Antibody-dependent enhancement in coronaviruses

11 April, 2020

This is a condensation / concatenation of a series of 13 tweets put up recently by someone who tweets as “The Immunologist” with the handle @eclecticbiotech. I was impressed enough by it that I thought it deserved to be all in one piece – and he agreed. He also declined any more accreditation, saying only “No credit necessary. This thread is entirely due to the important work carried out by fellow scientists”.


A thread on antibody-dependent enhancement (ADE) in coronaviruses from The Immunologist.

While developing vaccines, treating patients with convalescent plasma, and considering immunity passports, we must first understand the complex role of antibodies in SARS, MERS and COVID19.

Rabbits infected with MERS develop antibody responses but are not protected upon rechallenge and worsened pulmonary pathology observed. Passive transfer of infected rabbit serum to naïve rabbits not protective and enhances lung inflammation.

Analysis of 9 healthcare workers infected with MERS found most severe cases had highest anti-spike antibody titres. Three asymptomatic patients and one patient with mild disease had no detectable antibody response on the basis of ELISA and IFA.

Macaques vaccinated with MVA encoding full-length SARS-COV spike protein have worsened lung pathology upon rechallenge. Transferring purified anti-spike IgG into naïve macaques results in all recipients developing acute diffuse alveolar damage.

SARS-COV ADE is strongly mediated by anti-spike antibodies rather than anti-nucleocapsid antibodies. Diluted sera containing anti-spike IgG can increase in vitro infectivity.

Serum containing anti-spike antibodies enables spike-pseudotyped lentiviral particles to infect human macrophages (which do not express ACE2). Could this similarly allow SARSCoV2 to enter cell types outside the natural tropism?

Antibodies targeting the receptor-binding domain (RBD) of the spike protein can cross-neutralize both human and palm civet SARS coronaviruses. Could cross-neutralizing antibodies from previous common cold coronaviruses provide ADE to SARSCoV2?

Clinical data from SARS shows early seroconversion associated with more severe disease and higher mortality (also correlated with advanced age). 32/347 patients (9.2%) had no detectable antibodies.

A very thorough paper demonstrating immunization with various SARS coronavirus vaccine constructs results in pulmonary immunopathology after challenge with SARS-COV virus. Consistent findings in multiple animal models

In COVID19, anti-spike antibodies higher in elderly/middle-aged patients than young patients. 10/175 (5.7%) of patients have no detectable anti-spike antibodies. Anti-spike antibody titres positively correlate with CRP, an inflammatory biomarker.

Similarly, anti-spike IgG positively correlated with age in COVID19. Interesting how the relationship between age and antibody titres is more linear in females. Additionally, anti-spike IgG positively correlated with inflammatory marker LDH

Questions to consider:

Why do some COVID19 patients not make detectable antibody responses? Do these patients have a more potent CD8+ T-cell (CTL) response? Does cross-reactivity of anti-spike antibodies from previous coronavirus exposure increase risk of severe disease?

Are antibodies produced by SARSCOV2 infection protective from reinfection? If so, how durable is this protection and how long will it last? Do anti-spike antibodies provide ADE and worsen pulmonary immunopathology in COVID19 comparable to SARS and MERS in vivo models?


Sage questions indeed – and ones that anyone developing vaccines to SARS2 should take seriously.

Answers to questions can be directed to TI on Twitter, or put up here for relaying. Enjoy!

Plant-made vaccines and reagents for SARS-CoV-2 in South Africa

4 April, 2020

Plant-Made Vaccines and Therapeutics

I have published a number of reviews on plant-made vaccines (see below), and our Biopharming Research Unit (affectionately known as “The BRU”) has been very active in this research area for nearly twenty years now. The theme running through all our publications is always “Plants are a cheaper, faster, safer and more scalable means of producing pharmaceutically-relevant proteins than any of the conventional expression systems…” Since 2003 we have published 50-odd articles on plant-made recombinant proteins, including human and animal vaccine proteins and enzymes, so we have used this justification a lot.

Which begs the question, why isn’t Big Pharma using plant plant production, then?

After all, it’s been 30-odd years since the first “molecular farming” product was made, and many proofs of principle and several of efficacy of therapeutics and vaccines have been obtained, yet the pharmaceutical world has just two products that have been licenced or emergency licenced for use in humans. The first is Elelyso from Pfizer, better known in molecular farming circles as glucocerebrosidase developed by Protalix, which is an enzyme replacement therapeutic for persons suffering from Gaucher disease. This is not strictly speaking a plant product, though, as it is made in transgenic suspension cultured carrot cells, in 800 litre plastic bags.

The other is ZMapp, which is a cocktail of three “humanised” monoclonal antibodies (mAbs) which bind to Ebola virus, made by transient expression in Nicotiana benthamiana plants, and which were used in people as a post-infection therapy in the West African Ebola disease outbreak from 2014-2016.

If you consider that the first products to receive regulatory body approval – both in 2006 – were a mAb to hepatitis B virus surface antigen (HBsAg) that was used in purification by a Cuban company of the protein from yeast culture lysates, and tobacco suspension culture-produced Newcastle disease virus vaccine made for Dow AgroSciences that was never marketed, there has been effectively no market breakout at all for plant-made pharmaceuticals (PMPs).

Why is this? Why is it that a technology that can produce biomass containing product-of-interest between 100 and 1000 times more cheaply than mammalian CHO cells, or 10 – 100-fold cheaper than yeast or bacterial cultures, and be scaled from lab to industrial levels of production quicker than any other system, still languishing in the biotech industry doldrums?

