All posts by David Esteban

Guest Blogger, Immunology, Molecular Virology

Polydnavirus: Good for the Parasitic Wasp, Bad for the Host Caterpillar

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Contributed by guest blogger: Jason Adler 

An endoparasitoid wasp would disagree with the popular perception of viruses as malevolent. Parasitoids are organisms that spend a substantial portion of their life cycle in the host; unlike a parasite, a parasitoid usually kills or sterilizes the host. Endoparasitoid wasp oviposit into the body cavity of caterpillars. When the wasp larvae emerges, it then consumes the host as it develops.

Polydnaviruses (PDV), a family of double stranded DNA insect viruses, are symbiotic to some endoparasitoid wasps. Of two PDV genera, genus Ichnovirus is specific to ichneumoid wasps and Bracovirus to braconid wasps. The PDV genome is located on host wasp chromosomes in a segmented, proviral form. However, the integrated PDV genome is not fully functional as it cannot replicate independent of the wasp and capsid proteins are non-existent.  It is unknown if PDV is derived from wasp genes or if ancestral wasps integrated a beneficial PDV into their genome with resulting loss of the genes responsible for capsid formation and virus replication.

As such, PDV only replicates at specific ovarian cells during the late pupal phase, where it acquires two viral envelopes. PDV integration does not occur in the viral life cycle; instead, the viral genome is vertically transmitted to wasp offspring during meiosis. When the female wasp injects her eggs into the lepidopteran host, virions are co-injected and result in infection. Although, PDV does not replicate in the host caterpillar, it does result in immunosuppression and alters the host development (i.e. prevents metamorphosis) and metabolism to favor the parasitoid larva. The normal response of lepidopteran larvae to small foreign material is phagocytosis, but larger pathogens must be encapsulated. This is accomplished through melanization, where certain hemocytes, invertebrate immune cells found in the hemolymph, secrete melanin, which surrounds the pathogen so that anti-microbial peptides can destroy it. When immune suppressed, host hemocytes do not destroy the wasp egg by forming hemocyte nodules. Thus, PDV and the wasp share a mutualistic relationship.

Cotesia plutellae, a braconid wasp, possesses a PDV – C. plutellae bracovirus (CpBV) – and parasitizes larvae of the diamond-back moth Plutella xylotsella. Recent research has found that CpBV encodes a viral histone H4 that shares high sequence homology with histone H4 on P. xylostella, except for the last 38 residues comprising the N-terminal tail. Additionally, this viral histone H4 N-terminal tail have been observed in other Cotesia-associated PDVs. It has been suggested that the N-terminal tail is altering gene expression regulation as viral H4 histones less easily detach from DNA than host H4 histones, thereby inhibiting transcription. Is the N-terminal tail of CpBV-H4 causing immunosuppression? The researchers hypothesized that the N-terminal tail is causing the suppression of antimicrobial peptide (AMP) genes.

To examine the effects of CpBV-H4, the researchers constructed two viral recombinants: a WT CpBV-H4 and a truncated CpBV-H4 that lacks the N-terminal tail. After injection of the viral vector into the host caterpillar, RT-PCR was used to look at the expression of putative AMP genes. Although basal expression levels were unchanged, when E. coli was introduced to the host to present an immune challenge CpBV-H4 inhibited inducible expression, while truncated CpBV-H4 did not. Additionally, by counting the number of melanized black nodules on the host caterpillar after injection of E. coli and the viral vector, the researchers assessed the immune response. While the larvae show hemocyte nodule formation in response to E. coli infection, transient expression of CpBV-H4 significantly suppressed the immune response by decreasing nodule formation, while truncated CpBV-H4 had no effect. Finally, the researchers examined a possible synergistic effect of CpBV-H4 and the entomopathogenic bacterium X. nematophila. Without CpBV-H4, X. nematophila infection resulted in low mortality; however, with CpBV-H4, there was significantly increased mortality with this synergistic effect lost if CpBV-H4 was truncated.

Based on these results, the researchers concluded that the N-terminal tail appears to be responsible for immunosuppression by inhibiting inducible expression of AMP genes, possibly by altering a normal epigenetic control. CpBV-H4 containing nucleosomes may less easily detach from DNA during transcription due to the increased positive charge resulting from the increased number of lysine residues in the N-terminal tail. By introducing a virus that expresses a viral H4 histone with a N-terminal tail, the parasitoid wasp is able to suppress the host immune system. This is important as without the immune suppression, the host hemocytes would encapsulate and destroy the wasp egg.

