In the past months, Ebola has received a lot of attention. As of December 3, 2014, the Ebola Response Roadmap Situation Report published by the World Health Organization (WHO) counted 17,145 reported cases and 6,070 reported deaths. However, another viral disease deserves the same level of attention — dengue hemorrhagic fever, which is sickening up to 100 million people a year and killing more than 22,000. We’re in presence of a pandemic — the disease is present in more than 100 countries. It is a leading cause of hospitalization and death among children in some Asian and Latin American countries, but it’s also found in Southern Europe and the United States.
Dengue is not transmitted directly from person-to-person. Instead, it is transmitted by the bite of a mosquito infected with one of the four dengue virus serotypes. It is a febrile illness that affects infants, young children and adults. Symptoms range from mild fever to incapacitating high fever with rash, severe headache, pain behind the eyes, as well as muscle and joint pain. The disease is also known as “breakbone fever” due to the severe pain it can cause.
Severe dengue (also known as dengue hemorrhagic fever) affects mainly children, and is characterized by fever, abdominal pain, persistent vomiting, bleeding and breathing difficulty — it is potentially deadly.
The WHO estimates that about half of the world’s population is now at risk. However, at this time, there is no licensed vaccine or any specific medicine to treat dengue. Fortunately, there is hope. Several vaccines are in the final steps of development, with the one produced by the French pharmaceutical company Sanofi Pasteur awaiting regulatory approval — after a successful study showed it was safe and effective.
Results from the successful studyl — a phase 3 efficacy trial of a tetravalent dengue vaccine tested in five Latin American countries where dengue is endemic — were announced by Sanofi Pasteur on November 3, 2014. The results were published the same day in the New England Journal of Medicine (Efficacy of a tetravalent dengue vaccine in children in Latin America).
For the study, healthy children between the ages of 9 and 16 years were enrolled in Colombia, Brazil, Mexico, Puerto Rico, and Honduras from June 2011 through March 2012. The five countries were chosen on the basis of the incidence of dengue. The vaccine preparation included four recombinant dengue vaccine viruses, each constructed by substituting genes encoding the premembrane and envelope proteins of the yellow fever 17D vaccine virus with those from wild-type dengue viruses.
The researchers found that the vaccine had an efficacy of 60.8% against symptomatic dengue in children that followed a three-dose vaccination schedule. They also found serotype-specific efficacy against all four dengue serotypes. Over the 25-month trial period, the researchers observed efficacy of 80.3% against hospitalization for dengue and 95.5% against severe dengue.
Jianzhu Chen, an immunologist at MIT, told the Verge: “The dengue vaccine does not work so well. But it does appear to reduce hospitalization rates, which means that it probably reduces the severity of dengue symptoms. It’s the best dengue vaccine so far, and its eventual approval will be a milestone for tropical medicine after such a long effort.”
The New York Times points out that Sanofi Pasteur plans a tiered pricing approach to keep the vaccine within the reach of the many poor people who need it.
Copyright © 2014 Immunity Tales.
Many mosquito-borne diseases are successfully spreading worldwide, which are affecting children’s and adolescents. These diseases include malaria, dengue, Filariasis, and West Nile virus. Dengue fever is a very old disease and has reemerged in the past 20 years. As this article states, dengue is transmitted by the bite of a mosquito infected with one of the four-dengue virus serotypes. My question about dengue hemorrhagic fever, is the expression of CD8+ T cells being altered by the dengue viruses’ serotypes? This is important to know because the Dengue Hemorrhagic Fever is successful controlling the immune system in many humans. A recent study provides research on T Cell Responses in Dengue Hemorrhagic Fever. This study demonstrates that the cases that contribute to Dengue Hemorrhagic Fever are not suffering from a primary infection but are being reinfected with a virus of different serotype. Viruses are unique in their own way and being infected with different serotypes can trick the immune system. After being reinfected with a virus of different serotype, 50 percent of T cells showed no reactivity to stimulation with this epitope. The T cells are not bystanders because they have undoubtedly undergone proliferation during the secondary response. Also, a high number of cross-reactive T cells demonstrated cytokine production but does not degranulate in secondary infecting virus. Meaning that when the virus is finally controlled it will occur in an expansion of T cell response and a cytokine storm. It is great to see a vaccine that can help eliminate several of the serotypes in dengue. It will also be very interesting to see the long-term effects of the tetravalent dengue vaccine for one of the many mosquito-born diseases that are worldwide.
