Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Urgent need for uptake data on 3 doses of HPV vaccine
- Padmanabhan Badrinath (26 April 2008)
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If liberty means anything at all, it means the right to tell people what they do not want to hear.
- BM Hegde (27 April 2008)
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An encouraging trial
- Peter M English (2 May 2008)
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Clarification on effect of ethnicity would be welcome
- Gee Yen Shin (12 May 2008)
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HPV vaccination: unresolved issues around consent
- Elizabeth C.F. Brown (13 May 2008)
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HPV vaccination in the United Kingdom: Early days..
- Emmanuel Agogo (14 May 2008)
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HPV vaccination coverage rate: a successful example of public health governance for a prevention strategy
- Giuseppe Montagano, Gabriella Cauzzillo, MD (12 November 2008)
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Uptake of the third dose of human papillomavirus vaccine by adolescent schoolgirls: the Manchester study
- Loretta Brabin, Stephen A Roberts, Rebecca Stretch, David Baxter, Gloria Chambers, Henry Kitchener, Rosemary McCann (5 December 2008)
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Padmanabhan Badrinath, Consultant in Public Health Medicine Suffolk Primary Care Trust, IP8 4DE
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Dear Editor, Brabin et al need to be congratulated on their feasibility study of HPV vaccine administration in Manchester (BMJ, on line first, 24th April 2008) and also the BMJ for publishing the study on line within a few weeks of its acceptance. However, I would like to share some of my concerns with this study and the way it has been covered in the media. It is important to note that reference 2 cited in the paper, a systematic review (1), only included women aged 15 to 25 years and the authors caution against its external validity to women outside of this age group. They have also explicitly stated that “We did not find evidence that prophylactic vaccination against HPV types 16 and 18 reduces cervical cancer incidence or mortality”. However, reference 3 in the BMJ paper of which Brabin L is also the first author when presenting information to the participants of the study (2) stated, “Vaccination against HPV will prevent cervical cancer”.(Box 1, p 3088). There are also problems with response rates in both surveys cited as ref 3 and 4 with response rates of 22.7% (2) and 56.7% (3), respectively. The non response bias in lifestyle survey studies are well known (4). The key point of concern with this study is the way the study findings and conclusions were covered in the media. The first author has been quoted as saying “We were very encouraged, and believe that a coverage of 80% is very achievable”. This can be misleading as the study is only reporting the first two doses of the vaccine and not the full course which should include the third dose. As the authors have pointed out themselves “success of the vaccination programme depends on high coverage of third dose”. As stated in the Canadian consensus guideline (5) it is important to have all three doses of the vaccine to derive benefit. Hence one would have expected both the authors and the BMJ to have waited and published the uptake and acceptance at the completion of the proposed vaccination schedule. As the study commenced a year ago (February 2007), it is possible that this data might already be available. The sceptics among your readers might speculate about the possible uptake of the three doses at the end of 6 months and the potential reasons for it being not made available in the scientific literature. For both national planners and local implementers this will be key outcome which I hope will be made available as soon as possible. References 1 Rambout L, Hopkins L, Hutton B, Fergusson D. Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials. CMAJ. 2007 Aug 28;177(5):469-79. 2 Brabin L, Roberts SA, Farzaneh F, Kitchener HC. Future acceptance of adolescent human papillomavirus vaccination: a survey of parental attitudes. Vaccine. 2006 Apr 12;24(16):3087-94. 3 Marlow LA, Waller J, Wardle J. Parental attitudes to pre-pubertal HPV vaccination. Vaccine. 2007 Mar 1;25(11):1945-52. 4 Hill A, Roberts J, Ewings P, Gunnell D. Non-response bias in a lifestyle survey. J Public Health Med. 1997 Jun;19(2):203-7. 5 Canadian consensus guidelines on Human Papilloma virus. http://caonline.amcancersoc.org/cgi/content/full/57/1/7 Accessed on 25th April 2008. Competing interests: Conflict of interest: The author works in the area of clinical prioritisation and firmly believes in the deployment of health care resources based on the information on clinical & cost effectiveness of health care interventions. |
