Background
The case of HPV vaccines
Methods
Aim and objectives
Study period
Search strategy
-
media types: worldwide online health, science, news and tabloid media, online websites of television channels and blogs (no restriction was set by e.g. media type, size of readership or size of country of origin, as it was considered that some relevant news would possibly be disseminated only by media with a small reach or by blogs)
-
search terms: the colloquial and technical terms as well as tradenames: “HPV vaccin*”; “papilloma W/3 vaccin*”; “cervical cancer vaccin*”; “HPV jab”; “papilloma jab”; “cervical cancer jab”; “Gardasil”; “Cervarix”; “Silgard” (the asterisk symbol * indicates that the ending of ‘vaccin’ could vary (e.g. vaccine, vaccination); ‘W/3’ (or W/2, W/4, W/5, etc.) indicates the number of words that could be inserted between two word elements)
-
languages: all official EU languages except for Irish and Maltese, i.e. 22 languages (the search terms were translated by native speakers at the EMA).
Daily media screening
Weekly media content analysis
Presentation and categorisation of media content as derived questions
Evaluation of utility
Results
Media monitoring
Peak time | Peak-triggering event |
---|---|
1st peak, 14 September 2015 | Study published by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM, the French medicines agency) and the French health insurance, concluding that HPV vaccines do not increase the risk of autoimmune disorders but suggesting increase of the risk of Guillain-Barré syndrome [30] |
Call by two Republican Party lawmakers in the USA towards schools to oppose mandatory HPV vaccination of middle school students in Rhode Island [31] | |
2nd peak, 24 September 2015 | Statement of the Catholic bishop in British Columbia, Canada, saying abstinence is the only healthy choice over HPV vaccination [32] |
Announcement in Denmark of the replacement of Gardasil® by Cervarix® in the national HPV immunisation programme [33] | |
Report claiming that 1500 girls in Denmark have suspected adverse reactions to HPV vaccines [34] | |
3rd peak, 22 October 2015 | Study published in the journal Epidemiology, Biomarkers and Prevention concluding that a quarter of doctors in the USA do not strongly endorse HPV vaccination [35] |
4th peak, 26 October 2015 | Statement of the International Papillomavirus Society (IPVS) endorsing the use of HPV vaccines [36] |
Concerns in Denmark on the marketing authorisation holder’s restrictive search strategy on adverse effects of HPV vaccines [37] | |
Study published by the US Centers for Disease Control and Prevention (CDC) about low HPV vaccine uptake among adolescent males in the USA [38] | |
5th peak, 5 November 2015 | Publication by the EMA of the PRAC outcome of the referral procedure, concluding that the evidence does not support a causal association between HPV vaccines and CRPS or POTS [23] |
6th peak, 10 December 2015 | Statement by Health Canada referring to a review of international research data suggesting that there are no new risks associated with Gardasil® and that it can be used safely [39] |
Topics |
---|
Experiences of female adolescents with suspected adverse reactions of HPV vaccines and beliefs in causal association with HPV vaccines [40] |
Study on misleading information on HPV vaccines on the Internet [46] |
Lack of treatment options for CRPS and POTS [47] |
Call by the Irish government for investigations on suspected adverse reactions with HPV vaccines [42] |
Continued suspension of HPV vaccination recommendation by the Ministry of Health in Japan [55] |
USA presidential candidate Donald Trump claiming a causal association between vaccines and autism [56] |
Replacement of Gardasil® by Cervarix® in the national HPV immunisation programme in Denmark [33] |
Protection against mouth cancer by HPV vaccination and the importance of immunisation of boys [63] |
Responsibility of physicians for low HPV vaccination rates [35] |
Discussion about appropriate HPV vaccination age [65] |
Categories: themes and high-level questions | Sub-categories: additional aspect-specific questions |
---|---|
Theme 1 - Assessment scope: 1.0. What is the scope of the assessment conducted for the EU referral procedure for HPV vaccines? | 1.1. Why does the procedure focus on CRPS and POTS as defined by complex and difficult-to-apply/ascertain case definitions? |
