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Thursday, December 1, 2011

Developing a malaria vaccine: via IV or not via IV, that is the question


Malaria, the veritable scourge of Africa, causes almost 1 million deaths and 300 million sicknesses yearly, and is caused by a parasite that infects liver cells, or hepatocytes, and red blood cells.  This kind of parasite is known as an intracellular parasite—in the case of malaria, the most fatal causative agent is Plasmodium falciparumP. falciparum is transmitted by a mosquito bite, usually from an Anopheles mosquito. P. falciparum has development cycles that occur in the gut of the mosquito, and the liver and red blood cells of humans: because of this incredibly complex lifecycle, P. falciparum is very difficult to develop a vaccine.  In the past, vaccines that contain proteins from the surface of the parasite, but not the parasite itself—known as subunit vaccines—have been developed, but did not give high-level immunity (Draper et al 2010).  As a result, the development of a vaccine that contains the entire live parasite in a non-infectious form has been explored.  This type of vaccine, known as a live attenuated vaccine, has been manufactured—the results of the first human clinical trials are explained in a paper by Epstein et al published in Science Magazine.
The researchers developed a vaccine that contained live attenuated, non-reproductive sporozoites, the infective stage (but not the symptomatic stage) of P. falciparum.  The researchers wanted to test the effectiveness of the vaccine based on different transmission routes.  The transmission routes tested were: intra-dermal (ID)—in the skin—and sub-cutaneous (SC), or just below the skin.  These two routes were tested because of their similarity to the natural mode of transmission of the parasite.  A mosquito bite does not penetrate down to the muscle; instead the proboscis (the part that the mosquito sucks blood with) is inserted ID, and the researchers attempted to mimic this transmission.
 Differing concentrations of the live attenuated parasite were administered to three different groups once a month for four months.  Another group received the same treatment, but also received two boosters three and four months after the initial treatment.  After administering the vaccine, Epstein et al tested blood smears from patients every two weeks in order to ensure that the vaccine was properly attenuated and would not develop into the symptomatic stage of malaria, known as merozoites.  While none of the vaccines developed into merozoites, half the patients suffered from an “adverse event:” headache, malaise, fever, or aches.  While these data suggest that the vaccine may be bad because half of the patients had adverse reactions, something to keep in mind is that flu vaccines, tetanus boosters, and myriad of other vaccines cause similar “adverse events” in similar numbers of patients.
After establishing safety and tolerance of the vaccine, Epstein et al investigated the heart of the issue: whether or not the vaccine conferred immunity.  The researchers tested for interferonγ (IFNγ), a protein that is indicative of a cellular immune response, and were able to estimate the magnitude of the immune response by CD8 T-cells.  CD8 T-cells, also called CTLs, are responsible for recognizing cells that are being infected from the inside, as is the case in viruses and intracellular parasites, and mediating their destruction.  The researchers found that patients who received the vaccine SC had significantly greater magnitude of reactive CD8 T-cells with increasing concentrations of vaccine; the ID group however did not see this significant trend.  These data, while initially appear to be paradoxical, are not.  We must keep in mind that the route of natural infection is ID, and when humans are infected with P. falciparum they are unable to develop lasting immunity.  It should follow then that when a more direct route of transmission, in this case SC, should stimulate a stronger and longer-lasting response. 
Three weeks after administering the final dose, Epstein et al exposed the patients to Anopheles mosquitos infected with P. falciparum. Of the 18 controls, all 18 developed malaria, and of the vaccinated patients only two were protected and did not develop malaria.  As a result of these findings, the researchers conducted experiments on rhesus macaques (non-human primates NHPs), rabbits, and mice to test whether efficacy is affected by vaccine transmission route.  The two transmission routes tested were SC and intravenous (IV).  Two groups of NHPs were given the vaccine either by SC or IV routes, and tested for CD8 T-cells and IFNγ.  Of NHPs that were given the vaccine SC, only one developed CD8 T-cells reactive to sporozoites at an acceptable level (.08%).  When the NHPs were given the vaccine IV, three of five developed CD8 T-cells reactive to sporozoites.  After four months, the researchers tested the CD8 T-cell responses again and found that none of the NHPs vaccinated via SC had reactive T-cells, while all those vaccinated IV had some reactive T-cells.  The researchers were not able to test efficacy of the vaccine however, because rhesus macaques cannot be infected with malaria.
To test the efficacy of the vaccine, Epstein et al used the malarial mouse model to test the vaccine.  Mice were vaccinated via IV in three doses, and the researchers achieved 71-100% immunity in the mice.  In the mouse model, SC and ID routes were also tested: these routes were found to require up to ten times as much live attenuated parasite than IV to achieve the same results.  These data align very well with what was discussed earlier: more direct routes of transmission result in stronger, longer-lasting immunity. 
While we are still far from developing a working, tolerable, safe malaria vaccine, this study evidences that it is in fact possible.  There are several problems with this vaccine.  The biggest issues stem from the vaccine’s greatest strength: live attenuation.  The most obvious of these issues is that a live attenuated vaccine needs to be kept cold.  This may not be an issue in developed nations, but in places where malaria is rampant, keeping the vaccine cold poses a challenge.  As well, because the parasite is alive, it is possible for it do revert back to its wild type, and become infectious, thereby giving patients malaria instead of vaccinating them.  Finally, people who are immunocompromised (people with HIV/AIDS) cannot receive live attenuated vaccines—this poses an issue in sub-Saharan Africa where the HIV/AIDS rate is nearly 5%.  This research holds great promise for the future of vaccinations against P. falciparum and could eventually aid agencies such as the WHO and PAHO in fighting the scourge of the tropics. 
More likely than not, future clinical research will investigate the effectiveness of the vaccine in humans when administered via IV.  On a final note, this also poses an issue: whereas administration of vaccines via ID or SC requires minimal training, placing an IV requires a trained professional.