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BM Hegde, Retd. Vice Chancellor Mangalore-575 004, India
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Dear Editor, Estimated 10 million cases of cancer that develop annually throughout the world, only around 15% are estimated to be attributable to infectious agents (1). Of that lot only 30% is attributable to HPV virus. 80% of all cervical cancers occur in the poor developing world where these vaccines are prohibitively expensive at the moment. HPV vaccine does not protect against all types of HPV. One vaccine protects against two and the other four. Two of them are associated with cancer and the other two with anaogenital warts. Even when someone is vaccinated it is still possible to get infected with other viruses. The vaccine protects against a minority of cervical cancer producing viruses. That leaves the vast majority of viral aetiology cancers outside the purview of the vaccine. It is clear from the discussion above that the vaccine, if at all, protects against a microscopic minority of cervical cancers!(2) Judicial Watch, the public interest group that investigates and prosecutes government corruption, released recently new documents obtained from the U.S. FDA detailing 1,824 reports of adverse reactions to the vaccination for HPV including eight deaths. Judicial Watch had previously obtained 1,637 reports relating to the same vaccine on May 15, 2007, bringing the known total to 3,461 adverse reactions including eleven deaths. These vaccines have been followed up for only five years and we are yet to find out if they give life long immunity which is highly unlikely. Be that as it may, let us turn our attention to infectious diseases against many of whom we claim to have effective vaccines! The list of vaccines grows by the day, thanks to the greed of the pharmaceutical industry. Vaccines, with the whole population as their potential clients, are a trillion dollar industry pushed by some of the top business tycoons on the Forbes list. A child in the US today gets about 20 vaccines before it starts to walk and talk! A gold mine indeed! We claim that we have conquered many fatal infectious diseases because of our interventions. Truth is otherwise! Most of these diseases were on the wane long before the medical science came on the scene. Plague disappeared from Europe by the end of 18th century before any intervention or antibiotics came on the scene, diphtheria death rate plummeted well before anti-diphtheritic serum was made available, tuberculosis deaths had significantly come down long before streptomycin or BCG were discovered. Now let us take a look at the other side of the coin. With more than twenty vaccines given to a child, many of them in clusters, they might even confuse the 150 genes in the 9th chromosome resulting in, on rare occasions, the genes producing auto anti-bodies that might attack the body’s own cells resulting in the deadly auto-immune diseases dreaded by the father of immunology, Paul Ehrlich, in his own words as “horror auto- toxicus.” A study of African Americans, most of whom are of East African origin, shows that they have much higher prevalence of autoimmune diseases in the US compared to the Caucasians. Curiously, in East Africa the natives have hardly any auto-immune disease. What could be the possible reasons? One possibility is that in Africa the 150 genes in the 9th chromosome are kept busy all the time by numerous bacterial, parasitic and other infections that the genes have to be on their toes all the time on duty. Whereas in the US African Americans have such sterile surroundings, thanks to the anti-septic industry, that the genes might be lazing away doing nothing. If such genes are artificially tickled with vaccines could they, possibly, produce many auto antibodies in the bargain? Horror autotoxicus indeed! “Time has come” as Walrus said “to talk of many things….cabbages and Kings”… and the holistic view of vaccinations. Yours ever, bmhegde References 1) Pisani, P., Parkin, D.M., Munoz, N., Ferlay, J. 1997. Cancer and infection: estimates of the attributable fraction. Cancer Epidemiol. Biomarkers Prev. 1990; 6; 387-400. 2) McNeil, C., Who Invented the VLP Cervical Cancer Vaccines? Journal of the National Cancer Institute, 2006; 98(7): 433. 3) The article on school vaccination this week. Competing interests: Interested in human life |
