- Email: [email protected]
Global Prevention and Management of Human Papillomavirus Related Diseases: The Pressing Challenges and the Compelling Opportunities
Vaccine 30S (2012) vii–x
Contents lists available at SciVerse ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Foreword
Global Prevention and Management of Human Papillomavirus Related Diseases: The Pressing Challenges and the Compelling Opportunities
1. Introduction Where are we now? We have gained tremendous knowledge about human papillomaviruses (HPV) and their interactions with host cells, tissues and immune systems; have validated and implemented strategies for prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools; and substantially increased global awareness of HPV and the many associated diseases of women, men, and children. In so doing, we have come up against new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, the diverse societal standards around the globe concerning reproductive health, and the very wide ranges of national economic capabilities and health care systems. HPV is one of the very few agents of infectious diseases and carcinogenesis where the emerging opportunities for prevention have encountered some socio-political resistance, the nature of which depends on country and culture. In addition, there has been too quick a willingness for policy makers, funding agencies and corporate stakeholders to discount the need for significant new developments, particularly in the arenas of therapeutics and affordable interventions. An expanded repertoire of health care options is urgently needed to bring HPV under short term management and long-term elimination. Thus, we are at cross-roads that will require thoughtful discussions, compassionate decisions and concerted actions. 2. Basic and clinical research into the HPV-associated diseases, infection cycle, host responses, viral counter-responses and the roles of immunity Among the world’s leading causes of morbidity and mortality, cervical and other anogenital cancers have understandably been the primary focus of research and development and the dominant motivation for international cooperative efforts at prevention and control. Further incentive is now emerging from the increasing awareness of and attention to the head and neck manifestations of HPV infections, especially in the oropharyngeal and respiratory tracts. As in the genital mucosa, HPV16 is the predominant agent of severe disease, but the nature of precursor infections is not well understood. In addition, the benign and neoplastic HPV diseases of cutaneous epithelia are providing intriguing comparisons and contrasts with the mucosal lesions. Our appreciation of the size and complexity of the human and animal papillomavirus family continues to grow as many new genotypes are being discovered and characterized using the improved 0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2012.07.071
tools of next-generation DNA sequencing. Most HPV infections are subclinical. Activation of persistent HPV infections and generation of epithelial lesions are largely a function of immune status, and appreciation of the wide range of conditions that result in immunomodulation is growing. Individuals can experience immunosuppression from such causes as organ transplantation, chemotherapy or ionizing radiation treatment for cancers, and autoimmune diseases controlled with anti-proliferative drugs, as well as from debilitating chronic conditions such as physiologic and metabolic diseases, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and other infectious diseases, malnutrition, emotional and physical stresses, pregnancy and aging. Researchers continue to seek a deeper understanding of the mechanisms of HPV transmission and persistence, the molecular players that are engaged in virus–host cell interactions, the control of DNA replication and RNA transcription, including that mediated by regulatory RNAs, and the roles of host immunity and viral counter-measures. Key issues with respect to neoplastic progression of lesions toward cancer concern the changing parameters of gene expression and regulation, post-translational modifications of viral and host proteins, the causes of viral DNA integration into the host cell chromosomes, epigenetic changes in the viral genome during differentiation of the epithelium and during disease progression, and validation of biomarkers indicative of the stage of disease. The molecular details of the HPV life cycle and neoplastic progression are revealing very promising targets for novel therapies against benign lesions and cancer cells in situ or following tumor invasion and metastasis. 3. The success and promise of prophylactic vaccines The quadrivalent and bivalent HPV vaccines have proven to be very safe, with long-term durability of protection against primary infection and a moderate degree of cross-protection against non-vaccine types. Next-generation vaccines comprising many additional genotypes are completing clinical trials. As the formulations become increasingly multivalent, new questions arise concerning the relative efficacies in preventing infection by the different HPV types, wherein immune recognition may become confounded or, alternatively, might show synergy. While we can anticipate successively more effective vaccine strategies, such longer term prospects should in no way diminish the immediate distribution of the best available products to the most vulnerable populations. Much of the present value of vaccination programs resides in the public educational opportunities, increasing social acceptance of HPV vaccines, and the immediate opportunities to
viii
Foreword / Vaccine 30S (2012) vii–x
learn from the successes as well as challenges of the vaccination programs. Nonetheless, maintaining and even expanding research and development of ever better vaccines should remain a high priority commitment from all possible funding sources: governments, not-for-profit foundations and corporations. There is opportunity to confer upon the prophylactic vaccines more physical stability and shelf-life, improvements for long distance delivery, and far lower manufacturing and distribution costs, along with implementation of more comprehensive and embraced national programs for vaccinating girls and boys. Childhood vaccination programs are nearly universal. However, there are few effective strategies for vaccinating pre-adolescents, the currently recommended age for HPV vaccination. A good case can be made for clinical trials to evaluate vaccination at younger ages, within the schedules of pediatric vaccination against other common viral infections to improve coverage and to eliminate the negative rhetoric about the vaccines possibly altering sexual behavior. The significantly stronger immune response to the HPV vaccines at younger ages, compared to adolescents, combined with the durability of protection from infection that is becoming demonstrable, and the small but real risk of HPV infection of children as a result of abuse, together suggest that early vaccination of toddlers could become good public health policy. 