Rybicki, 2009: Drug Discov Today. 2009 Jan;14(1-2):16-24. doi: 10.1016/j.drudis.2008.10.002

Granted, biomass production is only the upstream part of pharmaceutical production; the downstream purification / refinement / vialling and packaging costs for plant-made products will be the same as for conventionally-made versions, and these are typically much higher than biomass production costs. My own back-of-the-envelope calculations, done at a conference I attended where these costs were broken down by an industry expert, came out with plant-made finished product in a vial being 32% cheaper than the conventional equivalent. Given the large markup on finished product, this “advantage” is in itself not sufficient motivation for Big Pharma to change the means of production, given their typically enormous investments in stainless steel and other infrastructure.

And yet…doubling production capacity for any given product by a single Big Pharma supplier using conventional cell culture technology would entail spending the same amount again to get more stainless steel – which is typically multiples of at least US$100 million – as well as spending an inordinately long time getting the new plant certified. Also, even making a new product from scratch using existing infrastructure would involve heroic cleaning and rejigging of tanks and feed pipes and other paraphernalia used for biomass production, recertifications and the like, which could take months.  With plant-based manufacture, on the other hand, doubling production capacity means using double the number of cheaply-grown plants, possibly doubling the volume of Agrobacterium tumefaciens suspension to dunk them into, and then having enough space to put them under lights for 5-7 days or so, all with the same downstream processing capacity.

Then, there is the speed of scalability, which is unmatched for plant-made proteins. Consider this: given a ready supply of plants, it is theoretically possible for a molecular farming industrial facility to scale plant production of any given protein from lab bench scale – say a few milligrams/batch –  to industrial scale (kilograms per batch), in as long a time it takes to culture the few hundred litres of Agrobacterium you would need for infiltration. Keeping a large reserve of plants is cheap; commercial greenhouses could do this very cheaply – meaning biomass is effectively instantly available to whatever volume required. Culturing Agrobacterium to scale would also literally take a couple of days, meaning infiltrating and incubation for target molecule synthesis could take just a few days from obtaining a gene. Scaling a new line of stably transfected CHO cells from a flask up to 30 000 litres, on the other hand…this takes many cell doublings, with the attendant problems of maintaining both genetic integrity and sterility, and is far more expensive and takes longer.

Plant-Made COVID-19 / SARS-CoV-2 Vaccines

In fact, in 2012 as part of the DARPA “Blue “Angel” challenge, Medicago Inc. of Quebec in their new North Carolina facility, managed to make 10 million doses of H1N1 influenza virus vaccine as virus-like particles (VLPs), vialled and labelled, within a month of being given the sequence of the virus. If one considers that seasonal influenza vaccines take at least six months to make by egg culture, even with accelerated clinical testing and certification, this is a truly impressive improvement on current technology, and probably the quickest development of an influenza virus vaccine ever*. The company has since advanced to making and testing a quadrivalent seasonal influenza vaccine candidate through Phase III clinical trial, for imminent commercial release, was awarded “Best New Vaccine Technology/Platform” prize at the World Vaccine Congress in 2019 – and on March 12th 2020 announced they had made a viable vaccine candidate against COVID-19. They did this in just 20 days after receiving (presumably) the S envelope glycoprotein gene, and moreover made VLPs using their proprietary technology: VLPs are better immunogens than soluble subunit proteins, as they are much better at stimulating both antibody and cellular immune responses.

Virus-like particles made the same way Medicago will probably make SARS-CoV-2 VLPs – from this paper: https://zoom.us/j/313676518?pwd=bnFrQmxtR3l2TjY4VGFWWEhjZklnZz09

They are not alone in this space: just two weeks later, British American Tobacco (BAT) gained a lot of media attention when they also announced a candidate plant-made vaccine against SARS-CoV-2. While many hailed the repurposing of tobacco by a cigarette-manufacturing company as being an unexpected and good thing, it was really the BAT subsidiary RJ Reynolds’ recent purchase of Kentucky BioProcessing Inc, itself a spinout of one of the pioneering molecular farming companies (Large Scale Biology Inc., now sadly defunct) and the firm that had produced the largest amounts of the anti-Ebola ZMapp mAbs, that allowed them to take the credit. History aside, KBP announced they had “cloned a portion of COVID-19’s genetic sequence to create an antigen, which induce an immune response in the body” – which almost certainly means the S glycoprotein, or a portion of it – and that they could potentially make 3 million doses a week.

These announcements are the most important in the molecular farming space – although there have been others, such as by my long-time friend George Lomonossoff in the UK –  and the vaccine candidates are almost certainly going to be cheaper and quicker to make than conventionally manufactured subunit-based equivalents like the Coalition for Epidemic Preparedness Innovations (CEPI)-sponsored University of Queensland product announced recently. Indeed, a local “futurist” – Pieter Geldenhuys, interviewed by Moneyweb on 29th March – said, of the news that Medicago had developed a vaccine:

“Once one of the multitude of medical research teams have developed an effective vaccine for the strain prevalent in South Africa, it will take several months, or even years, before enough vaccines could be produced to fill the global need. This is where tobacco plants come in”

Geldenhuys’s advice for various governments around the world is clear. Keep your ear on the ground and start reaching out to companies like these. Once initial tests show success, consider building your own tobacco cultivation plants to ensure that you can reproduce the vaccine at speed.

