Posts Tagged ‘HPV’

Papillomaviruses and human cancer

11 March, 2015

Human warts in all their forms – cutaneous, verrucous and genital growths and lesions – have been known since antiquity, and it was known since at least 1823 that at least some were infectious. Experiments done with human volunteers in the 1890s confirmed this, when it was shown that transplanting wart tissue resulted in typical disease.  As early as 1908, it was shown by a G Ciuffo that “verrucae volgare” – common warts – could be transmitted via a cell-free filtrate.  However, it was Richard E Shope who first showed that a papillomavirus was associated with animal tumours.  A useful review from 1931 on “Infectious oral papillomatosis of dogs” by DeMonbreun and the Ernest Goodpasture of egg culture fame covers the early history of the investigation of human disease as well as of animal papillomas very well, so we will not cover this further.

In light of later findings of the involvement of papillomaviruses, it was a prescient although premature observation by an Italian physician named Rigatoni-Stern in 1842 that cervical cancer appeared to be sexually transmitted, given that it occurred in married women, widows and prostitutes, but rarely in virgins and nuns.

Although papillomaviruses had been implicated as the first viruses known to cause a cancer in mammals as early as the 1930s, and the structurally very similar papovaviruses were similarly implicated in the late 1950s, it was only in 1972 that  Stefania Jabłońska proposed that a human papillomavirus (HPV; then called a papovavirus) was involved with the rare hereditary skin cancer called epidermodysplasia verruciformis.   

Meanwhile Harald zur Hausen had been investigating since 1974 the involvement of HPV in genital warts (condyloma accuminata) and squamous cell carcinomas, using DNA-based techniques such as hybridisation.  The rarely malignant condylomas had been shown to contain papillomavirus particles in some cases in 1968, with a better association in 1970; however, cross-hybridisation studies by zur Hausen’s group on DNA of these and common wart viruses showed no relationship despite their very similar morphologies. 

Virus particles from genital warts (6 &7) and a common skin wart (8).  Reproduced from Brit. J. vener. Dis., JD Oriel and JD Almeida, 46, 37-42, 1970 with permission from BMJ Publishing Group Ltd.

Virus particles from genital warts (6 &7) and a common skin wart (8). Reproduced from Brit. J. vener. Dis., JD Oriel and JD Almeida, 46, 37-42, 1970 with permission from BMJ Publishing Group Ltd.

Zur Hausen speculated on the role of HPVs in squamous cell carcinomas in 1977; Gérard Orth and Jabłońska and colleagues went on to define the “…Risk of Malignant Conversion Associated with the Type of Human Papillomavirus Involved in Epidermodysplasia Verruciformis” in 1979.

Because this was the new era of cloning and sequencing of DNA, the zur Hausen group and others went on to isolate and characterise a number of new HPVs associated with genital cancers and other lesions in the early 1980s.  In particular, they showed that HPV types 16 and 18 could be found both as free virus in cervical cell sample biopsies and integrated into the cell genomes of cell lines derived from cervical cancers.  A major finding in 1987 was that the legendary HeLa cell line – derived from a malignant cervical tumour from a Henrietta Lacks in 1951contains multiple copies of the HPV-18 genome.  The first HPV genome sequence (of type 1b) was obtained in 1982; the first genital type (6b, from condylomas) in 1983, and the first high-risk cancer virus (type 16) in 1985.

Later work involving large international surveys showed by 1995 that 99.7% of cervical cancers contained DNA from so-called “high risk” HPVs, leading to the conclusion that these were the necessary cause of cervical cancer, and that around 70% of these cancers were caused by HPVs 16 and 18.  Since then, HPVs have been found in more than 80% of anal cancers, 70% of vulval and 40% of vaginal cancers, around half of all penile cancers, and in roughly 20% of head and neck cancers.  If 16% of cancers are due to infection, and HPVs cause or are implicated in 30% of these, then they are a significant cause of cancers worldwide.

Harald zur Hausen was awarded a half share of the 2008 Nobel Prize in Physiology or Medicinefor his discovery of human papilloma viruses [sic] causing cervical cancer”.  I blogged on this at the time, here.

Work on vaccines against papillomaviruses (PVs) started early, after demonstrations presumably in the 1930s that domestic rabbits inoculated with the cottontail rabbit PV (CRPV) could become immune to reinoculation after recovery, and in 1962 that a “…formalin-treated suspension of bovine papilloma tissue” provided protection against challenge, but was not therapeutic.  However, progress was stymied by the fact that it proved impossible to culture any of the PVs, and challenge material had to be made from infected animal tissue, even though it had been shown that isolated viral DNA was infectious.

This changed after the advent of molecular cloning, when whole viral genomes could be prepared in bacteria.  Model systems for use in PV vaccine research by 1986 included cattle and bovine PVs, rabbits and CRPV and rabbit oral PV, and dogs and canine oral PV.  It had also been demonstrated that the L1 major structural protein of type 1 BPV produced in recombinant bacteria was protective against viral challenge in calves.  Jarrett and colleagues demonstrated, in 1991 and 1993 respectively, that they had achieved prophylactic and therapeutic immunisation against cutaneous (ie: skin; caused by BPV-2) and then mucosal (respiratory tract; BPV-4) bovine PVs, using E coli-produced proteins.  L1 and L2 proteins were protective against BPV-2, while L2 was protective against BPV-4 infection.  They suggested BPV-4 was a good model for HPV-16 given its mucosal tropism.

By the early 1990s several groups had demonstrated that it was possible to make PV virus-like particles (VLPs) by expression in eukaryotic systems such as yeast or animal cells of the L1 major virion protein either alone, or together with the minor protein L2.  In 1991 Ian Frazer’s group showed that expression of HPV-16 L1 and L2 together but not separately in animal cells via recombinant vaccinia virus, resulted in 40 nm particles resembling the virion being made.  In 1992 John Schiller’s lab showed VLP formation by L1 alone, with both BPV-1 and HPV-16 L1 genes expressed in insect cells via a baculovirus vector. In 1993 came the demonstration that expression of the plantar wart-causing HPV-1 L1 gene alone and L1 and L2 genes together in animal cells via vaccinia virus, as well as of the genital wart-causing HPV-11 L1 expressed in insect cells, resulted in VLP formation.  By 1995, it had been shown that immunisation of rabbits with CRPV L1-only or L1+L2 VLPs, and of dogs with canine oral PV L1 VLPs, protected completely against viral challenge.

hpv vlps

This groundwork made it possible for Merck and GlaxoSmithKline to develop and to push through to human trial and licensure, two independent VLP-based vaccines.  Merck’s vaccine – Gardasil – is quadrivalent, consisting of a mixture of VLPs made in recombinant yeasts from expression of L1 genes of HPV types 6 and 11, to protect against genital warts, and types 16 and 18, for cervical lesions and cancer.  GSK’s offering – Cervarix – is a bivalent HPV-16 and -18 vaccine only, consisting of VLPs made via recombinant baculoviruses in insect cell culture.  These are only the second anti-cancer vaccines on offer, and have gone on to blockbuster status within months of their release: Gardasil was licenced in June 2006, and Cervarix in October 2009.

