Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study

(Word count without footnotes and citations: 934)
In April 2019, Palmer et al [1] published a retrospective population study crediting vaccination against human papilloma virus (HPV) with reduction in HPV prevalence in Scotland, and the authors attributed a reduction in HPV prevalence among unvaccinated women with “herd protection.” However the authors did not mention Scotland’s population-wide public health campaigns to address endemic vitamin D deficiency. The Scottish Government recognized the high prevalence of vitamin D deficiency in its population and began recommending vitamin D supplementation not later than 2006. Vitamin D deficiency results in impaired mucosal and immune defenses and correlates in a dose-dependent manner with increased cervicovaginal HPV infection [2]. By 2009, coincident with the start of the HPV vaccination campaign in 2008, numerous vitamin D supplementation (and sun exposure) campaigns were being implemented throughout Scotland to combat the documented population-wide problem of vitamin D deficiency.

Our views of vitamin D experienced a paradigm shift in the early part of this century with landmark publications such as Vieth’s authoritative documentation of safety in 1999 [3], Zittermann’s “Vitamin D in preventive medicine” in British Journal of Nutrition in 2003 [4], and Vasquez’s “Clinical importance of vitamin D (cholecalciferol): a paradigm shift with implications for all healthcare providers” in 2004 [5] followed by an important partial summary of vitamin D usage guidelines in British Medical Journal in 2005 [6]. These and similarly themed articles have contributed to increased awareness of vitamin D’s safety and roles in preventive medicine and public health, including reducing the burden of infectious diseases such as viral infections and various types of cancer. Consistent with this evidence of safety and benefit, along with evidence that the human daily requirement is an order of magnitude greater than previously believed [7], use of vitamin D supplementation began to increase slowly and then exponentially in the United States [8] and other countries, especially English-speaking societies, most notably the United Kingdom. Indeed, according to the Scottish Health Survey 2003 [9], use of dietary supplements such as vitamins (including vitamin D), fish oils (a source of vitamin D) and minerals (magnesium supplementation improves vitamin D status and is necessary for vitamin D activation, binding, transport, metabolism, and gene expression [10]) had already begun to increase between 1998 and 2003. Certainly not later than 2006, the Scottish Government was already recommending widespread use of vitamin D supplements to combat the high prevalence of vitamin D deficiency in Scotland [11].

Widespread vitamin D deficiency in Scotland was followed by widespread recommendations for vitamin D supplementation starting in 2006 and 2009. In 2006, Burleigh and Potter published in Scottish Medical Journal [12] stating that, “The prevalence of vitamin D deficiency is high in older outpatients in this geographical area.” In 2007, Hyppönen and Power [13] showed that among British adults “Prevalence of hypovitaminosis D in the general population was alarmingly high during the winter and spring, which warrants action at a population level rather than at a risk group level.” In 2008, Rhein [14] further specified that “Vitamin D deficiency is widespread in Scotland.” In 2009, the Scottish Government acknowledged the need to educate its population about the importance of vitamin D3 supplementation [15]. From that time until the present, the Scottish Government, United Kingdom National Health Services, and various advocacy groups and programs (e.g., ScotsNeedVitaminD.com[16], Healthy Start, which provides vitamin D supplements to all children and pregnant women in Scotland [17]) continue assertive public health campaigns recommending vitamin D supplementation and increased vitamin D production via sun exposure via the “Shine on Scotland” program initiated in 2009 [18] for all of its citizens [19-23].