1.2. Why have concerns over autoimmune diseases with HPV vaccines been excluded from the assessment? | |
1.3. Why does the evaluation not cover the entire benefit-risk balance of HPV vaccines? | |
Theme 2 - CRPS and POTS case data: 2.0. What kind of case reports of CRPS and POTS in association with HPV vaccines have been reviewed by the authorities, and how? | 2.1. How many case reports of CRPS and POTS in association with HPV vaccines have been received by the authorities, who reported the cases to the authorities and who are the primary reporters? |
2.2. Who confirmed the cases as CRPS and POTS cases? | |
2.3. How many cases have been received with symptoms of, or similar to those of, CRPS and POTS but have not met the criteria of the case definitions, how were these cases reviewed/followed up and how did they have an impact on the assessment outcome? | |
2.4. Have all reported cases been followed up by the authorities in order to obtain more information (to allow for causality assessment)? | |
2.5. What is the outcome of the analysis of data recorded in EudraVigilance (the adverse reaction database of the EU regulatory network) requested by parents who have participated in the EMA meeting with concerned vaccinees and parents to present their concerns and experiences? | |
2.6. How were the cases reviewed that had been submitted to the authorities by the parents’ groups as invited by the EMA? | |
Theme 3 - Frequency assessment: 3.0. What are the reporting rates and actual frequencies of CRPS and POTS in association with HPV vaccines? | 3.1. How are these frequencies calculated? |
3.2. Where have background frequency data been obtained from, and how confident can one be in their accuracy? | |
3.3. What is the likely magnitude of underreporting, and has a sensitivity analysis been performed for the observed/expected analysis to take underreporting into account? | |
3.4. Why are the reporting rates for (any) adverse reactions higher for HPV vaccinesthan for other vaccines? | |
Theme 4 - Other (i.e. not case) CRPS and POTS data: 4.0. What kind of data has been reviewed for the EU referral procedure for HPV vaccines in addition to individual case reports? | 4.1. What is the nature of these data, and who provided them? |
Theme 5 - Assessment of causal association: 5.0. How has the assessment of CRPS and POTS in possible causal association with HPV vaccines been performed? | 5.1. Have all potential aetiological pathways been investigated, e.g. autoimmune pathway and impact of female hormones on susceptibility for autoimmune disease? |
5.2. How has causal association been ruled out? | |
Theme 6 - Overall safety and other safety concerns: 6.0. What are the overall safety database and safety study results for HPV vaccines? | 6.1. What was the knowledge base at the time of granting the marketing authorisation, and were the vaccines sufficiently tested at the time? |
6.2. How are data assessed for autoimmune diseases, including multiple sclerosis and Guillain-Barré syndrome? | |
6.3. How are data assessed for infertility, miscarriage and stillbirth? | |
Theme 7 - Aluminium: 7.0. What is the knowledge about the safety of aluminium/AS04 as adjuvant? | 7.1. What are the plasma levels for aluminium after vaccination with current HPV vaccines and with the future Gardasil-9® compared to typical food intake? |
7.2. How does the clearance process of aluminium in the human body work? | |
7.3. Since when has the rate of autism diagnosis been increasing, and is there a temporal association with the use of aluminium in vaccines? | |
7.4. What is known about a link between AS04 (aluminium hydroxide + monophosphoryl lipid A) and autism? | |
7.5. How similar is AS04 to AS03 (squalene + dl-α-tocopherol + polysorbate 80), which is the adjuvant in Pandemrix® for which cases of narcolepsy were reported as suspected adverse reactions? | |
Theme 8 - Data trustworthiness: 8.0. Are the data for the EU referral procedure for HPV vaccines trustworthy? | 8.1. What safeguards are there to ensure that marketing authorisation holders do not manipulate data they submit to the authorities? |
8.2. Have data been solicited by the authorities from independent sources? | |
Theme 9 - Assessment standards and integrity: 9.0. How can it be demonstrated that signal detection, risk evaluation and decision-making have been performed to highest standards during the EU referral procedure for HPV vaccines? | 9.1. Have the authorities taken seriously the vaccinated females experiencing CRPS and POTS? |