Both appear to protect very well against infection with the types specified, but not to affect established infections.  Their long-term efficacy against cervical cancer is still to be established, although Gardasil has certainly lessened the incidence of genital warts in Australia post introduction in 2007.  There is now also a VLP-based vaccine for canine oral PV.

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Antivaxer HPV nonsense!

14 March, 2014

Fair Lady magazine just published a short but very useful article on HPV vaccines, with question-and-answer format commentary from a number of local experts on safety and such.

Then some loony takes them on in this piece.

My comment to that:

OK: this is a sadly under-informed and over-complicated response to a very good, simple article, with expert comments that are no way out of line with what is known to be the case about these vaccines.

Please allow me to correct a few things: in the first place, you say “Several ingredients in the two HPV vaccines are known to be a problem. One is the use of the microbe Saccharomyces cerevisiae, common yeast, as the medium in which the Gardasil antigen is developed. S. cerevisiae is known to trigger autoimmune response, as discussed recently in Yeast in Vaccines Tied to Autoimmune Diseases. Cervarix, though, was produced with a different medium, Trichoplusiani.”

Yeast is known to trigger autoimmune responses? Really? Then what about all those millions of people who have received Hepatitis B virus vaccine, also made in yeast? There is NO documented correlation with vaccination with yeast-made products and autoimmunity. NONE.

Then, Cervarix is “made in a different medium” – you obviously mean cell type, because Trichoplusia ni [note!] is a species of insect, from which the tissue-cultured cells used to make the HPV vaccine are derived. And? You have no problem with that? You shouldn’t.

Further: “The two vaccines, Gardasil and Cervarix, are distinctly different in another way. Gardasil contains a single adjuvant… while Cervarix utilizes a combination …These differences, since they involve the hyper-activation of the immune system and a known trigger for autoimmune disorders in only one of the vaccines, suggest that a recent study’s finding that there are no adverse effects whatsoever in either vaccine beggar belief.”

So you have a problem with the finding that there are no adverse effects BECAUSE the adjuvant regime is different? Not because of the evidence? Sorry, that isn’t very good science!

And it gets better: “Most significantly, in every clinical trial evaluating safety for both Gardasil and Cervarix, the so-called placebo groups were given injections that included an active aluminum adjuvant!
Though this is a common practice in vaccine trials, it is obviously a blatant means of biasing the results.”

So – a perfectly acceptable placebo arm in a clinical trial, with adjuvant given so that any difference would not be due to just this, means the studies are meaningless? Really?? What about the UNvaccinated groups these were compared to? ALL vaccines are associated with SOME events – and I note that YOUR piece above contains the sentence “The high proportion of adverse events reported is mainly due to the design of the study, since women were requested to report all events occurring after the vaccination; however the majority of events were mild and transient”.

You then quote – at excruciating length – a number of articles purportedly supporting your case, that can be summarised as showing that “HPV vaccination does not have a therapeutic effect in young women with pre-existing human papillomavirus infection”.

Yes? And? The two licenced HPV vaccines are PROPHYLACTIC, and were never intended to be therapeutic! It is unfortunate that the vaccines do not in fact lessen ESTABLISHED infections; however, there is plentiful evidence that they PREVENT INFECTIONS FROM BEING ESTABLISHED.

You are being alarmist and spreading falsehoods from a very shaky evidential base. You should stop doing that, or risk being shown up as being an antivax crank.

Emergency response vaccines for H5N1 influenza in South Africa

1 November, 2013

Our group has been working for some time now – since 2006, in fact – on investigating the feasibility of providing South (and southern) Africa with emergency response pandemic influenza vaccines.  The research was initiated after the Virology Africa 2005 conference that Anna-Lise Williamson and I organised in the Cape Town Waterfront in November of that year – when a senior WHO official warned us in his talk that “…if a pandemic hits, you are on your own: no-one will give you any vaccine”.

A group of us sat down afterwards, and discussed the feasibility of looking at emergency response vaccine(s), given that we had no capability in the whole of Africa to make flu vaccines.  Anna-Lise and I put together a proposal, with the highly pathogenic avian H5N1 influenza A as a target, which was funded on a once-off one-year basis by the Poliomyelitis Research Foundation (PRF) here in SA for 2006 – and then again by the PRF as a three-year Major Impact Project  (MIP) from 2008-2010, and subsequently to a lower level by both the PRF and the Medical Research Council of SA.  What made it all the more impressive for a South African project was that we had proposed expressing a protein-based vaccine in plants – quite a revolutionary prospect at the time, but something that followed on from the highly successful production of Human papillomavirus virus-like particles by transient expression in Nicotiana benthamiana by  James Maclean, working as a postdoc in our lab at the time.

However, some of the most important work was done early: James was very quick to get the haemagglutinin (HA) gene for the A/Vietnam/1194/2004 strain of H5N1 synthesised by GeneArt in Germany, and cloned into the same Agrobacterium tumefaciens plant expression vectors from Professor Rainer Fischer’s lab in Aachen, Germany, that had been used for HPV.  His initial work showed that large amounts of HA protein could be produced, both as soluble protein which lacked a membrane localisation domain, and as the membrane-bound form.  This work formed the basis for a patent application on the transient expression of H5 HA that has now been granted.

Subsequently, when the PRF MIP started, we employed Dr Elizabeth (Liezl) Mortimer and Ms Sandiswa Mbewana to further the work: with collaborators from the National Institute for Communicable Diseases (NICD) in Johannesburg and State Veterinary Services in Stellenbosch, this investigated transient and transgenic expression of soluble and membrane-bound forms and their immunogenicity, as well as a DNA vaccine consisting of the HA genes cloned into Tomas Hanke’s pTH vector.

The protein expression work was published in 2012, as well as being featured here in ViroBlogy at the time.


What we had managed to show was that we could get excellent production of the H5 HA in both soluble and bound forms, and that especially the membrane-associated form of the protein was highly immunogenic, and elicited antibodies in experimental animals that were appropriately neutralising, indicating its suitability as a vaccine candidate.

Now this all happened despite our running out of money AND Liezl leaving to have a baby…and then we managed to get another paper out of the work, this time on the DNA vaccine side of things.


We pitched this at the South African Journal of Science as a vindication of the faith in us by exclusively South African funding agencies – and managed to get the cover of the issue in which it appears, thanks to the truly excellent artwork of Russell Kightley from Canberra, Australia.  Front AND back covers, as it happens…!



And this all made Sandiswa Mbewana, who is now a PhD student on another project, very happy:


This all came in excellent time to mark the establishment in the Department of Molecular and Cell Biology at the University of Cape Town, of a new URC Research Unit: namely, the Biopharming Research Unit (BRU).


Watch this space…B-)

HPV vaccines for South Africa: coming to a school near you!