Vitamin D supplementation has been the subject of many clinical trials documenting anti-inflammatory, antiviral, and anticancer benefits. Correction of vitamin D deficiency has significant anti-inflammatory [24] and immunomodulatory [25] benefits. Vitamin D and its direct metabolites promote production of antimicrobial peptides which have antibacterial and antiviral properties, while also reducing viral replication by inhibiting the NF-kappaB pathway. Consistent with these immunomodulatory and antiviral mechanisms, data from several placebo-controlled trials shows that vitamin D provides benefit in a variety of infectious conditions including human immunodeficiency virus (HIV) [26], hepatitis C virus [27-29] and upper respiratory infections [30-31]. Vitamin D administration displays impressive clinical effectiveness against dermal HPV as shown in case reports, clinical series, and placebo-controlled trials, with remarkable safety, high efficacy, and a consistent trend toward complete resolution of lesions [32-36]. In 2014, Schulte-Uebbing et al [37] published “Chronical cervical infections and dysplasia (cervical intraepithelial neoplasia [CIN] 1-2): vaginal vitamin D treatment” showing that among 200 women with cervical dysplasia, vitamin D vaginal suppositories (12,500 IU, 3 nights per week, for 6 weeks) provided “very good anti-inflammatory effects” and “good antidysplastic effects” in women with CIN 1. In 2017, Vahedpoor and colleagues [38] published a double-blind placebo-controlled trial of vitamin D in women with HPV, in which they found that vitamin D3 administration for 6 months among women with CIN1 resulted in its regression and had beneficial effects on markers of insulin metabolism and antioxidant status. In 2018, Vahedpoor and colleagues [39] published a double-blind placebo-controlled trial of vitamin D in women with HPV, in which they observed, “The recurrence rate of CIN1/2/3 was 18.5 and 48.1% in the vitamin D and placebo groups respectively”, thereby clearly favoring treatment with vitamin D over placebo.

In Scotland, programs advocating HPV vaccination (started in 2008) and vitamin D supplementation (started not later than 2006 and again in 2009) occurred in close chronologic proximity. Crediting the reduction in HPV-related disease solely to vaccination via retrospective population study is potentially invalid and misleading, especially when the authors make no account whatsoever of the national program for vitamin D supplementation which started in the same timeframe. Numerous studies have shown that vitamin D provides immunomodulatory, anti-inflammatory, microbiome-modifying, antiviral and anti-HPV benefits with high safety, good efficacy, low cost, wide availability, and clinically important collateral benefits.