4. A range of diagnostic methods Diagnostic screening for HPV lesions is generally available in the developed world but scarce everywhere else for lack of public health policy, professional and general education, media awareness, clinical settings, financial resources and, most crucially, insufficient capacity for effective follow-up treatment of identified lesions. Screening is typically visual and subjective, with even the most highly trained experts sometimes unable to agree. New tests for molecular biomarkers of infection and disease have greatly improved sensitivity and are beginning to help define the degree of present and future risk. Innumerable companies and entrepreneurs are recognizing the market potential for HPV diagnostic tools that will complement conventional Papanicolaou cytology. It must be appreciated that cytology provides an indication of disease, while molecular tests can be either a measure of HPV infection or a direct assessment of disease state. Official recommendations for screening methods and standards need to take into account the various capabilities of the diagnostic tests and recognize that significant improvements in molecular assessments emerge on a regular basis. This Monograph comprehensively reviews the new diagnostic options and the ever more sophisticated yet practical methods to evaluate a growing list of key biomarkers that provide an objective indication of the stage of infection and disease progression. 5. The potential for therapeutic inhibition of persistent infections As the essential follow-up to disease diagnosis, new therapies are needed and they must be effective, minimally impactful on normal tissues and organs, affordable, and available everywhere. We know a great deal about primary infection, long term maintenance of the viral genome, the mechanisms and regulation of RNA transcription and replicative DNA amplification, the dependency on usurping host processes while bypassing host defensive responses, and virion assembly, maturation and shedding. Each of these steps presents multiple opportunities and strategies for therapeutic intervention, which of course must be customized to anatomic site and epithelial type. For cutaneous warts, there are over-the-counter ointments and other topically delivered agents,
although they are relatively nonselective. Topical therapies should be a goal for the mucosal infections. Development of such pharmacological agents must be a funding and research priority. Rather than trying to develop a plethora of related inhibitors capable of blocking each and every viral genotype, a new paradigm could be to target the host processes on which the virus depends for its infectious cycle, with a goal of identifying activities for which the host has redundant pathways but for which the much smaller viral genome has no opportunity for backup. Such generic compounds will need to be variously formulated for application to cutaneous surfaces, to the accessible mucosal surfaces and ultimately to the harder to reach internal mucosa, for example, in the mid- to lower-airway and the esophagus. Also urgently needed are drugs for treatment of lesions that have advanced beyond the benign stage to dysplasias, and another set of inhibitors able to slow down or eradicate carcinomas-in situ and metastatic cancers. The armamentarium of therapeutic capabilities will necessarily include therapeutic vaccines and specific immune stimulants to augment natural immunity. All together, molecular-based therapies are absolutely essential partners in disease prevention and management. They will provide the safety net for anyone who did not receive comprehensive prophylactic vaccines and for all persons who are presented with a positive diagnosis during organized or opportunistic screening. Long into the foreseeable future, this group of patients will numerically dominate over the vaccinated cohorts and provides the compelling rationale for vigorous research and development toward far more effective and far less damaging therapeutic responses to the diversity of HPV diseases. Arguably, screening, early detection and (when eventually possible) relatively simple therapeutic intervention could emerge as more practical than attempts at annual global vaccination of some 100 million children (of any given age cohort), unless and until vaccination becomes affordable, deliverable, and essentially universal and has substantially broader coverage to include most pathogenic mucosotropic genotypes. 6. Appreciation of disease causality and need for management There is inadequate recognition of the social impact of the successive stages of HPV infections: the infants who acquire “low-risk” HPV types 6 and 11 and develop recurrent respiratory papillomatosis; the adolescents with benign but highly contagious lesions; the middle aged with consequences on reproductive capabilities and well being of the mother; the older persons with an increasing risk of oncogenesis. Of the major cancers of women, cervical cancer tragically ends with the most years of life expectancy lost (estimated at 29 years), considerably more than for women succumbing to breast cancer. This places an exceptional – and avoidable – burden on young families, and to a very serious degree on children who lose their mother. Yet these facts have not moved sufficiently into the public discourse. There is also a troubling disjunction between the popular culture, celebrities, and the media, entertainment and fashion industries that popularize sexuality and beauty versus the need for candid and frank discussion about sexual health and the impact of sexually transmitted infections. The biological reality is that early age exposure to and frequent reinfection with the mucosotropic HPV types can have serious long-term outcomes in the form of future cervical, penile and anal cancer, RRP and certain head and neck afflictions. HPV has been a somewhat hidden epidemic because many primary infections spontaneously resolve, while the advanced diseases caused by persistent infections with sporadic viral activity generally require many years to appear. Delayed onset of lesions and periodic episodes of gene expression or quiescence can be attributed to the nature of the papillomavirus family, to
Foreword / Vaccine 30S (2012) vii–x