With 157 putative genes, CpBV is likely to have more than this one mechanism to suppress host immunity. Are there other mechanisms of CpBV immune suppression?  How else is the complex ecological relationship of wasp, virus, and caterpillar host mediated at the molecular level?

Link:

http://www.sciencedirect.com/science/journal/0006291X/415/2

Jason Adler is a senior at Vassar College, majoring in biology.

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Uncategorized

Founding editor of JVI, Lloyd Kozloff, dies

The Journal of Virology was founded in 1967 by three scientists, including Lloyd Kozloff, who passed away this week.

Sarah Kozloff, Lloyd’s daughter, is a professor in the Film Department at Vassar College.  She told me of her scientist father about a year ago and I did a little digging to find out more about him and his career.   Kozloff began his career as a scientist in a very exciting time.  He was a part of a group of bacteriophage biologists at Cold Spring Harbor in the late 1940s and early 1950s.  Members of this group revolutionized biology by ushering in a new discipline called molecular biology.  Very little was known about viruses or the molecular mechanisms that make cells work.  Other members of this group would go on to demonstrate that DNA was the genetic material (A.D. hershey) and discover the structure of DNA (James Watson).  Sarah mentioned to me that she remembered the party that the Kozloff’s threw to celebrate Watson’s Nobel prize.  The names of scientists that are legendary to most of us were, to the Kozloffs,  part of everyday dinner table conversation about friends and colleages.

Lloyd Kozloff made some important contributions to phage biology and basic understanding of viruses.  He was one of few people using a new technique in biology: radioisotope labeling.  In a 1948 paper he used phosporus isotopes to determine that phages obtain their phosphorus primarily from the media, though he presumed it must be vis a cellular metabolic pathway.  That paper in Science, has a single table, the result of what appears to be a single experiment.  The phosphorus was all in the DNA component of the phage, something that would be important later when Hershey and Chase showed in 1952 that DNA was the genetic material.   In fact, the authors are careful to define the acronymn DNA, the macromolecule perhaps being something not too familiar to many at the time.    In a later 1956 paper, Kozloff demonstrated that the bacteriophage does something to the bacterial cell wall to allow the genetic amterial to enter, and that activity was conferred by some kind of protein.  We now know that what he was seeing was the action of lysozyme, an enzyme at the base of the bacteiophage tail that degrades the bacterial peptidoglycan wall to allow the DNA to enter the cell.

I rarely go so far back in the literature, although it is always interesting to see the foundational papers upon which our current knowledge is based, and to see the style of experiments, the difference in the style of scientific writing and presentation, and to imagine what it was like to explore virology without really understanding yet what viruses really are or how they work.

The journal of virology will be publishing an obituary and I will add a link once it is available.

The university of San francisco, where Kozloff spent the last part of his career, has a brief biography.

A scholarship fund to support graduate students has been created, to which donations can be made in his name.  (The family has specifically requested donations to this fund in lieu of flowers.  A card will be sent to the family.)

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Teaching and Research

How do you read popular science articles critically?

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It is increasingly important for us to become critical readers. It is easy to find information on any scientific topic, but it is often easier to find poor quality information than high quality, accurate information. Is it really a promising cure for cancer? Is the vaccine actually going to work or even come to market? Is this really the next outbreak that threatens us all? How do we make sense of this information? It is not always easy to distinguish the good articles from the bad.

Last semester in my Microbial Wars class, students selected news articles and presented the article along with a discussion of its merits and problems. Over the course of the semester, the students identified several features that helped in critically evaluating the articles. Below are some of the major points they came up with.  You can test your critical reading skills on this article on the HPV vaccine or this one on a transmissible H5N1 influenza virus.

1. Source: does the publication tend to publish reliable and accurate articles?

2. Author: does the author of the article have a science background? Have they written other science articles? Since a journalist has to interpret and explain the research, their ability to understand the research and its context are important, otherwise they may simply be repeating back information from press releases or other sources without critical evaluation of the information.

3. Is the original source easy to find? Are there links, or sufficient details to know who did the original research so that if you want to find the original source, you could do it fairly easily.  Do the sources or studies that the article cites or links to actually support their statements, and are they reliable?