[1] Palmer T, Wallace L, Pollock KG, Cuschieri K, Robertson C, Kavanagh K, Cruickshank M. Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study. BMJ. 2019 Apr 3;365:l1161. doi: 10.1136/bmj.l1161
[2] Shim J, Pérez A, Symanski E, Nyitray AG. Association Between Serum 25-Hydroxyvitamin D Level and Human Papillomavirus Cervicovaginal Infection in Women in the United States. J Infect Dis. 2016 Jun 15;213(12):1886-92. doi: 10.1093/infdis/jiw065
[3] Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999 May;69(5):842-56
[4] Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr. 2003 May;89(5):552-72
[5] Vasquez A, Manso G, Cannell J. The clinical importance of vitamin D (cholecalciferol): a paradigm shift with implications for all healthcare providers. Altern Ther Health Med. 2004 Sep-Oct;10(5):28-36 https://www.ncbi.nlm.nih.gov/pubmed/15478784
[6] Vasquez A, Cannell J. Calcium and vitamin D in preventing fractures: data are not sufficient to show inefficacy. BMJ. 2005 Jul 9;331(7508):108-9 https://doi.org/10.1136/bmj.331.7508.108-b and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC558659/
[7] Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003 Jan;77(1):204-10
[8] Rooney MR, Harnack L, Michos ED, Ogilvie RP, Sempos CT, Lutsey PL. Trends in Use of High-Dose Vitamin D Supplements Exceeding 1000 or 4000 International Units Daily, 1999-2014. JAMA. 2017 Jun 20;317(23):2448-2450. doi: 10.1001/jama.2017.4392
[9] "The proportion of adults who report taking dietary supplements (such as vitamins, fish oils, minerals etc) has increased slightly since 1998 (there was no change between 1995 and 1998). In 1998, 15% of men and 16% of women aged 16-64 took some form of dietary supplement, which increased to 20% and 26%, respectively, in 2003." The Scottish Health Survey 2003. Chapter 3 Fruit and Vegetable Consumption and Eating Habits. https://www.webarchive.org.uk/wayback/archive/20180602183443/http://www.... Accessed April 2019
[10] Reddy P, Edwards LR. Magnesium Supplementation in Vitamin D Deficiency. Am J Ther. 2019 Jan/Feb;26(1):e124-e132. doi: 10.1097/MJT.0000000000000538
[11] "Therefore, routine vitamin D supplementation is recommended for all children over 1 year of age and should be continued until 5 years unless the diet is diverse and plentiful." Scottish Government. Nutritional Guidance for Early Years: food choices for children aged 1-5 years in early education and childcare settings. Published: 23 Jan 2006. https://www.gov.scot/publications/nutritional-guidance-early-years-food-... Accessed April 2019
[12] Burleigh E, Potter J. Vitamin D deficiency in outpatients: a Scottish perspective. Scott Med J. 2006 May;51(2):27-31
[13] Hyppönen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr. 2007 Mar;85(3):860-8
[14] Rhein HM. Vitamin D deficiency is widespread in Scotland. BMJ. 2008 Jun 28;336(7659):1451. doi: 10.1136/bmj.39619.479155.3A
[15] Boy wins NHS backing in vitamin D campaign. The Scotsman 2009 December https://www.scotsman.com/news/boy-wins-nhs-backing-in-vitamin-d-campaign... Accessed April 2019
[16] “At scotsneedvitamind.com, we believe the people of Scotland would see health improvements by taking a regular Vitamin D supplement. We think there is enough evidence currently available to make all of us take action, from health care professionals to parents and teachers.” https://scotsneedvitamind.com/about-us/ Accessed April 2019
[17] "The United Kingdom National Health Services created a program called Healthy Start, which offers vouchers for free vitamin D supplements to qualifying pregnant women, women with a baby under one year old and children under the age of five years located in Scotland, Northern Ireland, England and Wales. In April of 2017, the Scottish government partnered with the Healthy Start program to offer free vitamin D supplements to all Scottish pregnant women, regardless of whether they qualify for vouchers. This joint effort was created to decrease the risk of rickets and other health complications caused by vitamin D deficiency. Scotland offers free vitamin D supplements for all pregnant residents. Posted on: November 28, 2017 by Missy Sturges and John Cannell, MD. https://www.vitamindcouncil.org/scotland-offers-free-vitamin-d-supplemen.... See also: National Health Services Scotland. Vitamin D. https://www2.gov.scot/resource/0038/00386784.pdf Accessed April 2019
[18] Scottish warning over vitamin D levels. 19 September 2010 https://www.bbc.com/news/uk-scotland-11355810 Accessed April 2019
[19] "Following recommendations from the Scientific Advisory Committee on Nutrition (SACN), Scottish Government advice on vitamin D for all age groups has been updated as follows: Everyone age 5 years and above should consider taking a daily supplement of 10 micrograms vitamin D, particularly during the winter months (October – March)." Scottish Government. Vitamin D. https://www2.gov.scot/Topics/Health/Healthy-Living/Food-Health/vitaminD Accessed April 2019