I would like to elaborate on the potential mechanism of the cytokine storm. A paper I found Dengue virus life cycle: viral and host factors modulating infectivity proposed that antibodies play a vital role upon reinfection with another serotype. They proposed the intentional targeting of cells carrying Fc receptors promoting an initial high viral load. This results in a large T cell activation in the early phase of the infection; and therefore, large amounts of cytokines are released into the system. The paper also refer to studies that discovered that the proposed hypothesis does not fit in what was observed with infants that was first infected with dengue. Which showed that their first infection was similar to the severe secondary dengue infection Dengue hemorrhagic fever in infants: research opportunities ignored. The complications of certain viral infections is certainly frustrating to researchers in hopes of providing a preventative measure or cure. The potential introduction of a vaccine to Dengue fever is a step forward to reduce and/or prevent deaths of this underrepresented disease.
In addition to formulating a tetravalent vaccine for Dengue fever, I believe researchers should also consider creating a vaccine containing a common structural/non-structural protein generated from its one open reading frame in order to combat all four serotypes. Examples include non-structural proteins, glycoproteins and precursor proteins.
This particular study proposes just that idea. Instead of creating the tetravalent vaccine, these researchers proposed an idea of formulating four separate vaccines containing the membrane and envelope proteins (pre-M and pre-E) common in all four serotypes, in addition to four separate non-structural (NS) proteins. Specifically, the NS proteins would serve as a “backbone” of the attenuated vaccine. The NS proteins in each serotype conserve common epitopes, therefore the vaccine would encourage antibodies to attach to areas of the epitopes that aren’t susceptible to neutralization.
Researchers believe a process termed antibody-dependent enhancement of infection (ADE), would stimulate viral uptake by monocytes via interaction of cell surface IgG receptors. Also, after a T cell response is activated, researchers hoped that these T cells would be cross-reactive to all the serotypes. However, while this method sounds somewhat promising, it is unsure whether T cell responses will be efficient for all four common epitopes because depending on the severity of infection, our immune system will target different locations of the particular epitope, therefore leading to an inefficient T cell response for all serotypes.
Rothman, AL. (2004). Dengue: defining protective versus pathologic immunity. The Journal of Clinical Investigation. 113(7): 946-951.
A few statistics (from a different source to emphasize a point) before I begin, according to the CDC there has been 17,256 cases of Ebola in West Africa in 2014. Among these cases there has been 6,113 deaths- that gives an approximate 35% mortality rate. Dengue infects approximately 100,000,000 people annually and kills 22,000- that gives dengue a 0.0002% mortality rate. Clearly, with these numbers though Dengue is a problem and is considered a pandemic, it does not have as high a mortality rate as Ebola. Unlike the Ebola virus, dengue is not transmitted directly by people but is spread via mosquitoes. The medical community has learned to treat dengue in an effective manner. If the symptoms and clinical diagnoses of dengue are made early enough, a health provider can effectively Treat via fluid replacement therapy and hospitalization. There are also many preventative measures for preventing dengue, such as eliminating places where mosquitoes thrive (places with standing water, etc.), sleeping in a bed net, etc., but there are not that many effective ways in preventing the spread of ebola. I believe that primarily because of the reason that dengue can be controlled and treated in a hospital setting, effective vaccine development has been put on the back burner. I also think that because many of the ebola-infected people were of the medical community, there has been a greater emphasis on developing a novel ebola vaccine.
I agree with you that the mortality rate of Ebola is much higher than the mortality rate of Dengue, I think it is important to look at the number of people are infected by each disease. According to your statistics, Dengue infects approximately ninety-nine million more people than Ebola currently. Know I realize that this statistic can change rapidly if Ebola is not kept in check and a viable treatment/vaccine are created. However I believe it would be a critical error not to put in as much research into Dengue as one would for Ebola. The reason being that preemptive measures do not always work. While the outbreak in the United States of Dengue is quite low due to the requirement of mosquito transmission, many other countries are not as lucky. The same holds true for Malaria, another disease that is spread by mosquitos. According to the CDC, in 2012 Malaria caused 207 million episodes of its symptoms and about 3.4 billion people live in the area where they are considered to be at high risk for the disease. While Malaria is caused by a parasite, Dengue is a virus which has the possibility of mutation. Now imagine that the virus infects one hundred million people a year and know that viruses have the tendency to mutate. If this virus unfortunately mutates into a more deadly strain, a large chunk of the population would be at risk, especially at the rate it spreading. There is a very interesting graph on the WHO website that shows the progression the virus has made since 1955. I really hope they do not decide to put the vaccine efforts on back burner so to speak because that might become a critical error.
Before I say anything, I am not disagreeing with you. One of the problems that we have in our society in general is that we don’t really care about any of these problems until it becomes too late. Another issue that we have is funding, especially at the government level. One of the first things that our lawmakers are willing to cut is research spending and education spending; and then when these problems (ebola, dengue, SARS, you pick your disease) arise, the entire public wants a response, treatment and cure faster than they can type a 140 character tweet. With that said, since Ebola is our problem of the moment, I think we should focus our energies on that. In order to achieve overall better results (effective vaccine development for everything), the entire spending structure needs to be formatted (but that is a whole different conversation).
