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….
Protection of Cattle against Rinderpest by Vaccination with Wild-Type Peste des Petits Ruminants Virus30 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
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
Researchers develop another mouse model of Zika virus infection that mimics the disease in humans.
Sourced through Scoop.it from: www.the-scientist.com
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
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.