Opportunities and challenges for human papillomavirus vaccination in cancer

Abstract

The discovery of genotype 16 as the prototype oncogenic human papillomavirus (HPV) initiated a quarter century of laboratory and epidemiological studies that demonstrated their necessary, but not sufficient, aetiological role in cervical and several other anogenital and oropharyngeal cancers. Early virus-induced immune deviation can lead to persistent subclinical infection that brings the risk of progression to cancer. Effective secondary prevention of cervical cancer through cytological and/or HPV screening depends on regular and widespread use in the general population, but coverage is inadequate in low-resource settings. The discovery that the major capsid antigen L1 could self-assemble into empty virus-like particles (VLPs) that are both highly immunogenic and protective led to the licensure of several prophylactic VLP-based HPV vaccines for the prevention of cervical cancer. The implementation of vaccination programmes in adolescent females is underway in many countries, but their impact critically depends on the population coverage and is improved by herd immunity. This Review considers how our expanding knowledge of the virology and immunology of HPV infection can be exploited to improve vaccine technologies and delivery of such preventive strategies to maximize reductions in HPV-associated disease, including incorporation of an HPV vaccine covering oncogenic types within a standard multitarget paediatric vaccine.

Figure 1 |. The life cycle of HPV.

Abrasion, which leads to denudation of the basement membrane (BM) from epithelial cells, provides access to the basal keratinocytes. During the course of human papillomavirus (HPV) infection, the virus binds to heparin sulfate proteoglycans (HSPGs) and/or laminin 5 on the BM through the major capsid protein L1 (REFS ,–151). This triggers conformational changes in the capsid that further expose the minor capsid protein L2, including a conserved site on the L2 amino terminus that is susceptible to cleavage by extracellular furin^,. Furin cleavage of L2 reveals several conserved protective epitopes of L2, including residues 17–36, on the capsid surface and is critical to infection. This is followed by virus uptake into the target basal keratinocyte. Several uptake pathways have been implicated, none of which are necessarily mutually exclusive. In the infected basal cells (which might include stem cells), the viral genome replicates and establishes ~50 HPV episome copies, which then segregate between the daughter progeny as the cells undergo cell division. The early viral proteins E6 and E7 are key to stimulating the continued proliferation and milieu for E1 and E2-driven vegetative viral genome replication to a very high copy number. Terminal differentiation of infected cells in the upper epithelial layers activates the expression of E4 and then L1 and L2 to package the very high copy numbers of the viral genome. The virions are released as E4 disintegrates the cytokeratin filaments, and the keratinocyte remnants are sloughed off the epithelial surface. Thus, the viral life cycle is completed without directly causing cell death and without systemic viraemia or apparent inflammation to avoid alerting the local immune responses. APC, antigen-presenting cell.

Figure 2 |. Hallmarks of cancer affected by high-risk HPV.

While high-risk human papillomavirus (hrHPV) infection alone is not sufficient to cause cancer, it regulates pathways that promote the hallmarks of cancer, via E6, E7 and E5 (REF. 12). This includes sustaining proliferative signalling via E7 and E5; enabling replicative immortality via E6; activating invasion and metastasis (that is, subverting keratinocyte differentiation via E6); deregulating cellular energetics via E6; and inducing local angiogenesis via E6 and E7, through the dysregulation of pathways as indicated in the figure. While this dysregulation triggers growth suppressors that promote cell death, they are restrained by E6 (via degradation of p53 and BCL-2 homologous antagonist/killer (BAK) and upregulation of BCL-2). The derailing of cell cycle control results in double-stranded (ds)DNA breaks, genomic instability and mutations that can lead to additional ‘hits’ that drive towards lethal cancer. Numerous mechanisms to avoid destruction by promoting immune deviation have been evolved by hrHPV, as reviewed in REFS ,. E6 and/or E7 expression interferes with several aspects of innate immune activation, including detection of viral DNA by cyclic GMP–AMP synthase–stimulator of interferon genes protein (cGAS–STING) and Toll-like receptor 9 (TLR9); production of interferon-κ (IFN-κ) and CXC-chemokine ligand 14 (CXCL14), which are important for Langerhans cell chemotaxis; suppression of pro-inflammatory responses — including through type 1 interferon signalling (interferon regulatory factor 1 (IRF1)) — and production of CC-chemokine ligand 20 (CCL20), to prevent the recruitment of antigen-presenting cells (APCs) to the site of infection. E5 interferes with T cell recognition through disruption of antigen presentation via modulation of major histocompatibility complex (MHC) I and MHC II cell surface expression and downregulation of transporter associated with antigen processing (TAP), while neutralizing antibody (nAb) production is hampered by release of virions outside the body rather than into systemic circulation. Furthermore, E6 and E7 expression induces production of interleukin-6 (IL-6), which recruits monocytes that generate tumour-promoting inflammation via local expression of CCL2 and matrix metalloproteinase 9 (MMP9). Such virus-mediated immune interference combines to promote the persistence of the infection and thereby promote the risk of cancer. EGFR, epidermal growth factor receptor; HDAC, histone deacetylase; HIF1α, hypoxia-inducible factor 1α; KDM6A, lysine-specific demethylase 6A; VEGF, vascular endothelial growth factor. Figure adapted with permission from REF. , Elsevier.

