Differential long-term bivalent HPV vaccine cross-protection by variants in the Costa Rica HPV vaccine trial

Abstract

The AS04-adjuvanted human papillomavirus (HPV)16/18 vaccine, an L1-based vaccine, provides strong vaccine efficacy (VE) against vaccine-targeted type infections, and partial cross-protection to phylogenetically-related types, which may be affected by variant-level heterogeneity. We compared VE against incident HPV31, 33, 35, and 45 detections between lineages and SNPs in the L1 region among 2846 HPV-vaccinated and 5465 HPV-unvaccinated women through 11-years of follow-up in the Costa Rica HPV Vaccine Trial. VE was lower against HPV31-lineage-B (VE=60.7%;95%CI = 23.4%,82.8%) compared to HPV31-lineage-A (VE=94.3%;95%CI = 83.7%,100.0%) (VE-ratio = 0.64;95%CI = 0.25,0.90). Differential VE was observed at several lineage-associated HPV31-L1-SNPs, including a nonsynonymous substitution at position 6372 on the FG-loop, an important neutralization domain. For HPV35, the only SNP-level difference was at position 5939 on the DE-loop, with significant VE against nucleotide-G (VE=65.0%;95%CI = 28.0,87.8) but not for more the common nucleotide-A (VE=7.4%;95%CI = -34.1,36.7). Because of the known heterogeneity in precancer/cancer risk across cross-protected HPV genotype variants by race and region, our results of differential variant-level AS04-adjuvanted HPV16/18 vaccine efficacy has global health implications.

Fig. 1. Flow diagram of included study participants in the analytical cohort.

This figure describes the flow of study participants included in the analysis from both the randomized trial phase of the Costa Rica HPV Vaccine Trial and the observational long-term follow-up phase through 11 years of follow up. The final analytical sample for the HPV vaccinated group and HPV-unvaccinated group for the full 11-year period is shown in the bottom most boxes.

Fig. 2. HPV vaccine efficacy against HPV31 variants through 11 years post-vaccination.

This figure shows the HPV vaccine efficacy, indicated by the “X” symbol, against incident HPV31 detections overall and by lineage and SNP, and the corresponding 95% CIs. The bolded estimates indicate statistical significance. For each SNP, both nucleotides are shown. The analytical cohort includes all women who received all three doses of either Cervarix or Havrix, and all women in the unvaccinated control group who had at least one HPV DNA test result after two years post-enrollment and who did not have an outcome of interest during the initial two-year period. CI confidence interval, HPV human papillomavirus, SNP single nucleotide polymorphism.

Fig. 3. HPV vaccine efficacy ratio comparing efficacy between HPV31 lineages and L1 SNPs through 11 years post-vaccination in the Costa Rica HPV Vaccine Trial.

This figure shows the HPV vaccine efficacy ratios, indicated by the circle symbols, against incident HPV31 detections by lineage and SNP, and the corresponding 95% CIs. The bolded estimates indicate statistical significance. For each SNP, both nucleotides are shown. The closed circles represent the vaccine efficacy ratio comparing vaccine efficacy against a specific variant compared to the vaccine efficacy against the reference group (open circles). The analytical cohort includes all women who received all three doses of either Cervarix or Havrix, and all women in the unvaccinated control group, who had at least one HPV DNA test result after two years post-enrollment and who did not have an outcome of interest during the initial two-year period. CI confidence interval, HPV human papillomavirus; SNP single nucleotide polymorphism.

Fig. 4. Enlarged view of superimposed homology models of HPV31 L1 illustrating the amino acid change at position 274.

This figure shows the superimposed homology models of HPV31 L1, which has an amino acid change at position 274 from Thr (threonine) to Asn (asparagine), and presents the vaccine efficacy estimates for each amino acid with the vaccine efficacy ratio between the two. The tan color on the figure represents threonine, while the blue color represents asparagine. CI confidence interval, HPV human papillomavirus.

Fig. 5. HPV vaccine efficacy against HPV33, 35, and 45 variants through 11 years post-vaccination in the Costa Rica HPV Vaccine Trial.

This figure shows the HPV vaccine efficacy, indicated by the “X” symbol, against incident HPV33, 35, and 45 detections overall and by variant, and the corresponding 95% CIs. The bolded estimates indicate statistical significance. The analytical cohort includes all women who received all three doses of either Cervarix or Havrix, and all women in the unvaccinated control group, who had at least one HPV DNA test result after two years post-enrollment and who did not have an outcome of interest during the initial two-year period. CI confidence interval, HPV human papillomavirus; SNP single nucleotide polymorphism.

Fig. 6. HPV vaccine efficacy ratio comparing efficacy between HPV33, 35, and 45 lineages and L1 SNPs through 11 years post-vaccination in the Costa Rica HPV Vaccine Trial.

This figure shows the HPV vaccine efficacy ratios, indicated by the circle symbols, against incident HPV33, 35, and 45 detections by variant, and the corresponding 95% CIs. The bolded estimate indicates statistical significance. The closed circles represent the vaccine efficacy ratio comparing vaccine efficacy against a specific variant compared to the vaccine efficacy against the reference group (open circles). The analytical cohort includes all women who received all three doses of either Cervarix or Havrix, and all women in the unvaccinated control group, who had at least one HPV DNA test result after two years post-enrollment and who did not have an outcome of interest during the initial two-year period. CI confidence interval, HPV Human papillomavirus; SNP single nucleotide polymorphism.