A delayed dose of quadrivalent human papillomavirus vaccine demonstrates immune memory in HIV-1-infected men

Abstract

Persistent infection of the anus with high-risk types of human papillomavirus (HPV) causes squamous cell carcinoma, one of the most common non-AIDS-defining cancers [1], [2]. HIV-infected individuals are at much higher risk for developing anal cancer than HIV-uninfected individuals [3], [4], [5], [6]. Approximately 70% of anal cancers are due to HPV types 16 or 18 and most genital warts are associated with HPV types 6 and 11 [7], [8]. The quadrivalent HPV (qHPV) vaccine, which induces neutralizing antibodies titers in recipients against HPV types 6, 11, 16, and 18, prevented 93% of persistent anal infections and 78% of anal squamous intraepithelial lesions caused by these types in HIV-uninfected men who have sex with men (MSM) [9]. While the qHPV vaccine series is highly immunogenic in HIV-infected adults and children, antibody titers are lower than those reported in HIV-uninfected populations [10], [11], [12]. In studies of both HIV infected and HIV-uninfected vaccine recipients, the titers developed in response to the standard three-dose qHPV series peak soon after the third dose then decline. HIV-uninfected women [13] and HIV-infected children [14] demonstrated an anamnestic response to a fourth dose of the qHPV vaccine suggesting that the qHPV vaccine induces immune memory. Published studies of HIV-infected adults receiving qHPV vaccine have relatively limited follow-up and the characteristics of the long-term humoral response have not yet been described. It is unclear how much immunity wanes in this population and whether the standard 3 dose series generates immune memory which is necessary for long-term protection against new infections. A delayed fourth vaccination can simulate antigen exposure and a robust increase in antibodies suggestive of an anamnestic response indicative of immune memory [13], [14], [15]. When exposed to specific antigens, long-lived memory immune cells generate an immune response to prevent or stop infection [13]. The AIDS Malignancy Consortium Protocol 052 (AMC052) demonstrated the safety and immunogenicity of the standard three dose qHPV vaccine series in HIV-infected adult males [10]. Here we describe the long-term titers after vaccination in this study population. Since there are no accepted criteria for an anamnestic response, we sought to describe the titers at one and four weeks after a fourth dose, similar to what has been shown in HIV-uninfected women [13]. We hypothesized that titers would be higher four weeks after a fourth dose compared with four weeks after the third dose.