Archive for the ‘General Virology’ Category
Subtype C gp140 Vaccine Boosts Immune Responses Primed by the South African AIDS Vaccine Initiative DNA-C2 and MVA-C HIV Vaccines after More than a 2-Year Gap
A phase I safety and immunogenicity study investigated South African AIDS Vaccine Initiative (SAAVI) HIV-1 subtype C (HIV-1C) DNA vaccine encoding Gag-RT-Tat-Nef and gp150, boosted with modified vaccinia Ankara (MVA) expressing matched antigens. Following the finding of partial protective efficacy in the RV144 HIV vaccine efficacy trial, a protein boost with HIV-1 subtype C V2-deleted gp140 with MF59 was added to the regimen. A total of 48 participants (12 U.S. participants and 36 Republic of South Africa [RSA] participants) were randomized to receive 3 intramuscular (i.m.) doses of SAAVI DNA-C2 of 4 mg (months 0, 1, and 2) and 2 i.m. doses of SAAVI MVA-C of 1.45 × 109 PFU (months 4 and 5) (n = 40) or of a placebo (n = 8). Approximately 2 years after vaccination, 27 participants were rerandomized to receive gp140/MF59 at 100 μg or placebo, as 2 i.m. injections, 3 months apart. The vaccine regimen was safe and well tolerated. After the DNA-MVA regimen, CD4+ T-cell and CD8+ T-cell responses occurred in 74% and 32% of the participants, respectively. The protein boost increased CD4+ T-cell responses to 87% of the subjects. All participants developed tier 1 HIV-1C neutralizing antibody responses as well as durable Env binding antibodies that recognized linear V3 and C5 peptides. The HIV-1 subtype C DNA-MVA vaccine regimen showed promising cellular immunogenicity. Boosting with gp140/MF59 enhanced levels of binding and neutralizing antibodies as well as CD4+ T-cell responses to HIV-1 envelope. (This study has been registered at ClinicalTrials.gov under registration no. NCT00574600 and NCT01423825.)
This is a pretty big deal – because it reports an extension of a wholly South African-originated vaccine trial, that consisted of a DNA prime with a subtype C gp150 gene and an artificial Gag-RT-Tat-Nef polyprotein gene, followed by a rMVA boost, that was as immunogenic as anything else trialled around the same time.
I was alerted via Twitter this morning to the fact that the CDC’s Morbidity and Mortality Weekly report that reported the first recognition of the syndrome we now know as AIDS, was published on 5th of June 1981. It appears – sadly – that their archive only goes back to 1982: there’s a missed chance to expose some history, CDC?!
Thirty five years: I was a novice lecturer, just starting out; the Web was still science fiction; HIV and its relatives were still undiscovered – but they had already started to spread out of Africa, after smouldering away in the tropical forests of Gabon and the Congos for decades.
I started an information web page on HIV/AIDS back in 2000 or so, largely in response to the ridiculousness of Thabo Mbeki’s pronouncements on the virus and the disease: thanks to tectonic shifts in the UCT Web policy, these disappeared – but thanks to the invaluable Wayback Machine, can still be found. If you want a slice of history, and to see how bad I am at designing web pages, go take a look. Still MOSTLY valid, although many of the links are now dead – sic transit the web content, unfortunately!
And here we are in 2016: I’m now an elderly academic, the Honours student who alerted me to the fact the the “GRIDS” syndrome virus may have been identified in 1983 is now a senior Professor and distinguished HIV researcher – there’s a whole career there, Carolyn! – and HIV/AIDS is still with us. And unfortunately, Thabo Mbeki is still being wilfully if not malevolently ignorant, and I am still feeling it necessary to crap on him.
At least the pandemic appears to have peaked in terms of incidence, and ARVs are increasingly good and employed widely; however, we still don’t have a decent vaccine, and people are still being infected. This pandemic will last out my career – but hopefully not those of some of the people I have trained.