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Peter M English, Public Health Physician Surrey KT19 9XF
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An uptake of nearly 70% for two doses of vaccine in a pilot programme such as this is very encouraging. This trial was performed before the national education programme had started, and therefore at a time when relatively few members of the public will have been aware of the vaccine or its benefits. It is to be hoped that when the national programme begins, following and accompanied by well -designed health promotion materials explaining the reason for the vaccination, an even higher uptake will be possible. The authors correctly state that "The effectiveness of the national immunisation programme depends on good coverage." It is true, of course, that the effect on the overall cancer burden is dependent on the uptake of the vaccine. The more people who reduce their chances of getting cervical cancer by 70%, the smaller the number of cases we can expect. But it is also true that the benefit to the recipients of the vaccine is NOT dependent on anybody else getting the vaccine: those girls who are vaccinated will (as long as they haven't already been infected with the virus) be reducing their odds of getting cervical cancer by about 70%. Of course, if enough people are vaccinated, there will be a herd immunity effect; but that must be considered a bonus. As another respondent has implied, three doses of vaccine are required to obtain maximum benefit; but on the other hand, there is evidence from "intention to treat" studies that two doses provide a good antibody response in most patients. Indeed, it is quite possible that the schedule might be changed to a two-dose schedule - although I hasten to point out that this is, at this point, speculation. Furthermore, since the vaccine manufacturers will presumably sell less vaccine if this is the case, accumulating the evidence necessary for making this change will probably need to be done via state-funded studies and/or evaluations of the vaccination programme. Competing interests: I have received payment from vaccine manufacturers for participation in boards to discuss how to implement HPV vaccination, and for speaking at meetings, and funding to attend the European Society for Paediatric Infectious Disease conference. |
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Gee Yen Shin, Locum Consultant Virologist Infection and Immunology Unit, 5th Floor, North Wing, St Thomas' Hospital, London SE1 7EH
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Sir, The publication of the article by Brabin et al on uptake of human papillomavirus (HPV) vaccine by schoolgirls[1] is timely, as it precedes the introduction of the national HPV vaccine programme in the UK this autumn. One of the most striking findings in this study was the apparent effect of ethnicity on compliance with vaccination. It was observed that "Vaccine uptake was significantly lower in schools with a higher proportion of girls from ethnic minority groups (P<0.001 for trend)". This statistically significant finding was referred to in the accompanying Editorial, which also highlighted the possible effect of religion on uptake[2], as two schools declined to participate in the study on religious grounds. However, this apparent effect of ethnicity on vaccine uptake is not as clear-cut as it first seems. One can only infer from the article that schoolgirls from "ethnic minority groups" have a lower vaccine uptake, at least this is what Brabin and colleagues appear to imply. Assuming that it is a valid inference, the effect of ethnicity and possibly religion on vaccine uptake are potentially important findings. They suggest that the successful implementation of the national HPV vaccine programme may vary across the UK, depending upon local variation in demography. Thus it was disappointing that the authors did not provide a more detailed exposition of their findings. One wonders whether the reduced uptake was uniform across all ethnic minorities or not. The last UK population Census contained no less than 16 ethnic groupings[3]. The collective term "ethnic minority" lacks precision; more detail would be welcome. It is not clear whether the research questionnaire gathered data on ethnicity on an individual basis or not. Presumably this data was not gathered or it would have been presented. This is a pity if this was the case as this information would have been very helpful to the authorities which must introduce the vaccine, especially in cities