Hello Reddit! We are M.G. Finn and Alexandre Marques, collaborators on the development of vaccines and diagnostic reagents against parasitic diseases. We recently published our research on a potential Leishmania vaccine in ACS Central Science http://pubs.acs.org/doi/full/10.1021/acscentsci.7b00311. For a generalist introduction to leishmaniasis, you can read the coverage from Newsweek http://www.newsweek.com/horrific-flesh-eating-parasite-called-next-plague-could-spread-us-spurring-663868
This is Alexandre: I am Associate Professor in the Institute for Biological Sciences, Parasitology Department, at the Federal University of Minas Gerais, Brazil. I graduated with a Bachelor’s degree in Pharmacy (July 1997) and a Ph.D. in Microbiology and Immunology (August 2007). During my doctoral dissertation, I worked with infectious diseases and vaccine development against microbial pathogens. From 2007 to 2012, I did my postdoctoral research in the Biological Sciences Department at The University of Texas at El Paso. My work there involved proteomics for the discovery of novel molecular targets for vaccine development and therapeutic treatment against parasites such as Trypanosoma cruzi, and Leishmania spp. I am currently on sabbatical as a visiting Senior Scientist in the Finn laboratory at Georgia Tech.
And this is M.G. Finn: I am Professor and Chair of the School of Chemistry and Biochemistry at Georgia Tech in Atlanta. Before moving here in 2013, I was on the Chemistry faculty at The Scripps Research Institute in La Jolla, CA for 14 years, and before that I was on the faculty at the University of Virginia. I am also the Editor-in-Chief of ACS Combinatorial Science (http://pubs.acs.org/journal/acsccc). In my lab, our research starts with the development of reliable chemical reactions – click reactions, which we then use in chemical biology and materials science. We have for many years combined chemical and biological techniques to make virus-like protein nanoparticles that have desired properties, usually for biological applications. The students and postdocs in Alex’s lab and mine in Minas Gerais and Atlanta are working together to make new vaccines against parasitic diseases using these virus-like particles, focusing on carbohydrates and peptides that are unique to the surfaces of the target parasites. Ask us anything about this work, vaccine development, or tropical parasites. But remember that neither of us are medical doctors; while we collaborate with clinicians, we can’t give medical advice.
We are back online now and answering questions. For this AMA Alexandre’s answers are tagged AFM, M.G.’s are MGF.
Thank you for your questions, we’re signing off now at 1:10 pm EST.
Good morning Alexandre,
it's very nice to hear from a fellow UFMG students, myself having graduated in medicine there in 2008. I currently work as a family care provider in a rural setting, 100km from Belo Horizonte. Leishmaniasis is endemic here.
and I have a few questions, shall we?
Brazil has some very good programs on infectious diseases, like tuberculosis, AIDS and hanseniasis but there are no fixed program for Leishmaniasis. Do you have any opinion as to why is that so?
How do you feel about the rule that we shouldn't give antimonials to dogs over fear of microbial resistance? Is there any reationale for this fear os is it theoretical?
There is a somewhat effective vaccine for dogs, how this product helped/is helping your team develop a human one?
Schistozomiasis is another endemic parasitic infection we struggle a lot where I work, and is still the 4th leading cause of paralysis. Every week I get a patient with a new infection. Is there any effort in order to create a vaccine for this parasite as well?
I have the same question as no.4 but for toxoplasmosis, any chance of a vaccine in the future?
Keep up the good work. I want to send a kiss to Nelson Vaz, is that possible?
Gosh I miss that buteco da bio every friday so much.