I agree that creating a vaccine for Dengue is important because of the number of people that are affected and killed every year. However, the problem doesn’t just end with creating a vaccine and hoping that everyone gets it and we eradicate the disease. There are many challenges to creating a safe and good vaccine that can give long-term protection for all four serotypes of the dengue virus. The second challenge is in getting the vaccine to many of these countries that have the highest number of these cases. Another underlining problem is having a good relationship between a medical unit and the patients. No one wants to just take a vaccine for a disease from someone they don’t’ know, so having a good bond and relationship is also very important. It is also important to be able to explain any side effects that could be caused by the vaccine, so that people don’t stop getting the vaccine for the simplest side effect. It is also important to realize that dengue is a vector transmitted virus and so there is no way to ever eradicate this virus because you can vaccine every human being, but the possibility of getting rid of the mosquitos carrying the virus is going to be almost impossible. However, the good news is that there should be a good dengue vaccine out in 2015. There are also two vaccines underway for Ebola, which is another tackle on its own.
Is it impossible to get rid of all mosquitoes? I personally believe they serve no purpose on this earth and spread numerous of deadly diseases worldwide. Out of the 3500 species of mosquitoes, only a couple hundred bite and bother humans. I say, out of those mosquitoes that bite and infect humans, we get rid of all the female ones since they are the ones who bite humans and carry the diseases. In fact, did you know that there is a laser (referred to as Weapon of Mosquito Destruction) that can do this for us by targeting only mosquitoes carrying malaria and zaps them while they are in the air?
Here is a video posted by the national geographic on YouTube that shows mosquito being zapped in slow motion:
Bill and Melinda Gates Foundation got scientists from intellectual ventures working on a prototype for this special laser gun. The scientists that invented this device claim that the handheld laser is made from inexpensive consumer electronics and only targets mosquitoes carrying the malaria parasite leaving bugs such as bumblebees and butterflies unharmed. The laser can also distinguish between male and female mosquitoes based on their wing beats so we can leave the males alone and eventually they’ll die off since the females of the particular species that cause illness will not be around to reproduce. I realize that this laser alone cannot be the cure but exterminating mosquitoes can aid in eradicating not only malaria but also the dengue fever, yellow fever, Japanese encephalitis, and many more diseases transmitted by mosquito bites. So I believe we can look further into implementing this idea of eradicating the disease carrying species of mosquito rather than ONLY trying to find a vaccine for that disease.
Are we to blame an insect? Yes , eradicating mosquitoes have its benefits but it depends on the routes would we take to start? I am glad you introduced the laser method here, because in the past it was more harmful to get rid of mosquitoes. I wonder how the late Rachel Carson, a marine biologist and conservationist and world renowned author of Silent Spring would feel with this new research? She put a great dent in the world in the 1950’s when she argued on behalf of nature and human kind against the harshness of using chemicals to destroy nature. I agree with her and believe insects are a part of nature. In the words of Carson, “Man’s attitude toward nature is today critically important simply because we have now acquired a fateful power to alter and destroy nature. But man is a part of nature, and his war against nature is inevitably a war against himself (Natural Resource Defense Council, 2014).” A common pesticide known as DDT, dichlorodiphenyltrichloroethane, was an effective insecticide that was commonly used to kill mosquitoes worldwide but was banned in 1979 in the US (EPA, 2014). Rachel Carson predicted the resistance in 1950 in her book, Silent Spring. She found that DDT entered the food chain and accumulated into fatty tissues of animals, including human beings and caused cancer and other genetic damage (2014). It is also noted that over time insects has become naturally resistant to pesticides. There are over 125 mosquito species with documented resistance to one or more insecticides (CDC, 2014). For example, Anopheles mosquitoes, responsible for causing Malaria have become resistant to DDT (Science daily, 2014).So you asked, “can we get rid of mosquitoes ?” Now with the new research of laser afforded by the Gates dynasty will create advancement on the subject for further future study, but I am curious to know how effective is the laser on large populations of insects? How will the laser effect the human population? Does it expose us to radiation or etc.? I guess I will have to wait and see.