Figure 3 |. Natural immune control of HPV infection.

The immune system controls most human papillomavirus (HPV) infections before cancer can develop. The process of virus uptake into epithelial cells occurs over several hours and thus offers a time window for the action of vaccine or naturally induced neutralizing antibodies (nAbs). The first step is the detection of damage by the innate immune response arm via local antigen-presenting cells (APCs) and their activation (step 1). The secretion of pro-inflammatory cytokines and chemokines supports the viral antigen processing and migration to loco-regional lymph nodes (LNs) (step 2). Here, activated APCs stimulate various viral-antigen-specific CD4+ T cells that can either help activation of CD8⁺ T cells (for example, in targeting early viral antigens) or help B cells to produce nAbs that are, for example, directed against capsid proteins (step 3). The local activation of the innate immune response results in the attraction of nonspecific effectors (such as natural killer (NK) cells), the secretion of interferons (which can directly affect the HPV infection) and the attraction of more APCs to further drive activation of adaptive immunity (step 4). This inflammatory state provides the signals to attract the effector CD8⁺ T cells, which can target the virus-infected cells in the basal layers of the epithelium and are critical to clearance of the virus infection (step 5). Long-lived plasma cells secrete nAbs that can access the infection site either by transudation from the blood to the mucosal secretions or by serous exudation. Only the viral particles, and not the HPV-infected cells, can be targeted by nAbs, which are thus unable to cure infection but can stop further infections (step 6). Such antibody responses in women occur many months after HPV infection, and the levels detected are not necessarily sufficient to prevent a subsequent infection by the same virus type. It is likely that long-term natural protection against a specific HPV-type infection is the result of cell-mediated immunity, with nAbs contributing to a much lesser extent. BM, basement membrane; MHC, major histocompatibility complex; TCR, T cell receptor.

Figure 4 |. Antibody-mediated protection.

Vaccination with human papillomavirus (HPV) capsid antigens can induce different types of type-specific antibodies, most of which can bind to the native virion, but not all will necessarily neutralize the virus by preventing uptake by the target cell. Antibodies depicted in black represent non-neutralizing antibodies (non-nAbs), which are not able to directly influence the infectivity of the virus. The available data suggest that an initial step that can be blocked by some L1- virus-like-particle (VLP)-induced nAbs is the binding to heparin sulfate proteoglycans (HSPGs) on the basement membrane (BM) (indicated by red cross)^,. Orange nAbs represent those that can potentially influence infectivity after HSPG-binding events that occur before and after changes to L2 (indicated by orange cross). These antibodies are detected with different assay types (BOX 1). Immunization with L1 VLPs cannot reflect all the potential structures through which antibodies may be able to block the infection process (FIG. 1), most notably L2, which is poorly immunogenic in natural infection. Nevertheless, L2 is a potentially effective target for prophylaxis. L2 vaccination induces nAbs (depicted in green) that neutralize the virion after binding and only after a conformational change in the capsid and cleavage of L2 by extracellular furin to render L2 protective epitopes, such as residues 17–36, accessible to antibody binding (indicated by green cross). L2-specific antibodies have a much lower titre and avidity than L1 VLP-specific antibodies. The L2 epitope spacing will probably not allow bivalent binding of this antibody. The different types of antibodies may include recognition of different epitopes of L1 or L2 molecules. Late events associated with virus uptake and processing by the cell may also be interfered with by nAbs. There are clearly still gaps in our knowledge of the infection process and the nature of antibodies that can influence the process, including the contribution of phagocytes that recognize the crystallizable fragment (Fc) of capsid-reactive antibodies.

Figure 5 |. Development and implementation of HPV vaccines.

a | The challenges and possible solutions to bringing a novel preventive human papillomavirus (HPV) vaccine from its initial invention through licensure. b | Challenges and possible solutions to achieving global use of licensed HPV vaccines and herd immunity and thus recognizing the full potential of cancer prevention. FDA, US Food and Drug Administration; Gavi, Global Alliance for Vaccines and Immunization; IP, intellectual property; WHO, World Health Organization.