By Rob Verkerk PhD, executive & scientific director

The last few days have seen the papers littered with news of the HPV vaccine’s success – under "real-world" conditions. Triggering this news is of course a published, peer-reviewed paper, this one being in Clinical Infectious Diseases. The article in the UK’s Guardian newspaper on 4 September is a good example. The study is a review, led by Prof Suzanne Garland, director of microbiological research at the Royal Women’s Hospital in Melbourne. It reviewed 58 studies in which 1, 2 or 3 doses of various HPV vaccines had been administered in 9 countries over the course of the last 10 years. The study authors found highly significant declines in the rate of HPV infection in vaccinated compared with unvaccinated children over this decade. They also found almost as big a decline in two key markers for HPV infection, namely genital warts and cervical lesions. Without so much as a squeak as to what other factors might be involved, the authors promptly related the entirety of these effects to the vaccination program and give the readers these reductions will translate, in a few decades, to equivalent reductions in cervical cancer rates.

Experience has told us that we need to read such research papers carefully to assess their methodological soundness and any distortions-of-translation that might have occurred between the original paper and its reporting in the media. We were immediately intrigued that the Guardian article suggested the authors “found that more than 187m doses of the vaccine had been administered in 129 countries, leading to significant declines in HPV”. The study actually involved, as I indicated above, just 9 countries. The authors of the paper also mention that over 205 million doses of the 4vHPV vaccine (not 187 million) had been administered up to the end of 2015, but only a tiny proportion of these were incorporated in the 58 studies included in the review. This triggers in ones' mind a lot more questions. For example; how do such reporting errors creep in, who was responsible for fact checking the pieces, were these misrepresentations restricted to the Guardian?

Beyond such glitches, one of the most important tasks in our review process is to look for possible confounding factors or sources of bias that have not been controlled for adequately. These may or may not be influenced by funding sources for the research.

Declared conflicts of interest

We were not surprised to find that the study leader, Prof (Dr) Suzanne Garland is a bigwig in the area of vaccine research, and HPV vaccine research in particular. However, Prof Garland’s work is far from independent of vaccine manufacturer interests. She’s run Phase III clinical trials for Merck and GSK, her lab is a reference lab for the WHO Western Pacific region, and she sits on Merck's Global Advisory Board.

The Acknowledgements in the review paper itself inform us, unashamedly, of very clear conflicts of interest that extend well beyond the study’s leader. In fact, they affect every one of the 14 co-authors. Here’s an extract:

“All academic authors have been investigators for Merck. S. M. G. has received funding through her institution to perform HPV vaccine studies for Merck and GlaxoSmithKline, received payment for board membership on the Merck Global Advisory Board, and received honoraria for lectures including services on speaker’s bureaus conducted during her personal time; she also serves as co-chair of the PATRICIA publication steering committee. S. K. K. has received lecture fees and payments for membership on scientific advisory boards from Merck and Sanofi Pasteur MSD, and received unrestricted institutional research grants to perform HPV natural history and vaccine studies from Merck. N. M. has received honoraria for serving on the Merck Global Advisory Board. S. L. B. has received grant support and speaker’s fees from Merck. Co-authors who are employees of Merck (as indicated on the title page) own stock and/or stock options in the company……”

It goes on – but you get the gist. This is about as deep a conflict of interest as you can get – but we now live in a world where it’s OK to publish papers in peer-reviewed papers if you have one or more conflicts of interest – as long as you declare it. And they have. Yet the media have failed to mention this, so most doctors and nearly all the public who get to read the newspaper articles will never realise there was a fully declared conflict of interest.

Study leader: Professor Suzanne Garland, MBBS MD FRCPA FRANZCOG Ad Eundem FAChSHM

Before we go on to look at probably the most important question, whether or not these conflicts of interest have contributed to any uncontrolled confounding factors or biases that may have influenced the results, let’s briefly examine the key findings.

Main findings

On the surface, the HPV vaccines appear like the business. They whip the human papillomavirus (HPV) into shape, causing reductions in HPV infection, genital warts and cervical lesions. The Abstract, which is the summary of the paper that will be the only part of the paper read by most people who go to the original source, refers only to maximal rates of reduction, as compared with average (or minimum) rates of reduction. These are impressive, the authors state that, “Maximal reductions of approximately 90% for HPV 6/11/16/18 infection, approximately 90% for genital warts, approximately 45% for low-grade cytological cervical abnormalities, and approximately 85% for high-grade histologically proven cervical abnormalities have been reported”.

When you dive into the paper, you’ll find different studies suggest a lot more variation, with reductions in incidences of HPV infection, genital warts and cervical lesions sometimes being less than half the maxima. The minimum apparent reduction in HPV infection for children receiving more than one dose, as compared with unvaccinated populations, was found to be 36% (based on a US study).

Associations vs causes

Let’s get to the nub of the paper. First, it’s a review of other studies, so there’s no new data, albeit the latest data coming from a study published in 2016. It’s really about comparing data from unvaccinated populations with populations who have received 1, 2 or all 3 doses of the HPV vaccine. It has compared vaccinated populations with unvaccinated populations both during the last 10 years, describing this as the “vaccine era” and then between the prevaccine and vaccine era. We might agree for the sake of simplicity that the figures for incidence rates of HPV infection, genital warts and cervical lesions show, typically, over 50% apparent reduction among vaccinated children.

