Comparison of adaptive and innate immune responses induced by licensed vaccines for Human Papillomavirus

Abstract

Two HPV virus-like particle (VLP) vaccines, HPV-16/18 (GlaxoSmithKline, Cervarix®) and HPV-6/11/16/18 (Merck, Gardasil®), are currently licensed in the United States. Given the similar antigenic content but different adjuvant formulations in the 2 vaccines, they provide an efficient method for evaluating adjuvants and comparing the kinetics of the innate and adaptive immune responses. We randomized women to receive either Cervarix® or Gardasil®, followed 6 month vaccination delivery schedules per manufacturer's recommendations, and analyzed the humoral immune response, T cell response, and circulating plasma cytokine levels in response to vaccination. Cervarix® recipients had higher anti-HPV-16 antibody and neutralization titers at month 7, and elevated anti-HPV-18 antibody and neutralization titers at months 7 and 12. Antibody avidity was similar for the 2 vaccines. HPV-31 was the only phylogenetically related non-vaccine HPV type, for which there is evidence of cross-protection, to be cross-neutralized and only in response to Cervarix®. Comparing CD4+ T cell cytokine responses at month 12, there was a trend of increased levels of IL-2 and TNF-α in the Cervarix® groups versus the Gardasil® groups that was consistent across all 4 tested HPV types (16/18/33/45). Elevated levels of circulating plasma cytokine/chemokines were observed post first vaccination in Gardasil® recipients and proinflammatory cytokines were elevated following 1st and 3rd Cervarix® vaccinations. Cervarix® and Gardasil® are both highly immunogenic vaccines. Higher antibody levels and CD4 T cell responses were achieved with Cervarix® after 3 doses, although similar affinity maturation was measured for the 2 vaccines. The clinical implications of the differences in immune responses are unknown.

Trial registration: ClinicalTrials.gov NCT01132859.

Keywords: adaptive immunity; adjuvant; human papillomavirus vaccine; immune signatures; innate immunity.

Figures

Figure 1.

VRC 902 CONSORT Diagram. Subject randomization is shown.

Figure 2.

ELISA antibody levels (IgG) for anti-HPV-16 (A) and anti-HPV-18 (B). *P < 0.05 (Mann-Whitney). Arrows indicate time of first (month 0), second (Cervarix® month 1, Gardasil® month 2), and third (month 6) vaccinations with respect to time points. Data presented as Geometric mean Titer (GMT) (95% CI).

Figure 3.

SeAP antibody titers for HPV-16 (A), -18(B), -31(C), -45(D), and -58(E). *P < 0.05 (Mann-Whitney). Arrows indicate time of first (month 0), second (Cervarix® month 1, Gardasil® month 2), and third (month 6) vaccinations with respect to time points. Data expressed as GMT (95% CI).

Figure 4.

Modified HPV L1 VLP ELISA avidity assay using chaotropic elution for HPV-16 (C) and HPV-18 (D). Arrows indicate time of first (month 0), second (Cervarix® month 1, Gardasil® month 2), and third (month 6) vaccinations with respect to time points. *P < 0.05 (Mann-Whitney). Data expressed as Geometric Mean of Avidity Indices (95% CI).

Figure 5.

CD4+ T cell HPV-specific responses in Cervarix® or Gardasil® recipients post-vaccination in response to stimulation in vitro with HPV-16 (A), HPV-18 (B), HPV-33 (C), or HPV-45 (D) L1 peptides. The horizontal bars represent the mean frequency and the error bars represent the SEM. *P < 0.05 (Mann-Whitney) Note: pre-vaccination levels for all responses (data not shown, Figure S2A) were significantly lower than post-vaccination for all responses (P < 0.001, Wilcoxon signed-rank test).

Figure 6.

Circulating cytokine levels pre and post first and third vaccination. Arrows indicate first and third vaccinations. Note: second vaccination time points are not shown. IL-12p40 (A), IL-8 (B), IP-10 (C) MCP-1 (D), MIP-1 β (E), IL-6 (F), IL-1β (G), IL-1α (H). Data expressed as median values with interquartile range. *P < 0.05, **P < 0.01, ***P < 0.001 (Mann-Whitney).