Efficiency of some papillomavirus vaccines is reduced in the presence of thimerosal

Background:

Figure: Structure of thimerosal

EVISA reported frequently about thimerosal (also called thiomersal),  an organomercury compound known for its antiseptic and antifungal properties and used as an antibacterial agent in pharmaceutical products, including vaccines and other injectable biological products (see the EVISA News related to thimerosal below). While thimerosal is a strong neurotoxin, its use as an adjuvant in vaccines is considered by the WHO  to be safe and the Organization continues to recommend the use of vaccines containing thimerosal for global immunization programmes because "the benefits of using such products far outweigh any theoretical risk of toxicity".

While often regarded as an "additive" (adjuvant), researchers from the University of Münster (with participation of EVISA director Michael Sperling) already in 2009 demonstrated that thimerosal reacts with proteins (namely human serum albumin, HSA)  in the human blood to form adducts. Later it was shown, that thimerosal not only reacts with HSA but also other proteins containing thiol-functions. More recently, researchers from Münster also showed that thimerosal is reacting with the protein in influenza vaccine, being the active part of the vaccine (see Strohmidel et al. 2018). That finding raised the question, whether adding thimerosal to a vaccine has an influence on the immunization efficiency, since the molecular structure of the target protein is changed by the adduct formation.

A group of researchers from China now studied the influence of the adjuvant thimerosal on the activity of thiol-containing immunogens. HEV p239 and four types of HPV VLPs were used in this experiment. HEV causes epidemic hepatitis, and HPV is the primary cause of genital warts and cervical cancer. Mice were immunized with formulations that contained different amounts of thimerosal via i.m. Serum samples were collected weekly to measure the immunogenicity. 

In each of the four HPV VLPs, a substantial portion lost all binding activity to antibodies due to the addition of thimerosal. For the most affected HPV18 VLP, the binding titre of the high dose thimerosal group (0.05 %) decreased by an average of 25-fold compared with that of the control. Using cryo-electron microscopy for 3D reconstruction, structural alterations were observed in HPV19 VLPs as a result of thimerosal treatment. The authors concluded from their results, that "the choice of vaccine preservatives should be carefully considered, particularly if the antigen contains thiol, in vaccine research and development where the addition of a preservative is deemed necessary".

The cited study: Siyi Chen, Xiaofen Huang, Yike Li, Xin Wang, Huirong Pan, Zhijie Lin, Qingbing Zheng, Shaowei Li, Jun Zhang, Ningshao Xia, Qinjian Zhao, Altered antigenicity and immunogenicity of human papillomavirus virus-like particles in the presence of thimerosal, Eur. J. Pharmaceut. Biopharmaceut., 141 (2019) 221–231. DOI: 10.1016/j.ejpb.2019.05.027