4. Is the research being described published in a peer-reviewed scholarly source? If its not peer reviewed, beware! Is it based on conference proceedings? Conference presentations and abstracts are very minimally reviewed, and should not be considered equivalent to a published study. Often the data from a conference proceeding hasn’t been seen by most scientists or the journalist, so use great caution when reading about this kind of unpublished information.

5. We talk a lot about articles being sensationalized, but what does that mean? It means presenting information in a way that provokes interest or excitement, at the expense of accuracy. Watch out: this happens a lot, even in the most reputable news sources and with top writers. Is the article making unsubstantiated claims? Consider carefully what the research has shown or what specifically was tested. Are the statements made in the news article accurately reflecting what the research shows, or is it taking it several steps beyond the results of the research? Remember that scientific research tends to move in slow, baby steps, not leaps and bounds.

6. Balance: What makes a balanced article? Should different perspectives be included? Should contrary opinions be presented? If so, how much weight should be given to “dissenting” views? A common problem is presenting two sides of a debate as if both sides are equally supported. This can lead to a false sense of how much debate there really is among those in the field.

7. Motivations: what are the motivations of the people quoted or referenced in the article? Are those individuals likely to have an unbiased perspective on the research? You will sometimes see comments or quotes from researchers not involved in the particular study being discussed; these can often provide a good perspective.

8. Headline: headlines are written to draw readers in, and so are likely to be sensationalized or inaccurate. (They are also often written by somebody other than the author of the article). Does the headline accurately portray what is in the article? If you only remember one key message from the article, it probably shouldn’t be the headline.

Considering these points when reading an article may help in reading it critically. No single point will make or break an article, but this is at least a good place to start.

Thanks to the students of Bio/STS 172 for interesting discussions and developing this list!

Any other suggestions?

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Epidemics, Evolution

Evolving Avian Flu for Enhanced Transmission

Avian influenza (H5N1) infections have about 60% mortality rate. Only around 600 people are known to have been infected, so it is still a very rare but certainly deadly disease. Those infected are individuals who have direct contact with infected birds. Although some cases of human-to-human transmission have been suspected, good evidence for this is lacking. Its an important virus in agriculture too. When H5N1 is identified in domestic birds, the usual response is a massive cull, resulting in millions of birds killed and farmers left in great financial difficulty.

The question of whether such a virus could mutate to cause a human pandemic is an important one. In the history of flu pandemics, only H1, H2, or H3 viruses have been involved. Is it impossible for H5 to cause a pandemic, or has it simply not happened yet? If it could, would it retain the same level of pathogenicity, or in adapting to human-to-human transmission, would it become less virulent?

To answer the question of the possibility of human-to-human transmission, some researchers in the Netherlands performed some experiment to evolve H5N1 to become more transmissible. They infected ferrets, and over several passages (moving the virus from one animal to the next) managed to encourage transmission between ferrets. The virus adapted to transmission between ferrets, changing slightly from the original virus. The changes are minor, only 5 mutations in 2 genes. However, this research has caused some significant concern: they have generated a transmissible form of a highly pathogenic virus. Is this a good idea?

Importantly, the results have not been published so all this information is from news reports and interviews. Few people have seen the data.

This is what scientists call “dual-purpose” research. On the one hand, it can answer important questions. On the other, it can lead to the development of biological weapons, ideas for biological weapons, or seriously bad accidents. The best science writers are having a hard time not sensationalizing this. Even the researcher who did it seems to be playing up the drama. What if it gets out? Millions will die! But is there a real risk from this virus?

Its hard to know the facts without the published data.

How well does the ferret model the pathogenicity and transmissibility in humans? It is commonly used and generally accepted to be quite good, but it seems a stretch to assume a human pandemic can occur based on transmission between ferrets in the lab. We need to be careful not to over-extend the findings of the study (this is especially the case since the data is not available). The experiment presumably shows that the virus can be transmitted between ferrets. It does not demonstrate that this virus can cause a human pandemic.

How pathogenic is the new virus? Does it cause the same disease as the original virus or did the mutations that allow transmissibility also decrease virulence? Maybe it can spread human-to-human, but its not clear how sick they would get. Further, usually when a virus is passaged several times through a different host species, it adapts to that species and results in attenuation in the original host. This has been observed many times, and has even led to the development of several attenuated vaccines.