New Approaches to Vaccines for Human and Veterinary Tropical Diseases. Or maybe sophisticated safari science?27 May, 2016
The Keystone Symposia organisation held a meeting entitled “New Approaches to Vaccines for Human and Veterinary Tropical Diseases” in Cape Town this week (May 22-26, 2016). A summary of the meeting was given as:
“Human and livestock vaccines can contribute to improved human welfare and income generation by maintaining human health and meeting the demand for meat, milk and fish in developing countries. All of these factors contribute to the growing importance of improving food safety, availability and nutritional security. An important component of this Keystone Symposia meeting will be to stimulate crosstalk between the human and veterinary vaccine communities by highlighting cross-cutting technical advances and new science and knowledge from laboratory and field research. The meeting will also provide a rare opportunity for scientists from the Northern and Southern hemispheres to interact and pool resources and knowledge in the common fight against tropical diseases.”
It succeeded admirably in a couple of these goals: there were delegates there from 31 African countries, as well as many Europeans, Brits and Americans; the juxtaposition of veterinary and medical talks on similar themes created an excited buzz among folk who hadn’t been exposed to the “other”; there was a wealth of dazzling new tech on display in talks, and intriguing insights into how similar – and sometimes, how different – human and animal responses to vaccines were. It was obvious that approaches used to develop malaria vaccines could benefit animal vaccinology, and indeed, Vish Nene and colleagues from ILRI in Kenya are following some of the same approaches in their work with the East Coast fever disease organism in cattle.
But, there were a couple of buts. An important one for me was that while there were many Africans there, they were not much exposed in talks, apart from several South Africans. While amazing results were displayed from deep sequencing of antibody gene repertoires of humans and animals and how these developed with affinity maturation; while grand predictions were made as to how bioinformatics and molecular design would revolutionise vaccinology – this was more of the same kind of thing we have got used to in HIV vaccine meetings over nearly twenty years, where Big Science is always going to provide a solution, but never quite gets to it. Why was there no mention of ZMapp antibody therapy for Ebola, when this (OK, I’m biased) was the single most exciting thing to come out of the Ebola outbreak and the international response to it?
I hate to be cynical, but seriously: is there one single vaccine in advanced human trial right now that is a result of intelligent molecular design? Has ANYTHING that has been designed from crystallographic evidence or from cryoEM data actually proven useful in animals or people? Has dissection of the anti-HIV antibody response development actually, really, taught us anything useful about how we should develop vaccines? Even if South Africans were involved?
I told you I was cynical – and my cynicism was reinforced by a couple of displays of “My Ebola vaccine is better than YOUR Ebola vaccine!”, by folk who shall remain nameless – when it was obvious that both ChAdOx and rVSV vaccines have their merits.
Mind you, the tale of how Ebola vaccines were deployed so rapidly, and how what could have been a 15+ year saga was compressed to less than a year for the rVSV-ZEBOV and ChAdOx vaccines was truly inspirational. It is indeed an object lesson in how to respond to an emerging disease that big companies and philanthropic organisations were able to make many thousand doses of different vaccine candidates in just a few months, and that these could be deployed in human “trials” – actually, genuine deployment in ring vaccination for the VSV candidate – almost immediately. Adrian Hill of Oxford asked the question, albeit outside the meeting at a seminar in our Institute: if this was possible for an Ebola outbreak, why isn’t it possible for everything else? Why can’t we do it for Zika virus, and for MERS-CoV too?
If there is a Big Lesson to come out of this meeting, why can’t it be – Let’s Make Vaccines Faster!
Oh, there were big plusses too. There were fascinating parallels to be drawn in the approaches to developing vaccines for malaria and TB and animal parasitic infections; some of the fancier techniques discussed for human vaccines could obviously find applications in veterinary vaccinology; there were even suggestions for vaccine candidates for animals that were drawn from homologous genes in human and animal apicomplexans (=malaria-like organisms).
I was especially impressed by Dean Everett‘s talk, from the Malawi-Liverpool-Wellcome Trust Clinical Research Programme in Malawi, on “Developing Appropriate Vaccines through Bioinformatics in Africa”: they were actually working in under-developed Africa, on pressing local problems, and making significant inroads into the problems.