The biggest problem with the interpretation of these "real-world" findings is that the authors assume that all of the apparent reduction is associated directly with vaccination. We need to remind ourselves that HPV is sexually transmitted, and therefore no one can become infected with HPV, or express manifestations of this infection such as genital warts or cervical lesions, without an unprotected sexual encounter.

For us, this is the greatest flaw in the paper. There has been no attempt to look at the primary factors that affect infection, namely the incidence of unprotected sexual encounters in each of the various age groups. What if, for example, the HPV vaccine campaign had drawn the attention of young girls (and boys) to this risk and they either abstained for longer or were more likely to use protection?

An obvious marker for unprotected sex among young people is teenage pregnancy rates. We know this is an area that is changing courtesy of major public education programs so we decided to look for recent evidence of this trend from the US. Low and behold, it also shows a significant decline over the last decade, a decline that follows the very same decline in HPV infection.

The above figure, from the Global Library of Women’s Medicine’s website demonstrates this dramatic decline in pregnancy rate (bear in mind the y-axis shows a logarithmic scale so the rates of decline would look even more pronounced on a normal scale).

Researchers have commented on the relationship between HPV awareness and the global HPV vaccine programs launched around a decade ago. A group of European authors provided evidence in a paper in Frontiers Oncology in 2014 that, “knowledge and awareness of HPV strongly increased in the years around the introduction of mass vaccination campaigns in 2007–2009”. In support of this, it’s also been confirmed that adolescents who are vaccinated don’t become more sexually active and therefore do not increase their frequency of sexual encounters.

Other factors relevant, especially to genital warts, cervical lesions and of course, ultimately, to the development of cervical or anal cancers associated with HPV vaccine, are the immunocompetence of the different cohorts and their respective epigenetic profiles. We know that patterns of diet and lifestyle in recent years are improving as governments, industry and non-profits place increasing emphasis on these areas given unequivocal evidence of their vital role in long-term health outcomes. The Kings Fund in the UK, for example, stated in 2009 that, “Rates of drinking, smoking and drug-taking in the young have fallen significantly over the past 10 years. Obesity rates in the young are also falling and levels of activity increasing, largely through increased activity at school.”

One relevant trend that appears related to the rate of HPV infection and age of sexual debut is that the incidence of HPV-related cancers is considerably higher in lower socio-economic groups. Additionally, 85% of the burden of cervical cancer is in the developing, not developed, world.

Reminding us that there are likely processes affecting infection rates other than just vaccination, are statements made by Garland et al in their paper. Here’s one,

“Irrespective of study design, declines were detected within 4 years after vaccine availability, even in settings with comparatively low vaccine coverage.”

There is a host of other factors that affect the likely future rate of cervical cancers from both vaccinated and unvaccinated populations, bearing in mind this is the intended bullseye for the global vaccination program. But before the marketeers make assumptions that infection rates translate directly to cancer rates, let’s not forget the huge impact that screening has. This influence is growing all the time, especially with the introduction of HPV gene tests that can be used in combination with Pap tests for greater reliability.

Confused?

This article doesn’t not set out to disprove that the HPV vaccine is effective. It does, however, make the case that if scientists and doctors are attempting to evaluate effectiveness, they need to use much more rigorous science than that used by Garland et al. These authors have produced what appears to be a propaganda effort to celebrate 10-years of HPV vaccination and the sale of well over 200 million doses of HPV vaccine. The biggest prize for the vaccine manufacturers — and their accomplices — is of course the developing world that shoulder the primary burden (85%) of cervical cancer.

In their propaganda effort, Garland et al barely offer a comment on the risks associated with the HPV vaccine. This being limited to a throw-away line, “Unfounded notions about vaccine-related adverse experiences have derailed implementation of HPV vaccination programs in some countries, despite the positive safety profile observed over a decade of 4vHPV vaccine use and >200 million doses distributed.”

There is no mention of the review of over 200 HPV vaccine injury lawsuits by the Vaccine Injury Compensation Program (VICP) in the USA, or the over $6 million paid out to victims of the HPV vaccine, with still over half the cases unreviewed.

Take-homes

The lowliness of the science and the inferences made from it by both the authors and subsequently by the media communicating it, reflects the degree of cronyism that has crept into the scientific and medical establishments.

It is a travesty that children a young as 11 —along with their parents — are not given sufficient information to make informed decisions. As a society, we have been coaxed into trusting everything doctors and scientists tell us, even if it is overt hogwash.

Parental communication is known to be one of the most powerful influences on the age of sexual debut and any subsequent promiscuity, the factors most directly related to transmission of HPV. Probably because it is seen as something of a taboo since its main risk is among ones so young — but also because there is so much money to be made — HPV has managed to escape being categorised alongside other common sexually transmitted diseases (STDs) like chlamydia, gonorrhea and genital herpes.

It is already clear that not all doctors, nurses and care-givers are staunchly behind HPV vaccination.

Our belief is that major health authorities are a very long way from providing a balanced view of both the benefits and risks of the HPV vaccine, especially to very young children, under the age of 12. Even more troubling, nothing like enough information is given to parents and children as to what can be done to minimise their risk of HPV-related cancers should they choose to not be vaccinated. Let the process of re-education begin — and let’s get back to the real-world, not Garland et al’s (un)"real-world" as seen through the lens of Merck and Sanofi-Pasteur.

Letter to the Editor of The Guardian regarding fundamental errors in their reporting of the paper.

ANH-Intl HPV Vaccine Choice campaign page

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