A very recent article in the Wall Street Journal also soberly assesses the prospects of plant-made vaccines against SARS2 – with some help from some molecular farmers we may know B-)

Molecular Farming Manufacturing Possibilities in South Africa

Our group in the BRU, our recent spinout partners* Cape Bio Pharms, and a group at the SA Council for Scientific and Industrial Research (CSIR) are the three premier molecular farming research and development teams in South Africa. We have jointly made a host of candidate vaccines, virus-derived reagents for use in molecular biology labs and in diagnostics, and mAbs for use as reagents and potentially as therapeutics. Presently, Cape Bio Pharms and possibly the CSIR represent the only pilot-scale manufacturing facilities in South Africa for plant-made biologics, despite initiatives over years involving us and the CSIR and various government departments. A symposium in Franschhoek in the Western Cape Province in November 2017, hosted by the BRU and by iBio Inc of Bryan Texas, pitched a plan to assembled invited delegates for public/private partnership to construct a facility in this country to make pharmaceutical products using molecular farming technology. In announcing it, we said the following:

iBio’s plant growth facility, October 2018

“The conference brings together leaders from public agencies, academic institutions, parastatals, private companies, regulators and private capital to map out concrete steps to establish the plant-based manufacturing platform in South Africa. The Department of Science and Technology (DST) leads a broad science and technology innovation effort including of advanced health care products to create socio-economic opportunities.   The Technology Innovation Agency (TIA) is an active funder of human and animal health care initiatives in South Africa.     The Industrial Development Corporation (IDC) is a primary developer of manufacturing capacity and has important initiatives in biotechnology. Other participating agencies include the Council for Scientific and Industrial Research (CSIR), with its own molecular farming pipeline, and the Department of Trade and Industry (DTI).

AzarGen Biotechnologies is a private South African biotechnology company will be part of the private sector representation. AzarGen, primarily funded by the IDC, has worked with iBio for the last three years to develop biotherapeutics that include surfactin for infant respiratory distress syndrome and a biobetter rituximab monoclonal antibody for the treatment of non-Hodgkin’s lymphoma and certain autoimmune diseases. The BioVac Institute and Onderstepoort Biologicals, manufacturers of human and animal vaccine products respectively, will also present. ENSafrica will speak to Intellectual Asset Management and Cape Venture Partners will overview the private capital opportunities in South Africa. Technology Innovation Group, a US based consulting group, will talk about the structure of successful public/private partnerships.”

While the idea of a full-scale facility similar to iBio’s – costed at around USD30 million/R450 million – did not appeal to funders present, the idea of a cGMP-certified pilot manufacturing facility costing USD10 million – R150 million at the time – constructed using iBio’s expertise and assistance, found more favour. In fact, various entities promised to survey interested parties to establish the need and feasibility of internally funding it.

To the best of my knowledge, nothing along the lines of a survey has happened to date. Since then, and in the absence of any apparent interest from what were DST, DTI, IDC, TIA and others, iBio has gone on in 2019 to announce a partnership with Azargen in the area of rituximab biosimilar production, and as of a few days ago, as a contract manufacturing organisation, is offering their services in making COVID/SARS2 reagents at industrial scale in plants. Cape Bio Pharms has also established itself as a reagent manufacturer independently of any outside associations, with only local investment and a THRIP grant from Dept of Trade and Industry (DTI). I note that a previous proposal from some years ago involving the CSIR and Kentucky BioProcessing for establishment of an even cheaper pilot facility, also fell flat. For comparison, I will point out that the cost of just the revamping of Onderstepoort Biological Products’ (OBP, SA’s premier veterinary vaccine manufacturer) facility to be able to achieve cGMP certification is estimated to be ~R500 million.

SARS2/COVID Vaccines and Reagents for South Africa

Very early on in the present pandemic, Dr Mani Margolin of both the BRU and the Vaccine Research Group (VRG) of Prof Anna-Lise Williamson ordered a synthetic gene for a soluble version of the SARS-CoV-2 S protein, and has since successfully expressed the protein in both tissue cultured human cells, and in Nicotiana benthamiana plants via transient Agrobacterium-mediated expression. Both expression strategies leveraged technologies for which our research groups have either applied for or been granted patents, and established the very real possibilities of making both a DNA vaccine and a protein subunit vaccine against SARS2. He has gone on to insert the S protein gene into other vaccine vectors in the VRG.

Cape Bio Pharms (CBP)*, acting in parallel, ordered a gene for the “head” portion of the S protein – termed S1 – which they have also successfully expressed in N benthamiana, along with several variants of the protein, and they plan to collaborate with another new biotech company in South Africa to use it to produce mAbs for use as reagents, and potentially as therapeutics.

The CSIR is planning to leverage their established expertise in making mAbs to HIV and rabies in plants to produce a panel of mAbs to SARS2 for the same purposes.

These efforts have already resulted in ad hoc partnerships with other research groups and organisations, with S and S1 protein being supplied to others for use in establishing enzyme immunoassays and other diagnostic tests for serosurveillance and bedside testing, and other genes being shared with us and CBP for expression as reagents. I will note that the efforts that have resulted in the S-derived products are probably the fastest production at scales greater than a few micrograms in this country of any protein-based reagents, and probably the most quickly and cheaply scalable of any reagents. We are presently awaiting news of possible funding for molecular farming projects involving SARS2, albeit in a very rapidIy changing landscape where every day brings new developments – and where the future economic prospects of our country look dire, which may work against us.

Lessons From the Past

We have been here before, though. In 2006 our group received “Emergency Response” 1-year funding for H5N1 vaccine development from the Poliomyelitis Research Foundation (PRF) in SA – a then-handsome amount of R250 000 – which we then parlayed into another PRF 3-year grant, as well funding from the SA Medical Research Council (SAMRC). This quote from a profile published in Human Vaccines & Immunotherapeutics nicely sums up what we did:

As a result of a conference held in Cape Town in 2005, where a WHO influenza expert warned us “When the pandemic comes, you in the developing countries will be on your own”, we applied for extraordinary funding from the PRF in SA to explore the possibility of making a pandemic flu virus vaccine in South Africa. We chose the highly pathogenic avian influenza virus A H5N1 type haemagglutinin (H5 HA) as a target, and James Maclean was again instrumental in designing and successful early testing of plant-made soluble and membrane-bound forms. Further funding from the PRF and the SA MRC allowed proof of principle that we could in fact produce flu virus vaccine candidates in South Africa – both as [plant-made] subunit protein and as DNA vaccines.

