Immunogenicity of bivalent and quadrivalent human papillomavirus (HPV) vaccines are correlated to their cross-protective efficacy, with significant differences in induced antibody concentrations 2 to 12 years after vaccination, according to study findings published in The Lancet Infectious Diseases.

Induced upon vaccination, neutralizing antibodies have been thought to be the main mechanism of protection against HPV infection; therefore, studies have measured vaccine-induced neutralizing antibodies for their use as a surrogate for vaccine efficacy. Ongoing studies are measuring the sustainability of vaccine-induced total antibodies and neutralizing antibodies.

A team of investigators conducted a follow-up analysis of data from 2 international, randomized, double-blind, phase 3 clinical trials of HPV vaccines (PATRICIA, Identifier: NCT00122681; and FUTURE II, Identifier: NCT00092534) to characterize the sustainability of antibody and cross-neutralizing antibody concentrations in trial participants who were administered 3 doses of the bivalent or quadrivalent HPV vaccine and donated blood samples up to 12 years after vaccination to the Finnish Maternity Cohort.

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The researchers also evaluated the relation between neutralizing antibody or cross-neutralizing antibody responses and vaccine efficacy against transient and persistent HPV infections. They assessed HPV type-specific seroprevalence of neutralizing concentrations to HPV6, 16, and 18, and cross-neutralizing responses to nonvaccine HPV types 31, 33, 45, 52, and 58.

In a subcohort analysis stratified by number of pregnancies, serum samples logged in the Finish Maternity Cohort were used to assess the effects of the number of pregnancies on the production of vaccine-induced neutralizing antibodies before the Finnish median age of pregnancy (age 29.5 years).

Of the serum samples included in the analysis, 568 were from the bivalent cohort and 577 were from the quadrivalent cohort.

Compared with bivalent vaccine recipients, quadrivalent vaccine recipients generally had lower cross-neutralizing antibody seroprevalence to nonvaccine HPV types 31, 33, 45, 52, and 58. Of the 681 first-pregnancy samples collected in the combined bivalent and quadrivalent cohorts, neutralizing antibodies to HPV6, 16, and 18 were found up to 12 years postvaccination. However, 15% of the 339 first-pregnancy samples from the quadrivalent arm did not have detectable HPV18 neutralizing antibodies, while all 342 first-pregnancy samples in the bivalent arm did.

The geometric mean titers (GMT) for HPV16 were reduced by nearly half from years 2 to 4 to years 5 to 7 (GMTs, 6642 and 3679, respectively) in seropositive quadrivalent vaccine recipients. In contrast, GMTs of neutralizing antibodies to HPV16 and 18 were 5.7 times and 12.4 times greater, respectively, in seropositive bivalent vaccine recipients from years 5 to 12 compared with quadrivalent vaccine recipients.

Although cross-neutralizing antibodies to HPV31, 33, 45, 52, and 58 were more prevalent among recipients of the bivalent vaccine, these antibodies were sustainable in both groups up to 12 years following vaccination with similar GMTs in both groups. 

There was a significant correlation between seroprevalence of HPV16, 31, 33, 52, and 58 and vaccine efficacy against persistent HPV infections in the bivalent vaccine group (2-tailed Spearman nonparametric correlation coefficient [rs], 0.90; P =.037) that was not observed in the quadrivalent vaccine group (rs, 0.62; P =0.27).

“The significant correlation between type-specific vaccine efficacy and the neutralising antibodies induced by the bivalent vaccine to clade A9-HPV types suggests that neutralising and cross-neutralising antibody concentrations probably have a protective threshold, which is different from the technical positivity cutoff level of our neutralizing antibody test…Protective antibody concentrations, however, still need to be defined,” the authors noted.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Mariz FC, Gray P, Bender N, et al. Sustainability of neutralising antibodies induced by bivalent or quadrivalent HPV vaccines and correlation with efficacy: a combined follow-up analysis of data from two randomised, double-blind, multicentre, phase 3 trials. Lancet Infect Dis. Published online May 28, 2021. doi:10.1016/S1473-3099(20)30873-2