Primary Source
Epstein, J. E., Tewari, K., Lyke, K. E., Sim, B. K. L., Billingsley, P. F., Laurens, M. B., et al. (2011). Live attenuated malaria vaccine designed to protect through hepatic CD8+ T cell immunity. Science, 334(6055), 475-480. 

Additional Scources
Draper, S. J., Biswas, S., Spencer, A. J., Remarque, E. J., Capone, S., Naddeo, M., Dicks, M. D. J., et al. (2010). Enhancing blood-stage malaria subunit vaccine immunogenicity in rhesus macaques by combining adenovirus, poxvirus, and protein-in-adjuvant vaccines. The Journal of Immunology185(12), 7583-7595.

"WHO | Global Health Observatory Data Repository- HIV/AIDS." Web. 01 Dec. 2011. <http://apps.who.int/ghodata/?vid=360>.

"WHO | Global Health Observatory Data Repository- Malaria." Web. 01 Dec. 2011. <http://apps.who.int/ghodata/?vid=440>.

89 comments:

  1. gonna be honest, your title is lame.

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  2. great post corey! i never realized that how a vaccine is affected by how its administered.

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  3. When I went to Africa I had to take pills to prevent malaria for several days before I left, how/why did these work and how do they differ from a vaccine?

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  4. Another great post Corey. I'm enjoying reading these. They are very educational. Before reading this I had a general idea of how malaria was contracted, but I never gave much thought to the process behind the making of suitable vaccine for it (or for that of any disease). Great use of test data to help make your arguments. A friend of mine when to africa three summers ago and caught malaria. Apparently he lost 50 pounds over the course of 3 days. Its nasty. I hope one day they find a an effective vaccine.

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  5. Interesting that the manner of injection makes a difference. What about the different strains of malaria ? There are different oral meds depending on the strain. As to the practicality of keeping the vaccine cold don't oral meds make more sense in these cases?

    To the first anonymous poster: if you have nothing intelligent to add , keep it to yourself.