In retrospect, while these projects were impossibly ambitious and not a little naïve, we and our co-workers received a crash course in both research vaccinology and the handling of big projects that has been crucial for all our subsequent work. We were also able to establish stable and well-qualified teams of people, with a nucleus of senior scientists who have been around us for up to 15 years. Another very important lesson was that we should patent our discoveries: in my case, this has led to me and my co-workers having the largest patent portfolio at our institution, and the largest molecular biotechnology-related portfolio in Africa – most of them to do with vaccines (14+ patent families). The development of a set of well-tried protocols around expression of novel antigens in a variety of systems has also been invaluable – especially when funding circumstances demanded that we change direction….

The potential importance of molecular farming for human health has been underlined recently with the apparently successful use of plant-produced MAbs (ZMapp) against Ebola virus disease in West Africa, and the proof of large-scale and rapid emergency-response production in plants of potentially pandemic influenza vaccines by Medicago Inc, among others [my emphasis] . We see our future role in exploiting niche opportunities for production of vaccine candidates and reagents for orphan or geographically-limited disease agents that do not attract Big Pharma attention – like CCHFV and RVFV – as well as for emerging animal diseases such as BTV and AHSV and BFDV, where rapid responses and small manufacturing runs may be needed [my emphasis].

Despite the fact that we ambitiously entitled our 2012 flu vaccine paper “Setting up a platform for plant-based influenza virus vaccine production in South Africa“, and our 2013 DNA vaccine paper as “An H5N1 influenza DNA vaccine for South Africa“, nothing happened. Nothing, despite the then Minister of Health Dr Aaron Motsoaledi saying during the influenza H1N1 2009 pandemic, that:

“South Africa has arrived at a situation where we have no option but to start developing our own vaccine capacity, not only for H1N1, but generally,” Motsoaledi told parliament.

“The disturbing feature about today’s world… has been expressed by the minister of health for Cambodia… who noted that the developed world, after producing the vaccine, may want to cover their own population first before thinking about the developing world,” Motsoaledi said.

It’s been nearly 11 years. Nothing has happened still. Despite distributing some 25 million doses of vaccines annually in South Africa, our only human vaccine firm – The Biovac Institute – still makes no virus vaccines. We have licenced our patented technology – for plant-made human papillomavirus vaccines and influenza virus vaccine – outside the country, for the lack of any interest locally.

This really should change. Maybe we have an opportunity now.


*= potential conflicts of interest due to partnerships.


Reviews on Molecular Farming

1: Dennis SJ, Meyers AE, Hitzeroth II, Rybicki EP. African Horse Sickness: A Review of Current Understanding and Vaccine Development. Viruses. 2019 Sep 11;11(9). pii: E844. doi: 10.3390/v11090844. Review. PubMed PMID: 31514299; PubMed Central PMCID: PMC6783979.

2: Rybicki EP. Plant molecular farming of virus-like nanoparticles as vaccines and reagents. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2020 Mar;12(2):e1587. doi: 10.1002/wnan.1587. Epub 2019 Sep 5. Review. PubMed PMID: 31486296.

3: Chapman R, Rybicki EP. Use of a Novel Enhanced DNA Vaccine Vector for Preclinical Virus Vaccine Investigation. Vaccines (Basel). 2019 Jun 13;7(2). pii: E50. doi: 10.3390/vaccines7020050. Review. PubMed PMID: 31200559; PubMed Central  PMCID: PMC6632145.

4: Margolin E, Chapman R, Williamson AL, Rybicki EP, Meyers AE. Production of complex viral glycoproteins in plants as vaccine immunogens. Plant Biotechnol J.  2018 Jun 11. doi: 10.1111/pbi.12963. [Epub ahead of print] Review. PubMed PMID: 29890031; PubMed Central PMCID: PMC6097131.

5: Chabeda A, Yanez RJR, Lamprecht R, Meyers AE, Rybicki EP, Hitzeroth II. Therapeutic vaccines for high-risk HPV-associated diseases. Papillomavirus Res. 2018 Jun;5:46-58. doi: 10.1016/j.pvr.2017.12.006. Epub 2017 Dec 19. Review. PubMed PMID: 29277575; PubMed Central PMCID: PMC5887015.

6: Rybicki EP. Plant-made vaccines and reagents for the One Health initiative. Hum Vaccin Immunother. 2017 Dec 2;13(12):2912-2917. doi: 10.1080/21645515.2017.1356497. Epub 2017 Aug 28. Review. PubMed PMID: 28846485; PubMed Central PMCID: PMC5718809.

7: Williamson AL, Rybicki EP. Justification for the inclusion of Gag in HIV vaccine candidates. Expert Rev Vaccines. 2016 May;15(5):585-98. doi: 10.1586/14760584.2016.1129904. Epub 2015 Dec 28. Review. PubMed PMID: 26645951.

8: Rybicki EP. Plant-based vaccines against viruses. Virol J. 2014 Dec 3;11:205.  doi: 10.1186/s12985-014-0205-0. Review. PubMed PMID: 25465382; PubMed Central PMCID: PMC4264547.

10: Scotti N, Rybicki EP. Virus-like particles produced in plants as potential vaccines. Expert Rev Vaccines. 2013 Feb;12(2):211-24. doi: 10.1586/erv.12.147. Review. PubMed PMID: 23414411.

