Holford Watch: Patrick Holford, nutritionism and bad science

Medscape has published HPV Vaccine Adverse Events Worrisome Says Key Investigator (free registration: we’ve had to change the link, see update Aug 6). Allison Gandey’s article is interesting but in some parts it is an annoyingly slight, inaccurate and inadequate exploration of some of the issues discussed in Professor Abby Lippman’s recently published editorial: Human papillomavirus (HPV) vaccination and the development of public policies.^[1] However, our reaction was unduly influenced by the introduction of topics that were not the subject of Lippman’s editorial.

Lippman’s editorial is a thoughtful and provactive look at the marketing campaign and story-telling that has been created to support the case for HPV vaccines.^[a] Lippman uses HPV vaccines to illustrate the many influences that drive the development of public policies. She argues that quantifiable and well understood public health needs can be fulfilled without recourse to fear tactics or enabling corporate promoters to determine health policies. Lipmann suggests that the non-crisis status of cervical cancer and the current availability of methods of prevention raise serious questions about whether or not HPV vaccination is a high priority for public policy that is designed to reduce inequities in healthcare provision in resource-rich countries. However, the coverage of those issues in Gandey’s article seemed to be insubstantial given the space allocated to the discussion of aluminium in the HPV vaccines and a familiar canard for germ theory dissent – neither of which is discussed in Lipmann’s editorial.

Gandey gives the figures for reported adverse events and the number of distributed vaccines in separate albeit consecutive paragraphs however it is practical to work out that:

• 16 millions doses of HPV vaccine have been distributed (possibly, this is just Gardasil, it’s unclear)
• the US Food and Drug Administration (FDA), as of June 30, 2008, reported more than 9700 adverse events since the vaccine was approved 2 years ago
• 94% of these adverse events were classified as nonserious events and 6% as severe.

So that is 6 reported adverse events per 10,000 doses and the breakdown for that is 5.64 are non-serious and 0.36 are severe. In more manageable terms 564 patients in 1m have a non-serious reaction and 36 have a severe one (or 56 in 100,000 and fewer than 4 in 100,000).

Gandey spoke to Dr Diane Harper who was a principal investigator of clinical vaccine trials for both Merck and GlaxoSmithKline. Harper was careful to emphasise that HPV vaccines can only prevent some strains of HPV and can only reduce the incidence of cervical cancer when used in conjunction with universal Pap screening programmes.

Harper outlines some sensible guidelines for administering the vaccine (e.g., the patients should be seated and have a full stomach). She also indicates some contraindications and cautions that should be taken into account when considering the appropriateness of vaccination such as a personal or family history of conditions that have been reported as adverse events associated with the vaccine. Harper sums up her recommendations when she declares:

Physicians have a responsibility to communicate risks to patients and if patients and families are concerned, it is reasonable to hold off on vaccinating.

However, Gandey then introduces a discussion of What is causing adverse events? These are not topics that were mentioned in Lipmann’s editorial. Professor Margaret Stanley of Cambridge University recently explained that Gardasil is a subunit vaccine^[b] and contains only specific protein subunits of a specific virus rather than the complete virion. HPV vaccines contain an adjuvant to assist in the stimulation of antibodies: the adjuvant is an aluminium salt (of which, more below).

Members of the antivaccine movement point to a number of potential perils, including the presence of aluminum in injections. Like many vaccines, Gardasil contains aluminum salts. Each 0.5-mL dose contains approximately 225 μg of aluminum, 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 μcg of polysorbate 80, 35 μg of sodium borate, and water.

“The scientific work to date seems to suggest that aluminum salts in vaccines are safe,” Dr. Harper said. But she told Medscape Oncology that she heard that 1 lot of Gardasil might have had an accidentally high yeast concentration, and this might be why there are problems. “No one knows for sure,” Dr. Harper said.

