Vaccines against Human
Papillomavirus
responsible officer: Dr Sonia Pagliusi
Human papillomavirus (HPV) have been known to be
associated with a wide spectrum of different mucocutaneous infections in humans including
common skin warts, genital warts and cervical cancer. Of the over 100 types of HPV
molecularly identified to date, over 30 types have been shown to infect the genital
mucosa. Indeed, genital HPV infections are among the commonest viral sexually transmitted
infections diagnosed in clinical sexual health practice.
Based on many epidemiological and experimental studies, a
causal link between HPV and the development of cervical cancer in women has been shown. In
fact, over 99% of cervical cancers contain HPV DNA, and four specific HPV types (16,18,31,
and 45) cause at least 80% of diagnosed cervical cancers. Most benign genital warts are
caused by other types.
The disease
Epidemiological estimates suggest that the world
prevalence of HPV infection is between nine and thirteen percent, which equates with about
630 million infected people. Because of its contagious nature approximately two thirds of
all people who have sexual contact with an infected partner will develop a HPV infection
within three months. 70% of genital HPV infections are subclinical, and do not progress to
disease. Most HPV infections regress spontaneously. However, cervical cancer develops in a
minority of women with persistent pre-malignant cervical intraepithelial neoplasia, and it
usually appears more than a decade after the initial infection. This time lag may be
attributed partly to a need for cofactors that promote carcinogenesis, such as smoking. In
immuno-compromised subjects infection tends to cause more severe and rapidly progressive
anogenital cancer – reinforcing a growing body of evidence that the immune system
plays a key role in controlling HPV disease. Researchers estimate the global prevalence of
clinically pre-malignant HPV infections at between 28 and 40 million. The International Agency for Research on Cancer (IARC) estimates
the prevalence of chronic persistent infections in developed countries at around 7% (based
on studies conducted in Spain and Japan) and 15% in developing nations (based on studies
undertaken in Colombia, Brazil, Thailand the Philippines and Morocco).
Cervical cancer has an incidence of 470.000 cases per
year worldwide, with 80% being in developing countries. Cervical cancer is second only to
breast cancer when it comes to disease incidence in women. The mortality associated with
cervical cancer is the most telling indicator of its impact on women, their families and
their communities. Globally, 232,000 women die of the disease each year with a majority of
those deaths (192,000) occurring in the developing world, where early diagnosis is not
well established.
Vaccines in clinical development
A vaccine to prevent oncogenic HPV infection, or
pre-malignant cervical lesions from progressing to cancer, would clearly offer a cost
effective long-term strategy to reduce the cervical cancer burden, particularly for
developing countries where effective screening programs are not available. The encouraging
experimental results obtained with testing vaccine preparations in animal models of
disease have prompted both commercial and public institutions to pursue the clinical
development of vaccine candidates. Recombinant DNA technology is being used to produce
vaccines against HPV, and are clearly a priority in this field for a number of
pharmaceutical and biotechnology firms. Both prophylactic and therapeutic vaccines are
under development.
- Viral Like Particles Vaccines (VLPs)
Recombinant L1 capsid protein from HPV has the useful
property of self-assembling into virus-like particles. These particles contain no viral
DNA and are therefore non-infectious. More importantly, these particles stimulate the
production of antibodies that bind and neutralize the infectious virus. Results from three
phase I human trials with L1 VLPs have been encouraging, with excellent tolerability and
high immunogenicity reported in each trial. Phase II studies are ongoing. Polypeptides of
non-structural viral proteins are being added to L1 and L2 minor capsid protein in the
hope that such additions will enhance protection and also confer therapeutic potential.
- Recombinant fusion proteins and peptides
Other subunit vaccine candidates based on expression
of viral early antigens as fusion proteins, or synthetic peptides corresponding to
immunogenic epitopes of viral proteins, are designed to have therapeutic properties to
treat already infected subjects. The E6 and E7 oncoproteins of HPV are selectively
expressed in pre-malignant lesions and cancer, and so are attractive vaccine targets.
These kinds of vaccines have the capacity to induce anti-tumor responses in experimental
models. Three fusion proteins and several peptides are being tested in human trials as
potential therapeutic vaccines. They have proven to be safe, but their immunogenicity and
efficacy has not yet been fully characterized.
Live recombinant vaccinia viruses, engineered to
express genes from HPV types 16 and 18, the most common viruses associated with cervical
cancer, have been tested in therapeutic settings. Results of phase I and II trials
conducted so far have been encouraging. These studies successfully demonstrated that the
vaccine induces no serious side effects. However, the initial study group was too small to
evaluate clinical efficacy. Live attenuated vectors, such as Salmonella, are being
investigated as potential second-generation vaccines.
Challenges
The development of a viable HPV vaccine has been hampered
by difficulties growing HPV in the lab and thus creating conventional, attenuated
vaccines. Furthermore, the presence of viral oncogenes poses a significant obstacle to
development of live attenuated HPV vaccines. HPV is species-specific and does not infect
animals. Hence, none of the animal models completely mimics the human disease or its
sexual transmission. It is therefore difficult to predict the effectiveness of HPV
vaccines in human studies. HPV enters the body through mucosal cells and do not spread
systemically. Therefore, an HPV vaccine will possibly have to induce a strong and
sustained immune response at the genital mucosa. In this respect, nasal and oral
immunization studies in animals have shown VLPs to induce antibodies in the genital
mucosa, and clinical trials are now being conducted to evaluate this strategy in women. In
addition, because HPV types differ significantly, antibodies raised against one type may
not protect against other types, creating the need to develop multivalent vaccines.
Despite of these problems, more than one VLP formulation will soon be in phase III testing
as a prophylactic vaccine in a developing country context.
WHO has initiated a variety of activities aimed to
accelerate the vaccine technology and to support vaccine development. A series of standard
reagents are being created to be used to monitor responses to vaccination in humans and
evaluating the biological effects of the vaccine.
Considering that cervical cancer continues to be a
serious public health problem, public awareness of HPV infections, its transmission
pathway, and the potential HPV related diseases is very low, specially in developing
countries. Given the long record of prophylactic viral vaccines as a cost-effective
approach to prevent infection or modify disease, an effective vaccine against oncogenic
types of HPV could have a tremendous impact on the global cervical cancer burden.
...read more about HPV and
cancer
last update of this page: 18 July 2001
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