The remarkable impact of bivalent HPV vaccine in ScotlandBMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1375 (Published 03 April 2019) Cite this as: BMJ 2019;365:l1375
All rapid responses
Re: Scotland's public health programs and trends improving nutritional status should be considered when discussing HPV trends
Julia Brotherton’s Editorial  accompanying the retrospective population study crediting vaccination against human papilloma virus (HPV) with reduction in HPV prevalence in Scotland  considers a variety of possibilities for the presumed success of the HPV vaccination program. However, her Editorial does not mention the concomitant public health programs organized by the Scottish Government and other groups to improve vitamin D nutriture throughout Scotland that occurred in the same time-frame. The Scottish Government recognized the high prevalence of vitamin D deficiency in its population and began recommending vitamin D supplementation not later than 2006. 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 key publications starting in 1999 [3-6]. We now have 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. 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 , use of vitamin D supplementation began to increase slowly and then exponentially in the United States  and other countries, especially English-speaking societies, most notably the United Kingdom. Indeed, according to the Scottish Health Survey 2003 , 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 ) 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 (and sun exposure) to combat the high prevalence of vitamin D deficiency in Scotland [11-23].
Vitamin D supplementation has been the subject of several placebo-controlled trials documenting anti-inflammatory, antiviral, and anticancer effects. Correction of vitamin D deficiency has significant anti-inflammatory  and immunomodulatory  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) , 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  published “Chronical cervical infections and dysplasia (CIN I, CIN II): vaginal vitamin D (high dose) 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  published “Effects of Long-Term Vitamin D Supplementation on Regression and Metabolic Status of Cervical Intraepithelial Neoplasia” in which they summarized, “In conclusion, vitamin D3 administration for 6 months among women with CIN1 resulted in its regression and had beneficial effects on markers of insulin metabolism, plasma NO, TAC, GSH and MDA levels.” In 2018, Vahedpoor and colleagues  published “Long-Term Vitamin D Supplementation and the Effects on Recurrence and Metabolic Status of Cervical Intraepithelial Neoplasia Grade 2 or 3” in which they noted, “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; use of nutritional supplements that contain or potentiate vitamin D had started to increase in the population by 2003. Crediting the reduction in HPV-related disease solely to vaccination via retrospective population study is potentially misleading, especially when these authors make no account whatsoever of the national program for vitamin D supplementation which started in the same time-frame. 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.
 Brotherton JML.The remarkable impact of bivalent HPV vaccine in Scotland. BMJ 2019;365:l1375 https://doi.org/10.1136/bmj.l1375 Published 03 April 2019
 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
 Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999 May;69(5):842-56
 Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr. 2003 May;89(5):552-72
 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
 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/
 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
 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
 "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
 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
 "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
 Burleigh E, Potter J. Vitamin D deficiency in outpatients: a Scottish perspective. Scott Med J. 2006 May;51(2):27-31
 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
 Rhein HM. Vitamin D deficiency is widespread in Scotland. BMJ. 2008 Jun 28;336(7659):1451. doi: 10.1136/bmj.39619.479155.3A
 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
 “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
 "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
 Scottish warning over vitamin D levels. 19 September 2010 https://www.bbc.com/news/uk-scotland-11355810 Accessed April 2019
 "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
 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
 "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
 "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
 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
 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
 Luthold RV, Fernandes GR, Franco-de-Moraes AC, Folchetti LG, Ferreira SR. Gut microbiota interactions with the immunomodulatory role of vitamin D in normal individuals. Metabolism. 2017 Apr;69:76-86. doi: 10.1016/j.metabol.2017.01.007. Epub 2017 Jan 13.
 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
 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
 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
 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
 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
 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
 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.
 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
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Competing interests: Dr Alex Vasquez is a lecturer and author of numerous articles, letters, and books related to topics of nutrition, clinical medicine, neuroinflammation, and the human microbiome. Dr Vasquez has served as a consultant to Biotics Research Corporation.
This epidemiology report was purely a paper exercise.(1) There were no face to face consultations with any of the screened women. It was interesting to note the authors were claiming herd immunity, for the convergence of both vaccinated and unvaccinated women in the graphical representation, showing a significant reduction in serious cervical lesions in the 20 year old women screened, between birth cohorts 1988 to 1996, (see figures 2 and 3). I am assuming David Thomas’s response is ‘tongue in cheek’ but he has a point. In Scotland, boys, who make up 50% of the ‘herd’, are not being HPV vaccinated until later this year in Scotland. The top two graphs in Figure 2 also demonstrated for the incidence of minor lesions ASCUS and LSIL the vaccine has made almost no difference during the time period studied.
