Peak neutralizing and cross-neutralizing antibody levels to human papillomavirus types 6/16/18/31/33/45/52/58 induced by bivalent and quadrivalent HPV vaccines

www.nature.com/npjvaccines BRIEF COMMUNICATION OPEN Peak neutralizing and cross-neutralizing antibody levels to human papillomavirus types 6/16/18/31/33/45/52/58 induced by bivalent and quadrivalent HPV vaccines 1234567890():,; Filipe Colaço Mariz1 ✉, Noemi Bender 2, Devasena Anantharaman3, Partha Basu4, Neerja Bhatla5, Madhavan Radhakrisna Pillai3, Priya R. Prabhu3, Rengaswamy Sankaranarayanan6, Tiina Eriksson7, Michael Pawlita 2, Kristina Prager2, Peter Sehr8, Tim Waterboer2, Martin Müller1 and Matti Lehtinen2,7 We performed an independent comparison of neutralizing and cross-neutralizing antibody (ab) levels seven months after initiation of three-dose, six-month vaccination schedules with the bivalent and quadrivalent human papillomavirus (HPV) vaccines in adolescent Finnish and Indian females, respectively. We used a semi-automated Pseudovirion-Based Neutralization Assay and observed significantly higher HPV16/18 peak ab-levels in bivalent as compared to quadrivalent vaccine recipients. Bivalent vaccine induced cross-neutralizing HPV31/33/45/52/58 antibodies significantly more frequently and to higher levels than the quadrivalent vaccine. The correlation of bivalent vaccine-induced HPV45 ab-levels with HPV16/18 ab-levels was stronger than that of corresponding quadrivalent vaccine-induced ab-levels, suggesting a qualitatively different cross-reactive response. Our findings on the comparison of the immunogenicity of two HPV vaccine tested in two different populations indicate that further head-to-head studies are warranted. npj Vaccines (2020)5:14 ; https://doi.org/10.1038/s41541-020-0165-x INTRODUCTION Differences in the breadth of cross-protective vaccine efficacies (VE) of prophylactic bivalent and quadrivalent human papillomavirus (HPV) virus-like particle (VLP) vaccines against infections with high-risk (hr) HPV types and associated neoplasia are well established. These extend to significantly different vaccinespecific overall efficacies against associated high-grade squamous intraepithelial neoplasia irrespective of HPV type.1,2 The considerable overlap, with regard to age, ethnicity and sexual risk-taking behavior of different female target populations in the major clinical phase III trials involving the two vaccines2,3, suggests that the differences in efficacy most likely are vaccine-specific.1–4 Neutralizing antibodies induced upon VLP vaccination have been suggested to be the primary mechanism in mediating protection from HPV infection.5 The impact of HPV crossneutralizing antibodies in promoting cross-protection against non-vaccine types is, however, uncertain. Independent studies, considering early adolescent girls or HIV-positive individuals, have demonstrated that cross-neutralizing antibodies induced by the bivalent vaccine confer wider cross-neutralizing antibody response and wider protection against cervical hrHPV infections and associated intraepithelial lesions than the quadrivalent vaccine.6–8 Also an independent study on vaccine-induced antibody sustainability in adolescent females found that bivalent vaccine-induced total HPV16 and HPV18 L1-VLP binding antibody levels were 5- and 18-fold (respectively) higher than those for the quadrivalent vaccine up to 12 years post vaccination.9 The launching of a nonavalent HPV6/11/16/18/31/33/45/52/58 VLP vaccine to the market raises two pivotal questions for public health decision makers in respect to national vaccination programs: (1) how broad is the cross-neutralization ability of the bivalent vaccine-induced antibodies? (2) How sustainable are the quadri/nonavalent vs. bivalent vaccine-induced neutralizing and cross-neutralizing antibodies? In this report, we particularly address the extent and typespecific pattern of cross-neutralization induced by two different HPV vaccines. Cross-neutralizing antibody titers are always substantially lower than titers against vaccine types. Specifically, we investigated peak (seven months post vaccination) neutralizing antibody titers induced by the bivalent and quadrivalent vaccines to HPV types 6/16/18/31/33/45/52/58 in adolescent Finnish and Indian women, respectively, to reveal the breadth of the cross-neutralizing antibody responses of bivalent versus multivalent vaccines. RESULTS Neutralizing antibody levels and seroprevalence All vaccinated study participants at Month 7 showed neutralizing antibodies to HPV types 16 and 18 (Fig. 1a) shared by both vaccines. Bivalent/Finnish and quadrivalent/Indian vaccine recipients differed in median titers (166,681 (5,373 IU/ml) versus 46,400 (1,495 IU/ml) for HPV16 and 57,369 (1,599 IU/ml) versus 8859 (247 IU/ml) for HPV18) and percentage of sera with titers >180,000 (47% versus 6% for HPV16, and 20% versus 0% for HPV18). Without correction for titers >180,000, geometric mean neutralization titers against HPV16 and HPV18 were, respectively, 2.7- and 6.9-fold higher in the bivalent/Finnish vaccine recipients than in 1 Tumorvirus-Specific Vaccination Strategies, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany. 2Infections and Cancer Epidemiology, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany. 3Rajiv Gandhi Centre for Biotechnology, Poojappura, Thiruvananthapuram 695014 Kerala, India. 4Screening Group, International Agency for Research on Cancer (IARC), 69008 Lyon, France. 5All India Institute of Medical Sciences, 110029 New Delhi, India. 6Research Triangle Institute International India, 6th Floor, Pullman Commercial Tower, Aero City 110037 New Delhi, India. 7Karolinska Institute, 17177 Stockholm, Sweden. 8EMBL-DKFZ Chemical Biology Core Facility, European Molecular Biology Laboratory, 69117 Heidelberg, Germany. ✉email: Published in partnership with the Sealy Center for Vaccine Development F.C. Mariz et al. 2 a b 1234567890():,; Fig. 1 Seropositivity and neutralizing antibody levels induced by the bivalent and quadrivalent vaccines. a Percentage of vaccine recipients with neutralizing antibody titers of >40 to vaccine HPV types ((6)/16/18 and non-vaccine HPV types (6)/31/33/45/52/58). Bars indicate boundaries of 95% confidence interval (CI). Sera of quadrivalent (Gardasil, 6/11/16/18) and bivalent (Cervarix, 16/18) vaccine recipients are shown in blue and orange columns, respectively. b Neutralizing peak (Month 7) antibody levels (Geometric mean titer, GMT) in neutralization-positive samples. The gray dots represent the EC50 values of one serum. Serum concentrations inhibiting 50% of the PsV infection (EC50 values) were calculated from median of triplicates. DISCUSSION We found significantly higher peak (Month 7) neutralizing HPV16 and HPV18 antibody levels in Finnish adolescent females, who received three doses of the bivalent vaccine, than in corresponding Indian quadrivalent vaccine recipients. We also found significantly increased seroprevalence to HPV33, HPV45, HPV52 and HPV58, and higher cross-neutralizing HPV31, HPV45 and HPV52 antibody titers in the bivalent/Finnish vacci (...truncated)