the immune status of the host, and to occasional local trauma reactivating latent infections. Some of the most serious lesions historically were not assigned to HPV and in many societies still are not attributed to infectious agents. For some in the younger generations, HPV is not seen as a crisis requiring action. Depending on the awareness of each individual concerning the diverse sites and manifestations of HPV diseases, infections may become of concern at different stages, from shortly after acquisition (for example, through sexual activity) and the development of genital warts to the rare and perplexing emergence of juvenile-onset or adult-onset laryngeal papillomas, all the way across the spectrum of disease to internally located high-grade dysplasias and invasive cancers that escape early detection in unscreened individuals. The unpredictable nature of HPV lesions creates a temporal disconnect between the actions leading to infection and the ultimate disease outcomes, and this poses real problems. These include the individual recognition of having an infection and the risk of transmitting it when symptoms are minimal or hidden to the consequences of having lived with an unmanaged infection for a long time, even forgetting about it, only to have serious outcomes arise years later and that are not obviously linked to the primary infection. As a matter of public health care policy, the idiosyncratic nature of HPV infections creates great uncertainty about when and how often to screen and treat. Vaccination obviates most of these uncertainties for individuals and for populations.
7. Implementation of effective public health measures depends on professional and public education, flexible and adaptable policies, and meaningful commitment of resources The current public health challenge is that, from a perspective of costs, the benefits of HPV disease prevention as a result of vaccination – if it is described as averting cancer as contrasted with preventing benign genital warts – are seemingly deferred to the extent that a legislative or executive policy would not show much apparent economic payback to society for many years. Yet no one should lose sight that successful HPV management depends on primary prevention as well as on early diagnosis and treatment of benign disease, where the benefits are immediate and tangible. There must be a conviction that the future matters but is best anticipated now. Significant progress will depend on a measure of faith that HPV prevention and care do not unleash promiscuity but rather sanctify the worth of life and health, personal and societal well-being. These factors seem to create a dilemma for some political leaders, especially because of what they likely perceive as advocating for sexual health starting with pre-adolescents. On the political as well as religious fronts, we cannot let ideologues usurp issues of HPV disease prevention and care to promote misinformation or to prevent sympathetic legislation concerning vaccination, screening programs, sexual health, and women’s and children’s rights. Family planning and contraceptives, as well as reproductive health and safety, are central to the same conversation. No society can fully succeed without respecting and empowering its women and the families they nurture and the communities they build. It is unconscionable that HPV continues to affect so many lives. We must transcend prejudice and marginalization and fully embrace the premise that health and a high quality of life trump at all levels: personal, family, community, ethnic circle, national, and global. General confidence within societies that its members will lead long and healthy lives comprises the foundation on which education of children and then economic opportunity can be built. If we can wrap our best ideas around the challenges of HPV diseases and make visible strides in controlling infections so they do not grow into cancers, then our field can serve as the beacon to
ix
give direction and motivation to those colleagues who are addressing other major medical challenges. After decades of global effort across the complementing disciplines, we are now so close to that capability. In parallel and with synergy, the brilliant research and public health efforts addressed to the AIDS epidemic, the hard-won achievements in HIV diagnosis, an ever-expanding arsenal of therapeutic agents used in combination, and the compassionate delivery of these capabilities based on multi-tiered pricing and cost-sharing are exemplary. Ultimately, the many lessons being developed in addressing the HPV diseases with respect to current and future generations of vaccines and therapeutic strategies will cycle back to inspire new approaches in AIDS public policy, education, implementation of vaccination programs, and early and regular screening to the benefit of controlling HIV. How do we estimate the cost of inaction as we consider the cost of action? Notably, how do we quantify the psychological impact of HPV infections, lesions and advanced diseases on the individual, the partner, and the family? How do we factor in the benefits of health within the community? How do we learn partnership for good preventive measures and responsive health initiatives and find common purpose, when it seems this may not be politically expedient, or perhaps economically appreciated? How do we justify prioritizing away well being and even life when the solutions are at hand to bring under control and largely eliminate the second most common cancer among women worldwide? It needs to be stated that there is a puzzling discrepancy between the public embrace of funding for breast cancer research and treatment vs. the far more limited support of research on anogenital cancers associated with HPV infections, when both afflictions affect women primarily and in nearly equal numbers globally. A sincere and meaningful investment in HPV management and health care needs to be seen as a centrist value benefitting the family, the community, and the economy. We must find ways to implement high technology in a diverse world where the education of health care providers concerning HPV diseases lags and there is a severe deficiency of adequately trained specialists to bring the current capabilities to all people. The challenge is to succeed when there are so many medical and nonmedical interests that are competing for limited resources. There do need to be various models for delivery of best possible care to individuals, depending on the local and national economic status. In some settings, long-term prevention is attainable, but not with current products and services. There remains an urgent need for public funding agencies as well as commercial entities to realize that anyone already harboring HPV is going to be a candidate for diagnostic tests and for therapeutics. Surgery is the least desirable option for treatment – a last resort – compared to early and regular screening, detection of incipient disease while the lesion is benign and the HPV is an autonomously replicating plasmid, and where immune stimulants, therapeutic vaccines and small molecule pharmaceuticals are most likely to be effective.