11: Thuenemann EC, Lenzi P, Love AJ, Taliansky M, Bécares M, Zuñiga S, Enjuanes L, Zahmanova GG, Minkov IN, Matić S, Noris E, Meyers A, Hattingh A, Rybicki EP, Kiselev OI, Ravin NV, Eldarov MA, Skryabin KG, Lomonossoff GP. The use of transient expression systems for the rapid production of virus-like particles in  plants. Curr Pharm Des. 2013;19(31):5564-73. Review. PubMed PMID: 23394559.

12: Rybicki EP, Hitzeroth II, Meyers A, Dus Santos MJ, Wigdorovitz A. Developing  country applications of molecular farming: case studies in South Africa and Argentina. Curr Pharm Des. 2013;19(31):5612-21. Review. PubMed PMID: 23394557.

14: Lotter-Stark HC, Rybicki EP, Chikwamba RK. Plant made anti-HIV microbicides–a field of opportunity. Biotechnol Adv. 2012 Nov-Dec;30(6):1614-26. doi: 10.1016/j.biotechadv.2012.06.002. Epub 2012 Jun 28. Review. PubMed PMID: 22750509.

15: Rybicki EP, Martin DP. Virus-derived ssDNA vectors for the expression of foreign proteins in plants. Curr Top Microbiol Immunol. 2014;375:19-45. doi: 10.1007/82_2011_185. Review. PubMed PMID: 22038412.

16: Rybicki EP, Chikwamba R, Koch M, Rhodes JI, Groenewald JH. Plant-made therapeutics: an emerging platform in South Africa. Biotechnol Adv. 2012 Mar-Apr;30(2):449-59. doi: 10.1016/j.biotechadv.2011.07.014. Epub 2011 Aug 3. Review. PubMed PMID: 21839824.

17: Rybicki EP, Williamson AL, Meyers A, Hitzeroth II. Vaccine farming in Cape Town. Hum Vaccin. 2011 Mar;7(3):339-48. Epub 2011 Mar 1. Review. PubMed PMID: 21358269.

18: Giorgi C, Franconi R, Rybicki EP. Human papillomavirus vaccines in plants. Expert Rev Vaccines. 2010 Aug;9(8):913-24. doi: 10.1586/erv.10.84. Review. PubMed PMID: 20673013.

19: Rybicki EP. Plant-made vaccines for humans and animals. Plant Biotechnol J. 2010 Jun;8(5):620-37. doi: 10.1111/j.1467-7652.2010.00507.x. Epub 2010 Mar 11. Review. PubMed PMID: 20233333.

20: Pereira R, Hitzeroth II, Rybicki EP. Insights into the role and function of L2, the minor capsid protein of papillomaviruses. Arch Virol. 2009;154(2):187-97. doi: 10.1007/s00705-009-0310-3. Epub 2009 Jan 25. Review. PubMed PMID: 19169853.

Endlessly revisiting a bad idea

10 December, 2019

I see, in my travels through TwitterSpace (thanks @evelienadri!) that the ICTV is mulling a major rework of virus taxonomy – and that they’re wanting, among other things, to

  1. have a binomial nomenclature system, like cellular organisms
  2. work some Latin into it.

A downloadable paper on this is provided here.

Now as a sometime Study Group Chair (two different groups of plant viruses; Bromoviridae and Geminiviridae), member of a third (Potyviridae) and longtime member of (since 1987) and contributor to the ICTV, I am frankly aghast that we are revisiting territory that we left behind more than fifty years ago. It was recognised then that viruses are not like cell-based organisms, and that we had a chance to get away from the straitjacket of Latinate binomials imposed on us several hundred years ago. And now – we are to return to binomials, and to Latin, yet??

No! Please, no! The idea has exercised me and some others sufficiently to cause a bit of a Twitter storm:

The problems with virus taxonomy and nomenclature, such as they are, are largely the making of folk who ignore established and customary rules, and establish names like “Marseillevirus”: what is this? The name gives absolutely no idea; neither does “mimivirus”, which I still think was named after someone’s dog.

Bean golden mosaic begomovirus, on the other hand, very aptly describes the type member of the genus Begomovirus, as does Panicum streak mastrevirus – both geminiviruses (family Geminiviridae) in good standing. Plant virologists seem to have been the most law-abiding of ICTV members, and it was from their ranks that the idea of using generic names as identifiers first came from, as in the usage shown above.

Now what could possibly be wrong with yellow fever flavivirus, or its relative hepatitis C hepacivirus? Very descriptive of exactly which virus you mean, rather than calling them flavivirus YF35 or hepacivirus H1, or some such gobbledegook.

I realise that virology has a problem with the enormous number of sequences that appear to be whole virus genomes, that no-one knows what to do with. The answer is that a sequence is NOT a virus, until it is shown to be one – at which point it can get a name, based on its phylogenetic relationships.

Jumbling up names that have been in common usage for many years is going to be resisted; having a taxonomic scheme that reverses the order by which virologists have known things, more so. Why bother?? What is so wrong with our present naming system, that we have to so drastically change it – and moreover, have species names that may be completely different to the common names of actual viruses?

I see no good reason to get in line with the rest of biology: viruses are, after all, the most numerous lifeforms on the planet; cramming them into an archaic straitjacket devised for organism with legs or leaves, and grudgingly extended to microbes, is simply retrograde.

So let’s not do it. Please?!

Influenza and History of Discovery of Viruses ebooks

14 November, 2019

I discover to my annoyance that the Apple Store changed the access URLs to my two ebooks without informing me – so I am re-advertising them here. Who knows, I may get more sales!

Influenza is available in the US Store via this link; Discovery of Viruses via this one. Please buy: you’ll be funding my impending retirement!