And yet, and yet: I have railed elsewhere about the J Craig Venter Institute’s grandstanding over their “synthetic” organisms; while the talk here by Sanjay Vashee on “Synthetic Bacterial and Viral Backbones as Antigen Delivery Vehicle” went some way to redeeming my negative impression of the use of this sort of work, I am still left with the impression that there are considerably easier ways of doing what they claim to be able to. Mind you, one of my colleagues was very impressed with the possibility of making Herpesmids (=infectious, engineerable whole genome clones) in yeast, and would love to do it with their poxvirus collection – so maybe I am a touch TOO too cynical.
I also felt that the final address, by Chris Wilson of the Bill & Melinda Gates Foundation, on: “Cross-Disciplinary Science to Accelerate the Discovery of Vaccines for Global, Zoonotic and Emerging Infectious Diseases” exemplified some of the problems inherent in trying to marry up developed and developing world science, especially in vaccinology. Part of the talk was great: he gave the best description I’ve yet heard of why it could be feasible to inoculate Aedes spp. with Wolbachia, and why it could significantly impact transmission of flavi- and other viruses. His description of gene drive technology for wiping out selected mosquito populations was also succinct, and masterly – and appropriate for a developing world audience. Then he got on to how dissection of antibody maturation pathways and flavivirus E protein design could provide paths to good vaccines, and the cynicism kicked in again.
We don’t need either technology to get to vaccines for HIV or for flaviviruses that we can test in the near future, and which could have very significant impacts on millions of people.
Really: we don’t. Extant HIV vaccine candidates are almost certainly better than the RV144 Thai trial vaccine components, and they had an efficacy of 60% in the first year. We already have YFV and dengue and JEV live vaccines – why don’t we use one or several of them in combination with an engineered YFV vaccine to protect against ALL epidemic flaviviruses? Given the Ebola example, we could deploy vaccines for HIV and for flaviviruses in a year or less, and they would have an impact that would tide us over while fancier products were being made. Seriously: we are always waiting for the next best thing; let’s just apply what we know and what we have NOW to make an impact – instead of, like theoretical physicists, perpetually considering the problem of the spherical horse instead of just going out and riding one.
And that should have been one of the Big Lessons, and we missed it. Instead, there was an element of Safari Science, which is what we in Africa call the kind of endeavour which involves people from the global North flying in to sort out our problems – and leaving with our organisms and disease samples.
Which we could do ourselves, given funding. And that’s another lesson for the folk that do Big Science funding….
Sixteen years ago, two colleagues and I wrote a letter to Nature expressing our concern about our then-President Thabo Mbeki’s denialist views on HIV and AIDS – views he then tried to push into national policy, and which almost certainly were highly influential in delaying the rollout of ARVs in South Africa. I was also active for several years in the media and in public lectures in trying to negate some of the damage he was causing – and I was very relieved when he took a back seat eventually, and then effectively vanished from the public stage.
However, in an unwelcome development as of this week, it appears that Mr Mbeki has finally, in his ongoing quest to rewrite history, addressed the elephant in the room: his views on HIV/AIDS.
To say this “letter” is self-serving would be to pay it a compliment. Indeed, he himself has this to say concerning the awful “Castro Hlongwane, Cats, Geese, Caravans, Foot and Mouth and Statistics…” that he almost certainly was the main author of, back there in 2002:
“Thirteen (13) years later today I would stand by everything said in this excerpt and still ask that the questions posed should be answered by those who have the scientific capacity to do so!”
So in other words, he still holds with much of the rubbish he wrote then. Right – well, so will I revisit something I helped write, back in 2000, after reading that Mbeki had written to Bill Clinton to dispute conventional ideas on HIV/AIDS.
“Nature 405: 273, 2000
Sir – As South African scientists working in the field of HIV/AIDS vaccine research, we are extremely concerned about the letter president Thabo Mbeki recently sent other heads of state (Nature 404, 911; 2000). As an individual Mr Mbeki is entitled to his point of view, but as our head of state we feel he risks binding our country to an untenable position.
