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J Infect Dis. Nov 1, 2013; 208(9): 1391–1396.
PMCID: PMC3789574
Efficacy of the HPV-16/18 AS04-Adjuvanted Vaccine Against Low-Risk HPV Types (PATRICIA Randomized Trial): An Unexpected Observation
Anne Szarewski,1 S. Rachel Skinner,2,3 Suzanne M. Garland,4,5,6,7 Barbara Romanowski,8 Tino F. Schwarz,9 Dan Apter,10 Song-Nan Chow,11 Jorma Paavonen,12 M. Rowena Del Rosario-Raymundo,13 Julio C. Teixeira,14 Newton S. De Carvalho,15 Maria Castro-Sanchez,16 Xavier Castellsagué,17 Willy A. J. Poppe,18 Philippe De Sutter,19 Warner Huh,20 Archana Chatterjee,21 Wiebren A. Tjalma,22 Ronald T. Ackerman,23 Mark Martens,24 Kim A. Papp,25 Jose Bajo-Arenas,26 Diane M. Harper,27 Aureli Torné,28 Marie-Pierre David,29 Frank Struyf,29 Matti Lehtinen,30 and Gary Dubin31
1Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, United Kingdom
2Vaccines Trials Group, Telethon Institute for Child Health Research, Perth, Western Australia
3Sydney University Discipline of Paediatrics and Child Health, Childrens Hospital Westmead, Sydney, New South Wales
4Department of Microbiology and Infectious Diseases, The Royal Women's Hospital, Parkville
5Department of Microbiology, The Royal Children's Hospital, Parkville
6Murdoch Childrens Research Institute, Parkville
7Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia
8Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
9Central Laboratory and Vaccination Centre, Stiftung Juliusspital, Academic Teaching Hospital of the University of Wuerzburg, Germany
10Family Federation Finland, Helsinki, Finland
11Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei
12Department of Obstetrics and Gynaecology, University of Helsinki, Finland
13San Pablo Colleges Medical Center, Barangay San Rafael, Maharlika Hi-way, San Pablo City, Laguna, Philippines
14Department of Obstetrics and Gynecology, Faculty of Medical Sciences, University of Campinas
15Department of Gynecology and Obstetrics, Federal University of Paraná, Infectious Diseases in Gynecology and Obstetrics Sector, Curitiba, Parana, Brazil
16Department of Obstetrics and Gynecology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid
17Institut Català d'Oncologia, L'Hospitalet de Llobregat, (IDIBELL), Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, (CIBER ESP), Catalonia, Spain
18Department of Gynaecology, University Hospital KU Leuven Gasthuisberg
19Department of Gynaecology, University Hospital Brussels, Belgium
20Division of Gynecologic Oncology, University of Alabama at Birmingham
21Pediatric Infectious Disease, Creighton University, Omaha, Nebraska
22Department of Gynecology and Gynecologic Oncology, Antwerp University Hospital, University of Antwerpen, Belgium
23Comprehensive Clinical Trials, West Palm Beach, Florida
24Jersey Shore University Medical Center, Neptune, New Jersey
25Probity Medical Research, Waterloo, Ontario, Canada
26Obstetrics and Gynecology Department, Santa Cristina University Hospital, Madrid, Spain
27Dartmouth Medical School, Hanover, New Hampshire
28Institut Clinic of Gynaecology, Obstetrics and Neonatology, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pii Sunyer (IDIBAPS), Faculty of Medicine, University of Barcelona, Spain
29GlaxoSmithKline Vaccines, Wavre, Belgium
30University of Tampere, Tampere, Finland;
31GlaxoSmithKline Vaccines, King of Prussia, Pennsylvania
Deceased.
Correspondence: Rachel Skinner, MBBS, PhD, FRACP, Discipline of Paediatrics and Child Health, University of Sydney, Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 205, Australia (rachel.skinner/at/health.nsw.gov.au).
Received February 14, 2013; Accepted April 12, 2013.
Background. Public Health England has reported a decrease of up to 20.8% in new diagnoses of external genital warts (GWs) among women aged <19 years since the national vaccination program with the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine began in 2008. A post hoc analysis of the phase III PATRICIA (PApilloma TRIal against Cancer In young Adults) trial (NCT00122681) was performed to ascertain whether protection against low-risk HPV types was apparent.