like London for example, where in 2003, about 40% of the population was not classified as "White British"[4]. Clearly, if the Manchester experience in relation to ethnicity and HPV vaccine uptake is reproduced in cities like London, public health officials will have a mountain to climb. With respect to religion, it would be very interesting to know the religious affiliation of the two schools which declined to take part in the study on religious grounds. Again, this information would be of use to those whose responsibility it is to implement this new vaccine. I hope the authors are in a position to clarify the situation as regards ethnicity and reveal the religious affiliation of the two non- participating schools as that would certainly add to an already valuable piece of work. References 1. Brabin L, Roberts SA, Stretch R et al Uptake of first two doses of human papillomavirus vaccine by adolescent schoolgirls in Manchester. prospective cohort study. BMJ 336:1056-1059 2. Waller J, Wardle J. HPV vaccination in the UK. BMJ 336:1028-1029 3. Bosveld K, Connolly H, Rendall MS. A guide to comparing 1991 and 2001 Census ethnic group data. Office of National Statistics 2006 available at: http://www.statistics.gov.uk/CCI/article.asp?ID=1471&Pos=2&ColRank=1&Rank=224 (accessed 09/05/08) 4. Large P, Ghosh K. Estimates of the population by ethnic group for the areas within England. Population Trends 2006;124:8-17 Competing interests: None declared |
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Elizabeth C.F. Brown, Academic F2 doctor Southampton University Hospital Trust, SO16 6YD
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Brabin et al’s success in achieving an uptake of 70% for two doses of HPV vaccine is extremely encouraging [1]. However, this pilot has raised important issues that will need to be addressed before the vaccination program is rolled out nationally. The GMC is clear that a fundamental component of seeking informed consent involves the process of providing adequate information for a patient to understand and make a decision, and that a mere signature on a form is not enough [2]. The main reasons for vaccine refusal in the pilot were insufficient information and fears of vaccine safety, evidently some parents seek more than an information sheet can provide. Hopefully a national publicity campaign will illustrate a clear rationale for vaccination, but additional opportunities for girls and their parents to ask questions are likely to depend on local provision. It remains unclear who will provide the answers to their questions: primary care is likely to be important but school-delivery of this vaccine may require further education of school nurses, possibly aided by ‘open evenings’ to discuss issues with parents. In addition, guidance is currently ambiguous on situations where there is a disagreement between a parent and child’s decision regarding vaccination. Parental opinion is divided as to whether a girl should be able to seek the vaccine without their knowledge [3]. The principle of ‘Gillick competence’ might apply, if a girl sufficiently understands the concepts involved and wishes to make the decision for themselves [4]. However, given that the long-term effects of this vaccine are not known, is it safe for children to be vaccinated unknown by those with parental responsibility? Furthermore, would it be ethical to apply ‘Gillick competence’ in such a setting? 1. Brabin L, Roberts SA, Stretch R, Baxter D, Chambers G, Kitchener H, et al. Uptake of first two doses of human papillomavirus vaccine by adolescent schoolgirls in Manchester: prospective cohort study. BMJ 2008; doi: 10.1136/bmj.39541.534109.BE. 2. Seeking Patients’ Consent: The Ethical Considerations, General Medical Council (1998) 3. Brabin L, Roberts SA, Kitchener HC. A semi-qualitative study of attitudes to vaccinating adolescents against human papillomavirus without parental consent. BMC Public Health 2007;7:20 4. Gillick v West Norfolk and Wisbech Area Health Authority and Department of Health and Social Security [1983] 3 WLR (QBD). Competing interests: None declared |
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Emmanuel Agogo, GP Registrar 2 The Slieve, Birmingham, B20 2NR
