I did a little research on the plasmids that INO has patents for. Everybody should. It is actually amazing.. Over 400 patents. Most are licensed from the University of Pennsylvania, through David Weiner, but other academic institutes have licensed their plasmids for plasmids to be made into proteins by the person's body. I will highlight 2.
The WT1 (Wilms tumor-1) protein is a tumor suppressor gene that was originally found in a kidney tumor in infants (Wilms tumor). It is a transcription factor that binds to another transcription factor p53 that is the gateway to apoptosis and is the main tumor suppressor gene in the body. If you lose either one of these, cells don't die when DNA is damaged leading to cells with mutated DNA sticking around and becoming malignant. This gene has been found to have a very specific mutation in chronic myelogenous leukemia, and investigators (Dr. Sugiyama's group) at Osaka University developed a plasmid for DNA vaccination that yielded robust in vitro cytotoxic T cell responses, and originally described it in the Journal of Immunology in 2000. There have been at least 7 subsequent papers from that group from 2000-2004 in the J. Immunotherapy, Journal of Clinical Immunology and International Journal of Cancer (but I stopped counting after that. They gave up on the idea though because they didn't get robust in vivo responses in humans. Then the University Hospital Southampton who has a large immunotherapy trial center in the UK took control of the plasmid containing the mutant WT-1 protein. Guess who they licensed this patent to be combined with electroporation for the further development during the clinical trials while they are actually performing the Phase II clinical trials? You guessed it, INO.
OK everyone. I don't want people to be scammed by others using scare tactics. So I am going to go really scientific.
VRC01 antibodies are produced by non-progressors of HIV infection (less than 10% of all HIV patients) and actually neutralize many diverse strains of HIV. It is also produced by many progressors of HIV (those that go onto AIDS), but usually way too late to help the person and they usually succumb to lethal infection or lymphoma.
Why do I bring this up? Dr. Nussenzweig from Rockefeller gave INO the plasmid of the recombined DNA of the B cells that produce the VRC01 antibodies. INO tested it out in monkeys, and basically monkeys given the plasmid made the HIV neutralizing antibodies.
OK, Phil you tell me. This is old news. That PR went nowhere. In fact after the first day of the PR in September the price went nowhere. You even came onto this board and said that this isn't going to be useful as a vaccine because after a week or two the cells stop producing the antibody, and they are no longer protected from HIV.
Well a paper from the NIH and Nussensweig came out in August in Immunity (impact factor over 20- very high impact journal of Cell Press- who also publish the top journal Cell). Go to pubmed. Type in 23911655 in the search line.
What this article is showing, is they are finding the determinants of the HIV gp120 protein as well as the host genetic determinants that result in the protective VRC01 antibodies. They are very close to figuring out the exact peptide sequence that they can immunize people with that can result in protective antibodies against the HIV protein that HIV uses to get inside T cells and dendritic cells. These antibodies exist. They are made by people infected with HIV. Now its getting people to respond appropriately so that everyone who gets the vaccine can make the equivalent of VRC01 antibodies.
What does this have to do with INO.
Seriously, Kyle? You're "pumping" another study that Inovio has not issued a PR on? According to the bashers, you are getting almost as desperate as INO looks. It looks pretty desperate right? The fact that they have not issued PRs on what is it, 8 or 9 of their studies? I sent you the Hanta virus one that was published in Vaccine on Sept 15th as well that showed 100% responses through their collaboration with the military. We haven't heard that PR either. They are SOOO desperate to keep the price of the stock up that they are NOT issuing PRs? That makes sense, right?
Seriously though, they have what, three or four other abstracts at that vaccine meeting at the end of the month in Spain, including one enhancing VGX3100 with Interleukin-33.
My take is I think they gave up on WallStreet for the short term. People who are with them now will be rewarded. They know they are going to be a 20 billion dollar biotech, and they don't give a rat's patooty what happens to the price over the next 1-36 months. They gave up on the PRing. They care about the science and that is it, because that is what is going to advance the vaccines, not dumb investors. They now have plenty of money to do it without wallstreet.
