The studies, reported in Vaccine, suggest that the Monocyte Activation Test (MAT) offers faster, more accurate results on the levels of fever-causing substances in the vaccine – known as pyrogens - than existing methods.
As the Rabbit Pyrogen Test (RPT) is currently the most widely used assay for testing pyrogen levels in biological medicines such as vaccines, these findings represent a significant step towards the 3Rs that aim to ‘Replace, Reduce and Refine’ the use of animals in research.
Old test, new vaccines
Before they can be used in humans, vaccines are tested to ensure they are free from pyrogen contamination that could otherwise result in fever, organ failure, or in extreme cases, death.
Traditionally the RPT has been used to measure pyrogen levels. It involves administering a sample of the vaccine to animals and monitoring any subsequent temperature increase. For vaccines like Bexsero, that naturally contain high levels of pyrogens as an integral part of the product, this testing method has proven difficult. In some cases, safe and effective batches of vaccine have been wrongly rejected.
The MAT acts as an alternative, offering a non-animal test that’s appropriate for inherently pyrogenic vaccines and more relevant for safety and consistency testing of medicines, as it uses human monocyte cells.
Improving confidence in the MAT
Although the MAT was introduced to the European Pharmacopoeia in 2010 and is a legally accepted method for testing pyrogens, many labs have not yet adopted it.
Dr Caroline Vipond, principal scientist at the NIBSC and author of one of the studies comments:
“The RPT has been in use for many years and is well established in laboratories worldwide- it’s thought of as the ‘gold standard’ for pyrogen testing. Therefore, strong evidence is needed to prove the benefits of the MAT to manufacturers and regulators and encourage its adoption.”
“This work aimed to validate the use of this test for ‘naturally’ pyrogenic vaccines like Bexsero, setting up clear pass/fail criteria and proving its specificity and precision.”
The paper established a reference comparison method using batches of the vaccine that had safely been used in clinical trials and one batch that was considered more pyrogenic.
New batches could then be compared to levels recorded for the clinically safe batches. As more batches of vaccines become available and are used in a clinical setting, the data can be used to review and update the proposed criteria.
Further work as part of a collaborative study highlighted the success for the MAT to consistently measure pyrogen levels of Bexsero batches across a wider number of laboratories.
Dr Vipond further said:
“By adopting the MAT in the testing of Bexsero vaccines, we’ve been able to release batches faster, and provide more reliable and meaningful results to our industry partners.”
Dr Karin Nordgren, Head of Pyrogen Science at the NIBSC added:
“We hope by addressing some concerns with the MAT assay, those performing pyrogen testing will consider its use. Although this method may be further refined in future, these studies prove it is still a strong alternative to the RPT.
Dr Lucy Studholme, Principal Scientist at the NIBSC and author of one of the studies comments:
’‘In terms of predicting vaccine safety, it can be a real challenge to develop non-animal tests that are superior to those involving animals. Here we have an example of where a strong collaboration between the regulator and industry has allowed this to happen”.
Papers
Development and validation of a monocyte activation test for the control/safety testing of an OMV-based meningococcal B vaccine by Caroline Vipond et al. is published in Vaccine
Evaluation of the monocyte activation test for the safety testing of meningococcal B vaccine Bexsero: A collaborative study by Lucy Studholme et al. published in Vaccine
Towards animal free and science based measures of critical quality attributes for vaccine quality control and release a commentary by Rino Rappuoli published in Vaccine
More information about the NIBSC work on meningitis