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Brabin et al have established that under 'ideal conditions' 70% uptake of the HPV can be achieved. I wish to raise two points of concern. Firstly, the major reasons that parents have given include insufficient information to make a decision, or many unknowns (36%) and concerns about safety (36%) (1). Both concerns stand to reason and therefore these parents cannot be criticised. The discussion of the acceptability and possible introduction of this vaccine has been in the public domain long before any scientific evidence to the effect. Secondly, these results suggest that uptake was lower among ethnic minorities. A qualititative study in the US identified different attitudes to HPV vaccination among African-Americans and Latinos concluding that 'unique educational strategies need to be developed, based on the needs and perceptions of the targeted audience' (2). I agree that these results are interesting but inconclusive. More research is needed. Loretta Brabin, Stephen A Roberts, Rebecca Stretch, David Baxter, Gloria Chambers, Henry Kitchener, and Rosemary McCann Uptake of first two doses of human papillomavirus vaccine by adolescent schoolgirls in Manchester: prospective cohort studyBMJ, May 2008; 336: 1056 - 1058 ; doi:10.1136/bmj.39541.534109. Isabel C. Scarinci, Isabel C. Garces-Palacio, Edward E. Partridge. An Examination of Acceptability of HPV Vaccination among African American Women and Latina Immigrants Journal of Women's Health. October 1, 2007, 16(8): 1224-1233. doi:10.1089/jwh.2006.0175. Competing interests: None declared |
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Giuseppe Montagano, MD, Hygienist, Department of Public Health of the Region Basilicata Department of Health, Safety and Social Solidarity. Via V. Verrastro, 8 - 85100 Potenza, Italy, Gabriella Cauzzillo, MD
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As estimated in the feasibility
study by Brabin et[1], an uptake of 68.5% for the second dose
of a Human Papillomavirus (HPV) vaccine is definitively a relevant projection
in a public health perspective. The goal of any public healthcare system consists
of a complex combination of objectives, not all of which are always clearly and
unequivocally assessable[2,3]. Indeed, governmental
procedures suggest that priority setting in the allocation of funds by the
Italian National Health Service through largely formal and structured processes
must be consistent with specific Regional healthcare requirements which are
autonomously measured and prioritized. In
randomized controlled trials, preventive vaccination against HPV demonstrated
to be a remarkably powerful tool to avert HPV-induced outcomes such as abnormal
pap smears, colposcopies, low and high-grade precancerous cervical lesions, cancer
in situ, invasive cervical cancers, vulvar dysplastic lesions, vaginal
dysplastic lesions, and genital warts[4-6]. However, as also
reported in the guidance for the introduction of HPV vaccines in EU countries
by the European Centre for Disease Prevention and Control, the penetration of
the vaccine within the target population and the proportion of the target
population that received all three doses are important parameters to predict and
assess the impact of HPV vaccination[7]. In September 2007 the Region of Basilicata,
located in southern The
implementation of a multi-cohort vaccination strategy in our Region should
provide clinical and economic results 8-10 years earlier than would be expected
with a single cohort vaccination strategy. This can be deemed as good evidence
of an optimal allocation of economic resources in public health. Table
I - Parameters of anti-HPV vaccination coverage rate in the Basilicata Region
*LHA = Local Health Authority References 1. Brabin L, Roberts SA, Stretch R,
Baxter D, Chambers G, Kitchener H, and McCann R. Uptake of first two doses of human papillomavirus vaccine by adolescent
schoolgirls in 2. Holm S. Goodbye to the simple
solutions: the second phase of priority setting in health care. BMJ 1998; 317: 1000-1007 3. Sassi F. Setting priorities for the
evaluation of health interventions: when theory does not meet practice. Health
Policy 2003; 63: 141-154 4. The FUTURE I Study Group.
Quadrivalent Vaccine against Human Papillomavirus to Prevent Anogenital
Diseases The 5. The FUTURE II Study Group. Effect of
prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of
cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in
situ: a combined analysis of four randomised clinical trials. The Lancet 2007;
Vol. 369: 1861-1868 6. Paavonen J,
Jenkins D,
Bosch FX,
et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle
vaccine against infection with human papillomavirus types 16 and 7.
Guidance for the introduction of HPV vaccines in EU countries. Guidance
Report | 8. Mennini FS, Francia L, Gitto L. CEIS
Health Report 2007. Available at: http://www.ceistorvergata.it/ricerca/areericerca/Publications/publications_health.htm
Accessed September 2008 9. Fleurence RL, and Torgerson DJ.