A new vaccine hope for African horse sickness, from an unlikely source

22 November, 2018

MEDIA RELEASE:

A new vaccine hope for African horse sickness, from an unlikely source

FOR IMMEDIATE RELEASE | 22 NOVEMBER 2018

 

Researchers at the University of Cape Town’s ​Biopharming Research Institute (BRU)​ have created a promising new vaccine candidate to help prevent the devastating effects of African Horse Sickness (AHS). And they’re producing it in tobacco plants.

“We’ve got a vaccine candidate that’s extremely immunogenic,” says Prof Ed Rybicki, Director of the BRU. “It also produces neutralising antibodies when administered to healthy horses.” That means that the vaccine works really well in initial tests, but needs to be tested against an actual outbreak of AHS before it can be sold. BRU recently published these results in the respected Veterinary Research​ journal.

The need for an effective AHS vaccine is pressing. The disease is a devastating one, particularly in Africa, with up to 90% of infected horses dying in some outbreaks. The current commercial vaccine is known as a live-attenuated vaccine, and while it remains effective, it carries some risks. According to Prof Alan Guthrie, Director of the ​Equine Research Centre​ at the University of Pretoria and a former collaborator on this project, live vaccines can and occasionally do cause outbreaks of their own.

“There are two problems with a live-attenuated virus vaccine – reassortment of the genome and reversion to virulence,” he says. “Both can lead to outbreaks, which is what happened in the Cape in three different AHS outbreaks over the last 15 years – in 2004, 2011, and 2014.”

This is why other parts of the world don’t use the currently-available vaccine, says Guthrie. And this is a looming threat, as a changing climate allows the midge that carries the virus to spread to new parts of Europe and the United Kingdom.

According to ​Sue Dennis, PhD candidate and lead author on this study, the BRU’s plant-produced vaccine doesn’t carry any of these risks, which makes it suitable for use around the world.

“We’ve used tobacco plants to produce four different virus proteins that automatically assemble to form a virus-like particle (VLP). It looks the same as the virus, just without any genetic material; so it cannot replicate or infect horses with the disease.”

This VLP is the vaccine – when injected into an animal, the immune system produces antibodies to the virus that will fend off the real thing and protect the animal from disease. Dennis says that initial results look very promising, but there is more work to be done.

“When we tested the plant-produced vaccine in healthy horses, we saw an immune response at the same level as the live vaccine,” she says. When first testing vaccines in live animals, the most important thing is to show that the animal’s health is not affected, and that the immune system produces neutralising antibodies – the best indication that the vaccine will work against the live virus. On both counts, the BRU study has been a success.

“The presence of neutralising antibodies is a strong indication that horses will be protected from the virus,” she says. “But to confirm that the vaccine offers complete protection, we need what’s called a live challenge.”

In addition, the VLPs produced by Dennis and colleagues represent just one strain of AHSV; they are currently working on producing vaccines against the other strains.

This success builds on more than 10 years of work at the BRU producing VLPs and other proteins in tobacco plants. In particular, years of work on bluetongue virus, which is related to AHS virus, has contributed to this breakthrough.

The next step is to test the protective power of the vaccine in horses against a challenge with live, virulent AHSV (the so-called live challenge), to see whether this promising vaccine candidate can stand up against the live virus. If it does as well as the current live-attenuated vaccine, BRU researchers believe they will be well on their way to a new global AHS vaccine.

This research was funded in part by the ​Technology Innovation Agency​, and related intellectual property has been protected through UCT’s ​Department of Research, Contracts and Innovation​, who receive a rebate from the DST National IP Management Office (NIPMO) to support patenting.

 

About BRU

The Biopharming Research Unit​ (BRU, Department of Molecular and Cell Biology at ​UCT) ​ makes recombinant proteins in plants for use as diagnostics or vaccines for human and animal diseases. The Unit comprises research groups led by Professor Ed Rybicki, Associate Professor Inga Hitzeroth and Dr Ann Meyers, and boasts the largest portfolio of biotechnology patents at UCT, as well as the largest molecular biotechnology portfolio in South Africa. ​

http://www.mcb.uct.ac.za/mcb/BRU-home

 

About UCT

The University of Cape Town (UCT) is the leading research-intensive university in South Africa and on the African continent, with a tradition of academic excellence that is respected worldwide. ​

http://www.uct.ac.za

 

About RCI

Research Contracts and Innovation (RC&I) acts as the liaison between UCT’s research community and the private sector with regards to intellectual property protection, commercialisation and business development activities. ​

http://www.rci.uct.ac.za

 

For media enquiries, please contact Dr Ann Meyers on 021 650 5712 | ann.meyers @uct.ac.za. To read the full paper, go to ​https://veterinaryresearch.biomedcentral.com/articles/10.1186/s13567-018-0600-4​.

 

Press release written and distributed for the Biopharming Research Unit by ​ScienceLink​.

 

Teaching Virology With Social Media

12 July, 2018

I have had a Web presence since we first had access to the Web, here at the University of Cape Town, back in 1994: a few of us had discovered this new and shiny thing, and asked our IT Services if UCT had a server – to be told “Yes, but you can’t use it”. We – my colleague Vernon Coyne and I – quickly disabused them of this notion, and got unfettered access to what was then a very primitive Webiverse. Imagine: we were still using FTP and Gopher to move stuff around on the internet at the time; we also had to compose our self-taught HTML using Windows Notepad, for browsers like Cello that didn’t support graphics!

