Our finding that 14% of the quadrivalent vaccine recipients (QVR) lack detectable total and neutralizing HPV18 L1-protein derived virus-like-particle (VLP) antibodies throughout 12 years of follow-up (Gray et al. 2024) is pivotal. To elaborate on the implications of this finding we first note that all the QVR (>99% of) received three vaccine doses as early adolescents according to the standard 0, 2 and 6 months regimen, and developed sustainable antibody responses to the HPV6 and HPV16 L1 antigens included in the quadrivalent vaccine (Artemchuk et al. 2019, Mariz et al. 2021). Secondly, all comparable BVR developed sustainable, total and neutralizing antibody responses to the HPV16 and HPV18 L1 VLPs, one logarithm higher than their QVR counterparts.

Reasons for these differences in the frequency (100% vs. 86%) and quantity (4942 to 4469 GMT vs. 400 to 360 GMT) of the bivalent and quadrivalent vaccine-induced antibody responses to HPV18 (Mariz et al. 2021) are still under debate. The vaccines are composed by VLPs comprising the capsid protein L1 obtained via genetic engineering of two distinct biotechnology systems  (yeast and insect cells), which in turn utilize different protein synthesis machinery. Repetition of antigenic epitopes in the VLPs is the one of the key determinants of their high antigenicity (Amanna and Slifka 2018) enabling reduced dose regimes (Lowy and Schiller 2018). To the best of our knowledge the sequences of HPV18 L1 genes used for the production of the L1 VLPs included in the quadrivalent and bivalent vaccine are identical, but the exposition and availability of the HPV18 L1 epitopes (protein structures to which antibody binds) probably differ when generated by distinct recombinantly engineered systems (Lehtinen and Paavonen 2012).

The two HPV vaccines are formulated with different adjuvants, i.e., compounds used to boost immune responses against a concomitantly given antigen (AS04 in the bivalent vaccine and aluminim salt in the quadrivalent vaccine). Adjuvants have been shown to trigger and coordinate immune responses in sensibly different ways. This could result in a more or less balanced (in respect to different targets), sustained (over time) and potent (in respect to avidity or binding strength) antibody response when stimulated by a cocktail of antigens (multivalent vaccines). Most likely, a combination of all these differences are collectively impacting the final antibody response against HPV infection. However, the difference in the quantity and quality of vaccine-induced antibody responses is probably not only due to different adjuvants. Even if the bivalent-specific AS04 strongly support vaccine-induced T-helper cell responses, crucial for the maturation of antibody avidity, there are no significant differences in the avidity of the HPV18 or HPV16 antibodies induced by the two vaccines (Kann et al. 2021).

Finally, it seems appealing to suggest that long-term protection against HPV is driven by persistence of antibodies and sustained neutralizing ability. Lack of such HPV18 antibody response in a notable proportion of vaccinees is an issue for further investigation even if both vaccines show identical efficacy against immediate cervical cancer precursors over 15 years of follow-up (Lehtinen et al. 2024). Blocking re-infections via functions beyond neutralization, known as antibody-dependent effector functions, also warrant future studies to answer all the remaining questions

References

Amanna IJ, Slifka MK. Mechanisms that determine plasma cell lifespan and the duration of humoral immunity.  Immunol Rev 2010;236:125-38.

Artemchuk H, Eriksson T, Poljak M, et al. Long-term seroresponse to human papillomavirus vaccines. Up to 12 years follow-up in the Finnish Maternity Cohort. J Infect Dis 2019;219:582-9.

Kann H, Faust H, Eriksson T, et al. Sustained cross-reactive antibody responses after human papillomavirus vaccinations. Up to 12 years follow-up in the Finnish Maternity Cohort. J Infect Dis 2021;223:1992-2000.

Lehtinen M, Paavonen J. Shared conformational epitopes and efficacy of prophylactic HPV vaccination. Oncoimmunology 2012;1:995-6.

Lehtinen M,Gray P, Luostarinen T, et al. Head-to-head comparison of bivalent and quadrivalent vaccines for efficacy against cervical intraepithelial neoplasia grade 3+. Frontiers in Cellular and Infection Microbiology.2024; in press

Mariz FC, Gray P, Bender E, et al. Sustainability of bi- and quadrivalent HPV vaccine-induced neutralizing antibodies. Lancet Infect Dis 2021;10:1458-68.

Schiller J, Lowy D. Explanations for the high potency of HPV prophylactic vaccines. Vaccine 2018;36: 4768-73.