Melanoma is a serious public health problem in many countries throughout the world, with an incidence increasing at a faster rate than that of any other cancer except lung cancer among women.1 In Europe and the United States, the incidence increased threefold between 1970 and 2000, although improved awareness meant that the mortality rate did not rise so steeply. The risk of melanoma varies greatly (around 100-fold) from region to region, with the highest risk being in Australia where, in 2003, the annual risk was 46.9 per 100 000 population, with estimated lifetime risks of one in 28 and one in 19 up to the ages of 75 and 85 years, respectively.2 With the exclusion of non-melanotic skin cancers, melanoma was the fourth most prevalent cancer in Australia, accounting for 10% of all cases, and the age-standardised risk of melanoma increased by 14% between 1993 and 2003.

There are anecdotal reports of regression and even complete resolution of melanoma in patients who had developed serious febrile infections.3 Although these cases are rare and perhaps coincidental, they encouraged us to conduct epidemiological studies on the impact of prior infectious diseases and vaccinations on the risk of melanoma. We therefore established the Febrile Infections and Melanoma (FEBIM) working group in six European countries and Israel, within the Epidemiological Section of the Melanoma Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC).

In an evaluation of our EORTC case–control study, the FEBIM group established that a history of severe but increasingly uncommon infections, with fever above 38.5°C, including sepsis, pneumonia, pulmonary tuberculosis and Staphylococcus aureus infection, was associated with a reduced risk of melanoma.4 Moreover, in patients with histories of severe infections, the extent of risk reduction was directly related to the number of infections. Thus those with histories of one, two to three, and four or more infections had odds ratios of 0.66, 0.63 and 0.32, respectively, and this trend was statistically significant (P = 0.004). It was also established that vaccination early in life against smallpox (with vaccinia vaccine) or tuberculosis (with BCG vaccine), or both, conferred a significant and enduring degree of protection against melanoma. Adjusted odds ratios were 0.40 (95% CI, 0.18–0.85) for BCG alone, 0.60 (95% CI, 0.36–0.99) for vaccinia alone and 0.41 (95% CI, 0.25–0.67) for both vaccines. Not only did these vaccinations afford protection against melanoma, it was subsequently established in an EORTC cohort study of patients with melanoma, that those who developed melanoma had a significantly better prognosis if they had received one or both vaccinations, or had previously had serious but uncommon infections.5 Although confirmatory studies in different settings are required, the multicentre nature of our studies, the high degree of internal consistency of the observations, and the close parallels between their retrospective and prospective arms enhance confidence in the findings.

A clue as to how certain vaccinations and infections might protect against melanoma came from the finding that a patient recruited for a trial of a melanoma vaccine had an expanded population of CD8+ T cells that recognised an epitope coded for by a human endogenous retrovirus of the HERV-K family.6 These viruses entered the human germ line millions of years ago and, although no longer capable of replication, can still code for gene products. A possible role of their gene products in the development of melanoma has been the subject of recent research.7 The HERV-K-MEL peptide is expressed on the surface of most human melanomas,6 and it was therefore postulated that a major component of the observed protection by certain infections and vaccinations is the generation of populations of CD8+ T cells cross-reacting with this epitope.8 Accordingly, amino acid sequences with homologies to HERV-K-MEL were sought among pathogens and vaccines, and were found in those associated with protection, but not in those that did not confer protection.

A structurally similar sequence was also found in the 17D yellow fever vaccine, suggesting that it might likewise confer protection, and this prediction was confirmed in a recent pilot study of 28 000 adults vaccinated with this vaccine; this pilot study also showed that there was a period of around 10 years between vaccination and observed protection, indicating that the induced immune response is most effective at the time of tumour initiation, which may precede clinical manifestation by several years.9 This protection seems, therefore, to result from prevention of tumour initiation rather than the killing of melanoma cells already present in the body.

So, it is important to emphasise that, in contrast to their likely preventive properties, BCG and vaccinia vaccines are of little or no value in treating established melanomas.4,7 Treatment of melanoma by immune modulation is much more complex than prevention, although several approaches of greatly varying complexity hold out hope for effective immunotherapeutic strategies in the future.10

However, our FEBIM studies indicate that certain currently available and relatively well tolerated vaccines against infectious diseases are able to make a significant impact on the serious and increasing public health problem of melanoma. Although it is unlikely that smallpox vaccination will be re-introduced for this purpose, the increasing global incidence of tuberculosis, including extreme drug-resistant forms, makes an additional case for considering widespread neonatal BCG vaccination. Yellow fever vaccine is another possibility as it is cheap and safe, although its efficacy in preventing melanoma requires confirmation in more extensive studies. The currently available evidence indicates the need for further studies to determine whether modifications of vaccination programs to include strategies to reduce the risk of melanoma would be of benefit, especially in high-risk countries such as Australia.