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Text Content

VIROBLOGY

Virology-related and hopefully educational posts for people in the field or
learning about it

--------------------------------------------------------------------------------


INSERTION OF SARS-COV-2 SEQUENCES INTO HUMAN CELL GENOMES

13 May, 2021

Updated 31/05/2021 – see end.

RE-updated 10/06/2021 – see end

A group of researchers who claimed in a preprint a while ago that they could
show integration of SARS-CoV-2 genomic sequences into the genome of cultured
human cells has now doubled down, with a Proc Natl Acad Sci paper (!!) further
claiming proof of ability to insert in cultured cells, and of proof of insertion
in patient tissue.

The authors were investigating their hypothesis that inserted fragments of viral
genomes that were not infectious, were responsible for the phenomenon of
prolonged positive PCR tests in patients who had completely recovered from
COVID-19, and who did not shed infectious virions. They investigated this by
transfecting HEK293 cells with human LINE1 transposable element-encoding
plasmids, then infecting them with SARS-CoV-2. The addition of LINE1 was “To
increase the likelihood of detecting rare integration events“. They isolated DNA
from cells 2 days post-infection, and did PCR amplification of the N gene from
gel-purified “large fragment DNA” that they claim was successful. While they
claim this as proof of reverse transcription and integration of the SARS2 N gene
into genomic DNA, they went further and subjected extracted cell DNA to Nanopore
long-read sequencing. This resulted in their finding evidence of integration of
63 instances of the whole or part of the genomic 3′-terminal N gene in a variety
of chromosomal locations, flanked by host DNA sequences in 2 cases and on one
side in 61, with a 20 bp direct repeat with “a consensus recognition sequence of
the LINE1 endonuclease” in the two whole sequence instances. There appeared to
be preferential insertion into exon-associated sites. The integrated DNA was
mainly from the 3′ end of the SARS2 genome.



Figure by Ed Rybicki, copyright 2021

Repeating this analysis with SARS2-infected HEK293T and Calu3 cells that had not
been transfected with LINE1 DNA gave 7 integrations, again characteristic of a
LINE1-type mechanism, and again preferentially associated with exons.

Another claim they make is that integrated sequences can be expressed. They
tested this by looking at published RNA-seq data for SARS2-infected cells and
organoids from a variety of human tissues, and “found” a number (0.004 – 0.14%
of all SARS2-specific reads) of “chimaeric reads”, or virus-human gene fusions
in RNA. The abundance of these reads, correlated with the level
(=concentration?) of viral RNAs, and most mapped to the SARS2 N gene – which
makes the most abundant mRNAs. An important observation was the following:

“Single-cell analysis of patient lung bronchoalveolar lavage fluid (BALF) cells
from patients with severe COVID … showed that up to 40% of all viral reads were
derived from the negative-strand SARS-CoV-2 RNA …. Fractions of negative-strand
RNA in tissues from some patients were orders of magnitude higher than those in
acutely infected cells or organoids”,

because they go on to say (after admitting that they showed no chimaeric
sequences in patient BALF samples), that:

“in some patient-derived tissues, where the total number of SARS-CoV-2
sequence-positive cells may be small, a large fraction of the viral transcripts
could have been transcribed from SARS-CoV-2 sequences integrated into the host
genome”.

Yes. Well. Ummmm…no. Seriously, no. Aside from the objections that others have
raised – such as the fact that the way they analysed other data as well as their
own undue notice of what could very well all be artefactual chimaeras – they do
not appear to have a very deep understanding of how ssRNA+ viruses replicate, or
that there may be circumstances – such as in dead or dying cells, or bits of
cells resulting from processes such as apoptosis – where there is NOT a
superabundance of ssRNA+ compared to RNA-. For example, in the “acutely infected
cells” – presumably in culture – virus is replicating vigorously, and there
could be expected to be a lot of progeny immature virions in addition to the
double-membrane-enveloped replication complexes, which is where the RNA- is,
engaged in making more ssRNA+. In quiescent, dying or dead cells, on the other
hand, one would imagine all the assembling virions had budded, that replication
would probably have stopped due to depletion of resources – and that only the
replication centres, safe and protected from RNAses by their vesicle membranes,
would be left. These might also form stable exosome-like structures, which would
be a good thing to look for. Moreover, replication complexes are largely dsRNA –
that is, essentially equal amounts of + and – strand RNA, which would account
for their observations with no integration of viral RNA being required.

However, my objections are mainly directed at the model system they used in the
first instance. The use of cultured cells in the first instance, and
transfection of them with LINE1 elements for over-expression of RT in the
second, is pretty much guaranteed to “force” outcomes that are highly unusual in
natural infections. This is akin to saying “See, if I force-feed mice with 100x
the recommended dose of X in the presence of known mutagens, it causes cancer!!”
It is a TOTALLY artificial situation, done in a transformed human cell line,
that has VERY little relevance to the real world. 

Of course, they also did the experiment in two cell lines without LINE1
transfection – and found a lower number of integrations. There is ALWAYS a
chance (albeit very small) that a nucleic acid – RNA or DNA – could be
integrated into a somatic cell, via illegitimate recombination or LINE1
element-mediated insertion. HOWEVER: integration of a random piece of SARS2
genome would almost certainly do nothing in that cell; moreover, even if the
whole genome inserted, the cell would be killed by T-cells the same way an
infected cell is – and they did not find very much more than N or partial N
genes integrated, which is a tiny fraction of the relatively huge genome. It
could be that the virus 3′ end has some unusual properties – it is an origin of
replication for the virus genome, after all – that favour mRNAs deriving from it
interacting with LINE1 transposition machinery, and being (occasionally)
integrated.