The phrase that put me out of sympathy with the entire article is “potential perils” and that was exacerbated by the lack of any contextual information for the aluminium dosage or any explanation as to why it is present. It was also a little unclear as to whether Harper’s remark in the latter paragraph was in reference to the aluminium salts or solely a putative ‘hot-lot’ with a high yeast concentration that might be contributing to adverse reactions through some unstated mechanism.

It might have been helpful in Gandey had set a context for the remarks about aluminum. Aluminium is ubiquitous in our environment and the third most common element of the earth’s crust^[c]: we are primarily exposed to aluminum through the consumption of food items and beverages. It is regrettable that Gandey does not explain that aluminium toxicity is related to the dose, the form, and the route of administration (e.g., inhaled, oral).^[d] Interested readers might consult the Children’s Hospital of Philadelphia resource on aluminium on vaccines or the European Food Standards Agency where they will learn about the aluminium content of common dietary items or OTC medications and proposed levels for tolerable weekly intakes from dietary sources.^[2]

There is a draft toxicological profile for aluminium (pdf). If anybody would like further information about the specific toxicokinetics of aluminium in either diet or vaccinations then we recommend the analysis by Keith et al.^[3] who conclude that there is a brief increase in aluminium levels following a vaccination but that it is not sustained and clears rapidly.^[e]

Gandey does not mention or discuss the reason that aluminium is present in the HPV vaccine. Aluminium salts are used as an adjuvant in vaccines. Adjuvants make a vaccine more effective; aluminium salts make some vaccine components more soluble.^[f] Adjuvants stimulate the immune system by activating inflammasomes.^[4] Overall, the benefit of this process is that it regulates the impact of certain antigens and moderates the scale and duration of the immune response.

Studies indicate that many vaccines with aluminium adjuvants provoke greater and more long-lived antibody responses than comparable vaccines that lack the adjuvant.

Typically, three aluminum salts are used as adjuvants: the appropriateness and effectiveness of each salt as an adjuvant varies according to the specifics of a particular vaccine and the manufacturing process used to produce it.^[5] One of the key roles of an adjuvant is to ensure that the antigen is clumped together with another substance (in this case, the aluminum salt) to keep the antigen at the site of injection where it triggers an appropriate immune response.^[6],[g]

HolfordWatch emailed Dr Harper to clarify the areas of potential confusion and to ask her to comment on the issue of aluminium as an adjuvant in HPV vaccines. We quoted the paragraphs that troubled us and then asked:

I assume that the last paragraph is the author’s slightly clunky writing and that you were referring to a potential hot lot with high yeast rather than expressing additional uncertainty about aluminium?

However, my principal concern lies with the first paragraph: if Gardasil contains 225 μg of aluminum (0.225 mg) that seems negligible when compared to sources of aluminium in the diet or OTC medications even if one allows for differences of absorption from injection into extravascular space^[g] as opposed to the oral route and the gut. Common antacids have an aluminium content of 104-208 mg/tablet according to the [Vaccine Education Center at Children's Hospital of Philadelphia]. [Note g added.]

Dr Harper has given us permission to quote her response.

[C]orrect — the aluminum adjuvants are safe.
[C]orrect — we regularly consume oral doses of aluminum that are higher than the injected doses in vaccines. [R]emember though that oral and injected doses provide different bioavailable concentrations to the body.

We should also highlight that although Merck’s Gardasil has been selected for public health vaccination programmes in many countries, including the US, it is GSK’s Cervarix that will be made available in the UK and some european countries. Cervarix has been licensed with a novel modification to a common aluminium adjuvant and GSK reports that its studies show that this offers a higher and more sustained immune response ^[7] and therefore more extended protection.^[h] Each dose of Cervarix contains 0.5 milligrams Al3+: it should be noted that this is still a negligible amount when compared to aluminium from dietary and other sources although, as for Gardasil, there may be differences in bioavailability.^[2]

HolfordWatch has given an overview of everyday exposure to aluminium and the use of aluminium adjuvants in HPV vaccines: in otherwise healthy subjects with no known contraindications it seems hyperbolic to describe aluminium as one of the “potential perils” of vaccines.^[i]

We were profoundly irritated to read Gandey’s interview with Dr Christiane Northrup who is a well-known gynaecologist and has a high media-profile. Primarily, our irritation is grounded in a particular loathing for anecdotes concerning the unconfirmed deathbed recantations of major figures and because such arguments seem to flirt with germ theory dissent.