19 May, 2013

From The Independent Online:

HPV and cervical cancer: courtesy Russell Kightley Media

HPV and cervical cancer: courtesy Russell Kightley Media

“Cape Town – Government will start administering cervical cancer vaccines in schools from February next year, Health Minister Aaron Motsoaledi has announced.

Speaking during the health budget vote debate in the National Assembly on Wednesday, Motsoaledi said government hoped to negotiate lower prices for the vaccine, which treats the Human Papilloma Virus (HPV) – the major cause of cervical cancer among women.

Quoting experts, he said cervical cancer affected 6000 South African women a year, 80 percent of them black. More than half the women affected died of the disease.

While the HPV vaccine presented an opportunity to prevent women from contracting cancer, there were still obstacles to overcome.”

This is a really, really big deal for South Africans – and pity is, the vaccine will not be given to boys, or universally to girls.

Seriously: all the science says that giving it to boys as well limits spread of the viruses far better; not making it universally available will mean all sorts of recriminations around unequal access (read: to less privileged kids ONLY as part of the government programme at first).

But a big step in the right direction!

Papillomavirus and HIV: a nasty combination

17 August, 2012

I started working on human papillomaviruses (HPVs) some 22 years ago, back at the dawn of PCR: I helped my then-new major collaborator (and wife of 2 years), Anna-Lise Williamson, design some degenerate primers for amplifying as wide a range as possible of high-risk HPVs from cervical biopsy samples.  These worked pretty well, and are still highly useful for the purpose, despite the many novel types found since then.

We went on to do another two papers together on looking at variation and typing of HPVs via PCR and and sequencing, then took a deviation into making candidate vaccines for HPV and HIV.  Anna-Lise carried on with surveilling for HPVs, however, and has ended up with a WHO Regional Laboratory for HPV work.  She also started working on HPV infections in HIV-infected women: work on a study cohort showed that while HIV-free women usually had only 1 HPV type, the 109 HIV-infected often were infected with multiple HPV types.  In association with Anna Salimo in my lab, we started a deep sequencing pilot study on the sample with the most HPVs.  This turned this into a regional study, with help on assembling and interpreting sequence data from Prof Johan Burger’s lab at the University of Stellenbosch, and it was revelatory: while a commercial kit could detect 12 HPV types in one sample, next-gen sequencing found 16.

We went on to do PCR on all 109 samples in the cohort with specific primers for the types not found by the kit, and showed prevalences up to 15% in the HIV-infected group.  This is an important result, because otherwise-innocuous HPV types that do not show up in normal women, may well be associated with disease in the HIV-infected – and will probably not be protected against by the current HPV vaccines.

We continue to do work on these samples, and it will be very interesting to see what the new methodologies show up.  Especially as sequencing becomes cheaper, and we can do more samples…!  Meantime, we have published the pilot study:

Next-generation sequencing of cervical DNA detects human papillomavirus types not detected by commercial kits

Tracy L MeiringAnna T SalimoBeatrix CoetzeeHans J MareeJennifer MoodleyInga I HitzerothMichael-John FreeboroughEd P Rybicki and Anna-Lise Williamson

Virology Journal 2012, 9:164 doi:10.1186/1743-422X-9-164

Published: 16 August 2012

Abstract (provisional)


Human papillomavirus (HPV) is the aetiological agent for cervical cancer and genital warts. Concurrent HPV and HIV infection in the South African population is high. HIV positive (+) women are often infected with multiple, rare and undetermined HPV types. Data on HPV incidence and genotype distribution are based on commercial HPV detection kits, but these kits may not detect all HPV types in HIV + women. The objectives of this study were to (i) identify the HPV types not detected by commercial genotyping kits present in a cervical specimen from an HIV positive South African woman using next generation sequencing, and (ii) determine if these types were prevalent in a cohort of HIV-infected South African women.


Total DNA was isolated from 109 cervical specimens from South African HIV + women. A specimen within this cohort representing a complex multiple HPV infection, with 12 HPV genotypes detected by the Roche Linear Array HPV genotyping (LA) kit, was selected for next generation sequencing analysis. All HPV types present in this cervical specimen were identified by Illumina sequencing of the extracted DNA following rolling circle amplification. The prevalence of the HPV types identified by sequencing, but not included in the Roche LA, was then determined in the 109 HIV positive South African women by type-specific PCR.


Illumina sequencing identified a total of 16 HPV genotypes in the selected specimen, with four genotypes (HPV-30, 74, 86 and 90) not included in the commercial kit. The prevalence’s of HPV-30, 74, 86 and 90 in 109 HIV positive South African women were found to be 14.6 %, 12.8 %, 4.6 % and 8.3 % respectively.


Our results indicate that there are HPV types, with substantial prevalence, in HIV positive women not being detected in molecular epidemiology studies using commercial kits. The significance of these types in relation to cervical disease remains to be investigated.

I thank Russell Kightley Media for use of the HPV and cervical cancer graphic. Virology News

11 February, 2012

This is just to announce that I will be regularly posting “Virology News” updates on a new site I have just set up – as well as occasionally updating another site – “Virology and Bioinformatics from” – which is curated by Chris Upton, of Univ Victoria in Canada.

Even more ways to get your daily viral fix…B-)

Virology Africa 2011: viruses at the V&A Waterfront 2

19 December, 2011

We thank Russell Kightley for permission to use the images

Marshall Bloom (Rocky Mountain Laboratories, NIAID) opened the plenary session on Thursday the 1st of December, with a talk on probing the pathogen-vector-host interface of tickborne flaviruses.   Although thoroughly infected with a rhinovirus, he held our attention most ably while reminding us that while many flaviviruses are tick borne, the hard and soft body ticks that vector them are very phylogenetically different – as different as they are from spiders – meaning that if similar flaviruses replicated in them, these viruses may have much wider host range than we know.

He pointed out that while about 95% of the virus life cycle takes place in a tick, transmission to a vertebrate means suddenly adapting to a very different host.  Infection in ticks is persistent, as befits their vector role – but vertebrate infection generally is not.  It was interesting, as a sometime plant virologist, to hear that they look for dsRNA as a marker for replication, and do Ab staining for it: the technique was invented with plant viruses, and very few other virologists seem to appreciate that dsRNA can be quite easily isolated and detected.

They compared Vero and tick cells for virus replication, and saw significant differences: while tick cells could go out to 60+ days and look fine, Vero cells were severely affected at much shorter times post infection.  There was also 100-fold less virus in tick cells, and prominent tubular structures in old infected tick cells.  He noted that ticks evade host defences quite efficiently: eg they suppress host clotting during feeding, and there is huge gene activation in the tick during feeding.  In another study to envy, they are doing array work on ticks to see what is regulated and how.

 Linda Dixon (Institute for Animal Health, Pirbright, UK) recounted her lab’s work on African swine fever (ASFV), a poxvirus-like large DNA virus.  The virus is endemic to much of Africa, and keeps escaping – and there is no effective  vaccine to prevent spread, so regulation is by slaughter.  There are 3 types of isolate, with the most highly pathogenic causing up to 10% fatality and a haemorrhagic syndrome.  She described how in 2007 the virus had spread from Africa to Georgia, then in 2009 to southern Russia and all way to the far north, in wild boar.