I pretty quickly got the notion that one could teach Virology via the Web, and set up teaching pages from 1995 or so that survived until UCT’s Big Clean Up a few years ago, which basically killed the whole legacy Web environment for us. Delightfully primitive they were, at first: I blogged about this here two years ago, noting that the ONLY record of all that work was via the Wayback server, that has an admirable if slightly spotty set of historical links to material that does not survive anywhere else.

Contents

Something that was potentially more valuable though, and which I pioneered at UCT from 1995, was the real-time updating of virological news – started in 1995 with the Ebola Zaire outbreak in Kikwit in the DRC, and commemorated here 20 years on. I was essentially compiling a daily digest of news on the Kikwit outbreak, and later also on others, and also on Marburg, via sources such as ProMed and internet discussion groups. It all started with an essay by my 1994 Honours student, Alison Jacobson, that was one of the first things I put up on the Web. This subsequently ended up being one of the only sources of information on the virus available online for a while, which terrified Alison, and which I commemorated here.

Occurrences_of_Ebola 2

I used this material at the time to inform undergrad students in second-and third-year courses as to what was going on in the moment – and give them cutting-edge material for exam purposes even after my section(s) of their course(s) had finished.

Inevitably things changed and moved on, and I got busy doing other career-related things – then my long-time internet guru Alan Cann introduced me to the concept of regular blogging via WordPress, and slicker news aggregators such as Scoop.it, and Twitter. The site you’re on right now is of course the blog site I set up in 2007 as a teaching blog for Virology, after guesting on his MicrobiologyBytes site a number of times – and I see with some sadness that his site no longer exists. I did things with ViroBlogy like blogging in detail in 2008 on a great paper describing single-round replication of a West Nile virus vaccine candidate – and then asking a detailed question on it in the 3rd year Defence and Disease course exam, despite there being no coverage of it during the course.

I also signed up for Twitter as @edrybicki in 2008 – mainly to tweet about cups of coffee and Marmite-coated biscuits, it would seem, although I see H1N1pdm flu getting to South Africa got a mention.

_edrybicki_coffee_-_Twitter_Search

I then started up Virology News in 2012 on the Scoop.it site, again following The Guru Cann, for disseminating a wider, more general set of news about viruses to a wider audience. Oh, and news about zombies. And sometimes Led Zeppelin too B-)

Virology_News___Scoop_it

Scoop.it turned out to be an excellent add-on to my existing sites, as it could be set up to automatically tweet anything I put up in it, or put it up on my WordPress ViroBlogy site. This actually marked the start of a new endeavour to supply up-to-date information to students of virology, as well as interested lay folk, despite the fact that I was not teaching undergrads between 2010 and 2017 because of secondment to a job as Academic Liaison to UCT’s Research Portal Project.

In any case, the blog site and Scoop.it site and being on Twitter kept me current with news in Virology, and were really useful in informing the two ebooks I published in 2015 on  “A Short History of the Discovery of Viruses“ and “Influenza Virus – Introduction to a Killer“, as well as the Introduction to Molecular Virology I am currently writing. The excerpts from those books that I trialled on this site – and tweeted about – have led to high and consistent page accesses from all over the world, as people search for things like “history of virus”.

Stats_‹_ViroBlogy_—_WordPress_com

What this has led up to, as I am now teaching undergraduates again, is the use of my Web-based news and other people’s materials via Twitter to inform students in the various modules I teach about current outbreaks, new discoveries and exciting developments in Virology and One Health. I tell them upfront in my first lecture that I want them to look at @edrybicki, ViroBlogy and Virology News, and that I will regularly be highlighting things of relevance to them. For instance, my daily trawl through Twitter invariably throws up a few papers I want to read, papers I think students should be interested in, and some news on outbreaks or breakthroughs. I then simply hashtag those with the course code, possibly add a comment, and retweet.

Cursor_and__edrybicki__MCB2020F_-_Twitter_Search

The value of this exercise can be seen in the fact that even well after I finished lecturing, students in the MCB2020F course were able to pick up on outbreak information that simply didn’t exist in that 5-lecture window weeks earlier – and give me material back in their final exam answers to the question “Describe one important virus disease outbreak this year and what it affected [3 marks]” that I had not taught them, from as short a time as 5 days previously. Which I commemorated thus, while marking their exam B-)

edrybicki__MCB2020F_-_Twitter_Search

I did the same thing for a third-year Viromics course, and while I got fewer non-lecture material-based answers, the value of pointing students to alternative material was again confirmed.

viromics edrybicki__MCB3026F_-_Twitter_Search

I shall continue to do this over the next three years of formal lecturing, for the simple reason that it engages students in the productive use of social media – and makes them go out and find information you didn’t have to teach them. You are warned, MCB2020F / 3026F / 3023S / 3024S and 2022S: hashtags, blogs, Scoops…are all waiting for you B-)

 

 

1918 Influenza Pandemic Case Fatality Rate

11 April, 2018
VIRUS-FLU-BIRDS-1-E-200

Influenza viruses and birds. Russell Kightley Media

Seeing as I have written an ebook on influenza that includes a short history of the 1918 pandemic, I have a rather keen interest in looking up things like case fatality rates, incidences and the like. I have also picked up on a rather worrying discrepancy in oft-quoted figures that just get recirculated without question, in serious and respected publications.

For example, here is one of the opening paragraphs from an influential review from Jeffery Taubenberger and David Morens, from 2006:

“An estimated one third of the world’s population (or ≈500 million persons) were infected and had clinically apparent illnesses during the 1918–1919 influenza pandemic. The disease was exceptionally severe. Case-fatality rates were >2.5%, compared to <0.1% in other influenza pandemics. Total deaths were estimated at ≈50 million and were arguably as high as 100 million.”

This figure of ~2.5% CFR is found in many references, yet it cannot be right: just from data in that paragraph, one could estimate that the CFR must have been between 10 and 20%!