Good day, everyone! We're online now, taking the questions in order. 1) [AFM] I'm not very familiar with now these kinds of priorities are set. I do know that researchers in Brazil are getting together to discuss how to tackle the problem. 2) [AFM] To my knowledge, it isn't yet known if antimonials eliminates the parasite from dogs. If that is true, the treated dog can then be a reservoir for the parasite, which would lead to drug resistance and more dangerous pathogens. So we need better drugs! 3) MGF: The canine vaccine works on a different molecular target. Our target so far (the carbohydrate alpha-Gal) wouldn't work in dogs because dogs make this same molecule. Humans don't make this molecule, so a vaccine against it has a chance of focusing on the parasite. But we are starting to work on other molecular targets that would be applicable to dogs. 4) [AFM] Yes, we're starting to work on this, and there are others that we know in the U.S., FIOCRUZ, and around the world engaged in this problem. 5) [AFM, MGF] This is one we don't know much about. We are aware of some work on toxoplasmosis, but can't assess its likelihood of success.
Great questions - thanks.
Hello, i have graduated in veterinary medicine in UFMG, nice to see this AMA reddit with you!
1 - What is the current effectiveness of the leishmania vaccine? When i was graduating, there was a experimental vaccine that did not offered high levels of protection for the dogs (since i do not work with veterinary, i am currently outdated about it).
2 - Why the leishmania vaccine needs to be "reinforced" every year? It does not generate a good memory response? Or is more due to "commercial" needs?
3 - In your opinion, what is the best way to control leishmaniasis? In tropical countries dealing with the mosquito is quite hard, maybe impossible, so what else is effective in order to control it?
I miss my class in the ICB, good old times!!!
Thank you and congratz!
1) [AFM, MGF] There is no human clinical leishmania vaccine. If you're asking about the vaccine candidate published in our recent paper, we have been very successful in immunizing mice (a strain that mimics key aspects of the human immune system) but this is very far from application to humans. So we don't know yet how good it will be. 2) [AFM] That's exactly right: a poor memory response (in this case, in dogs) requires reinforcement. 3) [AFM] A lot of progress could be made with better and more consistent application of methods that are already in place: mosquito control, monitoring and control of infected dogs. But of course a vaccine would be best.
What is the general molecular process for antigen selection for a given parasite? (ie, Do you focus on highly conserved regions of surface proteins or proteins expressed in higher concentrations?)
How many target antigens per vaccine?
What is an example of a parasitic life cycle that makes developing a particular vaccine challenging?
[MGF] As you imply, most of the time we search for a motif present on the exterior of the pathogen. In our case, we focus mostly on carbohydrates, but many others focus on proteins, lipoproteins, and other molecules. Something present in high concentrations on the surface might not be the best target - it depends on the uniqueness of the structure (is it on the pathogen and not on human cells?) and its immunogenicity (which is a difficult parameter to predict). How many targets per vaccine? This is not known for vaccines that are made from passivated pathogens, since the vaccine displays an enormous number of potential molecular targets. The field of "conjugate vaccines" (it has other names) seeks to limit the number of motifs presented so as to "focus" the immune system on particular targets.
Parasitic life cycle? [AFM] All parasites that have vertebrate-and-invertebrate life cycles are challenging, because the different forms express different proteins. Thousands of genes are differentially regulated and expressed in these organisms as they go through their rounds, and this makes focusing on a particular target difficult.
Open Science means transparent, reproducible research through open access, open data and so on. And of course it's due to rigour.
How important is it to your work to share everything you do with the public? Is open science something that would promote your personal research and your field?
[MGF] As a journal editor, I am committed to making the results of scientific research available to the public. This is now happening with most major publishers by various mechanisms.
Would this vaccine be specific to Leishmania or applicable to several species of Trypanosomatida?
[AFM, MGF] The particular paper that sparked this AMA is a somewhat unique case, in that we can answer "maybe yes." That's because the carbohydrate structure that we target, which humans don't make, is likely displayed by many different parasites, including other trypanosomes.
What exactly is Leishmania and why does it require a vaccine?