Methods. Vaccine efficacy (VE) at 48 months was assessed against 6-month persistent infection (6MPI) with low-risk HPV types in the total vaccinated cohort (TVC) and in the TVC naive (for 25 HPV types tested) populations.
Results. In the TVC naive cohort, VE against 6MPI (95% confidence interval) was 34.5% (11.3 to 51.8) for HPV-6/11, 34.9% (9.1 to 53.7) for HPV-6, 30.3% (−45.0 to 67.5) for HPV-11, and 49.5% (21.0 to 68.3) for HPV-74.
Conclusions. The HPV-16/18 AS04-adjuvanted vaccine appears to have moderate efficacy against persistent infections with a number of low-risk HPV types (HPV-6/11/74), which are responsible for the majority of external GWs, and recently, antibody and cell-mediated immune response to HPV-6/11 have been observed. These findings may help to explain the decrease in external GW diagnoses seen in England.
Keywords: human papillomavirus, HPV, HPV vaccine, genital warts
(See the major article by Howell-Jones et al on pages 1397–403.)
The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix®; GlaxoSmithKline Vaccines) has been demonstrated to have high efficacy against infection and both low- and high-grade cervical intraepithelial neoplasia (CIN; caused by oncogenic HPV types 16 and 18, with substantial cross protection against other high-risk HPV types 31, 33, 45, and 51 [1, 2]. Low-risk HPV types are found in approximately 12% of low-grade CIN, although there is likely to be coinfection with high-risk types [3]. While immunogenicity has been demonstrated in boys [4], the HPV-16/18 AS04-adjuvanted vaccine is not currently licensed for use in boys.
Genital warts (GWs) are the most common viral sexually transmitted infection in the Western world, and a 30% increase in new diagnoses was seen in the United Kingdom between 2000 and 2009 [5]. Treatment has a significant morbidity and can be frustrating, and recurrences are common. This causes psychosocial distress to patients and results in substantial financial costs [6, 7]. GWs result from persistent infection with low-risk HPV genotypes, predominantly 6 and 11, although other low-risk types were not evaluated in the former study [8, 9]. It has been suggested that a small proportion of GWs may be caused by HPV types 16 and 18; [10, 11] if true, limited efficacy against warts could occur with a vaccine directed against these types [10, 11].
The HPV-16/18 AS04-adjuvanted vaccine was chosen for the UK national vaccination program, which commenced in September 2008 and has achieved >84% uptake in 12- to 15-year-old girls for all 3 doses. A catch-up program to the age of 18 years achieved between 50% and 70% uptake for all 3 doses [12].
Public Health England (formerly the Health Protection Agency), which monitors rates of sexually transmitted infections in England, has reported a decrease in new diagnoses of GWs in genitourinary medicine clinics among young women since 2008 [13]. By 2011, the overall reduction was 13.3% among 16- to 19-year-olds, with the greatest decline (20.8%) in 17-year-olds, for whom HPV-16/18 AS04-adjuvanted vaccine coverage in 2011 was estimated at 64%. By contrast, rates in the older age groups were generally either static or increasing [14]. Among the potential reasons for this decrease, as discussed by Howell-Jones et al [14], is the possibility of an effect of the HPV-16/18 ASO4-adjuvanted vaccine on low-risk HPV types. A post hoc analysis of the PATRICIA (PApilloma TRIal against Cancer In young Adults) trial was therefore performed to ascertain whether any protection against low-risk HPV types was apparent.
PATRICIA (HPV-008 PATRICIA, NCT00122681) is a phase III, multicenter, randomized, double-blind trial of the HPV-16/18 AS04-adjuvanted vaccine vs a hepatitis A vaccine as control (1:1 randomization). The study design and methodology have been fully described elsewhere [1, 15]. It should be noted that neither a history of GWs nor current GWs were exclusion criteria and that no systematic collection of GW data was done. Written informed consent/assent was obtained from all participants and/or their parents, and the study was approved by independent ethics committees or institutional review boards.