While they had a hypothesis that integrated sequences were responsible for
positive PCR tests long after “recovery” from infection, their evidence does not
support this because they have not shown that all of the sequences targetted by
PCR primers are present in the genomes of patients, or even of cells in their
experiments. Presence of a product for just one viral gene does not constitute a
positive diagnosis. Moreover, there is evidence for SARS2 reactivation months
after initial infection, which could be explained far more easily by viral
persistence in immune privileged sites, such as has also been demonstrated for
Ebola virus disease. This persistence, or even the survival of dsRNA forms of
the genome or even of fragments of it in dormant replication centres, would be a
far more likely reason for persistence of PCR positivity.

However, and this is the important point I wanted to make, the ONLY way an
insertion from SARS2 (or anything else) could cause any sort of a problem is if
that insertion results in runaway malignant transformation (a lot more unlikely
than the insertion event itself), or if it inserts into germline cells (egg,
sperm precursors) AND is passed on to progeny. There, the probabilities start
getting very, very small indeed.

So: a fuss about nothing, is what this “result” is. I bet you they could have
showed the same for ANY RNA under the same set of conditions – and it would
still mean nothing. You are a LOT more likely to have bits of nucleic acid from
lettuce or tomatoes insert into gut cells, given you eat them FAR more often,
and in quantities FAR greater than you are exposed to from a virus – and has
anyone ever reported a problem with those?

No.

So don’t worry about this much-hyped “discovery”.

Added 31/05/2021:

Aaaaaaaand…here’s someone who disliked the paper enough to refute it thoroughly,
by experiment, no less! Nathan Smits et al. used nanopore long-read sequencing
to show they could find NO proof of SARS2 sequences flanked by human DNA, in a
context where they COULD find integrated single genomes of HBV, and multiple
LINE insertions.

Human genome integration of SARS-CoV-2 contradicted by long-read sequencing


ABSTRACT

A recent study proposed severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) hijacks the LINE-1 (L1) retrotransposition machinery to integrate
into the DNA of infected cells. If confirmed, this finding could have
significant clinical implications. Here, we applied deep (>50x) long-read Oxford
Nanopore Technologies (ONT) sequencing to HEK293T cells infected with
SARS-CoV-2, and did not find any evidence of the virus existing as DNA. By
examining ONT data from separate HEK293T cultivars, we resolved the complete
sequences of 78 L1 insertions arising in vitro in the absence of L1
overexpression systems. ONT sequencing applied to hepatitis B virus (HBV)
positive liver cancer tissues located a single HBV insertion. These experiments
demonstrate reliable resolution of retrotransposon and exogenous virus
insertions via ONT sequencing. That we found no evidence of SARS-CoV-2
integration suggests such events in vivo are highly unlikely to drive later
oncogenesis or explain post-recovery detection of the virus.



Added 09-06-2021

…and then someone else actually went and found SARS2 RNA in degraded lung
tissue!

PERSISTENCE OF SARS-COV-2 RNA IN LUNG TISSUE AFTER MILD COVID-19

On Dec 1, 2020, we reported a successful case of double-lung transplantation
from a SARS-CoV-2 seropositive donor 105 days after the onset of mild
COVID-19.1 Although repeated quantitative (q)RT-PCR analyses of donor
nasopharyngeal swabs were negative, this technique detected RNA of the
SARS-CoV-2 N gene (delta Ct 35) from a biopsy of the right lung taken during
organ procurement. Viral culture of this biopsy was negative and
donor-to-recipient transmission did not occur. Complementary orthogonal methods
were needed to corroborate and interpret the qRT-PCR results.Therefore, we did
ultrasensitive single-molecule fluorescence RNA in-situ hybridisation with
RNAscope technology on formalin-fixed paraffin-embedded sections of the same
lung biopsy (appendix p 1), and compared the results with those of a lung biopsy
from a deceased patient with acute COVID-19 (figure A and B; appendix p 2). We
stained 14 slides of the donor lung biopsy, each containing one 5 μm section, as
follows: five slides with a probe for the N gene; five slides with a probe for
the S gene; and four slides with probes for N and S. A probe for
the basigin gene, which has been proposed to encode an alternative host
recipient for SARS-CoV-2, served as a positive control on the ten slides stained
for N or S only.2 We identified characteristic RNAscope puncta in three out of
nine slides for the N probe, and in six out of nine slides for the S probe
(figure C and D). These puncta appeared to be located in clumps of sloughed-off
material, and no cells or cell nuclei could be discerned in this debris-like
tissue. [my emphasis]

Posted in Uncategorized | Leave a Comment »


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!

Tags: antibody, cellular immunity, coronavirus, immunity
Posted in General Virology, Viruses | 1 Comment »


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.

Tags: COVID-19, DNA vaccine, SARS-CoV-2, vaccine
Posted in biofarming, biotechnology | 31 Comments »


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?!

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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!

Posted in Uncategorized | Leave a Comment »


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 .

 





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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.



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.



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.



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-)



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”.



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.



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-)



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.



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-)

 

 

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1918 INFLUENZA PANDEMIC CASE FATALITY RATE

11 April, 2018

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.”



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.

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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

Posted in Uncategorized | 4 Comments »


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.

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