8. The time for universal response is now HPV is an equal opportunity pathogen. It is part of the human condition, well adapted to infecting the epithelia and so prevalent as to be almost unavoidable. Unlike the acute viruses that establish severe diseases shortly after infection, the modus operandi of HPV infections is primarily latent, subclinical, and opportunistic for sporadic reproduction and transmission, and HPV is generally in a state of quasi-equilibrium with the host. HPV is a real agent of affliction, a social disease of a sociable human species that is highly communicable, and susceptibility to it is most definitely not a life-style choice. HPV is both personal and interpersonal, just as it is intergenerational. We must diminish the barriers to informed options
x
Foreword / Vaccine 30S (2012) vii–x
and available choices, whether those impediments are financial, educational, political or religious, and then focus on proven management without prejudice. Societies need to acknowledge the extraordinary prevalence and virtual unavoidability of infection and put aside any inclination to cast blame, exploit shame, or castigate people for acquisition of HPV infections. Their importance as a precursor to carcinomas should not be dismissed for any reason – in fact, these diseases are the leading preventable cancers against which humanity can readily make progress at reduction. Nonetheless, as a result of substantial population growth in the most economically stressed nations of the world, combined with the presently limited possibilities for widespread introduction of vaccines, universal screening and effective early treatment in these regions, it is likely that the next 40 years will experience as much as a 50% increase in cervical and other HPV-associated anogenital cancer cases and deaths compared to the current terrible impact of more than one-half million new cancer cases each year globally. This trend and overall prospect should be regarded as a completely unacceptable. All phases of cancer discovery and clinical implementation are mutually dependent. Biomedical progress is cyclical, not linear, with revisions and updating perpetually necessary in all interconnected areas. Basic scientific research on all aspects of the HPVs remains essential. To move forward, we must not become complacent that enough has already been achieved. Professionals together with the student generation must proceed with the motivation that global efforts and entrepreneurship can continue to make dramatic advances and replace today’s best achievements. All stakeholders need to be mindful that research is an ongoing process of discovery and updating of priorities. Progress requires steady commitment and engagement. In the research and development community, as our understanding of fundamental principles of health and disease grows, we must identify all possible applicability to health care delivery and translate those scientific achievements into improved clinical capabilities. Effective public health policies, univerally available medical care, unsensationalized and factual education about HPV, and relentless advocacy for prevention, screening and treatment are current priorities of the highest order because they comprise proven deliverables. The details will necessarily differ by culture and society, and most of all across the spectrum from affluence to poverty. We must be advocates who can present compelling rationales for implementation of what is attainable today and for assuring the financial resources and public health infrastructures are available for making much more possible in the coming years. We need penetrance of this message to all global coordinates. We will be inspired by the greatest that we can achieve but will be judged by the least that we end up achieving. In a practical sense, we need expatriot students, scholars and health care workers with firsthand appreciation of HPV to identify and engage professional colleagues in their home countries to define the demonstration projects and provide guidance and driving force. We as a community cannot succeed if the effort is limited to passive receipt of services. We must have the will to create anew and find the regional relevance and value as part of the larger process of self-identity and purpose. Pragmatically, regional manufacture of products is essential, whenever possible, to contribute a direct benefit to the local economies.