Dr. Northrup recommended that the money going toward vaccines and related programs be allocated to general health and wellness initiatives and proper nutrition. This harkens back to the age-old debate between Louis Pasteur and Antoine Beauchamp, Dr. Northrup suggests.

For most of his career, Pasteur subscribed to germ theory, while Beauchamp backed the more unpopular theory of biological terrain. The question: Is it the germs themselves that make us sick or a weakened state of immunity that allows germs to take root? “Pasteur was widely supported, but on his death bed conceded that Beauchamp was right,” Dr. Northrup said during an interview. She suggests that this is what experts should be concentrating on now.

Instead of focusing on germ theory by pouring efforts into HPV vaccines, she says more resources should be dedicated to fostering the overall health of the host.

Peter Bowditch has a robust response to claims of a deathbed recantation by Pasteur:

I obtained a copy of Pasteur’s biography, and to nobody’s surprise, he said no such thing…For some reason, however, the story of how he had renounced the germ theory of disease gives comfort to those with minds so decayed that they believe that all medical knowledge was complete at the end of the American Civil War…

The quackery supporters’ derogation of Pasteur’s memory also implies an attack on the countless millions of people, both children and adults, who lived (and continue to live) longer and happier lives because of what this man did. Part of the reason that they need to damage his epitaph is that they realise that the witchcraft and pretend medicine which they espouse will never throw up a person with a millionth of Pasteur’s qualities, even if given a million years to do it. They resent goodness and genius because the presence of these shines a searchlight on the mediocrity and duplicity which are all they can offer.

The recent Dispatches programme on The Jab That Can Stop Cancer interviewed several public health experts who made a very strong argument that there were valid questions to be asked about whether or not the HPV vaccination programme offered a good return on investment when compared with other uses for those health funds: however, none of them found it necessary to object to germ theory. Lipmann mentioned similar issues about the appropriateness of spending priorities and the therapeutic intervention without recourse to anecdotes about Pasteur (see final section of the Lipmann extract^[a]).

It is unfortunate that Gandey does not report whether she pressed Northrup any further and asked her what sort of interventions and resources she had in mind and whether she has:

• any evidence that such interventions would affect the incidence of cervical cancer
• any ballpark figures as to the costs, when compared to that of the HPV vaccination programme.

There are probably some very sophisticated economic models that can answer the question of how many diet and lifestyle cancers and chronic illnesses might be avoided by (unspecified) interventions. However, such models are rarely worked out in detail. Very few of them address the issue that some of the public health education programmes such as 5-A-Day for fruit and vegetable consumption have not been markedly successful in countries like the US and UK despite substantial investment and expenditure.^[8,9,10]

It is essential that parents and doctors should have access to all of the relevant material to enable them to make an appropriate decision about HPV vaccination for girls and young women. However, such an important decision must be made with accurate and pertinent information. HolfordWatch would like to see a timely and more nuanced description of aluminium adjuvants in HPV vaccines (hint, the phrase “potential perils” should not appear). We would also welcome the retirement of Pasteur’s alleged deathbed recantation and an end to the willingness to allow people to use that as an argument in a discussion of public health interventions. RIP, germ theory dissent, you will not be missed.