The primary objective of the trial was to assess the efficacy of the HPV-16/18 AS04-adjuvanted vaccine against CIN2+ associated with HPV-16 or HPV-18 in women who were seronegative at baseline and DNA negative at baseline and month 6 for the corresponding type [15]. The objectives of this post hoc analysis, with the end-of-study data at month 48, were to assess vaccine efficacy (VE) against 6-month persistent infection (6MPI) with HPV types 6, 11 and other low-risk (non-oncogenic) HPV types in the total vaccinated cohort (TVC) and in the TVC naive population (see below).
Cervical samples were obtained from all women every 6 months for HPV DNA typing. A broad-spectrum polymerase chain reaction (PCR) SPF10 HPV LiPA25 version 1 and SPF10 HPV DEIA (Labo Biomedical Products, Rijswijk, Netherlands; based on licensed INNOGENETICS SPF10 technology) were used to test the cervical and biopsy samples for the presence of DNA from 14 oncogenic HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) and 11 non-oncogenic HPV types (6, 11, 34, 40, 42, 43, 44, 53, 54, 70, and 74) [16]. Because the PCR assay used in this study generated data for 11 low-risk types in addition to 14 high-risk types, we were able to perform these post hoc analyses.
Gynecological and cytological examinations were carried out every 12 months, and women were referred for colposcopy and appropriate treatment, as per the protocol-specified clinical management algorithm. Clinical data on the presence of GWs/condylomata acuminata were not systematically collected.
The TVC included all women (n = 18 644) who received at least 1 dose and included women regardless of their baseline cytological, serological, or HPV DNA status. Case counting began the day after the first dose.
The TVC naive (for all 25 HPV types tested) is a subset of this group (n = 11 286), comprising women who had received at least 1 dose and at baseline had normal cytology and were DNA negative for 14 oncogenic and 11 low-risk HPV types. In addition, they were seronegative at baseline for HPV types 16 and 18. However, their serological status for low-risk HPV types was not ascertained.
Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type (by PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval.
Vaccine efficacy and 95% confidence intervals (CIs) were calculated using a conditional exact method. Event rates were calculated as the number of cases divided by the total follow-up in years and were expressed per 100 woman-years.
The analyses presented here are all post hoc exploratory analyses and should be interpreted with this limitation.
Statistical analyses were performed using Statistical Analysis System (SAS) 9.1 and Proc StatXact-7 on Windows XP.
The trial was carried out between May 2004 and November 2009. In the TVC, mean and median follow-up times were 43.7 months (standard deviation, 11.7) and 47.4 months (range, 0–62; 3.6 and 4.0 years), respectively. There were no significant demographic differences between the HPV vaccine group and the controls; in particular, there was no difference in the reported number of sexual partners in the last year or reported sexually transmitted infections (data not shown).
Since women were not specifically screened, diagnosed, or treated for the presence of GWs, efficacy against clinical disease cannot be evaluated; however, results of vaccine efficacy against 6MPI infection with low-risk HPV types may be presented. In the TVC, no efficacy was seen for 6MPI with either HPV-6 or HPV-11 (Table (Table1).1). However, VE of 23.2% (95% CI, 0.5 to 40.9) was seen for HPV-70. In the TVC naïve (for all 25 HPV types tested) cohort, VE against 6MPI was 34.5% (95% CI, 11.3 to 51.8) for HPV-6/11 combined, 34.9% (95% CI, 9.1 to 53.7) for HPV-6, 49.5% (95% CI, 21.0 to 68.3) for HPV-74, and 26.7% (95% CI, 8.1 to 41.7) for HPV-53. VE against 6MPI with HPV-11 was comparable at 30.3% (Table (Table1),1), but the 95% CIs included 0.
Table 1.
Table 1.
