Abstract
Cervical cancer caused by infection with human papillomaviruses (HPVs) is the fourth most common cancer in women globally, with the burden mainly in developing countries due to limited healthcare resources. Current vaccines based on virus-like particles (VLPs) assembled from recombinant expression of the immunodominant L1 protein are highly effective in the prevention of cervical infection; however, these vaccines are expensive and type-specific. Therefore, there is a need for more broadly protective and affordable vaccines. The HPV-16 L2 peptide sequences 108-120, 65-81, 56-81, and 17-36 are highly conserved across several HPV types and have been shown to elicit cross-neutralizing antibodies. To increase L2 immunogenicity, L1:L2 chimeric VLPs (cVLP) vaccine candidates were developed. The four L2 peptides mentioned above were substituted into the DE loop of HPV-16 L1 at position 131 (SAC) or in the C-terminal region at position 431 (SAE) to generate HPV-16-derived L1:L2 chimeras. All eight chimeras were transiently expressed in Nicotiana benthamiana via Agrobacterium tumefaciens-mediated DNA transfer. SAC chimeras predominantly assembled into higher order structures (T = 1 and T = 7 VLPs), whereas SAE chimeras assembled into capsomeres or formed aggregates. Four SAC and one SAE chimeras were used in vaccination studies in mice, and their ability to generate cross-neutralizing antibodies was analyzed in HPV pseudovirion-based neutralization assays. Of the seven heterologous HPVs tested, cross-neutralization with antisera specific to chimeras was observed for HPV-11 (SAE 65-18), HPV-18 (SAC 108-120, SAC 65-81, SAC 56-81, SAE 65-81), and HPV-58 (SAC 108-120). Interestingly, only anti-SAE 65-81 antiserum showed neutralization of homologous HPV-16, suggesting that the position of the L2 epitope display is critical for maintaining L1-specific neutralizing epitopes.
Highlights
One in six global deaths is due to cancer, with the economic cost estimated at US$1.2 trillion in 2010 (World Health Organisation, 2017)
We report the purification of five plant-produced human papillomaviruses (HPVs)-16 L1:L2 chimeric VLPs (cVLP) with L2 substituted in the DE loop (SAC)
HPV-16 L2 peptides, 108-120, 65-81, 56-81, and 17-36 were substituted into HPV-16 L1 DE loop from position 131 to generate four SAC chimeras or into the C-terminal between the h4 and β-J structural region from position 431 to generate four SAE chimeras (Figure 1)
Summary
One in six global deaths is due to cancer, with the economic cost estimated at US$1.2 trillion in 2010 (World Health Organisation, 2017). Cervical cancer is the fourth most common cancer in women globally and results in an estimated 567,000 cases and 311,000 deaths every year (Bray et al, 2018). Most HPV infections are cleared by the immune system (Goodman et al, 2008; Rosa et al, 2008); some benign cervical lesions progress to invasive cervical cancer (ICC) caused predominantly by high-risk HPVs (zur Hausen, 2002). High-risk HPV-16 and HPV-18 are the most common cause of ICC and are associated with 70% of cervical cancer cases (Smith et al, 2007; de Sanjose et al, 2010), but at least 13 other high-risk HPVs cause cancer (zur Hausen, 2002; Parkin and Bray, 2006)
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