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  6. Very intersting post, but it is apparent that much testing still needs to be done. In any event, if the intra-dermal and subcutaneous routes had such little effect (and promise), it would seem that the greatest promise lies with the intravenous administration route. Of course, as you note, the major concerns with IV adminstration are the need to maintain the live vaccine in a refrigerated environment and the inability to adminster a live vaccine to immunocompromised individuals. The need to refrigerate the vaccine is, I must say, a political issue in that so many of the countries in which malaria is a problem (sub-Saharan Africa) are so sorely lacking in infrastructure that it will be decades before the vaccine could be properly transported and stored. As for immunocompromised indivduals, it is obvious that some other effective form or forms of vaccine must be developed.

    Now, I am not a doctor, nor a biologist, nor in any way formally or informally trained in infectious diseases, but I wonder if perhaps the best way in which to combat malaria is by identifying, containing and eradicating the source. From what I understand, West Nile virus, which is also spread by mosquitoes, is to a great extent, prevented or minimized by mosquito abatement programs. Such programs are likely more easily carried out than individual vaccination programs, less costly, and preclude any adverse effects of vaccination. . . but I digress.

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  7. Great to see new developments in malaria vaccine. I have missionary friends who are in Africa, and I am always worried that they may be infected with malaria. I am going to share this with them.

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  8. I am wondering if the two people that didn't develop Malaria when exposed to the virus had some kind of natural immunity to the disease. Even with HIV they have found that there are some people, although exposed to the virus, are not infected by it.

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  9. In an isolated, highly problematic, controlled, environment, this will work. Profilactic measures are always a more feasible way to keep diseases at "bay". Have you explored the possibility of a sublingual administration that won't require skilled workers, refrigeration or an IV set-up, but would have a better attenuation than a pill?

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  10. Very informative, Corey! I really enjoyed reading this one. What a great way to sum up the malaria vaccine situation!

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  11. really interesting corey. I was wondering, though, are there are different types of malaria and if so, would there would need to be different types of vaccines?

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  12. just as far as sheer practicality, isn't the distribution of nets a heck of a lot more effective than any sort of medicine in preventing the spread of malaria? I mean, medicine (especially medicine delivered by IV) will always require trained individuals to give it; nets only require the individual to put them up around their bed.

    i dunno, i feel like no matter how promising the aspect of developing a malaria vaccine is, nets will be only marginally less effective. Can't we (we being the global scientific community) use our resources where prevention is a lot more difficult than the application of nets?

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  13. Nice job Corey!! You make some great points that have given me a much better understanding of this subject.

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  14. Good post Corey. I know malaria is a very serious situation and you did a good job of assessing it.

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  15. This article is very interesting Corey. I was wondering why do you need to keep vaccines cold (is it in order to keep it efficient?) and if there were any viable solutions to this problem. Great article though

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  16. It's interesting how the disease is able to spread so efficiently when a mosquito bite seems unable to pierce the skin. Are there any other diseases of a similar infection process that have developed into as large a health concern? If so, do any of them have vaccines?

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  17. It's good to hear that you think science is coming to the point where we might feasibly see a functioning vaccination in the near future. I know when traveling to Africa and sometimes South America it is still necessary to receive some type of shots, or take pills before leaving for trips from the States. However, I have heard stories of these being ineffective, so it's promising that Epstein believes a vaccination can be attained in the near future.

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  18. John,

    I agree that it's promising that Epstein believes a vaccination can be attained in the near future. If we can ensure that people are healthy and don't contract malaria, society will be a better place.

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  19. Great Post Corey!!!

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  20. Another very scientific, eye opening article with sources to back you up. Keep 'em coming!

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  21. Great post Corey! It's really exciting that there's promising research on the horizon for a malaria vaccine.

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  22. Michael's comments are again not helpful. This master human race is not an attainable goal and is frankly insensitive to those who have dealt with illnesss in the family. That being said as opposed to naively dismissing the advances of Epstein it is clear this type of research should be celebrated and encouraged.