Incidence Rates and Vaccine Efficacy Against 6-Month Persistent Infections With All Low-Risk Human Papillomavirus Types (Total Vaccinated Cohort [TVC] and TVC Naive for All Types)
The finding that the HPV-16/18 AS04-adjuvanted vaccine demonstrates efficacy against 6-month persistent infection with low-risk HPV types is unexpected, as the low-risk types are phylogenetically not closely related to the oncogenic types [17]. However, in the last few years, cell-mediated immune responses to HPV-6 and HPV-11 in women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine have been observed. A study comparing L1-specific T helper cell responses induced by the HPV-6/11/16/18 vaccine and the HPV-16/18 AS04-adjuvanted vaccine showed that the latter induced cross-reactive T-cell responses to HPV-31 and HPV-45, which was to be expected from the efficacy data. In addition, HPV-6 and HPV-11 L1-reactive T cells were induced after administration of the HPV-16/18 AS04-adjuvanted vaccine at frequencies comparable to those in HPV-6/11/16/18 vaccine recipients [18].
A comparative trial showed that both HPV vaccines induced circulating antigen-specific CD4+ T cells to HPV-31 and HPV-45 [19, 20]. At month 24, the proportion of T-cell responders was overall significantly higher in the HPV-16/18 AS04-adjuvanted vaccine group than in the HPV-6/11/16/18 vaccine group for HPV-31 (86.7% vs 43.3%; P = .0009) and for HPV-45 (62.5% vs 37.5%; P = .0793) [20]. A follow-up study 4 to 6 years post vaccination showed that frequencies of L1-specific CD4+/CD154+/interferon-gamma/interleukin-2+ T cells in women vaccinated with the HPV-6/11/16/18 vaccine and the HPV-16/18 AS04-adjuvanted vaccine were similar for HPV types 6 and 11 (HPV-6: 0.045% vs 0.045%; HPV-11: 0.051% vs 0.033%, respectively) [10, 21]. Cross-reactivity at the T helper cell (CD4 receptor) level is a plausible mechanism for the vaccine-induced cross protection observed. The cross-reactivity between vaccine and non-vaccine HPV types may be explained by homology and/or structural similarities, which are conserved due to a cross-linking function within the L1 virus-like particle (VLP) [10].
Antibodies to HPV-6 and HPV-11 can also be measured in women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine [10]. To what extent these antibodies are directed against the monoclonal antibody identified epitope(s) in the conformationally identical FG loop of the HPV-6/11, HPV-16, and HPV-18 L1 protein remains to be defined [22]. Using VLP–enzyme-linked immunosorbent assay, the HPV-6/11 titers induced by the HPV-16/18 AS04-adjuvanted vaccine were significantly lower compared with those induced by the HPV-6/11/16/18 vaccine [10]. To date there is no known immune correlate of protection, and the finding that only minimal concentrations of neutralizing antibodies are sufficient to prevent HPV infection could help to explain the observed vaccine efficacy against nonvaccine low-risk types [23].
In this study, efficacy against 6MPI rather than GWs was assessed; ideally, a clinical trial should be conducted to determine the VE of the HPV-16/18 AS04-adjuvanted vaccine against GWs before definitive conclusions can be drawn. However, if the findings of Howell–Jones et al [14] are borne out in further ecological or clinical studies, the additional protection afforded against GWs could be included in cost–benefit analyses, and may assist governments in deciding which vaccine should receive public funding.
In conclusion, results from this post hoc analysis suggest that in the TVC naive (negative for all 25 HPV types tested) cohort, a population that approximates young women before sexual debut (the target population for public health vaccination programs), the HPV-16/18 AS04-adjuvanted vaccine appears to have moderate efficacy against persistent infections with a number of low-risk HPV types (including HPV-6/11, HPV-74), which together are responsible for the majority of external GWs. However, the clinical significance of these observations remains unclear. Some protection against low-risk HPV types afforded by the HPV-16/18 AS04-adjuvanted vaccine may help to explain the decrease in GWs diagnoses seen in the cohort of adolescent females who were offered the HPV-16/18 AS04-adjuvanted vaccine in England in recent years, contrary to expectation [24].
Notes
Acknowledgments. We thank all study participants and their families. We gratefully acknowledge the work of the central and local study coordinators and staff members of the sites that participated in this study.
A. S., S. R. S., S. M. G., T. F. S., B. R., and F. S. formed the manuscript core writing team. The corresponding author and the core writing team had full access to all the trial data, including existing analyses, and had final responsibility for the decision to submit for publication. All authors reviewed and commented upon a draft of the manuscript and gave final approval to submit for publication.
Contribution to statistical support was provided by M.-P. David (GlaxoSmithKline Vaccines, Wavre, Belgium).
