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 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?  Has dissection of the anti-HIV antibody response development actually, really, taught us anything useful about how we should develop vaccines?

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.

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: if this was possible for an Ebola outbreak, why isn’t it possible for everything else too?  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).

And yet, and yet: I 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.

Which we could do ourselves, given funding. And that’s another lesson for the folk that do this….

 

Protection of Cattle against Rinderpest by Vaccination with Wild-Type Peste des Petits Ruminants Virus

30 April, 2016

Although rinderpest virus (RPV) has been eradicated in the wild, efforts are still continuing to restrict the extent to which live virus is distributed in facilities around the world and to prepare for any reappearance of the disease, whether through deliberate or accidental release. In an effort to find an alternative vaccine which could be used in place of the traditional live attenuated RPV strains, we have determined whether cattle can be protected from rinderpest by inoculation with vaccine strains of the related morbillivirus, peste des petits ruminants virus (PPRV). Cattle were vaccinated with wild-type PPRV or either of two established PPRV vaccine strains, Nigeria/75/1 or Sungri/96. All animals developed antibody and T cell immune responses to the inoculated PPRV. However, only the animals given wild-type PPRV were protected from RPV challenge. Animals given PPRV/Sungri/96 were only partially protected, and animals given PPRV/Nigeria/75/1 showed no protection against RPV challenge. While sera from animals vaccinated with the vaccine strain of RPV showed cross-neutralizing ability against PPRV, none of the sera from animals vaccinated with any strain of PPRV was able to neutralize RPV although sera from animals inoculated with wild-type PPRV were able to neutralize RPV-pseudotyped vesicular stomatitis virus.

Sourced through Scoop.it from: jvi.asm.org

I have written before in ViroBlogy about the eradication of rinderpest, and what a big deal that was – and here are people taking the gloomy view of wanting to have vaccines against it in case it gets used as a bioweapon, or escapes from fridges or freezers somewhere.
Not that these concerns aren’t valid – but surely it would be a better idea to use recombinant viruses expressing rinderpest envelope glycoproteins, rather than another live virus related to rinderpest which needs to be eradicated itself?
Just asking – but a recombinant poxvirus would seem to me to be a MUCH better option!

See on Scoop.itVirology News

Dengue Virus Antibodies Enhance Zika Virus Infection

26 April, 2016

We tested the neutralizing and enhancing potential of well-characterized broadly neutralizing human anti-DENV monoclonal antibodies (HMAbs) and human DENV immune sera against ZIKV using neutralization and ADE assays. We show that anti-DENV HMAbs, cross-react, do not neutralize, and greatly enhance ZIKV infection in vitro. DENV immune sera had varying degrees of neutralization against ZIKV and similarly enhanced ZIKV infection. 

Conclusions / Significance 

Our results suggest that pre-existing DENV immunity will enhance ZIKV infection in vivo and may increase disease severity. A clear understanding of the interplay between ZIKV and DENV will be critical in informing public health responses in regions where these viruses co-circulate and will be particularly valuable for ZIKV and DENV vaccine design and implementation strategies.

Zika virus graphic from Russell Kightley Media

Sourced through Scoop.it from: biorxiv.org

This is a big deal: a really big deal.  While people have been speculating around the issue for months now – yes, you, Neil Bodie! – this prepub appears to provide proof that prior immunity to the related dengue virus(es) may enhance Zika virus infection, without neutralising infectivity.  This is termed “antibody-dependent enhancement” (ADE), and is also a major factor in dengue haemorrhagic fever which results from ADE due to reinfection with a different dengue type.
It is also interesting because this is one of the first high-profile uses of the online preprint archive bioRxiv (STUPID name!) for a virology paper – which may open the floodgates, as people see what a good idea it potentially is.
The possibility that ADE exacerbates Zika infection means that the manifestations of Zika may be very different depending upon the seroprevalence of dengue and possibly yellow fever virus antibodies in the target population: where this is very low – as in the USA or Europe – there may be no real problem.  Where the seroprevalences are high – as is the case in Brazil and much of Central America – Zika infections may be much more severe.
We will wait and see.

See on Scoop.itVirology News

New Zika Mouse Model Mimics Human Disease

6 April, 2016

Researchers develop another mouse model of Zika virus infection that mimics the disease in humans.