There are more than 50 proteins in the dsDNA-containing virion; two infectious forms similar to the poxviruses with multilayer membranes and capsid layers can form, and neutralising Ab play no part in protection as a result.  They studied the interaction of viruses with cells and the immune system, and compared the genomes of pathogenic and non-pathogenic strains, in order to understand how to develop an effective vaccine.

The biggest differences were large deletions in non-virulent isolates, including genes coding for  proteins responsible for binding to RBC, and various immune evasion multicopy genes.  They planned to target regions to delete to make an attenuated virus for vaccine.  They had found non-essential genes involved in immune evasion, and ones that lower virulence, and had been systematically cutting them out.  She noted that pigs can be protected if they survive natural infection and if vaccinated with TC-attenuated virus, and can be protected by passive transfer of Abs from immune pigs – which indicated that an effective live vaccine was very possible.

Subunit vaccines were being investigated, and they had found partial protection with baculovirus-expressed proteins.  They were doing genome-wide screens for protective Ag, and were pooling Ags expressed from predicted ORFs in immunization trials – up to 47 Ags without reduction in specific  T cell responses.

Discovery One

My former labmate Dion du Plessis (Onderstepoort Veterinary Institute, OVI) made a welcome return to Cape Town, with a talk entitled “2011: A Phage Odyssey”.  He explained the title by noting the distinct resemblance of P1 coliphage to the Discovery One spacecraft dreamed up by Arthur C Clarke and Stanley Kubrick – and then went on to exuberantly and idiosyncratically recount a brief history of bacteriophages and their use in biotechnology since their discovery.  A revelation from his talk was that the first discovery of phages was probably described by a gentleman named Hankin, in 1896 in Annales de l’Institut Pasteur: he

The 1896 paper from Annales de l'Institut Pasteur

showed that river water downstream of cholera-infested towns on the Jumma river in India contained no viable Cholera vibrio – and that this was a reliable property of the water.  We were also introduced to the concept of turtles as undertakers in the Ganges….

He took us through the achievements of the Phage Group of Max Delbruck and others – where science was apparently fun, but also resulted in the establishment of modern molecular biology – through to the use of phages as exquisitely sensitive indicators immunochemistry studies in the 1960s.

All too soon we got to the modern uses of phages, with 3 types of gene library – random peptide, fragmented gene, and antibody V regions – being used to make recombinant phage tail proteins to be used for “panning” and enrichment purposes, in order to select either specific antibodies or antigens.  Dion manages a research programme at OVI aimed at developing a new generation of veterinary vaccines – and has for some years now been making significant progress in generating reagents from a chicken IgY single-chain Fv phage display library.

Carolyn Williamson (IIDMM, UCT) gave us an update on CTL epitopes associated with control of HIV-1 subtype C infections.  She said that it was now known that genome-wide association studies (GWAS) gives you certain HLAs which are associated with low viral load, and others with high – meaning that to some extent at least, control of infection was down to genetic luck.  She noted that they and others had shown that CTL escape was quick: this generally happened in less than 5 weeks in acute phase infections.

They had looked for evidence of a fitness cost of CTL escape – and shown that it exists.  She noted that this meant that even if one has “bad” HLA genes, if one was infected with a virus with fitness cost mutations from another, that one could still control infection.

It had been shown that “controllers” mainly have viruses with attenuating mutations, or have escapes in the p24 region – and it was a possible vaccine strategy to include these mutated epitopes in vaccines to help people with infections control their infections.

An interesting topic she broached was that of dual infections – there was the possibility of modelling if infection with two different viruses results in increased Ab neutralisation breadth, and if one would get different results if infections were staggered, possibly with increased nAb evolution if isolates were divergent.  She noted it was possible to track recombination events with dual virus infections too.

It was interesting that, as far as Ab responses went, there were independent responses to 2 variants and one could get a boost in Ab titres to the superinfecting virus, but not a boost to Abs reacting with the originally-infecting virus

Carolyn was of the opinion that HIV vaccines needed to include CTL epitopes where escape is associated with fitness cost.  She also reiterated that superinfection indicated that one can boost novel responses, which I take to mean that therapeutic applications are possible.

Ulrich Desselberger (University of Cambridge) is a long-time expert on rotaviruses and the vaccines against them, and it was a pleasure to finally hear him speak – and that he was mentoring young people in South Africa.  He said that more than a third of children admitted to hospital worldwide were because of rotavirus infections, meaning that the viruses were still a major cause of death and morbidity – and they were ubiquitous.

He reviewed the molecular biology and replication cycle of rotaviruses in order to illustrate where they could be targeted for prevention of infection or therapy, and noted that drugs that interfere with lipid droplet homeostasis interfere with rotavirus replication because 2 viral proteins associated proteins of lipid droplets.

He stated that there were lots of recent whole-genome sequences – we already there were many types, based on the 2 virion surface proteins; we  now know that other genes are also highly variable.  As far as correlates of immunity were concerned, VP7 & 4 were responsible for eliciting neutralising Ab.  Additionally, protective efficacy of VP6 due to elicitation of non-neutralising Ab had been shown in mice – but not in piglets, and not convincingly in humans.  Abs to VP2, and NSP2 and 4 were also partially protective in humans.  It was interesting that protection was not always correlated with high titre nAb responses.

He noted that in clinical disease primary infections partially protected against subsequent infections which are normally milder; subsequently no disease was seen even when infection occurred.  Cross-protection occurred at least partially after initial infection, and this got better after more exposure.  There was evidence one could get intracellular neutralisation by transcytosed Ab, and especially to VP6.  Ab in the gut lumen was a good indication of protection.

As far as the live modern vaccines were concerned, Merck’s Rotateq elicited type-specific nAb, with 9% of recipients shedding live virus.  GSK’s Rotarix gets elicits cross-reactive nAb and one gets 50% of recipients shedding virus.

While the vaccines seemed safe, he noted that where vaccines had been introduced, efficacy ranged from 90% in the USA and Europe, down to as low as 48% in Bangladesh, Malawi and SA, due to type mismatch, and that efficacy was correlated inversely with disease incidence and child mortality generally.  He mentioned that there had been much VLP work, but that none of the candidates was near licensure.

Johan Burger (Stellenbosch University) spoke on one of the more important non-human virus problems in our immediate environment – specifically, those affecting wine grape production in our local area.  He opened by stating that SA now produced 3.7% of the world’s wine, making grapes a nationally and especially locally important crop.  Leafroll disease was a major worldwide problem – as well as being the reason for the wonderful autumn reddening seen in grapevines, it also significantly limited production in affected vineyards.  His laboratory has done a lot of work in both characterising viruses in grapevine, and trying to engineer resistance to them.  Lately they were also investigating the use of engineered miRNAs as a response to and means of controlling, virus infection.