Related to this, many evolutionary biologists believe that virulence and transmission are closely tied. That is, a virus that is too deadly will cause outbreaks that fizzle out (Ebola is a good example). Viruses that don’t cause enough disease might have a hard time transmitting too (coughing, sneezing or diarrhea are good examples – a little bit of disease helps get the virus out of your bod and into the next one). Paul Ewald argued that the high mortality rate of the 1918 influenza was in part due to the fact that the conditions at the time allowed for a more deadly virus to evolve. Due to WWI, factors such as overcrowding and troop movements may have allowed a highly virulent virus to be successful. Conditions today may not favor a pandemic by a highly virulent virus. So would a transmissible and pathogenic H5N1 cause a major epidemic or would it fizzle out?

There is also the issue of publication. There is debate on whether the research should be published or kept secret. Does publication provide a roadmap for someone who wants to do this for evil purposes to repeat the experiment and create a biological weapon? It seems to me that even without details of the experiment, enough information is already available to repeat it. Withholding publication would also prevent other researchers from understanding and extending the findings. Any benefits from having done the experiments would be significantly less without publication.

I have seen stories like this one before. Several years ago, an highly pathogenic ectromelia virus (causes mousepox, related to the smallpox virus) was made by adding the gene for Interleukin-4. The researchers did not intend to make a highly pathogenic virus, it was rather a surprise to see this effect. There was much debate about whether they should publish, that perhaps this was a roadmap for building a highly pathogenic poxvirus in humans. They published and we have since learned more about the virus, including the observation that the virus does not transmit effectively, and that doing the same thing in other viruses doesn’t have the same effect. The more we know, the better.

I’d make the same argument here. I’d like to see the research published. The information from this study is probably valuable, addresses an important question, and is only one small step in understanding H5N1 influenza.

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Epidemics, Teaching and Research, Uncategorized

I’ll take my milk pasteurized, thanks

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A recent article in Vassar’s newspaper, The Miscellany News, discussed the Vassar Raw Milk Co-op, which brings unpasteurized milk to Vassar College (Co-op offers raw milk delivery service, Nov 10,2011). The article raises several important questions about raw milk, pasteurization, and sustainable agriculture, but some of the information presented is incorrect. Importantly, Vassar’s Raw Milk Co-op website, to which readers are directed, has a great deal of misleading, incorrect or unsubstantiated information.

In the production and packaging of milk, it can become contaminated at virtually any stage of the process. That contamination, when it is by organisms like E. coli or Listeria, is what causes milkborne illness. Pasteurization, a process of heating milk to reduce the levels of microorganisms present, will kill those contaminating bacteria if they are present. The risk in drinking raw milk is due to the fact that if it does become contaminated, you will be consuming those pathogens. In a farm environment, it is safe to assume that contamination will, at some point, happen. Pasteurization is one check that we have to protect us from that.

The majority of cases of milkborne illness result in diarrhea and/or vomiting. Occasionally the symptoms can be more severe, such as in last week’s outbreak in California, in which five children have become sick. Three have been sent to the hospital with hemolytic uremic syndrome, which can lead to kidney failure. These cases have led to the recall of the organic raw milk, contaminated with E. coil 0157:H7, which has been linked to the outbreak. There are outbreaks associated with pasteurized milk as well, usually due to post-pasteurization contamination, such as at the packaging stage. However, it is estimated that only 1% of people consume raw milk, but from 2000-2007, 75% of outbreaks were associated with contaminated raw milk.

In NY consumers can choose to buy raw milk from a farm if they determine that they are comfortable with the level of risk. But it is also important that they know the facts behind the reported benefits to balance their decision. Many proponents of raw milk claim that industrially raised, antibiotic laden cattle given GMO corn feed produce milk that needs to be pasteurized because it is inherently of poor quality and unsafe, but that organically raised pasture fed cows produce milk that is safe. That is simply untrue. Pasteurization was developed in the mid 1800s to eliminate pathogenic and spoilage microorganisms, not to fix the problems of industrialized agriculture. There is no credible scientific evidence to support the suggestion that organic pasture-fed cows generate safer milk than cows from industrial farms. Contamination by pathogenic organisms comes from fecal matter, the environment, the handlers, packaging, storage, and undetected infections in the animals, and is unrelated to diet and housing conditions.

