Impact of vaccinations and infectious diseases on the risk of melanoma—evaluation of an EORTC case–control study B. Krone a , K.F. Ko¨ lmel b, *, J.M. Grange c , G. Mastrangelo d , B.M. Henz e , I.N. Botev f , M. Niin g , C. Seebacher h , D. Lambert i , R. Shaﬁr k , E.-M. Kokoschka l , U.R. Kleeberg m , O. Gefeller n , A. Pfahlberg n a Department of Virology, University of Go ¨ttingen, Germany b Department of Dermatology, University of Go ¨ttingen, Von-Siebold-Str. 3, D-37075 Go ¨ttingen, Germany c Centre for Infectious Diseases and International Health, University College London, London, UK d Department of Occupational Health, University of Padova, Italy e Department of Dermatology and Allergy, Humboldt University, Charite ´, Berlin, Germany f Department of Dermatology and Venerology, Alexander ´s University Hospital, Soﬁa, Bulgaria g Department of Surgical Oncology, Estonian Cancer Center, Tallinn, Estonia h Department of Dermatology, Hospital Friedrichstadt, Dresden, Germany i Department of Dermatology, University Hospital, Dijon, France k Department of Plastic Surgery, Sackler Faculty of Medicine, Tel-Aviv, Israel l Department of Dermatology, University Hospital, Vienna, Austria m Internal Oncology and Laboratory Medicine, Hamburg, Germany n Institute for Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander University, Erlangen-Nuremberg, Germany Received 18 November 2002; received in revised form 13 June 2003; accepted 4 July 2003 Abstract A signiﬁcant correlation between a reduced risk of melanoma and BCG and vaccinia vaccination in early childhood or infectious diseases later in life has already been reported from the FEBrile Infections and Melanoma (FEBIM) multicentre case–control study. This correlation is further evaluated in this study based on 603 incident cases of malignant melanoma and 627 population controls in six European countries and Israel by means of a joint analysis of the inﬂuence of vaccinations and infectious diseases. In addi- tion, the previously unconsidered impact of inﬂuenza vaccinations is evaluated for the whole study population. The strong eﬀects of the frequently given BCG and vaccinia vaccinations in early childhood, as well as of uncommon previous severe infectious diseases, were apparently not cumulative. With the Odds Ratio (OR) being set at 1 in the absence of vaccinations and infectious diseases, the OR dropped to 0.37 (95% Conﬁdence Interval (CI): 0.10–1.42) when subjects had experienced one or more severe infectious dis- eases, associated with a fever of > 38.5  C, and had not been vaccinated with BCG or vaccinia. The OR was 0.29 (CI: 0.15–0.57) in those who had had a severe infectious disease and were vaccinated with either BCG or vaccinia and 0.33 (CI: 0.17–0.65) for those with 1 or more severe infectious diseases and who had received both vaccinations. We conclude that both vaccinations as well as previous episodes of having a severe infectious disease induced the same protective mechanism with regards to the risk of mela- noma. Because of a ‘masking eﬀect’ by the vaccinia vaccination, the protective eﬀect of the BCG vaccination and of certain infec- tious diseases against cancer has remained undetected. The vaccinations contributed more to the protection of the population than a previous episode of having an infectious disease. In view of the termination of vaccinations with vaccinia in all countries and of BCG in many of them, these ﬁndings call for a re-evaluation of vaccination strategies. # 2003 Elsevier Ltd. All rights reserved. Keywords: Anticancer defence; Melanoma; Vaccination; Vaccinia; BCG; Innate immunity; Infection ‘‘Was du ererbt von deinen Va¨tern hast, Erwirb es, um es zu besitzen’’ (J.W. Goethe, Faust I) 1. Introduction There is increasing evidence that various microbial stimuli are necessary for the normal maturation of the immune system [1]. This insight stems mainly from epi- demiological data pointing to an inverse correlation between infectious diseases acquired early in childhood 0959-8049/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0959-8049(03)00625-7 European Journal of Cancer 39 (2003) 2372–2378 www.ejconline.com * Corresponding author. Tel.: +49-551-396081; fax: +49-551- 392047. E-mail address: kkoelmel@med.uni-goettingen.de (K.F. Ko¨ lmel).