Naturally acquired immunity against human papillomavirus (HPV): why it matters in the HPV vaccine era.

Scientists do not know precisely which elements of the immune system are important in preventing or resolving human papillomavirus (HPV) infections in unvaccinated women. HPV has a battery of immune-evasion mechanisms that include hiding within the host mucosal cells, lowlevel production of late (L) proteins, and inhibition of innate immunity and cellmediated response by early proteins [1]. HPV vaccine trials show that sufficiently high levels of neutralizing antibodies against viral capsid strongly protect women who are negative for vaccine types at baseline against homologous (same-type) HPV infection. The measurement of HPV antibodies is also important for identifying unvaccinated women who have mounted an antibody response following previous exposure to HPV infection and may, therefore, be naturally protected. However, only approximately half of women seroconvert within 18 months after HPV infection [2]. The interpretation of HPV serology is additionally complicated by substantial differences across assays used in different studies (eg, detection ranges, targeted HPV types, and epitopes) [3–5]. Despite these limitations, seroprevalence studies have been essential in understandingHPV exposure [6] and infection trends [7], and have more recently started providing prospective estimates of naturally acquired immunity after HPV infection [4]. In this issue of The Journal of Infectious Diseases, Castellsagué and colleagues [8] report on the association of HPV types 16 and 18 antibody levels and the development of new homologous HPV infections and cervical lesions in >8000 women (15–25 years of age) who comprised the control arm of a multinational randomized trial of the HPV-16/18 vaccine (PATRICIA). Findings are based on a virus-like particle (VLP)–based enzyme-linked immunosorbent assay (ELISA) that measures a broad spectrum of neutralizing and nonneutralizing antibodies directed against the L1 capsid protein. High titers of HPV-16 antibodies, but not of HPV-18 antibodies, were significantly associated with a lower risk of incident and persistent homologous type infection, and also with a lower risk of atypical squamous cells of undetermined significance (ASCUS) and cervical intraepithelial neoplasia (CIN) grades 1–3. Compared with HPV-16– seronegative women, new incident HPV-16 infections were reduced by 36% (95% confidence interval [CI], 22%–47%) in HPV-16–seropositive women (ie, 15% of unvaccinated women). Protection significantly increased with the increase in HPV-16 antibody titer; it was 66% (95% CI, 46%–79%) in the highest HPV-16 antibody quartile [8]. In the control arm of the Costa Rica Vaccine Trial, Safaeian et al [4] used the same VLP ELISA as Castellsagué et al [8] and reported the same seroprevalence (25%) at enrollment for HPV-16 and HPV-18. A significant reduction of new homologous type infections was observed in the highest tertile of HPV-16 and HPV-18 antibodies—protection of 50% and 64%, respectively. Naturally acquired protection in older women was assessed in a populationbased cohort study (median age, 37 years), also from Costa Rica [9], using a different VLP ELISA than the 2 vaccine trials [4, 8]. Seroprevalence at enrollment was 19% and 18% for HPV-16 and HPV18, respectively. A significant protection (46%) from subsequent homologous infection was shown for HPV-16 but not HPV-18. Received and accepted 4 March 2014; electronically published 8 March 2014. Correspondence: Dr Silvia Franceschi, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon cedex 08, France ([email protected]). The Journal of Infectious Diseases 2014;210:507–9 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jiu143