Immune responses to human papillomavirus infection and vaccination

Abstract

Human papillomavirus (HPV) is the most common sexually transmitted infection. About 90% of HPV infections are transient, resolving without any need for intervention. Most of HPV infections are low-risk non-oncogenic. However, persistent infection with high-risk oncogenic HPV types is the cause of cervical as well as various other anogenital and oropharyngeal cancers. HPV infection on either cutaneous or mucosal surfaces activates both innate and adaptive antiviral immune cells including Langerhans and keratinocyte cells, natural killer cells, B and T cells. These cellular responses alongside their corresponding cytokine profiles have been associated with clearance of HPV infection and regression of HPV associated disease although the actual immune mechanisms involved are not well understood. Current HPV vaccines are based on self -assembled virus-like particles (VLP) from the major viral capsid protein and target the high-risk HPV types as well as two low-risk types responsible for genital warts. The vaccines generate antibody protection against new infections with no effect on already established infections and HPV-associated diseases. Certainly, despite the high effectiveness of current prophylactic HPV vaccines, therapeutic HPV vaccines are needed for treatment of already established HPV infections and disease. Although there have been great efforts in development of therapeutic vaccines, none is yet to be licensed due to low efficacy and safety concerns. There is therefore a need to understand both natural and vaccine-induced immunity, for development of effective and safe therapeutic HPV vaccines. Additionally, a better understanding of the immunogenicity of HPV vaccines, which are among the best subunit vaccines developed to date, may identify immune pathways that could be targeted for development of similarly effective vaccines for other diseases. This review summarises available literature on immune responses to both HPV infection and vaccination, with an aim of improving overall understanding on this subject. This may provide insights for better targeting of both therapeutic and prophylactic vaccines, not only for HPV but also other antigen targets.

Keywords: efficacy; human papillomavirus; immune responses; infection; protection; therapeutic vaccines; vaccination.

Figure 1

HPV 16 genomic structure. LCR (Long control region): Controls transcription and replication of the viral DNA particularly E6 and E7 expression. Early genes. E1- DNA helicase responsible for recognition of origin for viral genome replication. E2 – Recruits E1 and DNA polymerase to the origin of replication, regulates viral gene transcription. E4 – Plays a role in viral release and transmission. E5 – Interacts with epidermal growth factor and activates immune evasion pathways. E6 – Oncoprotein that interferes with cell cycle by binding the tumour suppressor protein p53. E7 - Oncoprotein that interferes with cell cycle by binding the retinoblastoma gene product pRB. Late genes. L1, L2 – Major and minor viral capsid proteins respectively, assemble into capsomeres.

Figure 2

Mechanisms of HPV immune evasion leading to persistent infection and impaired clearance. HPV employs multiple strategies to evade host immune responses, as illustrated in this schematic. HPV infects basal epithelial cells without causing cell lysis or inflammation. The delayed expression of late structural proteins (L1 and L2) until keratinocyte differentiation in the upper epithelium minimizes immune detection and facilitates persistent infection. HPV early proteins (E2, E4, E5, E6, and E7) suppress innate immune signaling by downregulating type I interferon production (IFN-α, IFN-β, and IFN-κ), thereby limiting dendritic cell activation and antigen presentation. The E6/E7 proteins further impair natural killer (NK) cell function, reducing the clearance of infected or transformed cells. E5 inhibits expression of MHC class I and II molecules, leading to reduced CD8⁺ and CD4⁺ T cell activation. Consequently, this dampens the generation of effective cytotoxic responses and limits B cell activation and differentiation. This results to weak and delayed antibody response with low neutralising capacity, contributing to viral persistence and potential progression to HPV-related lesions or malignancies. Created with Biorender.com.

Figure 3

Potent activation of naïve B cells and CD4+ T cells by polymeric HPV virus-like particles (VLPs). Following intramuscular injection, HPV VLPs are trafficked to secondary lymphoid organs where they can activate B cells via two pathways. (A) T-independent activation involving B cell receptor cross-linking by repetitive L1 molecules. (B) T-dependent activation where the VLPs are preferentially taken up by antigen presenting cells such as dendritic cells which process and present them to naïve CD4+ T cells on MHC II molecules with co-stimulation via other surface molecules such as CD40-CD40L and ICOS-ICOS-L1 and cytokines. The CD4 T cells are activated to differentiate to Tfh cells which are further presented with the HPV antigen by cognate B cells. This interaction between cognate Tfh and B cells takes place in germinal centers. Both pathways can activate B cells to differentiate to short-lived plasma cells for early short-term protection, or to long-lived plasma cells and memory B cells, the sources of long-term antibodies. Tfh, T follicular helper cell; MHC II, major histocompatibility complex II; ICOS, inducible T-cell co-stimulator; ICOS-L1, ICOS Ligand; IL, interleukin; CCR/CXCR chemokine receptors, TCR, T cell receptor; IFN, interferon; IL, Interleukin. Created with Biorender.com.