Abstract
Capsomers were produced in bacteria as glutathione-S-transferase (GST) fusion proteins with human papillomavirus type 16 L1 lacking the first nine and final 29 residues (GST-HPV16L1Δ) alone or linked with residues 13–47 of HPV18, HPV31 and HPV45 L2 in tandem (GST-HPV16L1Δ-L2x3). Subcutaneous immunization of mice with GST-HPV16L1Δ or GST-HPV16L1Δ-L2x3 in alum and monophosphoryl lipid A induced similarly high titers of HPV16 neutralizing antibodies. GST-HPV16L1Δ-L2x3 also elicited moderate L2-specific antibody titers. Intravaginal challenge studies showed that immunization of mice with GST-HPV16 L1Δ or GST-HPV16L1Δ-L2x3 capsomers, like Cervarix®, provided complete protection against HPV16. Conversely, vaccination with GST-HPV16 L1Δ capsomers failed to protect against HPV18 challenge, whereas mice immunized with either GST-HPV16L1Δ-L2x3 capsomers or Cervarix® were each completely protected. Thus, while the L2-specific response was moderate, it did not interfere with immunity to L1 in the context of GST-HPV16L1Δ-L2x3 and is sufficient to mediate L2-dependent protection against an experimental vaginal challenge with HPV18.
Highlights
Persistent infection by high risk HPV types is a necessary, but not sufficient cause of cervical cancer, as well as a significant fraction of other anogenital cancers and subset of head and neck cancers [1]
A,5-fold lower dose of L1 as virus-like particles (VLPs) compared to capsomers is sufficient to induce immunity [19,32].to assess the immunogenicity of the GST-HPV16L1D and GSTHPV16L1D-L2x3 capsomers, groups of Balb/c mice were immunized three times at two-week intervals with 25 mg of capsomers formulated in 50 mg alum and 5 mg MPL per dose
An additional group of mice was vaccinated with 1/ 10th of a human dose of CervarixH, which was comprised of 2 mg each of HPV16 and HPV18 L1 VLPs formulated in 50 mg alum and 5 mg MPL
Summary
Persistent infection by high risk HPV types is a necessary, but not sufficient cause of cervical cancer, as well as a significant fraction of other anogenital cancers and subset of head and neck cancers [1]. In CervarixH, HPV16 and HPV18 L1 VLPs (20 mg each) are adjuvanted with aluminum hydroxide (500 mg) and 3-O-desacyl-49-monophosphoryl lipid A (MPL, 50 mg). Both vaccines have demonstrated remarkable protective efficacy against infection by the specific HPV types present in each vaccine [3,4,5,6]. Because more than a dozen high risk types are associated with cervical cancer and benign genital warts cause significant morbidity, there is an effort to develop a nonavalent L1 VLP vaccine targeting the seven most common oncogenic HPV types and the two most common types in genital warts, HPV6 and HPV11 [10,11]
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