Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Apr 15;39(16):2224-2236.
doi: 10.1016/j.vaccine.2020.11.076. Epub 2021 Mar 18.

Systematic literature review of cross-protective effect of HPV vaccines based on data from randomized clinical trials and real-world evidence

Darron R Brown  1 , Elmar A Joura  2 , Glorian P Yen  3 , Smita Kothari  4 , Alain Luxembourg  5 , Alfred Saah  6 , Anuj Walia  7 , Gonzalo Perez  8 , Hanane Khoury  9 , Danielle Badgley  9 , Margaret Stanley  10
Affiliations

Systematic literature review of cross-protective effect of HPV vaccines based on data from randomized clinical trials and real-world evidence

Darron R Brown et al. Vaccine. .

Abstract

Background: The extent of cross-protection provided by currently licensed bivalent and quadrivalent HPV vaccines versus direct protection against HPV 31-, 33-, 45-, 52-, and 58-related disease is debated. A systematic literature review was conducted to establish the duration and magnitude of cross-protection in interventional and observational studies.

Methods: PubMed and Embase databases were searched to identify randomized controlled trials (RCT) and observational studies published between 2008 and 2019 reporting on efficacy and effectiveness of HPV vaccines in women against non-vaccine types 31, 33, 45, 52, 58, and 6 and 11 (non-bivalent types). Key outcomes of interest were vaccine efficacy against 6- and 12-month persistent infection or genital lesions, and type-specific genital HPV prevalence or incidence. RCT data were analyzed for the according-to-protocol (bivalent vaccine) or negative-for-14-HPV-types (quadrivalent vaccine) efficacy cohorts.

Results: Data from 23 RCTs and 33 observational studies evaluating cross-protection were extracted. RCTs assessed cross-protection in post-hoc analyses of small size subgroups. Among fully vaccinated, baseline HPV-naïve women, the bivalent vaccine showed statistically significant cross-protective efficacy, although with wide confidence intervals, against 6-month and 12-month persistent cervical infections and CIN2+ only consistently for HPV 31 and 45, with the highest effect observed for HPV 31 (range 64.6% [95% CI: 27.6 to 83.9] to 79.1% [97.7% CI: 27.6 to 95.9] for 6-month persistent infection; maximal follow-up 4.7 years). No cross-protection was shown in extended follow-up. The quadrivalent vaccine efficacy reached statistical significance for HPV 31 (46.2% [15.3-66.4]; follow-up: 3.6 years). Similarly, observational studies found consistently significant effectiveness only against HPV 31 and 45 with both vaccines.

Conclusions: RCTs and observational studies show that cross-protection is inconsistent across non-vaccine HPV types and is largely driven by HPV 31 and 45. Furthermore, existing data suggest that it wanes over time; its long-term durability has not been established.

Keywords: Bivalent; Cross-protection; Human papillomavirus; Quadrivalent; Vaccine.

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest D Brown has received honoraria for speaking and royalties from patents, and research grant funding from Merck and Co., Inc. through an investigator initiated studies program award. E Joura has received a grant and advisory board fees from MSD. GP Yen, S Kothari, A Luxembourg, A Saah, A Walia, are employees of Merck & Co., Inc., and may own stocks and/or stock options. H Khoury and D Badgley are employees of Certara Evidence & Access who was paid consultant to Merck & Co., Inc. in connection with the development of this manuscript. M Stanley reports personal fees from MSD Merck, Member HPV Vaccine Global Advisory Board. G Perez declares no conflict of interest.

Publication types

Substances