Updates

The New York Times has a Reporter’s File on Gardasil and cervical cancer with some interesting statistics for the US and useful links.
July 30: Jeff Bercovici HPV Vaccine Inspires Yellow Health Journalism. “Edelman’s reporting, while heavy on scare-mongering, is suspiciously light on the critical context a layperson needs to evaluate the evidence.” Bercovici discusses the unhelpful nature of the current VAERS.
Jim Edwards comments on mainstream media clumsiness in presenting the numbers: Could Merck Be About To Stumble Over Gardasil Adverse Event Reports?.
August 4: Dr Dave Gorski weighs in: Germ theory denialism and antivaccination myths on Medscape. There is an extended discussion of the toxins canard; Dr Northrup and the inadequacies of the VAERS database.
August 6: The Medscape article – HPV Vaccine Adverse Events Worrisome Says Key Investigator – has been removed so we have linked to another copy for now.
Update 9 August: What Came First? The Chicken or the Gardasil?
Update 13 August: Medscape is just compounding their original offence: Why, Medscape, why? Or: Gardasil is hunky-dory except when antivaccinationists say it’s not.

Update August 20: NYT writes the article that Medscape should have written from the outset: Drug Makers’ Push Leads to Cancer Vaccines’ Rise.

Notes

[a] Lipmann writes:

Through heavy, profit-driven marketing, cervical cancer has been (re)constructed in the past couple of years in North America almost solely as an independent vaccine preventable disease. With the heady mix of young girls and their sexual behaviour as background, and an open-ended advertising budget providing memorable catchphrases, the powerful major story-tellers (pharmaceutical companies, physicians and their organisations, the media) have constructed a gripping story comprising a feared disease (cancer), a unique product (the human papillomavirus (HPV) vaccine, Gardasil) to address it, and hyped promises of prevention. This presentation has all too often silenced, or at least marginalised, other ways of talking about cervical cancer (and HPV infection), at the same time arousing controversies, confusions and conundrums in the minds of many…

[G]roups recall other ‘‘quick fixes’’ proposed to prevent women’s health problems (eg diethylstilbestrol (DES) for “recurrent’’ miscarriages; hormone replacement therapy (HRT) for menopause related cardiac conditions) that turned out to be quite harmful. Thus, their hesitations and cautionary words have an evidence base…

Worse, perhaps, ongoing marketing frames girls/women as responsible for ensuring they (or their daughters) are vaccinated and ‘‘protected’’, thereby ignoring the responsibility of the health system for ensuring the elimination of its failures that lead to the absence of Pap testing, follow-ups, etc., failures that, for example, appear to underlie at least 50% (Canada) and 80% (Spain) of the cases of invasive cervical cancer and explain inequities in the distribution of the disease everywhere…

Cervical cancer in developed countries is a disease of marginalisation, and simplistic approaches to its control will not suffice. If women’s health truly is a priority in these resource-rich countries, we might better push for a responsive and effective public system of care and for holistic health promotion and protection policies, rather than take on one disease that is first demonised at a time.

[b] A subunit vaccine is a vaccine that has been through chemical extraction so that it is free of viral nucleic acid and now contains only specific protein subunits of a specific virus rather than the complete virion: nonetheless, it stimulates the formation of antibodies that protect against infection.
[c] Oxygen and silicon are the most abundant: aluminium makes up almost 9 percent of the earth’s crust. Aluminium is obtained from aluminium-containing minerals because it is always found in combination with other elements such as oxygen, silicon, and fluorine.
[d] Vaccines are typically introduced to the body via the extravascular space (e.g., intramuscular injection); we mention this because a lot of anti-vaccination rhetoric states or implies that vaccines are injected into the bloodstream.
[e] Keith et al.^[2] conclude:

Children are born with a systemic aluminum body burden, which is increased throughout life by the inhalation and dietary intake of aluminum compounds as well as by injections of vaccines and allergy treatments containing aluminum adjuvants. Those injections may produce localized reactions without systemic impact. The body burden associated with dietary uptake from either breast milk or formula during the first several months of life and from semisolid food during the remainder of that first year is estimated to reach approximately 0.1 mg. This value is lower than the estimated body burden of approximately 4mg that would result from consuming aluminum at a rate equal to the MRL of 2 mg/kg per day. The body burden attributable to vaccines may be expected to fall between the two except for a period of a few days following individual vaccinations.