[20] Scottish Government. Vitamin D information for health professionals in Scotland. November 2017 https://www.gov.scot/binaries/content/documents/govscot/publications/pub... Accessed April 2019
[21] "Scots should consider taking vitamin D supplements all-year round, but particularly in autumn and winter, according to new health advice." All Scots advised to take vitamin D says new health guidance. 21 July 2016. https://www.bbc.com/news/uk-scotland-36856176 Accessed April 2019
[22] "International experts are calling for food in Scotland to be fortified with vitamin D, in an attempt to cut the large numbers of people who develop multiple sclerosis at sunshine-deprived northern latitudes." Add vitamin D to Scotland's food – experts: Dosing whole population would help cut levels of multiple sclerosis, say scientists. 23 Dec 2011 https://www.theguardian.com/uk/2011/dec/23/vitamin-d-scotland-food-multi... Accessed April 2019
[23] All Scottish babies should have vitamin D supplement, CMO says. The Pharmaceutical Journal 2017 Nov 30. https://www.pharmaceutical-journal.com/news-and-analysis/news/all-scotti... Accessed April 2019
[24] Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D, Aganna E, Price CP, Boucher BJ. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM. 2002 Dec;95(12):787-96
[25] Sánchez-Armendáriz K, García-Gil A, Romero CA, Contreras-Ruiz J, Karam-Orante M, Balcazar-Antonio D, Domínguez-Cherit J. Oral vitamin D3 5000 IU/day as an adjuvant in the treatment of atopic dermatitis: a randomized control trial. Int J Dermatol. 2018 Dec;57(12):1516-1520. doi: 10.1111/ijd.14220
[26] Stallings VA, Schall JI, Hediger ML, Zemel BS, Tuluc F, Dougherty KA, Samuel JL, Rutstein RM. High-dose vitamin D3 supplementation in children and young adults with HIV: a randomized, placebo-controlled trial. Pediatr Infect Dis J. 2015 Feb;34(2):e32-40. doi: 10.1097/INF.0000000000000483
[27] Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients. World J Gastroenterol. 2011 Dec 21;17(47):5184-90. doi: 10.3748/wjg.v17.i47.5184
[28] Nimer A, Mouch A. Vitamin D improves viral response in hepatitis C genotype 2-3 naïve patients. World J Gastroenterol. 2012 Feb 28;18(8):800-5. doi: 10.3748/wjg.v18.i8.800
[29] Komolmit P, Kimtrakool S, Suksawatamnuay S, Thanapirom K, Chattrasophon K, Thaimai P, Chirathaworn C, Poovorawan Y. Vitamin D supplementation improves serum markers associated with hepatic fibrogenesis in chronic hepatitis C patients: A randomized, double-blind, placebo-controlled study. Sci Rep. 2017 Aug 21;7(1):8905. doi: 10.1038/s41598-017-09512-7
[30] Jung HC, Seo MW, Lee S, Kim SW, Song JK.Vitamin D3 Supplementation Reduces the Symptoms of Upper Respiratory Tract Infection during Winter Training in Vitamin D-Insufficient Taekwondo Athletes: A Randomized Controlled Trial. Int J Environ Res Public Health. 2018 Sep 14;15(9). pii: E2003. doi: 10.3390/ijerph15092003
[31] Lee MT, Kattan M, Fennoy I, Arpadi SM, Miller RL, Cremers S, McMahon DJ, Nieves JW, Brittenham GM. Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease. Blood Adv. 2018 May 8;2(9):969-978. doi: 10.1182/bloodadvances.2017013979
[32] Moscarelli L, Annunziata F, Mjeshtri A, Paudice N, Tsalouchos A, Zanazzi M, Bertoni E. Successful treatment of refractory wart with a topical activated vitamin d in a renal transplant recipient. Case Rep Transplant. 2011;2011:368623. doi: 10.1155/2011/368623. Epub 2012 Jan 3.
[33] Aktaş H, Ergin C, Demir B, Ekiz Ö. Intralesional Vitamin D Injection May Be an Effective Treatment Option for Warts. J Cutan Med Surg. 2016 Mar-Apr;20(2):118-22. doi: 10.1177/1203475415602841. Epub 2015 Aug 20
[34] Raghukumar S, Ravikumar BC, Vinay KN, Suresh MR, Aggarwal A, Yashovardhana DP. Intralesional Vitamin D3 Injection in the Treatment of Recalcitrant Warts: A Novel Proposition. J Cutan Med Surg. 2017 Jul/Aug;21(4):320-324. doi: 10.1177/1203475417704180. Epub 2017 Apr 6.
[35] Naresh M. A Study of Effectiveness of Intralesional Vitamin D3 in Treatment of Multiple Cutaneous Warts. IOSR Journal of Dental and Medical Sciences (IOSR -JDMS) 2019:18(3),84-87
[36] Abdel Kareem IM, Ibrahim IM, Fahmy Mohammed SF, Ahmed AA. Effectiveness of intralesional vitamin D3 injection in the treatment of common warts: single-blinded placebo-controlled study. Dermatol Ther. 2019 Mar 28:e12882. doi: 10.1111/dth.12882
[37] Schulte-Uebbing C, Schlett S, Craiut I, Antal L, Olah H. Chronical cervical infections and dysplasia (CIN I, CIN II): vaginal vitamin D (high dose) treatment. Dermatoendocrinol 2014 Oct; 6:e27791. doi:10.4161/derm.27791
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In his Author Perspective, following this article, Tim Palmer writes
“ In Scotland, as elsewhere, no serious adverse effects have been demonstrably linked to the vaccine. The ratio of benefit to possible harm therefore strongly supports Immunisation.”

