, preventing the virus from binding the host receptor. The immune response that develops from natural exposure or vaccination generates neutralizing antibodies to HA, a viral envelope protein that is necessary for attachment to the host. I’ve mentioned HA in a previous post about influenza. The problem is that last season’s neutralizing antibodies dont bind to this season’s virus. Although it may be nearly identical to the virus from a past season, the new strain’s HA is slightly different, and those differences are enough to evade existing neutralizing antibodies.
Now a new approach to vaccination has shown that it may be possible to develop a vaccine that illicits broadly neutralizing antibodies, that is, antibodies that will protect against influenza strains with slightly different HAs. They used a prime/boost approach, in which a DNA vaccine was used to induce an initial response against HA, and then boosted with a regular seasonal flu vaccine. The only difference between this and what is currently done is the addition of the DNA vaccine. However the response seems quite different. Neutralizing antibodies were generated that can neutralize a variety of different influenza viruses. It seems the vaccine induced antibodies to a different part of HA. Antibodies are so specific, the dont recognize the whole HA, but rather discrete parts of it. The part recognized by these antibodies, called the stem, is highly conserved, meaning it doesnt change season to season.
This raises many interesting questions and possibilities. Could we soon have a universal vaccine that will protect us for life or at least for many years? Why did the change in vaccine regimen induce antibodies to a different part of HA? Why does the current vaccine or natural exposure fail to develop antibidies to the conserved portion of HA? Will the conserved portion of HA eventually change too, if sufficient selective pressure is applied through mass vaccination?