I would assume those schoolgirls would have received some counselling with their vaccines, particularly on the subject of safe sex and how HPV infection could be avoided. These lessons would be taught to both boys and girls, vaccinated and unvaccinated, and could very possibly account for the reduction in serious lesions reported for the 20 year old women screened. I was very concerned the authors deliberately discounted the data recorded for women who had received only one or two HPV vaccine doses, (see Top Table 3). For the vaccine to be proven effective, there should have been a significant reduction in cervical lesions in the women screened, but the data records little or no improvement in the overall figures. The authors claim the numbers are too small (6186) for an accurate assessment to be made, yet they include in their assessments the data for the relatively small numbers of women unvaccinated in Table 4, (2210, ages 12-13), (5472, ages 14-15), and (7896, ages 16-17).
Interestingly, there were no CIN Grade 3 lesions recorded for the unvaccinated 12-13 ages cohort, which rather backs up my point about school HPV counselling. The older unvaccinated and vaccinated age cohorts will have missed out on this essential information.
1. Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study Tim Palmer,1 Lynn Wallace,2 Kevin G Pollock,3,4 Kate Cuschieri,5 Chris Robertson,3,6,7 Kim Kavanagh,7 Margaret Cruickshank
Competing interests: No competing interests
Were males as well as females vaccinated in Scotland? If not, there must have been sufficient numbers of vaccinated women to reduce the likelihood that a man would have sex with both a vaccinated and an unvaccinated woman. An interesting opportunity for modeling HPV transmission.
Competing interests: No competing interests
I agree with Julia Brotherton[1,2] that these findings are remarkable but despite wide media publicity this morning they do not seem to provide direct evidence that the vaccines prevent cancer, or that they are safe [3-9].
 Julia ML Brotherton, ' The remarkable impact of bivalent HPV vaccine in Scotland'
BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1375 (Published 03 April 2019)
 Tim Palmer, Lynn Wallace, Kevin G Pollock, Kate Cuschieri, Kim Kavanagh, Margaret Cruickshank, '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)
Cite this as: BMJ 2019;365:l1161
 Jørgensen L, Gøtzsche PC, Jefferson T.'The Cochrane HPV vaccine review was incomplete and ignored important evidence of bias', BMJ Evid Based Med. 2018 Oct;23(5):165-168. doi: 10.1136/bmjebm-2018-111012. Epub 2018 Jul 27
 Nigel Hawkes, 'Cochrane director’s expulsion results in four board members resigning', BMJ 2018; 362 doi: https://doi.org/10.1136/bmj.k3945 (Published 17 September 2018)
 Lars Jørgensen, Peter Doshi, Peter Gøtzsche, Tom Jefferson, 'Challenges of independent assessment of potential harms of HPV vaccines', BMJ 2018; 362 doi: https://doi.org/10.1136/bmj.k3694 (Published 24 September 2018)
 Riva C, Tinari S, Spinosa JP. 'Lessons learnt on transparency, scientific process and publication ethics. The short story of a long journey to get into the public domain unpublished data, methodological flaws and bias of the Cochrane HPV vaccines review.'BMJ Evidence-Based Medicine Published Online First: 06 December 2018. doi: 10.1136/bmjebm-2018-111119
 Peter Doshi, Tom Jefferson, Mark Jones, Kyungwan Hong, Larissa Shamseer, Haeyoung Lee, O’Mareen Spence, Florence Bourgeois, 'Call to action: RIAT restoration of a previously unpublished methodology in Gardasil vaccine trials', 11 January 2019, https://www.bmj.com/content/346/bmj.f2865/rr-7
 Gayle Delong, 'A lowered probability of pregnancy in females in the USA aged 25–29 who received a human papillomavirus vaccine injection', Journal of Toxicology and Environmental Health, https://www.tandfonline.com/doi/abs/10.1080/15287394.2018.1477640
 Mary Holland, Kim Mack Rosenberg and Eileen Iorio, 'The HPV Vaccine On Trial: Seeking Justice for a Generation Betrayed' with an introduction by Luc Montagnier, Skyhorse, 2 October 2018
Competing interests: No competing interests