Duration of Cellular and Humoral Responses after Quadrivalent Human Papillomavirus Vaccination in Healthy Female Adults with or without Prior Type 16 and/or 18 Exposure

Human papillomavirus virus (HPV) vaccines aim to provide durable protection and are ideal to study the association of cellular with humoral responses. We assessed the duration and characteristics of immune responses provided by the quadrivalent HPV (4vHPV) vaccine in healthy female adults with or without prior exposure with type 16 and 18 HPV. In a prospective cohort, vaccine naïve females received three doses of 4vHPV vaccine and were followed for two years to assess cellular (intracellular cytokine staining, proliferation and B cell ELISpot assays) and humoral (multiplex L1/L2 viral-like particles (VLP) and M4 ELISAs) responses. Frequencies of vaccine-specific CD4+ T cells correlated with antibody responses. Higher HPV antibody titers were found at all time points in participants previously exposed to HPV, except for anti-HPV-18 at Day 187 (one week post the third vaccination). Retrospective cohorts enrolled females who had previously received two or three 4vHPV doses and tested antibody titers by M4 ELISA and pseudovirion neutralization assay along with memory B cells (MBCs). Almost all women enrolled in a retrospective cohort with two prior doses and all women enrolled in a retrospective cohort with three prior doses had sustained antibody and memory responses. Our findings indicate that HPV vaccination induces a long-lasting, robust cellular and humoral immune responses.

[1]CI is estimated using a two-sided Normal Approximation Method.
[2]Based on a regression analysis with baseline in the model using a 0.05% significance level testing that the slope equals one. [3]A responder was defined as subjects whose value is greater than baseline value and with >180 HPV-16+ or >296 HPV-18+ CD4 T cells per million of total CD4 T cells.
[5]HPV-16 test in one of the samples was not qualified for data analysis. Based on a regression analysis with baseline in the model using a 0.05% significance level testing that the slope equals one. [3] A responder was defined as seropositive by the laboratory. The denominator for percentages is based on the total number of subjects (n) with a result at the visit being summarized.
[4] CI is estimated using a two-sided Exact (Clopper-Pearson) Method. Based on a regression analysis with baseline in the model using a 0.05% significance level testing that the slope equals one. [3] A responder was defined as having a result two times above the baseline value. The denominator for percentages is based on the total number of subjects (n) with a result at the visit being summarized. [4] CI is estimated using a two-sided Exact (Clopper-Pearson) Method. Note: N=subjects with samples can be tested. [1] 95% CI was calculated using a two-sided test using Normal Approximation Method.
[2] P-value is based on a two-sample t-test using a 2-sided 0.05% significance level. [2] P-value is based on a two-sample t-test using a 2-sided 0.05% significance level. [3] A responder was defined as seropositive by the laboratory. The denominator for percentages is based on the total number of subjects (n) with a result at the visit being summarized. [4] CI is estimated using a two-sided Exact (Clopper-Pearson) Method.
[5] P-value is based on a two-sample Chi-square test using a 2-sided 0.05% significance level.
[6] Difference is the relative difference. A value of one means the response after two doses is the same as the response after three doses.
[7] Difference is the absolute difference. [1] CI is estimated using a two-sided Normal Approximation Method.
[2] Based on a regression analysis with baseline in the model using a 0.05% significance level testing that the slope equals one.
[3] A responder was defined as a subject whose value was greater than the baseline value and greater than the following threshold values: HPV-16: 455; HPV-18: 450.
The denominator for percentages is based on the total number of subjects (n) with a result at the visit being summarized.