Genetic secret of mosquito resistance to DDT, bed net insecticides discovered (2014). retrieved from the web: http://www.sciencedaily.com/releases/2014/02/140224204808.htm
Anopholes Mosquitoes.(2014) Retrieved from the web:
Mosquitos are important in nature however, they carry many viruses and parasites that infect humans and cause some severe diseases. If there was a way to get rid of all the mosquitos that were harmful for humans then I’m sure a lot of resources would be spent in this line of research. However, realistically thinking about this, if we sit and think of ways to get rid of mosquitos instead of preventing the spread of the disease, it would be detrimental. In my opinion it is very important to find ways like the laser technique to get ride of the harmful vectors, but it is not possible to eradicate all mosquitos using this method. There were some techniques like mentioned above using DDT to get ride of mosquitos in the past. However, using pesticides like these are very harmful for humans and animals and cause very damaging effects like convulsions and paralysis. They are lipid soluble and persist for a very long periods, we still have some of this found in our foods grown today from it being left over in the soil. For the meantime, there are other tools like bed nets, window screens and safe repellents to control these insects. That being said, our battle to find a good vaccine should still be a priority because it gives a more prolonged and effective method of survival using host immune response for the disease.
I see where you are coming from however that is the problem we have been facing for years now; we have not been successfully able to create a vaccine or medication that treats Dengue and many other mosquito related diseases. I am not suggesting that the focus needs to be entirely on killing all the mosquitos, and not worrying about finding a cure or vaccine, however, every website I have visited such as the CDC, WHO, WebMD, all talk about prevention and reducing the risk of getting Dengue and other mosquito related diseases by staying away from mosquitos. Wasn’t DDT used as a desperate form of prevention to rid of all mosquitos? Granted it failed because it had adverse human and animal health effects and caused an increase in resistance, but yet we still used it because nothing else worked and we were desperate enough to get rid of these disease causing mosquitos. When we used DDT and other chemicals, they were harmful and expensive and they did not target specific mosquitos, they target all of them as well as other species of animals and humans. This laser gun however, has been claimed inexpensive and has the power to distinguish between mosquitos that are male/female, and as well as ones that carry disease such as malaria. Female mosquitos that carry malaria fly in a different pattern than normal non-infected female mosquitos. I agree that there has to be a lot of thought put into it if we decide to kill all the female mosquitos species that bite humans as well as research and money in order to find ways to start a global campaign to eradicate Dengue and other mosquito related diseases. But with that being said, I would like to admit that I surely will not miss them and I would like to reiterate that the mosquitos that cause disease, in my opinion, truly serve no purpose on this planet.
The only problem with focusing on trying to kill off all mosquitoes is the affect of pesticides on humans and the environment as well as the ecosystem. Although mosquitoes carry disease they play a major role in ecosystems, especially the larvae, which serves as a major food source for many freshwater organisms. Because of this, it makes it hard to target only mosquitoes as the chemicals we use leach into water supplies and the soil causing harm to other animals or to humans. For instance, the chemical atrazine, found in many pesticides, can cause male frogs to become female frogs which affects the dynamics of a particular group. A promising alternative to harsh pesticides is the use of guppies. A study in Cambodia from 2009-2011 found that placing guppy fish in water storage containers resulted decreased numbers of mosquito larvae. Less larvae means less risks of spreading Dengue Fever. Although this may not completely solve the problem, it could reduce it while scientists work towards creating better vaccines.
As development on a dengue vaccine continues, I think serious consideration should be given to the mechanisms dengue virus uses to manipulate and evade the immune system. Dengue virus uses antibody-dependent enhancement (ADE), where non-neutralizing antiviral molecules aid in virus entry into host cells. Essentially, the virus exploits the antibodies that we normally associate with proper adaptive immune response. In the study “Mechanisms of Immune Evasion Induced by a Complex of Dengue Virus and Preexisting Enhancing Antibodies (2010) , published in The Journal of Infectious Diseases, dengue virions complexed with enhancing antibodies were able to disrupt IFN production, inhibiting later antiviral responses stimulated by IFN. Additionally, dengue-antibody complexes were able to bypass innate immune responses by stimulating early production of IL-10, a regulatory molecule of inflammation. The IL-10 diminished IFN-gamma production, muting the immune response. Most importantly, the study notes that these two evasion mechanisms were only seen in patients with dengue hemorrhagic fever, which causes incapacitating high fever, headache, and joint pain, and not in those with the milder dengue fever. Understanding how dengue virus manipulates the immune system may lead to new target sites in the viral genome to investigate for treatment and vaccine development against this debilitating disease.
The statistics for this vaccine are not the greatest. While 95.5% efficiency against the severe dengue is incredible, there is still only a 80.3% against hospitalized versions and 60.8% against symptomatic versions. The vaccine is obviously giving some protection against the virus just not full protection. I wonder if we could add either a very weak virus to the vaccine or an additive to give a more robust immune response. Maybe a virus besides yellow fever would work better as well. The Japanese vaccine DENVax is still in animal testing but it already shows that it might be more efficient than the attenuated DENV-2 PDK-53. Efficacy of a tetravalent chimeric dengue vaccine (DENVax) in Cynomolgus macaques. Only one of the monkeys showed any viral replication. I look forward to the human clinical trials.