There must be an ongoing efforts to achieve widespread – optimally universal – implementation of anti-HPV capabilities in the most affluent societies, wherein safety, efficacy and social value are demonstrated, and frankly, to assure the commercial success of vaccines and molecular screening strategies, and coordinately to balance those achievements with delivery of comparable products and services to the vast and diverse regions of the world where the toll of HPV diseases is most extreme, but where limited resources are over-extended and setting health care and other economic priorities are unimaginably difficult. To this end, major international governmental organizations such as the Global Alliance for Vaccines and Immunisation (GAVI) as a partnership of donor nations, non-governmental organizations, and corporate suppliers are developing and implementing plans that include tiered pricing based on economic abilities of the recipient nations, to expand and support vaccination and molecular-based screening. Such efforts would be dependent, as always, on public education, appreciation of the consequences of not addressing critical needs for HPV management, and on funding of the essential clinical infrastructures. 9. The chapters ahead The closely coordinated and intensively reviewed chapters comprising this up-to-the-moment Monograph introduce the progress in basic research, clinical capability and public health delivery of vaccines and diagnostic screening that have been realized over the 4 years since the previous edition of “Vaccine”. They importantly focus on the remaining challenges in very diverse but nonetheless representative geographic and ethnic regions of the world: (a) Central and Eastern Europe and Central Asia, (b) North Africa and the Extended Middle East, (c) Israel, and (d) Sub-Saharan Africa, thus greatly expanding on the previous attention dedicated to the Caribbean, Central and South American, and Asia Pacific regions. The availability of the series of Monographs in a wide range of world languages further expands their practical utility. Herein we celebrate that the many new achievements elicit a measure of gratification, generate realistic hope, and above all strengthen our resolve to deliver the essential future efforts. This article forms part of a special supplement entitled “Comprehensive Control of HPV Infections and Related Diseases” Vaccine Volume 30, Supplement 5, 2012. Disclosed potential conflict of interest The author has disclosed no potential conflicts of interest and no financial or consulting relations with any company. Thomas R. Broker ∗ University of Alabama at Birmingham, Biochemistry and Molecular Genetics, Birmingham, AL, USA ∗ Tel.:
+1 205 975 8200; fax: +1 205 975 6075. E-mail address: [email protected] 12 June 2012
Contents lists available at SciVerse ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Foreword
Global Prevention and Management of Human Papillomavirus Related Diseases: The Pressing Challenges and the Compelling Opportunities
1. Introduction Where are we now? We have gained tremendous knowledge about human papillomaviruses (HPV) and their interactions with host cells, tissues and immune systems; have validated and implemented strategies for prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools; and substantially increased global awareness of HPV and the many associated diseases of women, men, and children. In so doing, we have come up against new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, the diverse societal standards around the globe concerning reproductive health, and the very wide ranges of national economic capabilities and health care systems. HPV is one of the very few agents of infectious diseases and carcinogenesis where the emerging opportunities for prevention have encountered some socio-political resistance, the nature of which depends on country and culture. In addition, there has been too quick a willingness for policy makers, funding agencies and corporate stakeholders to discount the need for significant new developments, particularly in the arenas of therapeutics and affordable interventions. An expanded repertoire of health care options is urgently needed to bring HPV under short term management and long-term elimination. Thus, we are at cross-roads that will require thoughtful discussions, compassionate decisions and concerted actions. 2. Basic and clinical research into the HPV-associated diseases, infection cycle, host responses, viral counter-responses and the roles of immunity Among the world’s leading causes of morbidity and mortality, cervical and other anogenital cancers have understandably been the primary focus of research and development and the dominant motivation for international cooperative efforts at prevention and control. Further incentive is now emerging from the increasing awareness of and attention to the head and neck manifestations of HPV infections, especially in the oropharyngeal and respiratory tracts. As in the genital mucosa, HPV16 is the predominant agent of severe disease, but the nature of precursor infections is not well understood. In addition, the benign and neoplastic HPV diseases of cutaneous epithelia are providing intriguing comparisons and contrasts with the mucosal lesions. Our appreciation of the size and complexity of the human and animal papillomavirus family continues to grow as many new genotypes are being discovered and characterized using the improved 0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2012.07.071