His group has for a couple of years been involved in “metaviromic” or high-throughput sequencing studies of grapevines, with some significant success in revealing unsuspected infections.  In this connection, he and Don Cowan pointed out that they had lots of data that they ignore – but which we should keep and study, as a resource for other studies not yet thought of.

As far as Johan’s work went, novel viruses kept popping up, including grapevine virus E (GVE), which hitherto had only been found in Japan.  They were presently looking at Shiraz disease, which was unique to SA, and was still not understood.  This was infectious, typified by a lack of lignification which led to rubbery vines, and kills plants in 5 years.  It also limits the production of the eponymous grapes – a crime when SA shirazes seem to be doing so well!

Veterinary Virology and Vaccines parallel session.

I again dodged the clinical / HIV session because of my personal biases, and was again treated to a smorgasbord of delight: everyone spoke well, and to time, and I was really gratified to see so many keen, smart young folk coming through in South African virology.  It was also very interesting to see highly topical subjects like Rift Valley fever and rare bunyavirus outbreaks being thoroughly covered, so I will concentrate on these.

P Jansen van Veeren (NICD, Johaanesburg) was again a speaker, this time representing his absent boss, Janusz Paweska.  He gave an account of the 2010 Rift Valley fever outbreak in SA, and epidemiological findings in humans – something of keen interest to me.  He said there had been some forecasting success for outbreaks in East Africa; however, there were long gaps between outbreaks, which were generally linked to abnormal rainfall and movement of mosquito and animal hosts.  RVFV isolates differed in pathogenicity but were structurally and serologically indistinguishable – because virulence was due to the NSs protein, and not a virion component.  He recounted how artificial flooding of a dambo in Kenya resulted in a population boom in the floodwater Aedes mosquitoes responsible for inititating an outbreak, and then of the Culex which maintained the epidemic.  He said there was a strong correlation between viral load and disease severity.

In terms of South African epidemiology, there had been smaller outbreaks from 2008 round the Kruger National Park (NE SA), then in the Northern Cape and KZN in 2009.  People had been infected from autopsy of animals, and handling butchered animal parts.  The 2010 outbreak started in the central Free State after an unusually wet period, and had then spread to all provinces except Limpopo and KZN.  In-house serological methods at the NICD were validated in-house too: these were HAI screening and IgM and IgG ELISAs and a virus neutralisation test.  They had got 1600+ samples of human serum, and confirmed 242 cases of disease and 26 deaths for 2010.

He noted that with winter rains there was a continuous outbreak in the Western Cape, and in 2011 the epidemic had started again in the Eastern and Western Cape Provinces, but has since tailed off.  Some 82% of human cases were people who occupationally handled dead animals, although there was some possibility of transmission by mosquitoes.

In human cases there was viraemia from 2-7 days, with IgM present transiently from 3 days at low level.  They had sequenced partial GP2 after PCR from 47 isolates, and showed some recombination occurring.  The 2010 isolates were very closely related to each other, and to a 2004 Namibian isolate.  There had been no isolation from mosquitoes yet.

Two talks on FMDV followed: Belinda Blignaut (OVI and Univ Pretoria) spoke on indirect assessment of vaccine matching by serology, and Rahana Dwarka (OVI) on a FMDV outbreak in KZN Province in 2011.  Belinda’s report detailed how 6 of 7 serotypes of FMDV occur in SA, with SAT-1 and -2 and O the most common – and that vaccines needed to be matched to emerging strains.  This was done by indirect vaccine matching tests such as serological r-value, determined by the ratio of the reciprocal serum titre to the heterologous virus against that to the homologous virus.  They had put 4 different viruses into cattle and got sera to test a range of 26 newly isolated viruses.  While they had not got sequence from the test panel viruses, indications were that topotype 3 viruses are antigenically more disparate and that a vaccine consisting of topotype 1 or 2 antigens may not be effective in the control of FMD.

In introducing Rahana’s talk, the chair (Livio Heath, OVI) mentioned that there had been 5 different major animal pathogens causing outbreaks in SA over the last 3 years – and that they had to produce reagents and validate tests for ASFV, classical swine fever (CSF) and FMDV, etc, with each outbreak.  Rahana described how they had neutralisation assays and blocking and competition ELISA for FMDV, as well as a big database of isolates from buffalo in KZN – so they were well-placed to type viruses found in cattle in the region.

C van Eeden (Univ Pretoria) had an intriguing account of their investigation of the occurrence of an orthobunyavirus causing neurological symptoms in horses and wildlife.  Horses seem to be particularly vulnerable to many of the viruses involved in such disease, and so are a useful sentinel species.  Shuni virus was first isolated from Culicoides midges and sheep and a child in Nigeria in the 1960s.  SA workers subsequently found it in some livestock and Culex mosquitoes and in horses.  The virus was shown to be a neurologic disease agent in horses and wildlife – then disappeared for some 30 years, much like Ebola.  There is apparently a new research unit at UP with a BSL3 lab, so they are well equipped to do tests with the virus.

Ms van Eeden noted that the incidence of encephalitic disease in humans and animal in SA is underreported, and the causes are mainly unknown – a revelation to me!  Horses are susceptible to many of the agents, and are useful sentinels – workers have identified flavi- and alphaviruses in some outbreaks, but many are not IDed.  They had done cell culture and EM on samples from an ataxic horse: they got a bunyavirus-like virus by EM, and did bunya-specific PCR, and got Shuni virus back.  Sequence relationships showed no linkage to type of animal or date, in subsequent samplings from horses, crocodiles,  a rhino and a warthog, and from blood, brain and spinal cord.  All positive wildlife were sampled in Limpopo Province; horses only from most other provinces.

She noted that latest cases were neurological, whereas previously these were mainly febrile.  The virus accounted for 10% all neurological cases, with a 50% fatality rate.  She noted further that vets often work without masks or gloves, and so had no protection from exposure in such cases….  There was no idea on what the vector was, but they would like to test mosquitoes, etc.  Ulrich Desselberger suggested  rodents may be a reservoir, but they don’t know if this is true.

Stephanie van Niekerk (Univ Pretoria) investigated alphaviruses as neurological disease agents in African wildlife.  The most common alphaviruses in SA are Sindbis and Middelburg viruses.  Old World alphaviruses are usually not too bad, and cause arthritic and febrile symptoms, while New World cause severe neurological diseases.  Sindbis was been found in SA outbreaks in 1974.  However, Stephanie noted that a severe neurological type had appeared since 2008 in horses.  Accordingly, they looked at unexplained cases in wildlife in the period 2009-2011: brain and spinal cord samples were investigated for all cases.  They found alphavirus in a number of rhinos, buffalo, warthog, crocodiles and jackal – and all except for one rhino were Middelburg virus.  They want to isolate viruses in cell culture, and increase the size of regions used for cDNA PCR.  Stephanie said the opinion was that the values of the animal involved justifies the development of vaccines.


