Category Archives: Vaccines

Guest Blogger, Immunology, Vaccines

After many setbacks, cross-presentation provides new hope for a Herpes Simplex Virus 1 vaccine

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Contributed by guest blogger: Stephanie Mischell ’12

Herpes simplex virus type 1 (HSV-1) is making news due to a paper by Jing et al identifying two promising new candidate antigens for a vaccine. HSV-1 is a widespread public health issue, infecting approximately 60% of Americans and causing symptoms, most likely cold sores or genital sores but on rare occasion blindness or fatal brain damage. Furthermore, finding a vaccine for HSV-1 has proved difficult, in part because of the vital but elusive role of CD8+ T-cells in the HSV-1 immune response. Mice studies suggest that a CD8-response could facilitate memory cell formation and ameliorate chronic disease caused by HSV-1, but human blood does not have many HSV-1 specific CD8+ T-cells and very few CD8 epitopes have been identified.  Previous attempts at vaccines most recently using the HSV glycoprotein D (gD2), have focused on CD4+ T-cell specific epitopes. These attempts were unable to stimulate a CD8+ T-cell response, and the vaccine failed during clinical trials. A way to stimulate both CD4+ and CD8+ T-cell responses seems necessary to create an effective vaccine.

Jing et al’s work is significant because it harnesses properties originally used to study HSV-2 to identify HSV-1 epitopes recognized by CD8+ T-cells. An epitope, or antigenic determinant, is the part of an antigen that is recognized by the immune system; this interaction is what triggers a host immune response. Jing et al demonstrated previously that in vitro monocyte-derived dendritic cells (moDC’s), or antigen-presenting cells, can cross-present HSV-2  epitopes to create  HSV-2 specific memory T-cells. In this paper, they harnessed this cross-reactivity of moDC’s and applied it to HSV-1, stimulating and identifying HSV-1 specific CD8+ T-cells. 45 distinct CD8+ T-cell epitopes were identified. Furthermore, the genomes of host responder cells were cloned, and HSV-1 epitopes were analyzed for HLA restriction. Proteins from two genes, UL39 and UL46, were identified as most highly restricted, suggesting that they are most involved in the immunogenic response. PMBC assays confirmed these results quantitatively.

Jing et al conclude that the viral proteins coded by UL39 and UL46 are good candidate antigens for an HSV-1 vaccine because of their CD4+ and CD8+ T-cell  immunogenicity. However, they also acknowledge that their sample size is small and that subunit vaccines have not been successful vaccines for HSV-1. In fact, the large number of CD8+ T-cell   epitopes identified led the authors to conclude that a whole-virus vaccine may be more successful than subunits. Most of the failed vaccines showed similar promise until phase II or phase III of clinical trials, suggesting that the small amount of data from this study is just a start. This discovery is important but not a guaranteed vaccine.

While the identification of UL39 and UL46 are important steps in solving the public health issue posed by HSV-1, as is the identification of other CD8+ T-cell   epitopes, perhaps the most significant part of the study is the implications of their novel research methods on the study of viral vaccines. The enrichment techniques used could potentially make studying T-cell responses easier. The authors confirmed the applicability of their methods by using the same techniques to study the vaccinia virus, a microbe with a large genome of over 200 genes. This paper demonstrates a small advancement in HSV-1 research and control, but may have larger implications for this and other large viruses.

Link to original article: http://www.jci.org/articles/view/60556

Stephanie Mischell is a senior at Vassar College, majoring in biology.

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Epidemics, Vaccines

Does the Flu Vaccine Work?

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There is a photo circulating on Facebook that shows the package insert for a flu vaccine that appears to indicate that the vaccine has not been shown to be effective against influenza. Of course, this has gone viral, (sorry for the pun) especially among the anti-vax crowd.