tools of next-generation DNA sequencing. Most HPV infections are subclinical. Activation of persistent HPV infections and generation of epithelial lesions are largely a function of immune status, and appreciation of the wide range of conditions that result in immunomodulation is growing. Individuals can experience immunosuppression from such causes as organ transplantation, chemotherapy or ionizing radiation treatment for cancers, and autoimmune diseases controlled with anti-proliferative drugs, as well as from debilitating chronic conditions such as physiologic and metabolic diseases, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and other infectious diseases, malnutrition, emotional and physical stresses, pregnancy and aging. Researchers continue to seek a deeper understanding of the mechanisms of HPV transmission and persistence, the molecular players that are engaged in virus–host cell interactions, the control of DNA replication and RNA transcription, including that mediated by regulatory RNAs, and the roles of host immunity and viral counter-measures. Key issues with respect to neoplastic progression of lesions toward cancer concern the changing parameters of gene expression and regulation, post-translational modifications of viral and host proteins, the causes of viral DNA integration into the host cell chromosomes, epigenetic changes in the viral genome during differentiation of the epithelium and during disease progression, and validation of biomarkers indicative of the stage of disease. The molecular details of the HPV life cycle and neoplastic progression are revealing very promising targets for novel therapies against benign lesions and cancer cells in situ or following tumor invasion and metastasis. 3. The success and promise of prophylactic vaccines The quadrivalent and bivalent HPV vaccines have proven to be very safe, with long-term durability of protection against primary infection and a moderate degree of cross-protection against non-vaccine types. Next-generation vaccines comprising many additional genotypes are completing clinical trials. As the formulations become increasingly multivalent, new questions arise concerning the relative efficacies in preventing infection by the different HPV types, wherein immune recognition may become confounded or, alternatively, might show synergy. While we can anticipate successively more effective vaccine strategies, such longer term prospects should in no way diminish the immediate distribution of the best available products to the most vulnerable populations. Much of the present value of vaccination programs resides in the public educational opportunities, increasing social acceptance of HPV vaccines, and the immediate opportunities to
viii
Foreword / Vaccine 30S (2012) vii–x
learn from the successes as well as challenges of the vaccination programs. Nonetheless, maintaining and even expanding research and development of ever better vaccines should remain a high priority commitment from all possible funding sources: governments, not-for-profit foundations and corporations. There is opportunity to confer upon the prophylactic vaccines more physical stability and shelf-life, improvements for long distance delivery, and far lower manufacturing and distribution costs, along with implementation of more comprehensive and embraced national programs for vaccinating girls and boys. Childhood vaccination programs are nearly universal. However, there are few effective strategies for vaccinating pre-adolescents, the currently recommended age for HPV vaccination. A good case can be made for clinical trials to evaluate vaccination at younger ages, within the schedules of pediatric vaccination against other common viral infections to improve coverage and to eliminate the negative rhetoric about the vaccines possibly altering sexual behavior. The significantly stronger immune response to the HPV vaccines at younger ages, compared to adolescents, combined with the durability of protection from infection that is becoming demonstrable, and the small but real risk of HPV infection of children as a result of abuse, together suggest that early vaccination of toddlers could become good public health policy. 4. A range of diagnostic methods Diagnostic screening for HPV lesions is generally available in the developed world but scarce everywhere else for lack of public health policy, professional and general education, media awareness, clinical settings, financial resources and, most crucially, insufficient capacity for effective follow-up treatment of identified lesions. Screening is typically visual and subjective, with even the most highly trained experts sometimes unable to agree. New tests for molecular biomarkers of infection and disease have greatly improved sensitivity and are beginning to help define the degree of present and future risk. Innumerable companies and entrepreneurs are recognizing the market potential for HPV diagnostic tools that will complement conventional Papanicolaou cytology. It must be appreciated that cytology provides an indication of disease, while molecular tests can be either a measure of HPV infection or a direct assessment of disease state. Official recommendations for screening methods and standards need to take into account the various capabilities of the diagnostic tests and recognize that significant improvements in molecular assessments emerge on a regular basis. This Monograph comprehensively reviews the new diagnostic options and the ever more sophisticated yet practical methods to evaluate a growing list of key biomarkers that provide an objective indication of the stage of infection and disease progression. 5. The potential for therapeutic inhibition of persistent infections As the essential follow-up to disease diagnosis, new therapies are needed and they must be effective, minimally impactful on normal tissues and organs, affordable, and available everywhere. We know a great deal about primary infection, long term maintenance of the viral genome, the mechanisms and regulation of RNA transcription and replicative DNA amplification, the dependency on usurping host processes while bypassing host defensive responses, and virion assembly, maturation and shedding. Each of these steps presents multiple opportunities and strategies for therapeutic intervention, which of course must be customized to anatomic site and epithelial type. For cutaneous warts, there are over-the-counter ointments and other topically delivered agents,