9.2. How do the authorities manage their conflict of interests? | |
9.3. Why was the signal of CRPS and POTS with HPV vaccines not identified earlier, and why was the referral procedure only initiated at the request of Denmark and not earlier by the EMA? | |
9.4. Why did the EMA not apply the precautionary principle and suspend the vaccine while investigations were ongoing? | |
Theme 10 - Benefit: 10.0. What is the knowledge on the benefit and effectiveness of HPV vaccines? | 10.1. How does the vaccine intervene protectively in the pathway of cancer development? |
10.2. How long is the vaccination effective in vaccinees, and what should vaccinees do after immunity has decreased? | |
10.3. What is the potential of strain replacement, and how will this have an impact on cancer rates? | |
Theme 11 - Benefit-risk balance: 11.0. What does the statement ‘the benefits outweigh the risks’ mean? | 11.1. Is this statement only applicable at population level or also at the individual level, and does a positive benefit-risk balance apply to all potential vaccinees or are there individuals to whom the statement does not apply? |
11.2. How are healthcare professionals provided with information so that they can communicate well with potential vaccinees and parents about the individual benefit-risk balance? | |
Theme 12 - Further steps and research: 12.0. What will the impact of the EU referral outcome be, and will further research be done? | 12.1. How do vaccine evaluations by the authorities have an impact on immunisation policies? |
12.2. What kind of further research will be done, and what will be the study objectives? | |
12.3. How will independence of this research be ensured? |
Utility
(1) Feedback from users of the media monitoring results
(2) Review of the impact of the derived questions on the summary of PRAC recommendations
-
The PRAC reviewed the published research, data from clinical trials and reports of suspected side effects from patients and healthcare professionals, as well as data supplied by Member States; (addresses derived questions 2.0. and 4.1.).
-
The PRAC took into account detailed information received from a number of patient groups that also highlighted the impact these syndromes can have on patients and families (addresses derived question 2.6.).
-
Symptoms of CRPS and POTS may overlap with other conditions, making diagnosis difficult in both the general population and vaccinated individuals. and The PRAC noted that some symptoms of CRPS and POTS may overlap with chronic fatigue syndrome (CFS, also known as myalgic encephalomyelitis or ME). Many of the reports considered in the review have features of CFS and some patients had diagnosis of both POTS and CFS. Results of a large published study that showed no link between HPV vaccine and CFS were therefore particularly relevant. (addresses derived questions 1.1. and 2.3.).
-
…available estimates suggest that in the general population around 150 girls and young women per million aged 10 to 19 years may develop CRPS each year, and at least 150 girls and young women per million may develop POTS each year. The review found no evidence that the overall rates of these syndromes in vaccinated girls were different from expected rates in these age groups, even taking into account possible underreporting. (addresses derived questions 5.0. and 3.3.).
(3) Capacity of derived questions to predict queries from journalists
Discussion
-
Efficient media monitoring should be built into the process of vaccine benefit-risk monitoring, and benefit-risk assessment should ensure the provision of responses to all safety concerns, including those debated in the public domain.
-
Explanations on methods for benefit-risk monitoring and assessment should be provided in a language understandable to the public, and should be developed and ideally be tested with a view to explaining how the method works and how robust the results are.
-
Given that conflicts of interests are a major concern voiced by the public, procedures to ensure unbiased monitoring and assessment as well as, if applicable, the mechanisms of public-private partnership (PPP) governance models (as envisaged by ADVANCE as one option for a future platform for vaccine benefit-risk monitoring) need to be proactively communicated to the public.