I wanted to do a little investigating to understand the statement on the package insert. The insert says: “FLULAVAL is a vaccine indicated for active immunization against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine… This indication is based on immune response elicited by FLULAVAL, and there have been no controlled trials adequately demonstrating a decrease in influenza disease after vaccination with FLULAVAL”

Its the last statement that has triggered concern: no controlled trials adequately demonstrate a decrease of influenza disease after vaccination? Sounds bad, so lets take a look. The package insert actually has 14 pages. They show the results from a 2005-2006 clinical study involving 7482 people. About half received the vaccine and half received a placebo. Then they followed those individuals to see who got the flu. 23 people receiving the vaccine got a strain of flu against which the vaccine is supposed to protect. 45 receiving the placebo got those same strains of the flu. The statistical analysis shows a vaccine efficacy of about 46%, but the calculation of the confidence interval suggests the efficacy could be as low as 9.8%. Before doing the clinical study, they decided that the lowest limit of the confidence interval had to be above 35% to be considered successful. So it seems that the statement that clinical trials have failed to show efficacy is correct due to the large error range in their data.

Lets consider the other statement, that FLULAVAL is indicated based on it eliciting an immune response. Data from another study is shown in which people were given the vaccine and after 2 weeks, then checked for production of antibodies. In this study the levels of antibody increased to high enough levels in enough individuals that the vaccine met the criteria for success. Furthermore, they did a test called an Immunological Non-Inferiority test. Basically, they wanted to know if FLULAVAL induces an antibody response that is at least as good (ie not inferior to) another vaccine available on the market, FLUZONE. FLULAVAL induced as good a response as FLUZONE. (If you take a look at the FLUZONE package insert, they only report data on antibody responses, and state that no data is available on whether FLUZONE reduces incidence of influenza).

So there appears to be something of a conflict: the clinical trial was not successful but the vaccine appears to induce an appropriate response. Perhaps the measurement of antibodies is not the ideal indicator for predicting protection? This speaks to an important question in vaccine development, which is determining the correlates of protection. That is, what specific part of the immune response is needed for immunity?

Lets also look at other flu vaccines. FLULAVAL is one of seven different flu vaccines available.
Fluarix: Clinical studies show a reduction in influenza disease in vaccinated vs placebo groups.
FluMist: Clinical studies show a reduction in influenza disease in vaccinated vs placebo groups. The data for FluMist are the most impressive, getting as high as 96% efficacy with certain flu strains.
FluVirin: Only shows immunogenicity data, induces antibody response that exceeds the threshold defined for success.
FLUZONE: Only shows immunogenicity data, induces antibody response that exceeds the threshold defined for success.
Afluria: Only shows immunogenicity data, induces antibody response that exceeds the threshold defined for success.
Agriflu: Clinical studies show a reduction in influenza disease in vaccinated vs placebo groups.

Interestingly, it appears that approval of flu vaccines is based on showing that the vaccine can induce a strong antibody response, not showing that the vaccine prevents the disease.

Package inserts don’t communicate the whole story. We also have to consider the total body of evidence, not just one or two tests. There are many other clinical trials demonstrating the efficacy of flu vaccines. Such as this one, this one, this one, and this one.
In the clinical trials described in the package inserts, the severity of disease is not indicated. Did the vaccinated people get less severe disease than the non-vaccinated people? A vaccine that induces sufficient immunity so that it prevents severe disease although you might still get a sniffle, would still be pretty good. There are other outcomes to consider too. Does the vaccine reduce transmission or complications following influenza disease? In Canada, Ontario made efforts to dramatically increase influenza vaccination, with the result of reduced influenza associated mortality and reduced healthcare use. And take this study in which it was found that vaccination of healthcare workers didn’t reduce incidence of flu in those vaccinated but reduced the mortality rate of their patients.

There is an obvious need for a flu vaccine that induces better protection, especially in children and the elderly, and ideally, one that is universal so we dont have to go every year to get a shot and dont have to depend on predictions of what is going to circulate in the future. But the evidence that the flu vaccine is beneficial for individuals and society is pretty strong. Finally, I think this emphasizes the importance of digging deeper to understand the information around us. It is never as simple as it seems and we must avoid reducing information to the simplest single sentence thus removing the underlying complexities.

Disclaimer: I am “not that kind of doctor” so this is not intended to provide any medical advice or recommendations for which vaccine to use.

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Vaccines

Dear Hudson Valley Parent Magazine, Part 2

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Hopefully readers will remember that several months ago I posted a draft of a letter to Hudson Valley Parent Magazine, a local parenting magazine that can be picked up free pretty much everywhere in the Hudson Valley, including doctor’s offices and schools and anywhere families go. The magazine had published an article in support of the debunked idea that vaccines cause autism. Rather outraged, I felt it was my responsibility to write to the magazine and inform them of the current state of the research and the dangers of continuing to perpetuate this myth.