although they are relatively nonselective. Topical therapies should be a goal for the mucosal infections. Development of such pharmacological agents must be a funding and research priority. Rather than trying to develop a plethora of related inhibitors capable of blocking each and every viral genotype, a new paradigm could be to target the host processes on which the virus depends for its infectious cycle, with a goal of identifying activities for which the host has redundant pathways but for which the much smaller viral genome has no opportunity for backup. Such generic compounds will need to be variously formulated for application to cutaneous surfaces, to the accessible mucosal surfaces and ultimately to the harder to reach internal mucosa, for example, in the mid- to lower-airway and the esophagus. Also urgently needed are drugs for treatment of lesions that have advanced beyond the benign stage to dysplasias, and another set of inhibitors able to slow down or eradicate carcinomas-in situ and metastatic cancers. The armamentarium of therapeutic capabilities will necessarily include therapeutic vaccines and specific immune stimulants to augment natural immunity. All together, molecular-based therapies are absolutely essential partners in disease prevention and management. They will provide the safety net for anyone who did not receive comprehensive prophylactic vaccines and for all persons who are presented with a positive diagnosis during organized or opportunistic screening. Long into the foreseeable future, this group of patients will numerically dominate over the vaccinated cohorts and provides the compelling rationale for vigorous research and development toward far more effective and far less damaging therapeutic responses to the diversity of HPV diseases. Arguably, screening, early detection and (when eventually possible) relatively simple therapeutic intervention could emerge as more practical than attempts at annual global vaccination of some 100 million children (of any given age cohort), unless and until vaccination becomes affordable, deliverable, and essentially universal and has substantially broader coverage to include most pathogenic mucosotropic genotypes. 6. Appreciation of disease causality and need for management There is inadequate recognition of the social impact of the successive stages of HPV infections: the infants who acquire “low-risk” HPV types 6 and 11 and develop recurrent respiratory papillomatosis; the adolescents with benign but highly contagious lesions; the middle aged with consequences on reproductive capabilities and well being of the mother; the older persons with an increasing risk of oncogenesis. Of the major cancers of women, cervical cancer tragically ends with the most years of life expectancy lost (estimated at 29 years), considerably more than for women succumbing to breast cancer. This places an exceptional – and avoidable – burden on young families, and to a very serious degree on children who lose their mother. Yet these facts have not moved sufficiently into the public discourse. There is also a troubling disjunction between the popular culture, celebrities, and the media, entertainment and fashion industries that popularize sexuality and beauty versus the need for candid and frank discussion about sexual health and the impact of sexually transmitted infections. The biological reality is that early age exposure to and frequent reinfection with the mucosotropic HPV types can have serious long-term outcomes in the form of future cervical, penile and anal cancer, RRP and certain head and neck afflictions. HPV has been a somewhat hidden epidemic because many primary infections spontaneously resolve, while the advanced diseases caused by persistent infections with sporadic viral activity generally require many years to appear. Delayed onset of lesions and periodic episodes of gene expression or quiescence can be attributed to the nature of the papillomavirus family, to
Foreword / Vaccine 30S (2012) vii–x
the immune status of the host, and to occasional local trauma reactivating latent infections. Some of the most serious lesions historically were not assigned to HPV and in many societies still are not attributed to infectious agents. For some in the younger generations, HPV is not seen as a crisis requiring action. Depending on the awareness of each individual concerning the diverse sites and manifestations of HPV diseases, infections may become of concern at different stages, from shortly after acquisition (for example, through sexual activity) and the development of genital warts to the rare and perplexing emergence of juvenile-onset or adult-onset laryngeal papillomas, all the way across the spectrum of disease to internally located high-grade dysplasias and invasive cancers that escape early detection in unscreened individuals. The unpredictable nature of HPV lesions creates a temporal disconnect between the actions leading to infection and the ultimate disease outcomes, and this poses real problems. These include the individual recognition of having an infection and the risk of transmitting it when symptoms are minimal or hidden to the consequences of having lived with an unmanaged infection for a long time, even forgetting about it, only to have serious outcomes arise years later and that are not obviously linked to the primary infection. As a matter of public health care policy, the idiosyncratic nature of HPV infections creates great uncertainty about when and how often to screen and treat. Vaccination obviates most of these uncertainties for individuals and for populations.
