Intended for healthcare professionals

CCBYNC Open access
Research

Effectiveness of quadrivalent human papillomavirus vaccine for the prevention of cervical abnormalities: case-control study nested within a population based screening programme in Australia

BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g1458 (Published 04 March 2014) Cite this as: BMJ 2014;348:g1458

Re: Effectiveness of quadrivalent human papillomavirus vaccine for the prevention of cervical abnormalities: case-control study nested within a population based screening programme in Australia

Dear editors,

The paper by Crowe et al. (1) is among the first reporting the effectiveness of the quadrivalent human papillomavirus (HPV) vaccine for the prevention of cervical abnormalities. The main study results are consistent with efficacy data reported from clinical trials (2) and some previous dataset analyses (3, 4).

When discussing the effectiveness of partial vaccination, the authors mention that “data suggest reasonable effectiveness with fewer doses” and “partially vaccinated women were older than fully vaccinated women and therefore more likely to have been infected with HPV before vaccination”, as well as “we may have underestimated the effectiveness with fewer doses”. Additionally, it is mentioned that “the effectiveness of two doses seemed to increase with assumed latent periods of 180 and 365 days”. However, in the section “What this study adds” it is stated: “Receipt of two vaccine doses provided some, although lesser, protection”. This statement might mislead the readers.

First, the two-dose schedule is of particular interest for the 9-14-year-old group, which is the most frequently targeted for HPV vaccination. In the Crowe et al. study, only 2.6% of the subjects included in the analysis were vaccinated at the age of 11-14 years and only 13 high-grade cases were diagnosed in this group with no statistically significant difference in crude or adjusted odds ratios observed in fully vaccinated or partially vaccinated subjects. It is of note that no case of high-grade lesions was reported among girls vaccinated with two doses at the age of 11-14.

Second, despite relatively important sample size of 15-18, 19-22 and 23-27-year-old groups at the time of vaccination, no statistically significant difference (95% CI overlap) in the risk of high-grade cases was observed after two or three doses of vaccine. Moreover, the adjusted odds ratios for high-grade cases in the overall study population are not statistically significant when comparing results observed after two and three doses of vaccine.

Although these issues are important, our main concern is related to the fact that 1) authors do not mention that the first two doses of vaccine were probably given at a short time interval (i.e. around 2 months; schedule commonly named prime-prime); 2) these results should not be extrapolated in any way to recommended for consideration by WHO and CHMP two-dose schedule for pre-adolescent and adolescent girls (5, 6) (0-6 or 0-12 months; schedule commonly named prime-boost); and 3) available immunogenicity data consistently show that two doses of HPV vaccine are highly immunogenic when administered to young girls at 6 to 12 month-interval(7-9).

In our opinion, the effectiveness data reported by Crowe et al.(1) do not contradict previously reported immunogenicity data showing non-inferiority of two doses when given to girls compared to three doses of HPV vaccines when given to young women, a group for which excellent efficacy data are observed for at least 10 years.

1. Crowe E, Pandeya N, Brotherton JM, Dobson AJ, Kisely S, Lambert SB, et al. Effectiveness of quadrivalent human papillomavirus vaccine for the prevention of cervical abnormalities: case-control study nested within a population based screening programme in Australia. BMJ (Clinical research ed. 2014;348:g1458. PubMed PMID: 24594809. Pubmed Central PMCID: 3942076. Epub 2014/03/07. eng.
2. Munoz N, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez-Avila M, Wheeler CM, et al. Impact of Human Papillomavirus (HPV)-6/11/16/18 Vaccine on All HPV-Associated Genital Diseases in Young Women. Journal of the National Cancer Institute. 2010 Mar 3;102(5):325-39. PubMed PMID: 20139221. eng.
3. Herweijer E, Leval A, Ploner A, Eloranta S, Simard JF, Dillner J, et al. Association of varying number of doses of quadrivalent human papillomavirus vaccine with incidence of condyloma. JAMA. 2014 Feb 12;311(6):597-603. PubMed PMID: 24519299. Epub 2014/02/13. eng.
4. Tabrizi SN, Brotherton JM, Kaldor JM, Skinner SR, Cummins E, Liu B, et al. Fall in human papillomavirus prevalence following a national vaccination program. The Journal of infectious diseases. 2012 Dec 1;206(11):1645-51. PubMed PMID: 23087430. Epub 2012/10/23. eng.
5. Boseley's S. Two shots of HPV vaccine against cervical cancer enough, says WHO [On line] http://www.theguardian.com/society/sarah-boseley-global-health/2014/apr/... (Page accessed April 30, 2014).
6. PR Newswire. Gardasil®: New 2-dose Schedule Granted Positive CHMP Opinion for Europe's Leading HPV Vaccine [On line] http://www.prnewswire.co.uk/news-releases/gardasil-new-2-dose-schedule-g... (Page accessed April 30, 2014).
7. Dobson SRM, McNeil S, Dionne M, Dawar M, Ogilvie G, Krajden M, et al. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA. 2013;309(17):1793-802.
8. Sauvageau C. Two doses of quadrivalent HPV vaccine might be sufficient when vaccinating preadolescents. Oral presentation. International multidisciplinary conference EUROGIN 2013. Florence, Italy, November 3, 2013.
9. Lazcano-Ponce E, Stanley M, Munoz N, Torres L, Cruz-Valdez A, Salmeron J, et al. Overcoming barriers to HPV vaccination: non-inferiority of antibody response to human papillomavirus 16/18 vaccine in adolescents vaccinated with a two-dose vs. a three-dose schedule at 21 months. Vaccine. 2014 Feb 3;32(6):725-32. PubMed PMID: 24355090. Epub 2013/12/21. eng.

Competing interests: No competing interests

02 May 2014
Chantal Sauvageau
Public health physician
Vladimir Gilca
Institut national de santé publique du Québec, Centre de recherche du CHU de Québec
2400, d'Estimauville, Québec, (Canada), G1E 7G9