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  23. Very interesting. Any recommendations for where I can read up on this topic?

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  24. The only part that I feel like was not very well explained was why does a more direct route of transmission create a stronger, longer-lasting immunity. Beyond that very interesting and certainly warrants more research

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  25. It's been a long time since I answered questions, I apologize, but here they are:

    Balin: what you took was either Malarone or Chloroquine. Both act differently to kill the parasite. These differ from a vaccine in that they are needed constantly to prevent malaria. A vaccine will cause your body to develop a reaction, this case via CD8 Tcells, that will prevent malaria.

    Lsw: great question, there are three main strains of malaria. The vaccine tested is only for Plasmodium falciparum. The other two strains are Plasmodium vivax and Plasmodium malariae. These strains are much less common and much less infective. As a result the majority of malaria research focuses on P. falciparum. As for different medicines for differing strains, actually the different medicines are due to drug resistance in specific areas. Malaria in Costa Rica for example is largely resistive to Malarone, so chloroquine is suggested as the anti-malarial drug. Oral vaccines do make sense, but the reality is that creating a live attenuated parasite in oral form is very difficult, and we are only in the preliminary stages of a development of any vaccine.

    Mitchell: There is a large body of research out there about this topic. That being said, I am very wary of disrupting the environment in any way- once we change something there may be no going back, and we may alter the environment or ecosystem in ways we do not want to.

    Nancy: there is a sizable group of people out there that do have a natural immunity to malaria. This is due to a recessive blood disorder known an sickle-cell anemia. I don't want to get into too many specifics here, but in sickle cell anemia the shape of red blood cells changes, and it prevents them from sticking to the walls of arteries and viens, and this prevents the spread of malaria in the body. As a result these people (and carriers) are not susceptable to malaria. I imagine that the researchers tested for this before giving the vaccine, and so that might rule out natural immunity. For more information on sickle cell anemia check out the NIH's website: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001554/

    RSG: see my response to lsw

    Tyler: there are different parasites that cause malaria, and so yes, there would have to be different vaccines for each. For a greater explanation see my response to lsw.

    Andy: the issue with nets is that usually the family only receives one net. The net is then given to the breadwinner of the house (commonly the man) and so only the father and mother (assuming they sleep in the same area, without the child) will be protected. The reality of the situation is that children are more commonly the ones who die from malaria and so nets are not very effective.

    Albert N.: you have to keep live attenuated vaccines cold in order to keep the parasite (or whatever the infective agent is) alive.

    Mac: there are a wealth of other diseases that have a similar infective route. Three that I know well are Dengue Fever, Chagas, and Leishmaniasis. Dengue and Leishmaniasis are transmitted via bug bites. Dengue is caused by a virus, while Chagas and Leishmaniasis are caused by a parasite. Chagas is even less of a direct route, as the bug's fecal matter must be wiped into the bite within an hour of being bitten. Neither of these have vaccines, and both are big issues in the tropics. For more information on these follow the links. Dengue: http://en.wikipedia.org/wiki/Dengue_fever and Chagas: http://en.wikipedia.org/wiki/Chagas_disease Leishmaniasis: http://en.wikipedia.org/wiki/Leishmaniasis

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  26. Ben: I just saw your comment, I apologize it was not included in my first response. There was no real reasoning given in the paper about why the IV route is more effective than the SC or ID. I imagine that the cellular response is faster and more efficient, as the parasite is being directly introduced into the bloodstream. Other than that I am not really sure why. Great question.

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  27. If there's any chance a vaccination can actually cause malaria, I can't see this ever being approved.

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  28. Hey Corey. Great blog! It was really informative. Your last point, about the issues of administering the vaccines through an IV, I found very interesting. Do you have any ideas on how to solve this problem?

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  29. Great blog, Corey! Really informative!

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  30. Corey, I agree with the fact that "we are still far from developing a working, tolerable, safe malaria vaccine." Although there is some hope to be had for the progress made recently, it seems a lot more work must be done before we can say that malaria can be admonished with this vaccine.