Editing and publication coordinating services were provided by Jenny Andersson, PhD, CROMSOURCE Ltd, UK, on behalf of GlaxoSmithKline Vaccines, Wavre, Belgium.
The HPV PATRICIA Study Group: Collaborators.
Principal investigators/coinvestigators. Australia: I. Denham, S. M. Garland, A. Mindel, S. R. Skinner. Belgium: P. De Sutter, W. A. J. Poppe, W. A. Tjalma. Brazil: N. S. De Carvalho, P. Naud, J. C. Teixeira. Canada: F. Y. Aoki, F. Diaz-Mitoma, M. Dionne, L. Ferguson, M. Miller, K. Papp, B. Ramjattan, B. Romanowski, P. H. Orr, R. Somani Finland: D. Apter, T. Karppa, N. Kudjoi, L. Kyha-Österlund, M. Lehtinen, K. Lönnberg, T. Lunnas, M.-S. Mattilla, J. Paavonen, J. Palmroth, T. Petäjä, M. Vilkki. Germany: T. Gent, T. Grubert, W. D. Höpker, K. Peters, K. Schulze, T. F. Schwarz. Mexico: J. Salmerón. Philippines: C. Crisostomo, J. E. Raymundo, M. R. Del Rosario-Raymundo, M. J. Germar, G. Limson, C. Remollino, G. Villanueva, S. Villanueva, J. D. Zamora. Spain: J. Bajo-Arenas, J. Bayas, M. Campins, X. Castellsagué, M. Castro-Sanchez, C. Centeno, L. Rodríguez de la Pinta, A. Torné, J. A. Vidart. Taiwan: S. N. Chow, M. H. Yu. Thailand: S. Angsuwathana, U. Jaisamrarn. United Kingdom: M. Cruickshank, E. Abdulhakim, H. Kitchener, D. Lewis, A. Szarewski. United States: R. T. Ackerman, M. Caldwell, C. Chambers, A. Chatterjee, L. Demars, L. Downs, P. Fine, S. Gall, J. Hedrick, W. Huh, T. Klein, J. Lalezari, S. Luber, M. Martens, C. Peterson, J. B. Rosen, L. Seidman, M. Sperling, R. Sperling, M. Stager, J. T. Stapleton, K. Swenson, C. Thoming, L. Twiggs, A. Waldbaum, C. M. Wheeler.
Other contributors. GlaxoSmithKline clinical study support: A. Camier, B. Colau, S. Genevrois, P. Marius, N. Martens, T. Ouammou, P. Peeters, M. Rahier, N. Smoes, B. Spiessens, A. Meurée, N. Houard, F. Dessy, S. Poncelet, A. Tonglet , C. Van Hoof (Xpe Pharma), A. S. Vilain, T. Zahaf, D. Descamps.
Laboratory contribution. E. Alt, B. Iskaros, A. Limaye, R. D. Luff, M. McNeeley, C. Provenzano, B. Winkler (Quest Diagnostics Clinical Trials, Teterboro, NJ), A. Molijn, W. Quint, L. Struijk, M. Van de Sandt, L. J. Van Doorn (DDL Diagnostic Laboratory, Voorburg, The Netherlands).
Endpoint Committee. K. P. Klugman, P. Nieminen, N. Kiviat.
Independent Data Monitoring Committee: C. Bergeron, E. Eisenstein, R. Marks, T. Nolan, S. K. Tay.
CERVARIX is a registered trademark of the GlaxoSmithKline group of companies.
Financial support. This work (NCT00122681) was supported by the GlaxoSmithKline group of companies, which designed the study in collaboration with investigators and coordinated collection, analysis, and interpretation of data. Investigators from the PATRICIA Study Group collected data for the trial and cared for the subjects. The authors had full access to all the trial data and had final responsibility for the decision to submit for publication.