Oh, by the way. A different vaccine for Tb targeting different Tb proteins was granted orphan status, but failed its clinical trial in 2012. If you want to know why INO is targeting ESX proteins of Tb type in this number in the pubmed search browser. 22340629 or 20006311. ESX proteins are what mycobacterial species use to communicate with their microenvironment. ESX-1 encodes ESAT-1, which M. tuberculosis uses to prevent the body's innate immune system from attacking the pathogen. ESX-5 is important for cell wall development of M. tuberculosis, and if you disrupt it, you kill M. tuberculosis. If you can immunologically target the ESX proteins, you may be able to get an immune response to it, and destroy the cell wall at the same time. Seems to be a good target to me.
Inovio wasn't willing to give up those vaccines that are closest because
A) Roche didn't make it to be the largest biotech company without being a value investor. They got the best value for the prostate cancer vaccine and the Hep B vaccine because they are still very early stage and can make boat loads of money (the market is extremely large on the most common internal cancer in men, and most people already get a Hep B vaccine).
B) Dr. Kim is pretty thrifty himself. Inovio wasn't going to give up the flu program, HIV program, or HPV program for 10 million dollars now and 400 million later on. Each one of those is worth a potential of a few billion dollars (with HIV being the riskiest but definitely if it works the most profitable).
C) Now that someone else made a statement that INO is the real deal (Roche) that makes them much more marketable to other biotechs. If INO gets an offer for partnership on a vaccine, there is a chance Roche may try to outbid them to get that technology too.
Well these scientists already gave INO the plasmid that makes VRC01 antibodies directly. What makes you think that they won't give INO the plasmid that makes the HIV protein sequence that corresponds to the part of the protein that can make the person get protective immunity to HIV.
You add that to the plasmid that INO currently has (Pennvax GP) that can generate protective CD4+ and CD8+ T cell mediated immunity to HIV, and I think you may have a pretty good vaccine on your hands INO. Good job Dr. Kim and INO.
I was originally very skeptical of INOs HIV vaccines (ask Kyle, I've talked to him privately about it). But I think they have a decent shot within the next 5-10 years to produce something worthwhile. I'm not saying 100% protection in everybody. But a vaccine that may help in HIV/AIDS devastated parts of the world... That would be something special.
I am not saying the scientists will just give the plasmid to INO for free. I'm sure there will be licensing fees through Rockefeller, etc. But I think INO (and scientists in general) may be closer than anyone, including myself, previously thought to having something for HIV.
It covers 4 strains of flu (quadrivalent): two influenza A viruses and two influenza B viruses. The old fashion that's been used for 30 years covered 3 strains (wo common Type A strains called H1N1 and H3N2, and one strain of Type B). Big whoop.
They are marketing egg free ones as well, and ones that are allegedly just for the elderly (I don't know what would make a vaccine work only in the elderly.
Now, Inovio is developing a universal flu vaccine that works against type A subtypes H1N1, H2N2, H3N2, H7N9, and H5N1 as well as Type B and targeting multiple influenza antigens, including the most frequently changing hemaglutanin antigen. They can mix and match these individual DNA plasmid constructs as desired to create vaccine candidates, or giving all of them for the universal vaccine. This vaccine will treat 90% of the flu strains that affect humans, compared to 50-60% of people of the current year like the flu vaccine now treats (only 50-60% of people, and that's a good year, get an effective immune response to the flu).
The current vaccine only yields antibody responses, whereas INOs vaccine generates T cell immunity as well which will allow cross protection against numerous strains of influenza that are not vaccinated for.
1) MDSCs are #$%$. They are basically immature myeloid cells that are released from the bone marrow due to stress (infection, cancer, are the two big reasons for MDSC expansion- I studied them in sepsis). You stop the stress (cancer, infection), they go away. They are a signal that something ain't right in the body. People believe that because they produce growth factors and cytokines when they get to a tumor they can cause tumor growth. There is another company, I think its PPHM that is using some phosphatydyl serine orsomething or other I numerous times to get rid of MDSCs as a strategy to kill tumor but the trials always fail because the tumor is still there and they are getting rid of a cell that is not mutated (its supposed to be there). That being said, if they found that MDSCs are going down in vaccinated mice, that could only mean that the tumor is shrinking (they probably could have just told me that the tumors are shrinking and I would be fine with that. I would only use MDSCs as a marker of tumor or infection activity.