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  31. Any idea how much it will cost? Not just the medicine itself but also the cost of transportation and keeping it cold...

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  32. Wow Corey, you really opened my eyes to the world of malaria, a disease I never knew existed. You are truly a godsend.

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  33. Corey, What would you say is the best way to combat the cold temperature problem for third world countries? Would you say that they should put funds toward something that can keep the vaccine cold or funds toward a different vaccine?

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  34. And if that cost is high, won't nets suffice?

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  35. is there any more you can tell me about this subject?

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  36. Please continue with these science briefs. You are an incredibly gifted writer!

    Kudos!

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  37. I agree the writing is very clear and precise. I am not a science-oriented thinking, yet this makes perfect sense. Thank you!

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  38. In terms of the research, what is the next step? How far in the future to expect this vaccine to be ready for the public?

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  39. I really don't know much about science, but your writing is exemplary....u really do a good job of explaining the subject clearly and concisely

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  40. This is really very interesting, I love the way you go into detail

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  41. Im sure that a vaccine will one day be available for the public in developed countries but when do you think it will be available for poor countries where the demand is high?

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  42. Great post corey!

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  43. What are the typical symptoms of malaria and what sort of tests are used to diagnose the pathology?

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  44. What other types of vaccines - as opposed to live attenuated - are used in medicine?

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  45. If using IVs have always caused this problem, what are some cost-effective ways to go about eradicating this issue?

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  46. Tyler also brings up a very good point in the cost. The cost of hiring people professionally trained in administering IV's could also factor into the issues of bring the vaccines to humans.

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  47. As you note above, live attenuated vaccines need to be kept cold. If keeping the vaccines cold is a legitimate concern in underdeveloped regions, what other types of vaccines could potentially be useful? Would the environmental versatility come at a cost of efficacy in eliminating malaria?

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  48. The authors used measurements of IFN-gamma to get a sense of the immunity level in the subjects as a result of the vaccine. Is it sufficient to base immunity off of one measurement type? What other sorts of proteins or macromolecules are correlated (either positively or negatively) with immune response?

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  49. What are the current methods of keeping vaccines cold while stockpiled or in transit? What are the prospects for mass-production? How much do they expect the vaccine to cost to the patient? Would this type of vaccine, if produced, help to evolve IV technology?

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  50. It seems that a vaccine is not the way to go when dealing with this pathology. Provided one is found, consider the mutation rate and how long before the vaccine becomes ineffective at fighting the parasite. We have the same problem with the flu (which is different in that it is caused by a virus).

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  51. This vaccine seems terribly energy inefficient. Are there efficient ways of storing storing the large quantities that will be distributed, donated or bought? Is there any drive to promote energy efficient health care products?

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  52. How do the mutation rates between parasites and viruses compare? I know pretty much nothing about viruses, except that it causes HIV.

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  53. Do you know of any links to similar or conflicting articles on the subject? Is there a website that details thsi research? I would also like to know what the government's role in the research is.

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  54. What other vaccines are currently in the research phase? How do they compare to the one in this paper in terms of immunity effects and vaccine type?

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  55. What are the pharmaceutical companies doing for malaria? Do they see potential profit in providing vaccines for the disease? Do they stand by this one? Do they contribute to this research? Are there applications for this type of vaccine to other diseases?

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  56. How does the parasite affect the body and what is the specific molecular mechanism? Is the mechanism known?

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  57. Do you think the researchers got their inspiration for this solution from prior cases of "live medicine," such as probiotics and weavles? I would love to meet the people working on this. Thanks for the info.

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  58. I am a bit curious about the methods. When testing the injection methods, did the authors compare the results to a control (a vehicle - injections with a salt solution or something)? If they didn't, why wasn't it necessary to do so?

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  59. What is the survival rate of infected people in developed and underdeveloped regions?

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  60. What sort of treatments are available to people in poorer regions of the world?