Virology Africa 2011: viruses at the V&A Waterfront 1

12 December, 2011

We thank Russell Kightley for permission to use the images

Anna-Lise Williamson and I again hosted the Virology Africa Conference (only the second since 2005!), at the University of Cape Town‘s Graduate School of Business in the Victoria & Alfred Waterfront in Cape Town.  While this was a local meeting, with just 147 attendees, we had a very international flavour in the plenaries: of 18 invited talks, 9 were by foreign guests.  Plenaries spanned the full spectrum of virology, ranging from discovery virology to human papillomaviruses to HIV vaccines to tick-borne viruses to bacteriophages found in soil to phages used as display vectors, and to viromes of whole vineyards.  There were a further 52 contributed talks and 41 posters, covering topics from human and animal clinical studies, to engineering plants for resistance to viruses.

A special 1-day workshop on “Human Papillomaviruses – Vaccines and Cervical Cancer Screening” preceded the main event: this was sponsored by Merck Sharp & Dohme, Roche and Aspen Pharmacare, and had around 90 attendees.  Anna-Lise Williamson (NHLS & IIDMM, UCT) opened the workshop with a talk entitled “INTRODUCTION TO HPV IN SOUTH AFRICA – SCREENING FOR CERVICAL CANCER AND VACCINES”, and set  the stage for Jennifer Moodley (Community Health Dept, UCT) to cover health system issues around the prevention of cervical cancer in SA, and the newly-minted Dr Zizipho Mbulawa (Medical Virology, UCT) to speak on the the impact of HIV infection on the natural history of HPV.  This last issue is especially interesting, given that HIV-infected women may have multiple (>10) HPV types and progress faster to cervical malignancies, and HPV infection is a risk factor for acquisition of HIV.  The Roche-sponsored guest, Peter JF Snijders (VU University Medical Center, Amsterdam), gave an excellent description of novel cervical screening options using primary HPV testing, to be followed by two accounts of cytological screening in public and private healthcare systems in SA, by Irene le Roux (National Health Laboratory Service) and Judy Whittaker (Pathcare), respectively.  Ulf Gyllensten (University of Uppsala, Sweden) described the Swedish experience with self-sampling and repeat screening for the prevention of cervical cancer, especially in groups that are not reached by standard screening modalities.  Hennie Botha and Haynes van der Merwe (both University of Stellenbosch) closed out the session with talks on the effect of the HIV pandemic on cervical cancer screening, and a project aimed at piloting adolescent female vaccination against HPV infection in Cape Town.

The next part of the Workshop overlapped with the Conference opening, with a Keynote address by Margaret Stanley (Cambridge University) on how HPV evades host defences (sponsored by MSD), and another by Hugues Bogaert (HB Consult, Gent, Belgium)) on comparisons of the cross-protection by the two HPV vaccines currently registered worldwide (sponsored by Aspen Pharmacare). Margaret Stanley’s talk was a masterclass on HPV immunology: the concept that such a seemingly simple virus (only 8 kb of dsDNA) could interact with cells in such a complex way, was a surprise for all not acquainted with the viruses.  Bogaert’s talk was interesting in view of the fact that the GSK offering, which has only only two HPV types, raises far higher titre antibody responses than the MSD vaccine with four HPV types, AND seems to elicit better cross-protective antibodies: this should help inform choice of product from the individual point of view.  However, the fact that MSD seems able to respond better to national healthcare system tenders in terms of price per dose is also a major factor in the adoption stakes.

The Conference proper started with a final address by Barry Schoub, long-time but now retired Director of the National Institute of Virology / National Institute of Communicable Diseases in Johannesburg, and also long-time CEO of the Poliomyelitis Research Foundation (PRF): this is possibly the premier funding agency for anything to do with viruses in South Africa, and a major sponsor of the Conference.  He spoke on the history of the PRF, and how it had managed to shepherd an initial endowment of around 1 million pounds in the 1950s, to over ZAR100 million today – AND to dispense many millions in research project and bursary funding in South Africa over several decades.

The first session segued into a welcoming cocktail reception and registration at the Two Oceans Aquarium in the V&A Waterfront: this HAS to be one of the only social events for an academic conference where the biggest sharks are the ones in the tank, and not in the guest list!  I think people were suitably blown away – as always, in the aquarium – and the tone was set for the rest of the meeting.  The wine and food were good, too.

The first morning session of the conference featured virus hunting and HIV vaccines, as well as plant-made vaccines and more HPV.  W Ian Lipkin (Columbia University, USA) opened with “Microbe Hunting” – which lived up to its title very adequately, with discussion of a plethora of infectious agents.  As well as of the methods newly used to discover them, which include high-throughput sequencing, protein arrays, very smart new variants on PCR….  I could see people drooling in the audience; the shop window was tempting enough to make one jump ship to work with him without a second thought.  He said that probably 99% of vertebrate viruses remain to be discovered, and that advances in DNA sequencing technology were a major determinant in the rapidly-increasing pace of discovery.  He made the point that while the emphasis in the lab had shifted from wet lab people to bioinformatics, he thought it would move back again as techniques get easier and more automated – meaning (to me) that there is no substitute for people who understand the actual biological problems.  It was interesting that, while telling us of his work on the recently-released blockbuster “Contagion” – where “the virus is the star!” – he showed a slide with a computer in the background running a recombination detection package called RDP, which was designed in South Africa.  It can also be seen in the trailer, apparently.  Darren Martin will not be looking for royalties or screen credits, however.

Don Cowan (University of the Western Cape) continued the discovery theme, albeit with bacteriophages as the target rather than vertebrate viruses.  It is worth emphasising that phages probably represent the biggest source of genetic diversity on this planet – and given how even the most extreme of microbes have several kinds of viruses, as Don pointed out, it is possible that this extends to neighbouring planets too [my speculation – Ed].  He occupies an interesting niche – much like the microbes he hunts – in that he specialises in both hot and cold terrestrial desert environments, which are drastically understudied in comparison to marine habitats.  He made the interesting point that metagenome sequencing studies such as his own generate data that is in danger of being discarded without reuse, given that folk tend to take what they are interested out of it and neglect the rest.

Anna-Lise Williamson (NHLS, IIDMM, UCT) then described the now-defunct SA AIDS Vaccine Initiative vaccine development project at UCT.  It is rather sobering to revisit a project that used to employ some 45 people, and had everything from Salmonella, BCG, MVA, DNA and insect cell and plant-made subunit HIV vaccines in the pipeline – and now employs just 5, to service the two vaccines that made it into into clinical trial.  The BCG-based vaccines continued to be funded by the NIH, however, and the SA National Research Foundation funds novel vaccine approaches.  Despite all the funding woes, the first clinical trial is complete with moderate immunogenicity and no significant side effects, and two more are planned: these are an extension of the first – HVTN073/SAAVI102 – with a Novartis-made subtype C gp140 subunit boost, and the other is HVTN086/SAAVI103, which compprises different commbinations of DNA, MVA and gp140 vaccines.

It was clear from the talk that if South Africa wants to support local vaccine development, the government needs to support appropriate management structures to enable this – and above all, to provide funding.  However, all is not lost, as much of the remaining expertise in several of the laboratories that were involved in the HIV vaccine programme can now involve themselves in animal vaccine projects.