Setting Priorities for Research. Health Policy 2004; 69: 1-10 Competing interests: None declared |
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Loretta Brabin, Reader in Women's Health University of Manchester, Stephen A Roberts, Rebecca Stretch, David Baxter, Gloria Chambers, Henry Kitchener, Rosemary McCann
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In September 2007 two primary care trusts in Greater Manchester offered the bivalent vaccine Cervarix® (GlaxoSmithKline, Rixensart, Belgium) to schoolgirls as part of an acceptability and feasibility study ahead of the UK’s national HPV immunisation programme.[1] In April 2008, halfway through the study, we reported in the BMJ that vaccine uptake for the first and second doses was 71% and 70% respectively. Here we report on uptake of the third dose which we planned to give at least three months after Dose 2, with all three doses administered within the same academic year between 161 days (5.3 months) and 216 days (7.1 months). This was the accepted interval on which efficacy was established in the HPV008 clinical trial of Cervarix (personal communication, GlaxoSmithKline), but differs from the Department of Health’s recommendation of a minimum interval of six months between dose 1 and 3. [2] At the third round 67.8% (1913) of girls were immunised and only 4.2% (85) of girls who had received Dose 1 failed to complete the three dose vaccine course within the school year. Of these, 48 girls were scheduled for follow-up in the following academic year (autumn 2008) and 38 were immunised, bringing the completion rate to 69.1%, a loss of only 2%. This contrasts with the New South Wales HPV vaccination programme in Australia in which coverage dropped from 83% to 74% at dose 3.[3] Most girls (89.7%) received all three doses between 5.3 and 7.1 months (Figure 1) although 7.8% (149), mainly girls who were late consenters, completed the course in less than 5.3 months. Over half (57.3%) were vaccinated at just under six months. Had we been following Department of Health recommendations, we would have deferred their Dose 3 to the following academic year, which may well have increased loss to follow-up. Inappropriately timed vaccinations may affect the level or duration of the immune response and a longer interval between the second and third doses is generally preferred,[4,5] although young adolescents exhibit an enhanced immune response compared to adults that may compensate for mistimed doses.[6] High coverage is the primary public health goal for the HPV vaccine programme but is unlikely to be achieved in the school setting without some compromise of the recommended dosing schedule.
REFERENCES 1. Brabin L, Roberts SA, Stretch R, Baxter D, Chambers G, Kitchener H, et al. Uptake of first two doses of human papillomavirus vaccine by adolescent schoolgirls in Manchester: prospective cohort study. BMJ 2008;336:1056-58. 2. Department of Health. The “Green Book” chapter on Human papillomavirus (HPV). London 2008. Available at www.dh.gov.uk/greenbook 3. Brotherton JML, Gold MS, Kemp AS, McIntyre PB, Burgess MA, Campbell-Lloyd S, on behalf of the New South Wales Health HPV Adverse Events Panel. Anaphylaxis following quadrivalent human papillomavirus vaccination. CMAJ 2008;179:525-33 4. Hadler SC, Alcala de Monzon M, Lugo DR, Perez M. Effect of timing of hepatitis B vaccine doses on response to vaccine in Yucpa Indians. Vaccine 1989;7:106-10. 5. Middleman AB, Kozinetz CA, Robertson LM, DuRant RH, Emans SJ. The effect of late doses on the achievement of seroprotection and antibody titer levels with hepatitis B immunization among adolescents. Peds 2001;107:1065-69. 6. Pedersen C, Petaja T, Strauss G, Rumke HC, Poder A, Richardus JH et al. Immunization of early adolescent females with human papillomavirus type 16 and 18 L1 virus-like particle vaccine containing ASO4 adjuvant. J Adolesc Health 2007;40:564-71. Competing interests: Loretta Brabin and Henry Kitchener have received research funds, conference fees and honoraria for speaking at GSK-sponsored meetings. The remaining authors declare they have no conflicting interests. |
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