We would like Mr Mbeki and others to consider how the mass of South Africans would react if he were to give a sympathetic ear to unrepentant proponents of apartheid. His willingness to be influenced by people with no credibility causes as much anguish to those of us working to combat HIV/AIDS.
The simple facts, as shown by a huge volume of scientific and medical research, are that HIV causes AIDS; that in Africa (as in other developing regions) the disease is mainly spread heterosexually; and that AIDS kills poor people in disproportionate numbers. We most emphatically do not need to revisit the debate on the causation of AIDS. What we do urgently need is to educate, train and medicate, to save lives.”
This is germane, because Mbeki has the gall to go back to his Castro Hlongwane crap at the end of his latest letter, and say:
“Beneath the heartening facts about decreased mortality and increasing life expectancy, and many other undoubted health advances, lie unacceptable disparities in wealth. The gaps between rich and poor, between one population group and another, between ages and between sexes, are widening. For most people in the world today every step of life, from infancy to old age, is taken under the twin shadows of poverty and inequity, and under the double burden of suffering and disease.”
“Castro Hlongwane…” says: “Given that our minds on this matter (of HIV and AIDS) have become thoroughly clogged by the information communicated by the omnipotent apparatus, a miracle will have to be achieved to get all our people to use their brains, rather than perish on emotional responses based on greatly heightened levels of fear.”
Really, Thabo?? You’re going to harp on about poverty, again? Oh, and the “omnipotent apparatus” that is Western Pharma, and of course US capitalism?
Please do us a favour, Comrade: go back to your pipe, and your old friends Johnny and Jack, and stop trying to justify the indefensible. And I will close with something I wrote for the Mail & Guardian on March 1st back in 2002:
“It does not seem to matter what happens in our country; it does not matter how many people try to engage the slippery python that is the president’s policy and thinking on HIV/Aids; it does not seem to matter how many people die of Aids, and how many babies are needlessly born with HIV – there remains the stubbornness and wilful failure to comprehend that is leading us into disaster. Mr Mbeki, you make an idiot of yourself, and fools of us all for putting up with your views. Leave health policy alone, or resign. Please.
Ed Rybicki, Pinelands”
I see no reason to change my views either, Comrade.
We don’t have much practice at this sort of thing, but seeing as we just got something REALLY cool published, and the man who largely made it possible is now a science writer, we decided to ask him to write a press release. So he did. Thanks, Paul Kennedy – take a bow, twice!
“In a pioneering step towards using plants to produce vaccines against cervical cancer and other viruses, University of Cape Town (UCT) researchers have generated synthetic human papillomavirus- derived viral particles called pseudovirions in tobacco plants.
“We’ve succeeded in making a completely mammalian viral particle in a plant – proteins, DNA, everything. That’s enormously exciting,” says Dr Inga Hitzeroth of the Biopharming Research Unit (BRU) at UCT.
In an Open Access study just published in Nature Scientific Reports, BRU researchers report using tobacco plants to create a synthetic viral particle known as a pseudovirion.
A pseudovirion looks like a virus, but it contains no infectious viral DNA. A virus is usually made up of a shell surrounding the virus’s own genetic material. Pseudovirions instead carry whatever DNA the researcher wishes to include within the shell of proteins that make up the outer coating of the virus.
Until now, such particles have only ever been created in yeast or mammalian cell cultures – this is the first time researchers have successfully created pseudovirions in plants.
The BRU is part of a new movement known as biopharming, which means using plants as biological factories. Biopharming has been used to create flu vaccines, potential Ebola drugs, and an enzyme used to treat Gaucher’s Disease in humans. The technique employs the cellular machinery within tobacco plants or other plant cells to manufacture enzymes, antibodies or even the viral capsid proteins (the proteins that make up the shell of a virus), which act as vaccines.
In this research, the BRU has taken biopharming one step further by using plants to create a viral shell that encloses ‘custom’ DNA selected by researchers. “What’s unique here is that DNA that was manufactured within the tobacco plant is now being incorporated into a viral particle to form a pseudovirion,” says Hitzeroth.