Plant-made HPV16 VLPs

Ed Rybicki made it an organisational one-two with an after-tea plenary on why production of viral vaccines in plants is a viable rapid-response option for emerging or re-emerging diseases or bioterror threats.  The talk briefly covered the more than 20 year history of plant-made vaccines, highlighting important technological advances and proofs of concept and efficacy, and concentrated on the use of transient expression for the rapid, high-level expression of subunit vaccines.  Important breakthoughs that were highlighted included the development of the Icon Genetics TMV-based vectors, Medicago Inc and Fraunhofer USA’s recent successes with H5N1 and H1N1 HA protein production in plants – and the Rybicki group’s successes with expression of HPV L1-based and E7 vaccine candidates.  The talk emphasised how the technology was inherently more easily scalable, and quicker to respond to demand, than conventional approaches to vaccine manufacture – and how it could profitably be applied to “orphan vaccines” such as for Lassa fever.

Ulf Gyllensten had another innings in the main conference, with a report on a study of a possible linkage of gene to disease in HPV infections – which could explain why some people clear infections, and why some have persistent infections.  They used the Swedish cancer registry (a comprehensive record since the end of the 1950s) to calculate familial relative risk of cancer of the cervix (CC): relative risk was  2x for a full sister, the same for a mother-daughter pair and the risk for a half sister was 50% higher while risk was not linked to non-biological siblings or parents, meaning the link was not environmental.  A preliminary study found HLA alleles associated with CC, and increased carriage of genes was linked to increased  viral load.   A subsequent genome wide association study using an Omni Express Bead Chip detecting700K+ SNPs yielded one area of major interest, on Chr 6 – this is a HLA locus.  They got 3 independent signals in the HLA region and can now potentially link HPV type and host genotype for a prediction of disease outcome.  Again, the kinds of technology available could only be wished for here; so too the registry and survey options.

Molecular and General Virology contributed talks parallel session

I attended this because of my continued fascination with veterinary and plant viruses – and because Anna-Lise was covering the Clinical and Molecular session – and was not disappointed: talks were of a very high standard, and the postgraduate students especially all gave very good accounts of themselves.

Melanie Platz (Univ Koblenz-Landau, Germany) kicked off with a description of a fascinating interface between mathematics and virology for early warning, spatial awareness and other applications.  She gave an example using a visual representation of risk using GIS for Chikungunya virus, based on South African humidity and temperature data going back nearly 100 years: this had a 3D plot model, into which one could plug data to get predictions of mosquito likelihood.  They could generate risk maps from the data, to both inform public and policy / planning.  They had a GUI for mobile devices for public information, including estimates of risk and what to do about it, including routes of escape.

Cover Illustration: J Virol, October 2011, volume 85, issue 20

This was followed by one of my co-supervised PhD students, Aderito Monjane – who recently got the cover of Journal of Virology with his paper on modelling maize streak virus (MSV) movement and evolution, so I will not detail more here.  However, even as a co-supervisor I was blown away by the fact that he was able to show animations of MSV spread – at  30 km/yr, across the whole of sub-Saharan Africa.

Christine Rey of Wits University provided another state-of-the-art geminivirus talk, with an account of the use of siRNAs and derivatives for silencing cassava-infecting geminiviruses.  They were using genomic miRNA precursors as templates to make artificial miRNAs containing viral sequences, meaning they got no interference with nuclear processing and there was less chance of recombination with other viruses, a high target specificity, and the transgenes would not be direct targets of virus-coded suppressors.  They could also use multiple miRNAs to avoid mutational escape.  The concept was successful in tobacco, and they had got transformation going well for cassava, so hopes were high for success there.

Dionne Shepherd (UCT) spoke on our laboratory’s 15+ year work on engineered resistance in maize to MSV.  She pointed out that the virus threatens the livelihood of 200 million+ subsistence farmers in Africa, and is thought to be the biggest disease concern in maize – which is still the biggest edible crop in Africa.  Most of the work has been described elsewhere with another journal cover; however, new siRNA-based constructs still under investigation were even more effective than the previous dominant negative mutant-based protection: the latter gave 50-fold reduction in virus replication, but silencing allowed > 200-fold suppression of replication.

2-colour surface rendition of HcRNAV

Arvind Varsani – a former UCT vaccinology PhD who is now a structural biology and virology lecturer at Univ Christchurch (NZ) – described what is probably the first 3D structure of a virus to come out of Africa.  This was of a 30 nm isometric ssRNA virus – Heterocapsa circularisquama RNA virus (HcRNAV) – infecting a dinoflagellate, which is one of the most noxious red tide bloom agents and is a major factor in killing farmed oysters.  The virus apparently controls the diatom populations.  There are two distinct strains of virus, and specificity of infection is due to the entry process, as biolistic bombardment obviates the block.  The single capsid protein probably has the classic jelly-roll β-barrel fold, but they observe a new packing arrangement that is only distantly related to the other ssRNA (+) virus capsids known.  They will go on to look at structural differences between strains that change cell entry properties.

FF Maree from the Onderstepoort Veterinary Institute and the Univ Pretoria spoke on structural design of FMDV to improve vaccine strains: they wished to engineer viruses by inserting the cell culture adapted HSPG-binding signature sequence and to mutate capsid residues to increase the heat stability of SAT-2 subtype virus vaccines.  If they put the signature sequence in a SAT1 virus, they found it could infect CHO cells – which do not express any of 4 integrins that FMDV binds to, but are far better for large-scale production of the virus than the BHK cells used till now.  It was also possible to increase hydrophobic interactions in the capsid by modeling: eg a VP2 Ser to Tyr replacement gave a considerably better thermal inactivation profile to the virus.

Daria Rutkowska (Univ Pretoria) detailed how African horsesickness orbivirus (AHSV) VP7 protein had significant potential as a scaffold that could act as a vaccine carrier.  The native protein formed as trimers assembled in a VP3+VP7 “core” particle; however, the VP7 when expressed alone could form soluble trimmers – and the “top” domain hydrophilic loop can tolerate large inserts.  The group had very promising FMDV P1 peptide responses from engineered VP7 constructs, including protection of experimental animals.

P Jansen van Veeren of the National Institute of Communicable Disease in Johannesburg finished off the session, with a description of the cellular pathology caused by Rift Valley fever bunyavirus (RVFV) in mice in acute infections.  The virus seems to have been of particular international interest recently as a potential bioterror agent; however, global warming is also responsible for its mosquito vector spreading outside of its natural base in Africa to the Arabian peninsula, and there are fears of the virus getting into Europe soon.  While there are vaccines against the virus, including a live attenuated version, none are licenced for human use.  It was interesting to hear that the viral NP appears to be the main immunogen, as there are massive amounts of NP produced in infection, and huge responses to it in infected animals – and NP immunisation protects mice.  There is a good Ab response but it is not neutralising, while NP is released independently of other proteins from infected cells.  The liver is the major target of virus infection, with a bias to apoptosis of hepatocytes and severe inflammatory responses.  Viral load is linked to these effects and is much lower in vaccinees.  Immunisation reduces liver replication markedly; that in the spleen less so.  A screen of cytokines and other gene responses showed a big down-regulation of many genes in non-vaccinated mice to do with cytokines, and down-regulation of B and T cells and NK cells.  He thinks recombinant vaccine candidates should have both the surface glycoproteins and the NP in order to be effective – and that there is a major need for proper reagents for big animal studies.

