Relationship between Humoral Immune Responses against HPV16, HPV18, HPV31 and HPV45 in 12-15 Year Old Girls Receiving Cervarix® or Gardasil® Vaccine

Abstract

Background: Human papillomavirus (HPV) vaccines confer protection against the oncogenic genotypes HPV16 and HPV18 through the generation of type-specific neutralizing antibodies raised against virus-like particles (VLP) representing these genotypes. The vaccines also confer a degree of cross-protection against HPV31 and HPV45, which are genetically-related to the vaccine types HPV16 and HPV18, respectively, although the mechanism is less certain. There are a number of humoral immune measures that have been examined in relation to the HPV vaccines, including VLP binding, pseudovirus neutralization and the enumeration of memory B cells. While the specificity of responses generated against the vaccine genotypes are fairly well studied, the relationship between these measures in relation to non-vaccine genotypes is less certain.

Methods: We carried out a comparative study of these immune measures against vaccine and non-vaccine genotypes using samples collected from 12-15 year old girls following immunization with three doses of either Cervarix® or Gardasil® HPV vaccine.

Results: The relationship between neutralizing and binding antibody titers and HPV-specific memory B cell levels for the vaccine genotypes, HPV16 and HPV18, were very good. The proportion of responders approached 100% for both vaccines while the magnitude of these responses induced by Cervarix® were generally higher than those following Gardasil® immunization. A similar pattern was found for the non-vaccine genotype HPV31, albeit at a lower magnitude compared to its genetically-related vaccine genotype, HPV16. However, both the enumeration of memory B cells and VLP binding responses against HPV45 were poorly related to its neutralizing antibody responses. Purified IgG derived from memory B cells demonstrated specificities similar to those found in the serum, including the capacity to neutralize HPV pseudoviruses.

Conclusions: These data suggest that pseudovirus neutralization should be used as the preferred humoral immune measure for studying HPV vaccine responses, particularly for non-vaccine genotypes.

Fig 1. Percentage of responders to each humoral immune measure.

Percentage of Cervarix^® (Blue) or Gardasil^® (Red) responders in the (A) neutralization assay, (B) binding assay or (C) B cell ELISpot assay against the indicated vaccine (HPV16, HPV18) and non-vaccine (HPV31, HPV45) genotypes. Error bars, 95% CI. * p<0.05; ** p<0.01; *** p<0.001.

Fig 2. Magnitude of humoral immune responses.

Box (median and IQR) and whisker (10^th - 90^th percentiles) plots of the magnitude of humoral immune responses elicited by Cervarix^® (Blue) and Gardasil^® (Red) vaccinees in the (A) neutralization assay, (B) binding assay or (C) B cell ELISpot assay against the indicated vaccine (HPV16, HPV18) and non-vaccine (HPV31, HPV45) genotypes. * p<0.05; ** p<0.01; *** p<0.001.