The shell of this pseudovirion was that of human papillomavirus (HPV) type 16, the virus responsible for over 50% of cervical cancer cases worldwide.
The BRU team hope this new plant-based technology could one day be used to test future HPV vaccines. First author of the study, Dr Renate Lamprecht, explains: “We need pseudovirions to test any new HPV vaccine candidates. At the moment it is very expensive to make pseudovirions – we need to make them in mammalian cell culture, it needs to be sterile, and the reagents are very expensive.”
All these factors contribute to the high cost of current HPV vaccines, which are actually virus-like particles. Virus-like particles (VLPs) are similar to pseudovirions, but they contain no DNA. Plant- made pseudovirions, as demonstrated by this study, could reduce the cost of testing and manufacturing such vaccines, thus helping to make HPV vaccines affordable where they are needed most: the developing world.
The BRU team compared these new plant-made pseudovirions against the more widely-used mammalian cell culture-produced particles by using what’s known as a neutralisation assay. In this test (which is commonly used to test new HPV vaccine candidates), cells are ‘infected’ with pseudovirions, with or without pre-treatment with neutralising antibodies. The DNA inside the pseudovirion carries a ‘reporter gene’ that produces a protein that can give off a light signal. Thus, an infectious pseudovirion gets into the cell and gives off light, but one that is stopped by neutralising antibodies does not.
“I was jumping up and down the first time I saw the neutralisation results, but I repeated the experiment a few times to be sure, asking myself, ‘is everything correct, are all the controls there?’” explains Lamprecht. “It was a very exciting moment for us when we confirmed that neutralisation had occurred.”
Right now, every laboratory makes pseudovirions for such neutralisation experiments themselves. Dr Hitzeroth hopes that one day, they won’t have to: “we’re in the initial stages, but if we optimise the process and get the yield much higher, we think it’s a product that could be sold all over the world.”
For Professor Ed Rybicki, Director of the BRU, this achievement was enormously satisfying, as it brought together two strands of his research interests that have co-existed for over 20 years.
“Seventeen years ago, I had the idea to combine making HPV VLPs in plants with a DNA plant virus we were working on, to see if we could make pseudovirions. It took until now for the technology to finally come together, but it shows what can happen in biotechnology if you’re willing to persevere.”
The BRU are also hoping to use this technology to create a therapeutic vaccine, which would also be a first of its kind. The idea would be to use the pseudovirion to deliver DNA that could treat an ongoing HPV infection or even a tumour.
With global acceptance and support for the biopharming movement growing rapidly, it might not be too long before the first plant-produced HPV vaccine is making a difference in Africa and around the world.”
The means of engineering potentially deadly avian influenza is freely available on the internet.
Despite continuing global efforts to contain avian influenza, or bird flu, the means of engineering this potentially deadly H5N1 virus to render it transmissible to humans is freely available on the internet. So too are similar instructions for engineering a virus like the “Spanish flu”, which killed some 50 million people in the pandemic of 1918-19.
The digital floodgates opened in 2011 when a peak US regulatory watchdog came down in favour of scientists seeking to publishing their work engineering the H5N1 virus. The decision to uphold such “scientific freedom” was and remains, highly contentious among the global scientific community. Its implications, however, are readily available as online “recipes” for potentially dangerous viruses, which add a new risk to the already considerable challenges of maintaining global biosecurity in the 21st century. For all the recent advances in biomedical science, drugs, vaccines and technology, this is a challenge we remain ill-equipped to meet.
Read more: http://www.theage.com.au/comment/online-recipes-for-contagious-diseases-means-australias-bioterrorism-threat-is-real-20151208-gli97v.html#ixzz3tvWn63AE ;
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Sourced through Scoop.it from: www.theage.com.au
OFFS: seriously! Again?! Someone else has just discovered that entire virus genomes are freely available via PubMed, along with papers on gain-of-function experiments, and immediately leaps to the conclusion that this means “…the means of engineering this potentially deadly H5N1 virus to render it transmissible to humans is freely available on the internet”.