The WHO has a website which collects global reports of adverse events (1).
When Steve Hinks drew attention to the totals for the HPV vaccine in 2017, there were over 300,000 adverse events recorded, and more than 400 deaths, following HPV vaccination. (2,3 )

In the UK, the MHRA collects Yellow Card reports of adverse events.
Hinks has commented on the inconsistent nature of replies from the MHRA, and the confusion this may cause (3).

However, a Freedom of Information request to the MHRA last year, revealed that in the period May 2006- -Feb 2018, in the UK, adverse event reports for the HPV vaccine totalled 3194, total reactions 12,783, fatal outcome reports, 8. (4)
(NB The MHRA will email copies of FOI reports to interested people. The BMJ has seen the emails from the MHRA, which confirm these figures ).

Tim Palmer appears to make light of concerns that have been expressed about safety issues with the HPV vaccine. The background to these concerns has been comprehensively referenced and discussed in a recent book (5). An awareness of these safety issues is essential when individual young people and/or their parents are being acquainted with what is known about the HPV vaccine.
The UK Supreme Court judgement, re Montgomery, in 2015, made that quite clear. (6,7)

Palmer’s final sentence, “ This is a veritable triumph for medicine “, is his opinion.

His opinion does not diminish the very clear clinical responsibilities that follow from the Montgomery judgement.
Unless information is provided, by the vaccinator, about the risks, rare or not, valid informed consent is not possible.

This article, together with Palmer’s remarks re “ no serious adverse effects “ may be widely read.
Perhaps distributed freely, as an educational reprint, to doctors.
Doctors may be encouraged by Palmer’s views not to consider or mention to patients the evidence of serious adverse events following HPV vaccination referred to above. If they didn’t, it could invalidate any consent (to any intervention) that was given.
The England and Wales High Court recently awarded a patient £4.4 million in damages following a failure to obtain informed consent (9).
Have Palmer and the other authors considered how their paper might influence this aspect of practice ?

1. http://www.vigiaccess.org

2 https://www.bmj.com/content/358/bmj.j3414/rr-22

3 https://www.bmj.com/content/358/bmj.j3414/rr-13

4 https://www.gov.uk/government/publications/mhra-requests-under-the-freed...
FOI 18/014 Human Papilloma Virus (HPV) Vaccine Drug Analysis Print

5 Mary Holland, J.D, KIM Mack Rosenberg J.D., and Eileen Iorio.
The HPV Vaccine on Trial. Skyhorse Publishing 2018.

6 https://www.supremecourt.uk/cases/docs/uksc-2013-0136-judgment.pdf

7 https://www.bmj.com/content/357/bmj.j2224

8 https://www.supremecourt.uk/decided-cases/docs/UKSC_2013_0136_Judgment.pdf

9 http://www.bailii.org/ew/cases/EWHC/QB/2018/164.html

Success inevitably depends on what you are measuring [1]. The HPV vaccines were marketed not on their ability reduce Human Papilloma viruses but on their ability to reduce cervical cancer, but manifestly this has not happened. In a recent article Castanon and Sasieni 'Is the recent increase in cervical cancer in women aged 20–24 years in England a cause for concern?' [2] argue that the steep rise in England of cervical cancers in what is the first generation of women targeted with these products is an artefact of lowering the screening age by seven months, but manifestly the levels have not gone down. I cannot help thinking a lowering of incidence of cervical cancer rates among young women our health officials would be shouting it from the roofs. And it has not happened.

[1] Palmer et al, '
Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study',
BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1161 (Published 03 April 2019)

[2] Alejandra Castanon, Peter Sasieni, 'Is the recent increase in cervical cancer in women aged 20–24 years in England a cause for concern?', Preventive Medicine Volume 107, February 2018, Pages 21-28, https://www.sciencedirect.com/science/article/pii/S0091743517304802

The study is interesting but with all the limitations of an observational study.
Unfortunately, no data are given to calculate the absolute risk.
It would be necessary to access raw data.
The best approximate calculation of the absolute risk allows us to calculate an NNT of 4,300 for CIN 3 and worse. This result is clinically irrelevant.
It would be very important that the journal give access to the complete data, even in complementary tables.