Tyrosinase vaccine is not #$%$, though. Tyrosinase is the enzyme in melanocytes that is the rate limiting step needed to convert tyrosine into melanin pigment. Some melanomas (30-40%) may actually lose tyrosinase expression, but the majority of them still express it. This is a step in the right direction for sure, but they need to add other melanoma antigens to this to cover the tyrosinase negative melanomas. Do you hear me ONCS: You need an antigen in your IL-12 melanoma vaccine!!
Short volume is down considerably.
Who are the shorts left?
We got schizo mmmmmux, who can't decide if its gonna short squeeze or go down to 70 cents.
We got heb.jester who is more an #$%$ than a jester.
We got ino.scam who is miami.gent reincarnated who actually brings a little comedic relief.
We got louie.bianco/hugocesarchavez who is a racist that doesn't like Dr. Kim's Korean heritage and calls him a moonie.
And then we got stockprick/stockdick who admits what he is to let us know incessantly 34 years, Vancouver, Vancouver... He has to buy his underwear at K-mart. Fish sticks on Tuesday. Fish Sticks on Tuesday. Judge Wapner. Hot water burn baby!! Hot Water burn baby!!
Can any of them be taken seriously?
In another month we'll see them in the homeless shelter with all the good things going on with INO.
2) This is huge. I repeat huge. They will not use this vaccine (solo) for HIV, but the results showing therapeutic anti-HIV responses in humans is integral for the success of this INO program. The results are very near publication. Don't despair that they will not move forward with this vaccine. The reason I say that this vaccine will not be used solo, is they already have a better vaccine (one that also targets B cell antigens to make antibodies against HIV), since this vaccine only targets T cell antigens. This was a proof of concept vaccine as nobody has shown any effective T cell responses against HIV. Nobody.
3) We already know what Roche thinks of this vaccine, so my input is not needed here.
4) The most important part of their whole program. Transdermal patch vaccines. The Ron Popeil of vaccines: Set it and forget it. This is what the military is working on with INO. I am a troop going to Congo, I need my Ebola, Marburg vaccines please. Slap it on his arm and he's good to go. Also, you can put a Lightning McQueen sticker on it and give it to a kid and say its a cool sticker. Meanwhile, he's getting his flu vaccine, Hep B vaccine, MMR vaccine, and chickenpox vaccine. Much less painful than an intramuscular shot with an electric jolt :-)
5) RSV: very needed vaccine, but they won't be first to market. NVAX will be there first and they are getting pretty robust vaccine responses in their own right.
6) MRSA: MRSA incidence is going down, but it is still a serious problem. The problem is there are different strains of MRSA that use different virulence factors. Some MRSA strains cause superficial infections (impetigo) and never go deep. Some cause abscesses. Some can cause blood infections resulting in sepsis. We are still learning the virulence factors. This will require some thought. All vaccines have failed to date because the antibodies made by people after the vaccine don't neutralize the bug. The kicker: see my next post...
It was not reported because Dr. Kim stopped caring about wallstreet. He got his first of many contracts for 2 vaccines. He is now producing the product (the DNA plasmids encoding the hepatitis B proteins for vaccination purposes.
Why did Roche buy the hep B vaccine? According to the World Health Organtization here were over 59million health care workers worldwide in their census in 2005. Most are working in unsafe health conditions, but every one of them should be vaccinated with the Hep B vaccine. The current Hep B vaccine vaccinates against one protein of Hep B (the surface antigen), and that should be enough for protective immunity. However, the vaccine is #$%$ poor, and everyone knows it.
It works very poorly in men for some reason. When I was in medical school, I had to prove a positive titer for the vaccine to go on away rotations to other medical schools. Well my original vaccine in high school (a set of 3 vaccines), yielded an undetectable titre of protective antibody. So I had to get another round of 3 more hep B vaccines.
Well guess what. They checked my titre again after this set of 3, and my titre was still undetectable. I got another set of 3 vaccines 1 month later, and finally I showed a demonstrable (protective) titre of Hep B surface antigen antibodies, but just barely.
My brother also required 2 rounds (not 3) of the vaccine to get protective immunity.
I bet you if you check my titre, it will be back down to zero.
Roche knows this. INO knows this.