HPV vaccines: good, but out of reach for most

28 October, 2010

Human papillomavirus and cervical cancer - copyright Russell Kightley Media

The fact that genital Human papillomaviruses (HPVs) cause cervical cancer in women, as well as a variety of other growths and lesions in both men and women, is not in dispute.  The fact that cervical cancer is a major and growing scourge of women in developing countries is also non-contentious: of the more than 500 000 cases and 300 000 deaths due to the disease every year, more than 80% occur in the developing world.  This is largely because, unlike their counterparts in the developed world, poor Third World women either do not get screened using the relatively simple cytological detection method known as the Papanicolau (Pap) smear, or do not get treated thereafter.  Thus, cervical cancer really is a disease of poverty, given that most deaths occur due to a lack of simple procedures being provided in clinics.

The best method of prevention of an infectious disease is almost always a vaccine: HPV vaccines have been around a while now, and have proved to be both safe and efficacious – both primary requirements of a vaccine.  Both Merck and GlaxoSmithKline’s vaccines – the yeast-produced Gardasil and insect cell-produced Cervarix respectively – are virus-like particles (VLPs) composed of the major HPV coat protein L1 only; Cervarix contains particles of the high-risk HPV types (or species) 16 and 18 and Gardasil contains VLPs derived from HPVs 16 and 18 as well as the genital wart-causing 6 and 11.

The vaccines are both “blockbusters” – that is, they both have sales of over US$1 billion – are are possibly the best-researched human vaccines ever made.  They are also possibly among the most expensive: Gardasil went on sale in the USA at $120 per dose – and a full treatment consists of 3 doses, for a total cost per person treated of $360; Cervarix retails at around the same price.

This is so far beyond the budget of most people in most countries as to be akin to their expectation of winning a lottery – and of the order of 1000x as expensive as possibly the most widely distributed vaccine in the world, which is Bacillus Calmette-Guerin (BCG), the Mycobacterium tuberculosis vaccine.

It is a sad fact of life that the whole WHO Expanded Programme on Immunisation – EPI – six vaccine bundle of polio, measles, neonatal tetanus, diphtheria, pertussis (whooping cough) and tuberculosis vaccines “… costs no more than US$1 … (at UNICEF-discounted prices), and another US$14 for programme costs (laboratories, transport, the cold chain, personnel and research) to fully immunize a child”.  It is also a sad fact that the new generation of vaccines – exemplified by the yeast-made recombinant hepatitis B virus (HBV) subunit vaccine – are expensive even when discounted after patents have expired: thus, HBV vaccine launched at US$150 for three doses in 1986, and came down to around $10 now.  It is included in EPI bundles in some countries because of even greater discounting (down to ~$1); however, its cost is generally greater than the rest of the bundle combined.

So what should happen with HPV vaccines?  How are they going to get to the people who need them most, at the price they can afford – which is nothing?  The simple answer is that governments and international agencies must buy them, as is presently the case with the EPI package – and that they must be very heavily discounted, to allow this.

In fact, at the recent Papillomavirus Conference in July in Montreal (which we should write up in more detail elsewhere), I heard that the Mexican government has managed to secure  HPV vaccine at US$27/dose – or 25% of the regular price – for a campaign they are mounting in some regions to supply vaccine for free.  So it is possible – however, even this price is far too high, as it represents about the per capita per annum public health expenditure in the poorest countries who probably need it most.

It raises my blood pressure, therefore, when I read that in several highly-developed western countries there are a number of controversies (see also here) around HPV vaccination: yet again, on the heels of the measles and MMR (measles-mumps-rubella viruses) vaccines-cause-autism idiocy, people who can afford vaccines are among the most stupid when it comes to having them.

The facts, as opposed to the hype, are these:

  • the vaccines were proven to be safe in extended clinical trials
  • they were proven to be efficacious in preventing infection and development of precancerous lesions and genital warts - in men as well as in women

Inflammatory stories about deaths due to HPV vaccines are just that – stories.  A recent publication from India, where the government suspended a vaccine study due to deaths of girls involved in the trial, puts things into perspective:

“The causes of death had been scrutinized by the State Government and reported to ICMR and Drugs Controller General of India; all were satisfied that no death was vaccine-related [ my emphasis]. We understand that there is an unusually high frequency of death among girls in this community, which is what deserves immediate enquiry and remedial interventions….
The death of a 14-year old British girl shortly after receiving HPV Vaccine,evoked considerable media attention across the world. The necropsy studies showed that she had malignant tumor affecting her heart and lungs…. The vaccine was not her cause of death.”

There is also considerable silliness surrounding the vaccination of girls – and, hopefully, boys! – against what is very largely a sexually transmitted virus.

Do people have the same problem with HBV?

Or – is it possible?? – they don’t know that it is also frequently a sexually-transmitted disease, among adults at least?

In any case, the kinds of prudishness-by-proxy that result in non-vaccination against HPV or HBV are simple foolishness.

And I would be happy to tell anyone so.

Meantime, we want to make HPV vaccines in plants. Any sponsors??

Umm…no, they don’t

28 November, 2008

For shame, New Scientist!!  There I go recommending you to all and sundry – and especially my students – as a fount of general scientific knowledge, and you do this!!  In the 22nd November issue – freshly on my desk, down here in the Deepest South – there is, under the column heading “60 Seconds”, the following snippet:

Shot thwarts warts

A human papilloma virus vaccine already approved in women to prevent cervical cancer has proved equally effective in men against genital wartswhich can lead to cervical cancer in women. In a trial of the vaccine in 4000 men only three recipients developed HPV-related lesions compared with 31 who received a placebo.

Note the bolded section: BECAUSE IT IS VERY WRONG. 

No, New Scientist, genital warts in men do NOT lead to cervical cancer in women: warts in men and women are caused by a number of what are termed “low risk” viruses (for low cancer risk), and especially by HPV types 6 and 11 – which are two of the types included in Merck’s Gardasil.  The other two types in this vaccine – which are the same ones as in GlaxoSmithKline’s Cervarix – are the high cancer risk HPV types 16 and 18.  Which do NOT cause genital warts, in men or women: rather, they cause inapparent infections of the epithelial tissue of the penis in men, and of the vaginal and cervical mucosa in women. 

The lesions can most often only be seen in both men and women after they have been painted with an acetic acid solution – hence the name “aceto-white lesion”.

The fact that warts are apparently prevented in men is a very welcome development: this means that in all likelihood the other infections will be prevented too, and men will not be able to transmit HPV 16 and 18 to women.

Which is presumably what you meant.


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