Potential conflicts of interest. G. D., F. S. and M. P. D. are employees of the GlaxoSmithKline group of companies. G. D. and F. S. own stock in GlaxoSmithKline Biologicals SA, and G. D. has received royalties from Wyeth Vaccines. All investigators at study clinical sites were funded through their institutions to do the study protocol. A. C., A. S., J. C. T., M. L., P. D. S. and S. R. S. have received, via own institution, grants/funding and/or have grants pending from GlaxoSmithKline Biologicals SA; J. P. has received research grant from GlaxoSmithKline Biologicals SA and Merck Sharp & Dohme through the Helsinki University Hospital Research Institute to conduct clinical trials on HPV vaccination; M. M. has received grant support by University of Oklahoma via his institution; A. C. has received, via own institution, grants/funding and have grants pending from Merck Sharp & Dohme; S. M. G., W. H. and X. C. have received, via own institution, grants/funding and have grants pending from GlaxoSmithKline Biologicals SA, Merck Sharp & Dohme, and X. C from Sanofi Pasteur MSD; D. A. has received grants through his institution by VL-Medi, Väestöliitto; S. M. G. and S. R. S. have received grant support/have grants pending from CSL Ltd. S. M. G. has held shares in CSL Ltd; B. R. has received grant support/ has grants pending via her institution by University of Alberta; K. P. has received grant support; N. S. D. C. has received grant support/grants pending from IPC via his institution; N. S. D. C. has received consulting fees and honorarium and support for travel to meetings for the study or other purposes and payment for board membership and for lectures including service on speakers bureaus; W. A. J. P. has received money via his institution for board membership, consulting fee or honorarium, expert testimony, payment for lectures including service on speakers bureaus, support for travel and fees for participation in review activities; A. S., M. C. S., S. M. G. and T. F. S. have received consultancy fee from GlaxoSmithKline Biologicals SA; B. R. has received money for consultancy and expert testimony and payment for lectures including services on speakers bureaus and travel support via her institution by B Romanowski Professional Corporation; M. R. D. R. R. has received consulting fee or honorarium from GlaxoSmithKline Biologicals SA; M. C. S. has received fees for expert testimony from GlaxoSmithKline Biologicals SA; X. C. has received consultancy fees from GlaxoSmithKline Biologicals SA, Sanofi Pasteur MSD; W. H. has received consultancy fee from Roche Diagnostics, Becton Dickinson; W. H. have received consulting fee or honorarium from GlaxoSmithKline Biologicals SA and Merck Sharp & Dohme; A. C. has received payment for board membership from Cerexa; J. C. T., P. D. S., S. R. S. and T. F. S. have received payment for board membership from GlaxoSmithKline Biologicals SA; W. A. T. and X. C. have received payment for board membership from GlaxoSmithKline Biologicals SA, Merck Sharp & Dohme, Sanofi Pasteur MSD; S. M. G. has received payment for board membership from GlaxoSmithKline Biologicals SA, Merck Sharp & Dohme and CSL Ltd; A. S., J. C. T., M. C. S., M. R. D. R. R. and T. F. S. have received payment for lectures including service on speakers bureau from GlaxoSmithKline Biologicals SA; P. D. S and X. C. have received payment for lectures including service on speakers bureau from GlaxoSmithKline Biologicals SA, Sanofi Pasteur MSD; A. C. and S. M. G. have received payment for lectures including service on speakers bureau from GlaxoSmithKline Biologicals SA and Merck Sharp & Dohme; S. M. G. has received payment for lectures including service on speakers bureau from CSL Ltd; A. S., M. C. S., S. M. G. and T. F. S. have received payment for the development of educational presentations from GlaxoSmithKline Biologicals SA; W. H. has received fees for surgical courses from Intuitive Surgical; A. C., A. S., J. C. T., M. R. D. R. R. and S. R. S. have received travel reimbursements from GlaxoSmithKline Biologicals SA; W. A. T. and S. M.G. have received travel reimbursements from GlaxoSmithKline Biologicals SA, Merck Sharp & Dohme and W. A. T. from Sanofi Pasteur MSD; S. M. G. has received travel reimbursements from CSL Ltd; X. C. has received travel reimbursements from GlaxoSmithKline Biologicals SA and Sanofi Pasteur MSD; D. A. has received travel support from VL-Medi; R. T. A. has received support for travel from Comprehensive Clinical Trials, LLC; A. T., J. B. A., D. H. and S. N. C. declare that they have no conflicts of interest.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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