No less a publication than Nature, in their 25th January issue, has an editorial entitled “The Great Flu” – wherein they say the following – and add to the problem:

“One hundred years ago this month, the 1918 influenza virus was just starting to spread. It would become the greatest public-health crisis of the twentieth century, claiming some 50 million to 100 million lives….

There are few data points to go on — flu pandemics happen only three or four times a century — but one risk is certainly higher: 7.6 billion people share the planet in 2018, up from 1.9 billion in 1918….

The case-fatality rate in the 1918 pandemic was around 2.5% (compared with less than 0.1% in other flu pandemics), and a comparable or worse rate in a future pandemic cannot be discounted.”

pig flu

Influenza viruses in pigs. Russell Kightley Media

From their own figures, then, between 50 and 100 million people died, of 1.9 billion alive at the time. This is a death toll of between 2.6 and 5.2% of the WHOLE POPULATION, and is NOT a case fatality rate. If about one-third of the population was affected, then the CFR would be ~7.5 – 15%, which is far higher than the 2.5% quoted.

Here is a more realistic quote, for me at least, from Influenza Virus Net.com:

“The global mortality rate from the 1918/1919 pandemic is not known, but it is estimated that 10% to 20% of those who were infected died. With about a third of the world population infected, this case-fatality ratio means that 3% to 6% of the entire global population died. Influenza may have killed as many as 25 million in its first 25 weeks. Older estimates say it killed 40–50 million people while current estimates say 50—100 million people worldwide were killed. This pandemic has been described as “the greatest medical holocaust in history” and may have killed more people than the Black Death.”

Wikipedia even seems to have got it right, in their entry on the 1918 pandemic:

“The global mortality rate from the 1918/1919 pandemic is not known, but an estimated 10% to 20% of those who were infected died. With about a third of the world population infected, this case-fatality ratio means 3% to 6% of the entire global population died.

 So, all you virologists out there: please stop quoting that ludicrously low case fatality rate for the 1918 influenza pandemic of 2.5%, and get real! Oh, and let’s stop calling it the “Spanish Flu” too, please: it’s a much a misnomer as “swine flu” is for the 2009 pandemic, or “Aussie Flu” is for the recent and ongoing H3N2 epidemic.

Test version of a Introduction to Viruses eBook

1 March, 2018

Dear everyone:

I am trialling Viruses Introduction: this is an excerpt of what will be a much longer book, as a PDF for all you Mac-less folk out there. It is the Introduction segment of the book, which I will be using as a text for a course here at UCT in a couple of weeks.

I’d like to see your comments!

Ed

INTERNATIONAL HPV AWARENESS DAY 2018 – KNOW THE FACTS, GET THE VACCINE

1 March, 2018

The University of Cape Town (UCT), National Institute for Communicable Diseases (NICD), the Health Promotion South Africa Trust and the Cancer Association of South Africa (CANSA) will jointly observe the first international Human Papillomavirus (HPV) Awareness Day on the 4th of March 2018. The team has organised an HPV awareness day on Friday 2nd of March 2018 at 10am, at the Health Information Centre at Baphumelele Children’s Home, Z118 Dabula Street, Khayelitsha.

HPV is a sexually transmitted disease that infects most sexually active adults in the world (up to 80%). HPV is the primary cause of cervical cancer cases and a major cause of oral, anal, and penile cancers, as well as genital warts. Sexually active men and women of all ages should get vaccinated for protection against these cancers as well as genital warts, experts say.

Please see the full press release attached. MEDIA RELEASE International HPV Awareness Day 2018
For further enquiries or to arrange interviews, please contact Dr Zizipho Mbulawa at zizipho.mbulawa@uct.ac.za or 021 406 6352.
 
Distributed by ScienceLink on behalf of UCT Medical Virology and the National Institute for Communicable Diseases.

Sensationalist hype in South African newspapers could damage vaccine trials

20 January, 2018

The Cape Weekend Argus has a report in it today – by “Staff Reporter and Daily Mail” – that exemplifies everything I hate about lazy, irresponsible journalism. It’s not the first time this newspaper stable of floor-wiping material has hyped the so-called dangerous TB vaccine, but this is the first time it’s been so prominent.

So, let us clear things up a little.

1. Monkeys died in the TB CHALLENGE part of the study – NOT because of the vaccine, which has been determined to be absolutely safe.

2. Because the vaccine was proved to be safe in MULTIPLE animal species, and in humans, and had been shown to have some efficacy in OTHER animal studies, it was used in babies – in studies approved by multiple Ethics Committees, including here at UCT.

3. IT WAS SAFE IN BABIES – as it was in every other organism it was tested on.

4. Despite the picture and caption leading one towards the conclusion that SA’s Minister of Health Dr Aaron Motsoaledi disapproved of use of the vaccine, he in fact was very supportive.

So, all in all, an appallingly bad piece of journalism, which sensationally hypes a very serious issue by ascribing harm to a vaccine that is in fact very safe. Not necessarily efficacious in humans as a similar one was not for malaria, but SAFE. In addition, the trial was over in 2012 – meaning any harm would have been obvious by now, and there has been none.

The British Medical Journal, in its analysis of the whole issue, had this to say:

“While we strongly agree with calls for rigor in conducting, and openness in reporting, preclinical studies, we are confident that moving forward with this efficacy trial was justified”.

So there you have it. The ONLY controversial aspect of the use of this vaccine was the fact that it failed to protect monkeys in a live TB challenge. The vaccine was NOT dangerous; use of it in babies was NOT unethical, and in fact has been lauded as a step forward in our understanding of TB vaccinology.

Time to up your reporting game, Weekend Argus!!