Even if 1/4 of the 59 million health care workers in the world get this vaccine, that's still a large number of people. And there is more people going into the health care profession everyday. Also there will be some high risk patients that want to get the vaccine as well.
15 million x $40= $600 million right now, for a truly protective vaccine. Not too shabby.
Really good history of DNA vaccines as well, and explains why it has taken so long to get good results since 1992, as well.
I wonder why bashers keep referring to 34 years as well. It just doesn't make sense does it, when DNA vaccines were first tried in 1992.
I went into medicine because I am not very good at math, so correct me if I am wrong, but 2013-1992= 21 years right?
So how can Inovio have nothing to show in phase III trials for 34 years worth of investigation for a technology that was based on science that was first reported in 21 years ago? To develop that much science in 21 years is actually mind blowing if you a.
Oh wait, I know the answer, bashers have no idea what they are talking about.
To develop that much science in 21 years is actually mind blowing if you ask me.
OK, so just to be clear: This is your governments tax dollars at work, using none other than Inovio's science, but more importantly, their technology as well. Inovio is so confident in their methodology, they gave their DNA plasmid and electroporation devices to generating antibody responses to two SIV proteins similar to the human HIV gp120/gp41 proteins to get the best immune responses. These internal scientists employed by the NIH combined the priming Inovio DNA vaccine (encoding the MPER and Gag proteins and Interleukin-12) for SIV with an attenuated rubella vaccine that also expresses the same antigens while it infects. This led to prolonged and extremely robust anti-SIV antibodies. However, the kicker is this particular prime boost strategy, definitely yielded memory B cell responses. The importance of memory B cells is that these are the B cells that can mutate their antibodies to get the highly effective anti-HIV neutralizing antibodies. The first round of IgM and IgG antibodies that develop against HIV are usually ineffective at neutralizing. That is why it takes years for an HIV infected person to get antibodies that neutralize and control HIV.
They now have to take this one step further. They have to see if when they use this strategy for HIV (in macaques of course), if this particular prime boost strategy can yield those effective neutralizing antibodies from the memory B cells. If that is the case, then whoa nilly.
What other drug company does this? Give their technology to the government? A g-darn confident one. That's for sure.
So, the problems that people have with vaccines:
1) Can a vaccine make you sick: yes, very. If a baby has an immunodeficiency, and it is not diagnosed yet because the baby is getting mother's milk (which has antibodies and protects the baby for up to a month after the mother stops breast feeding), and receives a live, attenuated vaccine such as MMR, they are at risk for developing the infection that they are trying to prevent.
Can a DNA vaccine make you sick? No. Your body produces only the antigenic portions of the viral (or whatever your vaccinating against) proteins, and never produces a complete virus. Safety first!!!
2) Can you be allergic to a vaccine? Absolutely. If you are allergic to eggs, you can be allergic to albumin (egg protein) that is used to stabilize proteins in a vaccine. You can also be allergic to other components in a vaccine, such as thimerasol, but most vaccines don't contain thimerasol anymore anyway (but other preservatives are still there.
Can you be allergic to a DNA vaccine? In theory yes; All it is is DNA, water, and an electric jolt; but there are some people that can be allergic to water when it touches the skin, so in theory, anything is possible. DNA is so stable, there is no need for preservatives or stabilizers. That's why we can get DNA from cavemen that are preserved in amber. Elimanates many allergens.
3) Can you get autism from a vaccine? Absolutely not. The most preposterous thing I have ever heard. The actual data from that guy in Britain has been refuted many times, but don't tell Jenny McCarthy that :-)
Can you get autism from a DNA vaccine? Absolutely not. In theory its only the measles component of the MMR vaccine that was reported to be possibly be associated with autism. INO does not have a measles vaccine.
As to question of stigma of DNA therapy. I cannot answer that question. In theory its a form of temporary genetic engineering. Your cells make a foreign protein for two weeks, then they stop.
For some reason, Yahoo is censoring my follow up post.
VRC01 plasmid for HIV neutralizing antibody that was recently published. Created from science published in Science, Nature, Cell Host Microbe, Journal of Experimental Medicine and Proceedings of the National Academy of Science by one of the top B cell experts in the world.
