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After nearly eight years of meticulous collaborative effort, the HPV Serology Laboratory at the Frederick National Laboratory for Cancer Research (FNL) has achieved a major milestone in advancing global human papillomavirus (HPV) research. They and their research network have developed and established International Standards for antibodies to seven types of HPV—HPV6, HPV11, HPV31, HPV33, HPV45, HPV52, and HPV58.
These are the first-ever serology International Standards for these HPV types. Each small glass vial contains precisely measured amounts of antibodies, tested to ensure they consistently perform key activities, such as binding to viral proteins, during lab experiments. HPV researchers use these standards as trusted testing materials in clinical virology and vaccine studies, providing reliable reference points for measuring immune responses.
Laboratories that adopt these standards can directly compare findings across different studies, leading to more reliable conclusions. Their availability also supports the harmonization of HPV serology assays, establishing consistent methods to detect and quantify HPV antibodies in blood samples.
This harmonization is key for optimizing and monitoring public health measures to prevent and control HPV infections. Additionally, these benchmarks are invaluable for tracking the spread of HPV and assessing the impact of various interventions across different populations and regions.
Troy Kemp, Ph.D., scientific manager of FNL’s HPV Serology Laboratory, co-led this complex effort in close collaboration with the National Institute for Biological Standards and Control (NIBSC), which resulted in approval of these seven HPV International Standards by the World Health Organization (WHO) Expert Committee on Biological Standardization.
These standards are now available for distribution via NIBSC, and the resulting manuscript was published in late 2024 in NPJ Vaccines.
“It was great to be able to get these International Standards set up for the community,” said Kemp.
Sizing Up the Problem: Cervical Cancer
HPV is responsible for nearly all cases of cervical cancer, and currently one woman dies every two minutes from the disease globally, said Ligia Pinto, Ph.D., director of the Vaccine, Immunity, and Cancer Directorate at FNL, home to the HPV Serology Laboratory.
This cancer is preventable and curable if detected early enough; however, it remains one of the top five cancers that predominantly affect women worldwide, particularly where access to cervical cancer screening is limited.
HPV vaccines are effective in preventing HPV infections and related cancers, with studies showing significant drops in cervical cancer rates in vaccinated people.
The catch is that there are more than 200 HPV types—12 of which are high-risk for causing cervical cancer, in particular HPV16 and HPV18, and two of which are responsible for HPV-associated soft-tissue lesions. Developing vaccines for so many viral types has been a long journey.
Another key hurdle was the lack of standardization in serology assays among researchers and vaccine developers. The absence of standard measurements for antibody responses, standardized assay conditions, and consistent antibody reference materials, such as International Standards, made it challenging for laboratories to combine and compare their results.
“We need International Standards so the community can use them and report [their] results in the same units,” Pinto said.
That’s easier said than done. Developing antibody International Standards is a time-intensive process that follows a formal protocol and requires extensive collaboration between research institutions, regulatory bodies, and international organizations, as well as financial support and a specialized team—a team like the HPV Serology Laboratory.
How It (Really Got) Started: Gardasil®9
FNL’s HPV Serology Laboratory was established in 2017, with Kemp at the helm, to address a crucial gap in vaccine research. Scientists worldwide needed a standardized way to measure immune responses in HPV vaccine studies, and this laboratory became the hub for harmonizing those efforts.
That need had been building for years. Before 2014, HPV vaccine options were limited to a first-generation Gardasil formula, which targeted four HPV types—HPV6, HPV11, HPV16, and HPV18—and Cervarix, which focused exclusively on HPV16 and HPV18, the most prevalent in cervical cancer. These vaccines were effective, but gaps remained. Cervical cancer still claimed a quarter-million lives annually by 2012.
In 2014, a major breakthrough arrived: Gardasil®9. This next-generation vaccine targeted nine HPV types at once—HPV6, HPV11, HPV16, HPV18, HPV31, HPV33, HPV45, HPV52, and HPV58—boosting the field of HPV prevention and triggering a wave of new research.