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  61. This is very informative. Good job with the post.

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  62. if we need the trained professionals, we better have some way to get people trained professionaly so they can volunteer or create some incentive to help if they are truly in need

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  63. I also think this is like TB from the last blog post (which was fantastic). If the direness of the issue is spread, people will put more funds toward helping solve the problem.

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  64. Corey this is a great blog! You demonstrate really deep knowledge of the subject. Very interesting!

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  65. Corey I'm very impressed with your work. How do you think we can best combat this problem?

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  66. That's true, Jeremy. I think your point proves that there is a lot more to be done.

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  67. referring to the vaccine you said, "it is possible for it do revert back to its wild type, and become infectious, thereby giving patients malaria instead of vaccinating them." If this is true, then there is no way it will be accepted as a drug administered to humans. This is very concerning.

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  68. Wouldn't hiring and training individuals to administer the IVs be a minor cost to the good we could do by saving the individuals affected by malaria?

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  69. I am concerned more with the ethics of this study done by Epstein. How is it that he could release malaria-infected mosquitoes on humans before testing the vaccine on other mammals? Why are we putting humans in danger before seeing if the thing will even work?

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  70. Otherwise, this is another excellent review of another important issue,

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  71. How can this research contribute to research on other diseases? Have these solutions been proposed, or is there no disease for which this might work?

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  72. absolutely phenomenal post, so rewarding to read

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  73. Wow... great job Corey! Well done!

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  74. This is amazing. I knew nothing about this disease until now

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  75. I concur with many of the above posts. This is a phenomenal article. All that research paid off

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  76. Corey, I commend you on this article. I have learned much about malaria after reading it. I wish you well and hope you go far in the pursuance of a career in the medical field

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  77. I have always wanted to learn about malaria. I think it is a fascinating disease. I always here stories about people dying from it in Africa or see movies/read books in which people got shipwrecked on an island and eventually catch the disease.

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  78. Where can I find additional information on this subject? Any books you recommend? I find this stuff fascinating and would love to delve into it further

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  79. This post is gonna come off sounding weird, but its a serious question. Is there any way we can channel this disease and use it against our enemies (i.e. Iran, North Korea)? I think it would be very effective

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  80. Test subjects. It sucks that the way we come up with vaccines for diseases is by experimenting on an unfortunate group of people or animals. Reminds me of the how someone back in the days of old had the job of tasting a king's food to make sure there was no poison

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  81. How can you tell that someone has malaria? Like what are its symptoms?

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  82. Is malaria only a problem in Africa? My apartment in Italy is basically a nesting for mosquitos. They are chilling out and breeding like rabbits inside the toilet pipes. Do I have to worry about contracting malaria if they bight me?

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  83. What is the death rate of malaria in africa as compared to that of AIDS?

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  84. While I want vaccines to be developed for deadly diseases such as this one, human clinical trials is morally suspect. I wish there was some other way to test vaccines.

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  85. Thank you for enlightening me on this topic. I had actually never heard of this disease before. I have very little knowledge on immunology, so I have really enjoyed reading your posts. It has peaked my interest and I am now considering taking an immunology class. While I am not planning on pursuing a career in the medical field, I believe some knowledge in the area could prove useful. Again thank you for teaching me something new and I look forward to your next post, if there are any more.

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  86. Russian Playwright Antonin Chekhoff once wrote, "“When a lot of remedies are suggested for a disease, that means it can't be cured". As you mention, a lot of different experiments have been made to cure malaria. Malaria is a terrible disease. I have heard nasty stories about it. Therefore, I hope Chekhoff statement does not hold true in this case

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  87. We are not spending near enough money to counteract this horrible disease, this "scourge of Africa". People need to come to their senses. This is a dark mark on the world

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  88. I completely agree with the above post. Here is a quote by Bill gates to back that up, "“For far too long, malaria has been a forgotten epidemic, ... a disgrace that the world has allowed malaria deaths to double in the last 20 years.”

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