I’m sorry, this is being simple-minded to the point of parody. I have written elsewhere – here in ViroBlogy, and in Nature Biotech’s Bioentrepreneur blog section – on how it is MOST unlikely that bearded fellows in caves in Afghanistan or remote farms in Montana are going to whip up weaponised batches of H5N1 flu or Ebola.
Yes, the papers are available; yes, the sequences necessary to make a potentially (and I say potentially advisedly) deadly virus are available online; yes, one can bypass the blocks on getting resynthesised genes in developing countries (hint: China).
But could anyone outside of a sophisticated lab environment use these to make anything nasty?
Just think about what you would need to make weaponised flu, for example. There are two ways to go here, these being the totally synthetic route (“mail order” DNA – HATE that term!), with some serious molecular biology and cell culture at the end of it, and the “natural” route – which would involve getting a natural and nasty isolate of H5N1 / H7N9 / H9N2, and being able to culture it and engineer it as well.
Both routes require a minimum of a serious 4-yr-degree-level training in microbiology / mol biol, as well as laboratory resources that would include incubators, biohazard cabinets, and disposables and reagents that are not on your normal terrorist’s priority purchase list.
In fact, the kinds of resources you’d find at a University or Institute Infectious Disease unit – or state-sponsored biowarfare lab.
Seriously, now: in order to use the information that is “freely available”, you’d have to do what amounts to an entire postgrad degree’s worth of work just to set up the kinds of reverse genetics necessary to WORK with recombinant flu, presuming you already had an isolate, and even more than that if you were to start with synthesised DNA and try to recreate infectious virus.
Again, this is the kind of work they do in biowarfare / biodefence labs (funny how they’re pretty much the same thing, isn’t it?) – because it’s finicky, expensive, laborious – and potentially dangerous to the researcher.
And it’s interesting that the only rumoured escapes of biowarfare agents have been of flu in 1977 in the old Soviet Union, and of anthrax in Sverdlovsk in the USSR in 1979. And in the US in 2001, and again in 2014. ALL of them from official facilities, I will discreetly point out.
Oh, there have been rumours that Saddam’s Iraq weaponised camelpox; that the USSR/Russia cloned Ebola into a poxvirus; that Al-Qaeda tested anthrax – but the first two took state resources, and if the third happened at all, it’s nothing that the UK and USA and friends hadn’t already done in the 1940s.
IT IS NOT THAT EASY TO MAKE RECOMBINANT VIRUSES.
Like my recent books on History of Viruses and Influenza, I’m constructing an ebook Introduction to Virology textbook – and I’d like people’s opinions.
It’s going to look something like this:
It will be based on my web pages that were so cruelly destroyed, but will be PROFUSELY illustrated, using all of the bells and whistles built into the iBooks Author app, with liberal use of Russell Kightley’s very excellent virus picture library.
And I will sell it for US$20 or less.
Tell me what you think of the taster – and there will be more.
Rinderpest, or cattle plague, was declared eradicated in 2011. But many research institutes still have samples of the rinderpest virus in storage. Disease experts want those samples destroyed.
Sourced through Scoop.it from: www.npr.org
And if they haven’t yet, despite years of debate, why should rinderpest virus stocks?
Consider: we have an effective vaccine(s); we still have the related peste des petits ruminants virus knocking around, with vaccines to it – so why shouldn’t stocks of the live virus strains be preserved?
How many viruses have in fact made it out of fridges, and back into the world? Well, there was that purported 1977 H1N1 release in Russia/Mongolia…but can anyone think of another well-documented one? Just one?
The fact is that it is FAR easier to deliberately spread endemic viruses around – like foot-and-mouth disease virus – than it would be to reactivate and spread something from a lab freezer.
Rather let us conduct an inventory of who has what, consolidate it like they did with smallpox, and forget about the unknowable, which is obscure freezers in far-flung rural centres where no-one remembers what is there – and where powercuts have probably thawed the samples more than once.