As vaccine trials accelerated, researchers needed more precise ways to assess immune responses—leading to a push for standardized antibody tests. Yet at the time, antibody International Standards existed for only HPV16 and HPV18. The other seven HPV types covered by Gardasil®9 lacked reference materials, making it difficult for labs to compare their results.
Recognizing that developing these reference standards would be no small task, the HPV community came together to formulate a plan. Pinto and Kemp teamed up with key figures from industry, government, and academia in 2016 to convene a landmark meeting at NIH to map out a strategy for advancing HPV serology standardization.
Less than a year later, in partnership with the National Cancer Institute and the Bill & Melinda Gates Foundation, the HPV Serology Laboratory was born—a dedicated resource to support HPV vaccine studies worldwide.
Setting Global Standards
The new lab’s first mission was to lead an international push to standardize and harmonize data comparisons between different HPV vaccines and related studies. That involved teaming up with NIBSC to develop antibody International Standards for the seven additional HPV types covered by Gardasil®9.
That mission quickly scaled into a global study involving 11 laboratories.
Blood samples from volunteers provided the foundation for new serology standards against HPV6, HPV11, HPV31, HPV33, HPV45, HPV52, and HPV58. Participating labs assigned measurement units and ran rigorous validation tests to ensure reliability.
Most importantly, each lab assessed the new standards independently and found that they could consistently compare their results with others. That meant the standards were not only valid but ready for use worldwide.
In 2022, the WHO Expert Committee on Biological Standardization officially recognized these International Standards, establishing them as the international benchmark for accurately measuring antibodies to these HPV types.
How It’s Going: Education and New Resources
The HPV Serology Laboratory’s antibody International Standards are now widely used, and the team continues their work to standardize other laboratory materials and protocols for HPV research. They promote these resources through outreach, sharing standard operating procedures, presenting updates, and advising other research groups on best practices —along with monitoring how well various HPV vaccines work in ongoing trials.
They also regularly meet with other HPV research groups to provide guidance on how to access and use the suite of antibody standards most effectively.
International Standards are precious and meant to be used sparingly—as reference calibrators that help labs establish their own day-to-day standards. These working controls are essential for measuring antibody levels in routine HPV serology testing. Using International Standards directly in routine assays leads to rapid depletion, underscoring the need for careful management.
“We want to encourage the community to use these International Standards, but in an appropriate and sustainable way,” said Kemp.
The HPV Serology Laboratory also wrote their NPJ Vaccines publication to be a guide for other laboratories looking to produce international serological standards. “It explains really well the process involved in the production of a WHO standard, step by step, so anyone interested in the field could definitely adopt a similar approach,” said Pinto.
Given that supplies of International Standards need periodic restocking, the HPV Serology Laboratory is looking ahead to their next production project.
“We do have to replenish the HPV18 International Standard,” said Kemp, noting ongoing discussions with other experts about this extensive undertaking.
The HPV Serology Laboratory also continues to monitor the evolving needs of HPV research, said Pinto. The team gathers annually with stakeholders to assess and plan for new developments and to identify and address other key needs.
“We are trying to update our standards and assays in a timely manner to ensure we are ready to conduct immunogenicity studies of new HPV vaccines,” Pinto said.
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Figure 1: Process flow diagram for testing, selection and formulation of donations from naturally infected women to produce the 7 candidate WHO International Standards for HPV antibodies. (Image source: WHO International Standards for antibodies to HPV6 HPV11 HPV31 HPV33 HPV45 HPV52 and HPV58) |
Lisa Simpson is a technical editor in Scientific Publications, Graphics & Media (SPGM). She writes for the Poster newsletter and edits corporate reports, client projects, and scientific manuscripts. SPGM is the creative services department and hub for editing, illustration, graphic design, formatting and multimedia training and support for NCI Frederick and Frederick National Laboratory.