Additional claims such as that pasteurized milk causes allergies, asthma or other conditions are not supported by the scientific literature. The claim that raw milk is better for individuals who are lactose intolerant is not supported by scientific data either, and represents a clear misinterpretation or misunderstanding of available information. The level of nutrients in raw compared to pasteurized milk is not significantly different, invalidating yet another central claim in support of raw milk.

There is an abundance of misinformation on the topic of raw milk. Unfortunately, groups like Vassar’s Raw Milk Co-op perpetuate this misinformation. At Vassar, we often say “go to the source.” This is an opportunity to practice that principle. Rather than seeking confirmation of one’s beliefs in the websites of others, we must check the original research. What is actually supported by credible scientific investigations? Is the information you are reading being correctly interpreted? Are you getting the whole story or just fragments?

There are many good things about the locavore and Slow Food movements. Supporting small local farms and sustainable agriculture, humane treatment of animals and having the sense of community achieved from getting to know the farmer who raises your food, are important to me and many people. But you don’t need to consume raw milk to do that. These issues are distinct from the question of pasteurization. If you want, you can even get the raw milk and pasteurize it yourself. Just heat your milk on the stove to 63C for 30min before drinking it.

Thanks to the students in STS/Biol 172 for discussion and research on this topic

A few links:
FDA Milk Safety

CDC Milk Safety

Review on Milk Safety and Pasteurization

A recent review of the scientific literature. Note that they included many studies of poor design, which should have been ignored.

Slightly updated and edited on December 1, 2011

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Molecular Virology

Discovery of an Ebola-like virus in Spain

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Fans of Richard Preston’s The Hot Zone will know Ebola virus and Marburg virus as ones that causes their victims to die a horrific death, bleeding from every opening and turning organs into a bloody pulpy mess. Ebola outbreaks occur sporadically in central and west Africa, and despite extensive efforts, its still not known where the virus comes from. The best evidence is that bats carry the virus, and contact with bats or bat excrement in caves sparks the outbreaks. Ebola RNA has been detected in bats, but no one has been able to find live virus in bats.

But now a close relative of Ebola and Marburg viruses has been discovered in bats in Spain. And unlike Ebola and Marburg, which don’t cause disease in bats, it is possible that this newly identified virus is killing the bats. A recent bat die off in Spain killed several bat colonies in a little more than a week. So researchers searched for viral sequences in the bats and identified an new filovirus, and called it Lloviu virus, after the cave in which it was found. They found the same viral sequence in other caves that experienced die offs, and could not find evidence of the virus in healthy bats.

This finding is significant for several reasons. It is the first detection of a naturally occurring filovirus outside of Africa and The Philippines. The bats in Spain do not overlap with the known geographic range of Ebola and Marburg viruses so its unlikely that it would have been picked up there. There have been bat die offs across parts of western Europe, and it will be interesting to see if Lloviu virus is found at all these locations.

Also, it might be making the bats sick. The key word being might. In my class called “Microbial Wars” we have discussed Koch’s postulates and hopefully my students will recognize that these are far from fulfilled. Live virus has not yet been isolated from diseased animals, only detection of the viral genetic material. Researchers will need to demonstrate that experimental inoculation of bats with live Lloviu virus will cause the expected disease.

Cueva de Lloviu is frequented by tourists, so its possible that many people have been exposed to the virus without ever developing disease. So this is not a human health concern but it is an important discovery that may help us understand filoviruses better, especially with respect to their ecology.

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Evolution, Molecular Virology

Taking control of the host to spread virus laden goo

Viruses are experts at hijacking cells to replicate, manipulating the conditions in the cell to optimize viral processes. But they manipulate their hosts on a higher level too, sometimes manipulating host behaviour to increase the chances of transmission. Take rabies virus for example: the virus induces aggression, then replicates abundantly in the salivary glands and stimulates salivation. The aggressive host is driven to bite, spreading the virus to its next host.

The basis for these bahavioural changes is poorly understood, on both the viral and host ends. However an experiment published in Science recently identifies the genetic basis for host behaviour manipulation by a baculovirus that infects the gypsy moth. When a baculovirus infects its host, the host eventually dies in a gruesome death appropriately called “virus melt.” The insect is liquefied, and the gooey, virus laden liquid drips down from the remains of the host on to the leaves below. Unsuspecting insects will then eat the contaminated leaves, becoming infected themselves.

