The World Health Organization has recommended 2-dose HPV vaccine schedule separated by 6 months to girls <15 years old as an alternative to the current 3-dose schedules. However, the long-term protection following reduced-dose schedules is unknown. This study examined long-term immunity by comparing the cellular immune responses in girls previously given 3 doses of 4vHPV (Gardasil®, Merck Inc.) 6-7 years ago with reduced doses (1 or 2 doses).
A prospective cohort study was undertaken in 200 Fijian girls (15-19 years old) who previously received 0, 1, 2 or 3 doses of 4vHPV 6-7 years ago (N=50/group). Blood was taken pre- and 28 days following a single dose of 2vHPV (Cervarix®, GSK), and cellular immune responses in terms of IFNγ producing cells and cytokines production (IFNγ, IL-2, TNFα, IL-10 and IL-5) were measured against HPV16 and 18 using the IFNγ-ELISPOT assay and Multiplex Bead Array assay, respectively.
Six years following the last dose of 4vHPV, girls who received 2 doses of 4vHPV (p=0.008) had significantly lower HPV18-specific IFNγ producing cells compared with girls who received 3 doses. Significantly lower cytokine responses (IFNγ: p=0.002; IL-2: p=0.022; TNFα: p=0.016, IL-10: p=0.018) against HPV18 were also observed in girls who received 2 doses of 4vHPV when compared with girls who received 3 doses. These differences were no longer significant 1 month following a dose of 2vHPV. There was no significant differences in cellular immunity against HPV16 between the 2- and 3-dose groups six years after the last dose of 4vHPV and 1 month after a dose of 2vHPV. Interim analysis for the comparison of cellular responses between 1- and 3-dose groups are ongoing, which showed a similar trend (significant lower responses against HPV18 but not HPV16) as the 2-dose group.
Lower HPV18-specific IFNγ producing cells and cytokines were observed in the 2-dose group when compared with the 3-dose group after 6 years. These data suggest that cellular immunity against HPV18 following reduced-dose schedules may not persist as long as a 3-dose schedule, although the clinical significance is unknown. Despite the lower cellular immune responses, the neutralising antibody responses between the 2- and 3-dose groups were similar as shown previously, although lower antibody responses against HPV18 than HPV16 were observed (Toh et al., Clin. Infect. Dis, 2016). Longer follow-up studies on reduced-dose schedules are needed to determine whether cellular immune responses has a role in the long-term protection against HPV18.
Toh, Z. Q., F. M. Russell, R. Reyburn, J. Fong, E. Tuivaga, T. Ratu, C. D. Nguyen, R. Devi, M. Kama, S. Matanitobua, S. N. Tabrizi, S. M. Garland, R. Sinha, I. Frazer, L. Tikoduadua, J. Kado, E. Rafai, E. K. Mulholland and P. V. Licciardi (2016). "Sustained antibody responses six years following one, two, or three doses of quadrivalent HPV vaccine in adolescent Fijian girls, and subsequent responses to a single dose of bivalent HPV vaccine: a prospective cohort study." Clin Infect Dis.