The magazine doesn’t publish letters to the editor so I wasn’t sure if anything would come of it. I sent the letter to the editor, who replied quite quickly. She posted my letter, along with a letter from a local pediatrician, on the website. She also requested an interview so that she could write a follow up to the article. The interview appears in this month’s issue of the magazine. Although short, and perhaps unlikely to undo the damage of the original article (and, I think, not as good as the letter I wrote), I am thrilled that the editor agreed that this was important enough to include in the print edition of the magazine.

This experience has been very valuable to me. I usually clam up and can’t confront people about this sort of issue, because I become fired up and perplexed and feel like I can’t make coherent arguments in support of my position. However, I realized that my target audience wasn’t the “true believers” but parents on the fence about vaccination or simply in need of accurate information. We are never going to be able to convince those who so blindly believe something in spite of overwhelming evidence against it, but I think (or at least hope) that most people are not like that and are simply seeking good, reliable information to inform their decisions. I am glad to contribute to the pool of good information.

In related news, the Institute of Medicine has, after a review of apparently 1000s of studies, once again determined that vaccines are safe and don’t cause autism. Shocker!

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Epidemics, Uncategorized, Vaccines

Goodbye Rinderpest, Hello Measles

Variola virus, the agent of smallpox, once held a lonely spot on the list of globally eradicated diseases. Now it is joined by rinderpest, the cattle plague. The OIE (Organization for Animal Health) declared the disease eradicated and the UN’s Food and Agriculture Organization (FAO) is expected to adopt a resolution in June declaring it eradicated. The disease affects cloven-hoofed animals and can have an extremely high mortality rate in some cattle and buffalo. It is also extremely contagious, so its rapid spread through livestock can have an obviously large impact on animal health, food production and livelihood of cattle farmers. Thanks to an intensive word-wide vaccination effort, rinderpest virus can now be added to the list of organisms we actually intended to make extinct.

Rinderpest is caused by rinderpest virus, a member of the Morbillivirus genus. Another member of that genus is measles virus. Oh, and there is a vaccine for that too. In fact North America was free of measles in 2002 and perhaps it was on track for global eradication. But not anymore.

My son recently turned one, so I took him to get his measles, mumps and rubella (MMR) vaccine, feeling confident that Im helping protect him from three pretty nasty viruses, and not giving him Autism. In fact, before he turned one, I’d been feeling a little anxious about getting him the vaccine soon enough. My email inbox keeps filling up with notices from ProMED mail (Program to Monitor Emerging Diseases) with news of various measles outbreaks across the globe.

There are outbreaks all over Europe, especially in France, the UK, Spain and Switzerland. The epidemic in France that started in 2008 has now reached over 14,000 people, with 9000 of those infections reported in the last 6 months. (France has a vaccination rate of about 60%. Vaccination rates in the UK bottomed out at 80% and are slowly on the rise again). Outbreaks in the USA and Canada have been small, the vaccination rates are higher but not high enough. Many of these can be tracked to travel of unvaccinated individuals to areas where measles is still endemic or flaring up. In Minnesota, an outbreak counting 21 people has sent 13 people to the hospital (an unusually high number). Of the 21 people, 8 were old enough to be vaccinated but weren’t, 7 were too young to be vaccinated, 1 was vaccinated and the status of the others is unknown.

The Minnesota outbreak emphasizes an important point: it is necessary to maintain a sufficiently high level of herd immunity to prevent outbreaks and protect those who can’t be vaccinated. For most diseases, vaccination rates need to be at or above 95% to prevent outbreaks, and may need to be even higher for measles. Virus transmission depends on the virus finding a susceptible host. If a population is primarily made up of immune individuals, the virus has a hard time maintaining a chain of transmission.

Vaccination is therefore not just a matter of personal health, but community health. Maintaining high herd immunity helps protect babies too young to be vaccinated by limiting the chances that they ever encounter the virus. Don’t just get your kids vaccinated to protect themselves, do it to protect us all.

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Epidemics, Evolution, Guest Blogger, Vaccines

Swine Flu: New and Improved!