Sourced through Scoop.it from: www.the-scientist.com

…and strains from Africa, Polynesia and Asia were used in it – and all did the same thing?  Interesting…meaning there is no clear differentiation between “original” (=older) African strains and more recent incarnations?  Meaning, obviously, that background immunity due to endemicity will probably prevent the nastiness seen in adult infections in S America?  Possibly…watch this space!

See on Scoop.itIDM News

“Minimal cell raises stakes in race to harness synthetic life”. Really??

29 March, 2016

Genomics entrepreneur Craig Venter has created a synthetic cell that contains the smallest genome of any known, independent organism. Functioning with 473 genes, the cell is a milestone in his team’s 20-year quest to reduce life to its bare essentials and, by extension, to design life from scratch.

Venter, who has co-founded a company that seeks to harness synthetic cells for making industrial products, says that the feat heralds the creation of customized cells to make drugs, fuels and other products. But an explosion in powerful ‘gene-editing’ techniques, which enable relatively easy and selective tinkering with genomes, raises a niggling question: why go to the trouble of making new life when you can simply tweak what already exists?

Thomas Deerinck and Mark Ellisman/NCMIR/UCSD
Each cell of JCVI-syn3.0 contains just 473 genes, fewer than any other independent organism.
Unlike the first synthetic cells made in 20101, in which Venter’s team at the J. Craig Venter Institute in La Jolla, California, copied an existing bacterial genome and transplanted it into another cell, the genome of the minimal cells is like nothing in nature. Venter says that the cell, which is described in a paper released on 24 March in Science2, constitutes a brand new, artificial species.

Sourced through Scoop.it from: www.nature.com

So: JC Venter and team have stripped down a pre-existing organism to what appears to be the essential set of genes, added “watermarks” and inspirational quotes – and this is part of a race to harness synthetic life?  If so, they’re pretty much racing themselves, because precious few others are trying to do the same things.
And if you DID want to, why make a completely artificial cell genome?  Why not use tailored viruses?  It’s a great development, don’t get me wrong, but it is very much part of the “because we can” school of biology, rather than anything directed towards something as coherent as a race to harness synlife*.
* = I should TM that…B-)

See on Scoop.itVirology News

Thabo Mbeki rides again. Let’s knock him off his horse, then!

7 March, 2016

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

AIDS dissidents aren’t victims – but the people their ideas kill will be

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.

Was I wrong on HIV/AIDS: Thabo Mbeki. Answer: yes. Yes, you were.

7 March, 2016

In 2002 a few of us here in South Africa wrote a booklet entitled “Castro Hlongwane…”‚ and sub-titled it “HIV/AIDS and the Struggle for the Humanisation of the African”.

AN OVERVIEW

Here is an excerpt from that booklet, which speaks for itself: “The first report on the incidence of HIV in South and Southern Africa was published in the “New England Journal of Medicine” and the “South African Medical Journal”, both in 1985. Two of the most important findings in this report were that in our country and region: 

HIV infection was confined to male homosexuals; and,

HIV was not endemic in this region of the world.

To quote this report, it said: “The only positive subjects were in the group compromising male homosexuals. The majority of these positive subjects had either recently been to the United States or had had sexual contact with other homosexuals who had visited the United States…

Sourced through Scoop.it from: www.timeslive.co.za

Yes, Cde Mbeki, yes: you were wrong on HIV/AIDS, and you continue to be wrong.  And if you are going to revisit your nonsense, then I am going to revisit mine – just to show what some people thought of you.
Because you wrote that “booklet”, Cde Mbeki. There are those of us who know how to see who authored something, and the copy I had of that scurrilous piece of rubbish said it came from your laptop. It was rubbish then, and can be seen to be even more rubbish now.
And if you are still a denialist, then I sincerely hope that there is a tribunal in your future.

See on Scoop.itVirology News

How Mbeki’s character and his AIDS denialism are intimately linked

3 March, 2016

Critics say that Thabo Mbeki’s character matters less than his AIDS denialism. But these things are actually intimately linked.

Sourced through Scoop.it from: theconversation.com

So Thabo Mbeki is attempting to rewrite history, or at least his place in it, and he may or may not get to writing about his beliefs on HIV/AIDS.
As someone who was actively involved in telling him how wrong he was, I cannot say I am looking forward to seeing him attempt to explain himself.
Because he was wrong in so many ways: wrong in his disbelief; wrong in his actively courting the loony dissidents; wrong in buying into the “ARVs are just poisons” belief; wrong in buying into the conspiracy theories around Big Pharma.
And wrong not to believe scientists in his own country, who did their very best to convince him, using the best evidence on hand, that HIV causes AIDS, and ARVs mitigate the effects.