[AFM] Leishmaniasis is the disease caused by the Leishmania parasite. This is a single-celled organism that propagates either mostly on the skin (causing so-called cutaneous leishmaniasis, or a "flesh-eating" disease) or in internal organs (usually liver and spleen, causing visceral leishmaniasis which can be deadly if not treated). The parasite is transmitted by an insect - the sand fly - and infects millions of people around the world, mostly in tropical areas. However, with climate change the insect is moving and adapting to new territories.
You say you can target the virus because of what is on its surface, but how? How does that targeting work and what's unique to the virus?
[MGF] Our immune systems are evolved to recognize viruses because viruses can cause disease. (Most of them don't, but that's another discussion.) So we say that virus particles are "naturally immunogenic." In our research, we take advantage of this by attaching to the outer surface of a virus particle (or a "virus-like particle" that is not infectious) a molecular structure that is on the surface of an organism we want to protect against. For example, in the paper we've recently published, we attach a carbohydrate molecule (called "alpha-Gal") to the virus-like particle. This molecule is also displayed on the surface of the Leishmania parasite. The immune system sees the alpha-Gal on a particle that activates immune responses, and so part of that response gets directed against the target structure. If we're lucky, and in this case we were, that immune response also acts against the structure on the parasite.
we can't give medical advice.
Well I've got this itch..... kidding! What does the virus-like protein nano particle do and why is it useful? What kind of biological applications?
[MGF] As noted in the answer to the previous question*, in this case the virus-like particle is used because it naturally activates several components of the immune system, but doesn't make you sick. Most viruses are harmless, and they can be used by scientists and bioengineers for a wide variety of things. But we're focused on immunology for the most part.
*https://www.reddit.com/r/science/comments/7hp80z/hi_reddit_we_are_mg_finn_and_alexandre_marques/dqt47qk/ -ACS clarifying referenced answer
how collaborative research takes on devastating diseases
How would uncollaborative research take on devastating diseases? :)
But speaking of vaccines that don't exist yet, meningococcal vaccine when?
[AFM] No idea - it's an important target, but we don't know where the research is on this.
It looks like you're using Qβ as the scaffold for your vaccine but Qβ has repeatedly failed when reacted with antibodies in vaccines for things like Nicotine in phase 2 clinical trials. What makes you think this will work this time?
[MGF] The previous work with Qb, done by the magnificent Martin Bachmann and his colleagues, was excellent in every way but, as you point out, failed in the clinic. One can speculate as to the reasons, but I don't really know. (Although I will point out that immunizing against small molecules in addiction is very different than immunizing against a cellular parasite.) It highlights the difficult nature of translating laboratory research to clinical application.
I have a few more questions after reading the Newsweek article.
1 - Would your vaccine differentiate between Visceral leishmaniasis, Mucosal leishmaniasis, and Cutaneous leishmaniasis?
2 - Is Leishmania generally communicable between people or does it require the sandfly host vector?
3 - What is CDC quarantine protocol for infection and given that the virus is not present in local or regional communities are general medical professionals even equipped to properly diagnose?
1) [AFM] In our published work, we used two strains of Leishmania, one that causes cutaneous and one that causes visceral. It worked on both, but of course we have to test more of the 20+ strains that exist. So far, so good.
2) [AFM] It requires the sandfly vector. 3) [AFM, MGF] We're not 100% sure, but we think that there is no official CDC quarantine protocol for Leishmania. At present, the main way the parasite would reach the US is via travelers infected in endemic areas, but the parasite would not spread in places that don't harbor the sandfly. It may be that physicians might not recognize the symptoms, but the number of cases in the US is still low. There are no approved drugs for leishmaniasis in the US; however, physicians can request waivers from the FDA to treat patients here with drugs used elsewhere. The FDA has recently approved the first drug in the US for Chagas disease (caused by a different trypanosome).
Would a Leishmania vaccine need to be refrigerated?
[MGF] Ours wouldn't, at least as currently constituted, but others might. This is an improtant consideration for distributing vaccines in many parts of the world.
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