[f] At the risk of sounding like we are rooting for a more science-y version of 70s TV series, we introduce the professional antigen-presenting cells (pAPCs). Adjuvants function in two main ways:

• they bring about a pro-inflammatory state and encourage the infiltration of pAPCs: pAPCs take up the vaccine antigen (they can literally internalise it by an engulfing or coating and folding manoeuvre) and signal the immune system
• they make antigens and components more soluble and therefore more accessible to pAPCs.

[g] Typically, after vaccines are injected, they remain at the site at a fairly high concentration until they are ‘inspected’ by the dendritic cells that are involved in assessing the appropriate response. To keep the antigens in place, they need to be clumped to (say) aluminium hydroxide: the aluminium hydroxide then acts as an adjuvant because the antigens are attached to it.
[h] GSK’s novel AS04 adjuvant is formulated with aluminium hydroxide (which is a common aluminium salt used as an adjuvant) combined with a novel substance known as monophosphoryl lipid A (MPL). According to GSK MPL directly activates key immune mechanisms that produce an improved cellular and humoral adaptive immune response.
In clinical studies that compared Cervarix adjuvanted with AS04 to the same antigens adjuvanted with aluminium hydroxide alone,^[7] GSK report that the AS04 formulation returned:

• antibody titres at least two fold higher (analysed up to four years after 1st dose)
• ‘significantly higher’ functional antibody titres (analysed up to four years after 1st dose)
• B cell memory frequency approx. two fold higher (analysed up to two years after 1st dose).

[i] Dr Dave Gorski discusses some of the usual canards about aluminium in vaccines and traces the origin of many of the scares back to Dr Hugh Fudenberg. Dr Steve Novella addresses some of the mixed science around Fudenberg, aluminium and Alzheimer’s Disease.

References

[1] Lippman, A. Human papillomavirus (HPV) vaccination and the development of public policies. J Epidemiol Community Health. 2008 Jul;62(7):570-1.
[2] Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Food Contact Materials on a request from European Commission on Safety of aluminium from dietary intake. The EFSA Journal (2008) 754, 1-4.
[3] Keith LS, Jones DE, Chou CH. Aluminum toxicokinetics regarding infant diet and vaccinations. Vaccine. 2002 May 31;20 Suppl 3:S13-7.
[4] Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 2008 Jun 19;453(7198):1122-6.
[5] Baylor NW, Egan W, Richman P (2002). Aluminum salts in vaccines-US perspective. Vaccine, 20: S18-23. doi:10.1016/S0264-410X(02)00166-4
[6] Hunter RL (2002). Overview of vaccine adjuvants: present and future. Vaccine, 20(Supplement 3):S7-S12. doi:10.1016/S0264-410X(02)00164-0
[7] Giannini SL, Hanon E, Moris P, Van Mechelen M, Morel S, Dessy F, Fourneau MA, Colau B, Suzich J, Losonksy G, Martin MT, Dubin G, Wettendorff MA. Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine, 2006 Aug 14;24(33-34):5937-49. doi:10.1016/j.vaccine.2006.06.005
[8] Casagrande SS, Wang Y, Anderson C, Gary TL. Have Americans increased their fruit and vegetable intake? The trends between 1988 and 2002. Am J Prev Med. 2007 Apr;32(4):257-63.
[9] Counseling to Promote a Healthy Diet, Topic Page. January 2003. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD.
[10] Ransley JK, Greenwood DC, Cade JE, Blenkinsop S, Schagen I, Teeman D, Scott E, White G, Schagen S. Does the school fruit and vegetable scheme improve children’s diet? A non-randomised controlled trial. J Epidemiol Community Health. 2007 Aug;61(8):699-703.

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