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Contributed by guest blogger: Marni Hershbain ’11

Flu season is never enjoyable, but some seasons are certainly worse than others. The 2009 swine flu outbreak was particularly serious because the 2009 H1N1 strain was a novel virus, formed via the reassortment of swine, avian and human flu viruses. There were over 600,000 confirmed cases of H1N1 and over 18,449 deaths during the course of the pandemic. While this sounds pretty bad, it could have been much worse. The transmission efficiency of H1N1 was actually much lower than those of other pandemic strains, such as the 1918 H1N1 strain. Unfortunately, recent research demonstrates that this could change.

Flu strains are characterized by the hemagglutinin and neuraminidase found on their surfaces, hence names like H1N1. In order for the virus to infect a cell, hemagglutinin on the surface of the virus must bind to glycan receptors on the cell. Therefore, to explain the low transmission efficiency of 2009 H1N1, researchers looked to its hemagglutinin.
In most flu strains, the amino acids at positions 219 and 227 within the hemagglutinin are both hydrophobic or both charged. In 1918 H1N1 both are hydrophobic. However, the 2009 H1N1 strain has isolucine, a hydrophobic molecule, in position 219 and glutamic acid, a charged molecule, in position 227. Researchers hypothesized that lacking either hydrophobic or ionic interactions at these positions would disrupt the positioning of neighboring residues and decrease the hemagglutinin’s binding affinity. They further hypothesized that if they replaced isolucine with the charged amino acid lysine, stable inter-residue interactions would occur and binding affinity would increase.

When researchers compared the ability of wild type and isolucine→lysine mutant strains to bind to an array of glycans representing human binding sites, they found the binding ability of the mutant strain was 30 times greater. The mutant version also bound more intensely to receptors in human tracheal tissue. Researchers also infected ferrets (commonly used as models in human influenza studies) with either wild type or mutant virus. Only the ferrets infected with mutant virus spread the infection to all of the previously uninfected ferrets placed in close proximity to them.

The mutation of just one amino acid could greatly impact the transmission efficiency of 2009 H1N1. Flu viruses tend to mutate frequently, which is why a new vaccine needs to be developed every year. Predicting what these mutations will be is not an easy task, but mutations at the positions in this study will certainly be monitored closely.

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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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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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Guest Blogger, Immunology, Vaccines

Eat Your Vaccines

6 Comments

Contributed by guest blogger: Nicole Engelhardt ’11

Usually when you get a vaccine it means you get a needle and a bandage. Not only that, but you get an attenuated virus. These weakened virus particles are strikingly similar to viable ones; they even infect cells. Because of their weakened state, they infect slower than natural virus particles, giving the body time to react. However, people who have weakened immune systems can still exhibit symptoms as if they were infected by the natural virus.

But a new tool may make this issue obsolete. What really matters when it comes to a vaccine is the shape of the particle, not the contents. The shape is recognized by B-cells in the body which then reproduce creating antibodies that attack all of the virus particles. However, these B-cells are very specific and very picky. Normally, it makes sense to use a weakened virus because it has the exact same shape as a normal virus and your B-cells will react to the vaccine as if it were the real thing. Is there any way, then, to produce the exact shape of the virus and therefore the correct antibodies without having the harmful side effects?

This paper explores the rotavirus particle which is the leading cause of gastroenteritis in the world. In some parts of the world, gastroenteritis can be deadly for many children. As it happens, the shape of the rotavirus particle can be mimicked almost exactly in plants. The shape of this virus is a capsid made out of proteins. First, the authors take the genes that code for the capsid proteins and insert it into the genome of the plants. Then the plants express the viral genes, creating the virus capsid proteins inside the cells of the plants. More incredible than that, these proteins self-assemble into the exact shape of the rotavirus capsid. Now you have a plant containing just the shell of the virus!

The experiments are still in their early stages, but when mice were fed these plants, the authors found they were producing the same antibodies that are produced when mice are actually infected with rotavirus. This bodes well for future research in humans. Once the antibodies are created, the severity of future infections is greatly decreased. If these transgenic plants do work, it could mean a safer and perhaps more affordable form of the vaccine that could help people the world over fight rotavirus before it can infect.

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