I think he should appear before a tribunal of some kind, one day, to explain himself – and be prepared to take the withering criticism of those like me who believe he was partially culpable in the deaths of several hundreds of thousands of people in South Africa who could otherwise have been saved by ARVs.
Manto Tshabala-Msimang should be alongside him, of course – but she has taken herself and her several livers off to the grave, and he would stand alone.

See on Scoop.itVirology News

‘Alien DNA’ raining down on Earth could mix with Zika and form super disease – NOT!

2 March, 2016

“Scientists have warned that  panspermia – the theory of genetic material raining down from space – could make Zika stronger and more deadly”

Genetic material falling on Earth from outer space could create a supercharged version of the Zika virus, scientists have warned.

Experts claim that the virus, which is spreading across the globe, will become more prevalent and deadly in the future.

Changes in Zika have already been noted, as it’s changed to be passable through sexual contact.

The disease, first discovered in monkeys in 1947, had previously only been transferable by mosquito bite.

But now, scientists are warning that it could mutate, growing stronger and spreading more easily – with its victims suffering more serious consequences.

They have warned that future strains could become worse thanks to panspermia – the theory of genetic material constantly raining down on Earth from outer space.

Sourced through Scoop.it from: www.mirror.co.uk

The bullshirt is strong with this one…I have to include some conspiracy nonsense from time to time, just to show what’s out there!
And what’s out there for Zika is Fred Hoyle’s old mate, Chandra Wickramasinghe, who really should stick to astronomy or astrophysics – because he’s just making an idiot of himself.
Consider these statements:
“Genetic material falling on Earth from outer space could create a supercharged version of the Zika virus, scientists have warned.”
“Changes in Zika have already been noted, as it’s changed to be passable through sexual contact.”
“Professor Chandra Wickramasinghe, of the University of Buckingham, has long held panspermia as a common route of viral and bacterial mutation….
Worryingly, he said, is the apparent ability of the Zika virus to pick up foreign DNA and adapt quickly to become more virulent.”
OK: just how, exactly, is Zika supposed to be able to interact with the genetic material falling from space? And how in heaven’s name can anyone tie sexual transmission of Zika – which has only not been documented before, NOT shown not to happen – with picking up genetic material? Which, if Professor W is to be believed, is DNA – and Zika is a (+)sense RNA virus, which are not much given to picking up DNA fragments?
As I said, bullshirt: Zika is quite capable of mutating all by itself, without extraplanetary influences.

See on Scoop.itVirology News

Structural and molecular basis for Ebola virus neutralization by protective human antibodies

27 February, 2016

Ebola virus causes hemorrhagic fever with a high mortality rate and for which there is no approved therapy. Two human monoclonal antibodies, mAb100 and mAb114, in combination, protect nonhuman primates against all signs of Ebola virus disease, including viremia. Here, we demonstrate that mAb100 recognizes the base of the Ebola virus glycoprotein (GP) trimer, occludes access to the cathepsin-cleavage loop, and prevents the proteolytic cleavage of GP that is required for virus entry. We show that mAb114 interacts with the glycan cap and inner chalice of GP, remains associated following proteolytic removal of the glycan cap, and inhibits binding of cleaved GP to its receptor. These results define the basis of neutralization for two protective antibodies and may facilitate development of therapies and vaccines.

Sourced through Scoop.it from: science.sciencemag.org

Why is it that structural / molecular immunologic studies always "may facilitate development of therapies and vaccines"?  Really??  How about looking at what the actual vaccines did in terms of eliciting sterilising immunity, or controlling viral load?

So nice work, but it characterises the mode of action of just two monoclonal antibodies from the spectrum of many thousand that would be involved in reaction to infection, and of the hundreds that are involved in vaccine responses, and the many in any single individual that would be involved in actual neutralisation of infectivity / ADCC / infected cell killing, etc.

What I’m getting at is that whole protein responses, in the context of live vaccine vector inoculations, are almost certainly more complex than anything that involves just these two antibodies, and elegant immunological / structural studies are a minor part of understanding the whole problem.

See on Scoop.itVirology News


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