So how could a virus maximize the dissemination of said liquid? How about having the host climb to the top of the plant and stay there to die, dripping all the liquid on the leaves below? The normal behaviour of the gypsy moth is to climb up a tree and munch on leaves during the night, and hide in crevices or climb down to the soil during the day, thus avoiding predation by birds. This behaviour is regulated by a hormone, 20-hydroxyecdysone, which tells the gypsy moth when to stop feeding and move down the tree (it also regulates molting and pupation). Baculovirus infected gypsy moths, however, climb up but don’t climb back down, staying up in the tree to die.

Baculoviruses expresses a gene that deactivates 20-hydroxyecdysone and prevents the infected host from leaving its “feeding state” and descending the tree. When researchers deleted the gene from the virus, the infected gypsy moths displayed normal behaviour.

I’d love to see a transmission experiment to see if the presence of this gene really helps with transmission to the next host.

(Also discussed on TWiV)

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Epidemics, Guest Blogger, Uncategorized

I Don’t Want Dengue Fever

When a student is absent from class, they usually send me an email to explain why. Occasionally I get emails from students in my microbiology or virology classes explaining their absence from class as a result of some infectious disease and they actually seem excited about the fact that they are hosting a virus. Perhaps they feel that they are participating in the class on a whole new level or are appreciating and understanding what is going on in their body, despite feeling awful. However, I was surprised recently when I mentioned Dengue Fever and a student piped up and said “I’ve had that!” I asked Caitlyn to write about her experience, and she kindly agreed. While she is interested in learning more about the virus, I suspect she would have preferred to learn about it without first hand experience. Here is her story.

Contributed by Caitlyn Anderson ’13

Photos of Angkor Wat in Siem Reap, Cambodia. Taken by Caitlyn Anderson.

“I was infected with Dengue virus in Cambodia during the summer of 2007 while working as an intern for the Clinton Foundation. I knew before going that there was a Dengue epidemic across the country but was unwilling to give up the opportunity. It is likely that I was bitten by a mosquito carrying the virus while I was sight seeing in Siem Reap towards the end of my stay. The virus incubated within my body for a period of approximately 5 days. Thankfully, I was back on U.S. soil when the virus began to present itself. I remember feeling slightly odd as I worked the night shift at Starbucks. After I returned home I immediately went to bed. In the morning I had developed flu like symptoms with a fever of 100 degrees. My body began to feel achy and I remained in bed throughout the afternoon. By 3:00 pm my temperature had reached 103 degrees and by 5:00 pm, my temperature was up to 104 degrees and I could barely move. My mother immediately called my pediatrician who then instructed us to go to the Emergency Room. I had immense difficulties walking from my bed on the second floor to the car. When we got to Norwalk Hospital in Connecticut, I was unable to walk and required the assistance of a wheel chair. The initial reaction of the emergency room doctor who saw to me first was that I was presenting with Lyme like symptoms. However, the unbearable pain caused by the insertion of the IV into my arm was not indicative of Lyme disease so I was immediately admitted to the hospital for further tests and supportive care. A few hours later my fever had reached 105 degrees and was coupled with the sudden onset of rash covering my entire body. The virus began to affect my nervous system causing extreme skin tenderness. Infectious disease specialists were brought in to evaluate my case. A Haitian doctor was immediately convinced I had Dengue Fever because she had witnessed the disease many times. Unsure of which of the four strains I had been infected with, the doctors could not predict the clinical evolution of the disease.
My fever remained between 103 and 105 degrees for 3 days. I was treated with fluid intravenously and pain medication for my body aches and severe skin sensitivity. My body was packed with ice in an effort to lower my body temperature. While Dengue Fever is commonly referred to as “breakbone fever” because people often feel as if there bones are being crushed, I did not experience this sensation. My skin, rather than my bones and joints, was the greatest cause of my discomfort. On day 4 of my hospital stay, my fever began to go down to 100 degrees but I was transitioned to the telemetry unit so that my heart could be monitored more closely. I continued to receive IV fluids and pain medication. I remained in the telemetry unit until day 6 when I was moved to a general ward where I remained until my release from the hospital on day 8. My fever had completely dissipated but I was very weak and had trouble walking. When I returned home I slept for 16 hours a day for about a week and was able to return to school a few days later with a reduced academic schedule. About a month later I regained my strength was symptom-free.”

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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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