Search for VRC01 and Inovio, and Search for Nussenzweig and VRC01
They are getting their plasmids licensed from very prominent scientists, not from Joe Schmo
Wow. Yet another vaccine trial completely paid for... When are other pharmas gonna realize this is just a "scam." Vancouver, Vancouver, 34 years, Petri dishes. Dumb bashers. You will get your #$%$ handed to you very soon
From the Methods section of the full text:
"NHP inoculation methods and regimens. SIV-negative Indian rhesus macaques (Macaca
mulatta) were housed at SUNY Downstate/IAVI in accordance with the guidelines of the
Association for Assessment and Accreditation of Laboratory Animal Care and with the approval
of the University of Pittsburgh’s Institutional Animal Care and Use Committee (IACUC)
standards and regulations. The protocols were approved and assigned the IACUC number
0803208. EP of plasmid DNA into the NHPs was performed using an Elgen 1000 (Inovio, BC)
consisting of a pulse generator and a combined injection electrode device. Two parallel injection
needles (22G) spaced 4 mm apart inserted 13-18 mm into the quadriceps muscle and DNAs were
injected through the needles which were subsequently used as electrodes."
Translation: this study used Inovio's electroporation system. I do not know if they used Inovio's DNA plasmids for the generation of the viral proteins used in the study, however. They say they got those from two papers:
Scheid, J. F., H. Mouquet, B. Ueberheide, R. Diskin, F. Klein, T. Y. Oliveira, J. Pietzsch,
D. Fenyo, A. Abadir, K. Velinzon, A. Hurley, S. Myung, F. Boulad, P. Poignard, D. R.
Burton, F. Pereyra, D. D. Ho, B. D. Walker, M. S. Seaman, P. J. Bjorkman, B. T. Chait,
and M. C. Nussenzweig. 2011. Sequence and structural convergence of broad and potent
HIV antibodies that mimic CD4 binding. Science (New York, N.Y 333:1633-1637.
Pancera, M., and R. Wyatt. 2005. Selective recognition of oligomeric HIV-1 primary
isolate envelope glycoproteins by potently neutralizing ligands requires efficient precursor
cleavage. Virology 332:145-156.
Kyle, I have no time right now, but can you look at those papers and see if those papers were affiliated with INO?
This is great news, but it would be amazing news if this is the actual vaccine used in the human therapeutic vaccine study that they cited back in April on their website
Oops, I didn't see this thread. I wrote a reply on the Tuberculosis topic discussing some of the topics here. Good work Kyle. Like always.
Very good analysis, but I would like to say that pricing should be more similar to Gardasil. $130 each vaccine for a series of 3 total shots= $390. I would put the price around that to be conservative. If you want to be speculative, you could price the cost of the vaccine up to $1900 (median price), which is the cost of the LEEP procedure (loop electrocautery), that is the procedure considered standard of care for CIN3 dysplasia. Freezing with liquid nitrogen costs less but is less likely to be curative.
So the DNA sequence of a string of nucleotides (consisting of Adenosine Thymidine Guanine Cytosine or As Ts Gs and Cs) gets converted to messenger RNA in the nucleus (this is called transcription). This mRNA is transported out of the nucleus into the endoplasmic reticulum where the mRNA gets converted to proteins by ribonecleoproteins (this is called translation). Once the ribonuceoproteins see the sequence for a methionine (encoded by ATG) on the mRNA sequence, that tells the cells to start stringing amino acids together. Each 3 subsequent nucleotides (A T G or Cs) encode for an amino acid to be added. There are 20 something amino acids (sorry I forgot how many), and several nucleotide sequences encode the same amino acid. For instance ATG and ATC both encode methionine.
So basically you cannot patent genes or DNA (see Myriad Genetics etc). What you can patent (and this is what INO owns the patents to) is a plasmid (a circular piece of DNA that contains a specific DNA sequence) corresponding to a protein that can be produced once the plasmid gets into the cell. However, until electroporation, the patents for the plasmids were useless, because you couldn't get enough into the cell to get the cells to start making the protein. But guess what, INO owns the patents to both the plasmids and the electroporation device. They don't need to patent any proteins, because the body makes the patents themselves, and allows for the robust generation of proteins for vaccine purposes or protein manufacturing (see their enhanced plasmids for monoclonal antibody generation). Very ingenious company.
Does that make sense? If not let me know. Or let me know what parts don't make sense.