7. Implementation of effective public health measures depends on professional and public education, flexible and adaptable policies, and meaningful commitment of resources The current public health challenge is that, from a perspective of costs, the benefits of HPV disease prevention as a result of vaccination – if it is described as averting cancer as contrasted with preventing benign genital warts – are seemingly deferred to the extent that a legislative or executive policy would not show much apparent economic payback to society for many years. Yet no one should lose sight that successful HPV management depends on primary prevention as well as on early diagnosis and treatment of benign disease, where the benefits are immediate and tangible. There must be a conviction that the future matters but is best anticipated now. Significant progress will depend on a measure of faith that HPV prevention and care do not unleash promiscuity but rather sanctify the worth of life and health, personal and societal well-being. These factors seem to create a dilemma for some political leaders, especially because of what they likely perceive as advocating for sexual health starting with pre-adolescents. On the political as well as religious fronts, we cannot let ideologues usurp issues of HPV disease prevention and care to promote misinformation or to prevent sympathetic legislation concerning vaccination, screening programs, sexual health, and women’s and children’s rights. Family planning and contraceptives, as well as reproductive health and safety, are central to the same conversation. No society can fully succeed without respecting and empowering its women and the families they nurture and the communities they build. It is unconscionable that HPV continues to affect so many lives. We must transcend prejudice and marginalization and fully embrace the premise that health and a high quality of life trump at all levels: personal, family, community, ethnic circle, national, and global. General confidence within societies that its members will lead long and healthy lives comprises the foundation on which education of children and then economic opportunity can be built. If we can wrap our best ideas around the challenges of HPV diseases and make visible strides in controlling infections so they do not grow into cancers, then our field can serve as the beacon to
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give direction and motivation to those colleagues who are addressing other major medical challenges. After decades of global effort across the complementing disciplines, we are now so close to that capability. In parallel and with synergy, the brilliant research and public health efforts addressed to the AIDS epidemic, the hard-won achievements in HIV diagnosis, an ever-expanding arsenal of therapeutic agents used in combination, and the compassionate delivery of these capabilities based on multi-tiered pricing and cost-sharing are exemplary. Ultimately, the many lessons being developed in addressing the HPV diseases with respect to current and future generations of vaccines and therapeutic strategies will cycle back to inspire new approaches in AIDS public policy, education, implementation of vaccination programs, and early and regular screening to the benefit of controlling HIV. How do we estimate the cost of inaction as we consider the cost of action? Notably, how do we quantify the psychological impact of HPV infections, lesions and advanced diseases on the individual, the partner, and the family? How do we factor in the benefits of health within the community? How do we learn partnership for good preventive measures and responsive health initiatives and find common purpose, when it seems this may not be politically expedient, or perhaps economically appreciated? How do we justify prioritizing away well being and even life when the solutions are at hand to bring under control and largely eliminate the second most common cancer among women worldwide? It needs to be stated that there is a puzzling discrepancy between the public embrace of funding for breast cancer research and treatment vs. the far more limited support of research on anogenital cancers associated with HPV infections, when both afflictions affect women primarily and in nearly equal numbers globally. A sincere and meaningful investment in HPV management and health care needs to be seen as a centrist value benefitting the family, the community, and the economy. We must find ways to implement high technology in a diverse world where the education of health care providers concerning HPV diseases lags and there is a severe deficiency of adequately trained specialists to bring the current capabilities to all people. The challenge is to succeed when there are so many medical and nonmedical interests that are competing for limited resources. There do need to be various models for delivery of best possible care to individuals, depending on the local and national economic status. In some settings, long-term prevention is attainable, but not with current products and services. There remains an urgent need for public funding agencies as well as commercial entities to realize that anyone already harboring HPV is going to be a candidate for diagnostic tests and for therapeutics. Surgery is the least desirable option for treatment – a last resort – compared to early and regular screening, detection of incipient disease while the lesion is benign and the HPV is an autonomously replicating plasmid, and where immune stimulants, therapeutic vaccines and small molecule pharmaceuticals are most likely to be effective.
8. The time for universal response is now HPV is an equal opportunity pathogen. It is part of the human condition, well adapted to infecting the epithelia and so prevalent as to be almost unavoidable. Unlike the acute viruses that establish severe diseases shortly after infection, the modus operandi of HPV infections is primarily latent, subclinical, and opportunistic for sporadic reproduction and transmission, and HPV is generally in a state of quasi-equilibrium with the host. HPV is a real agent of affliction, a social disease of a sociable human species that is highly communicable, and susceptibility to it is most definitely not a life-style choice. HPV is both personal and interpersonal, just as it is intergenerational. We must diminish the barriers to informed options
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and available choices, whether those impediments are financial, educational, political or religious, and then focus on proven management without prejudice. Societies need to acknowledge the extraordinary prevalence and virtual unavoidability of infection and put aside any inclination to cast blame, exploit shame, or castigate people for acquisition of HPV infections. Their importance as a precursor to carcinomas should not be dismissed for any reason – in fact, these diseases are the leading preventable cancers against which humanity can readily make progress at reduction. Nonetheless, as a result of substantial population growth in the most economically stressed nations of the world, combined with the presently limited possibilities for widespread introduction of vaccines, universal screening and effective early treatment in these regions, it is likely that the next 40 years will experience as much as a 50% increase in cervical and other HPV-associated anogenital cancer cases and deaths compared to the current terrible impact of more than one-half million new cancer cases each year globally. This trend and overall prospect should be regarded as a completely unacceptable. All phases of cancer discovery and clinical implementation are mutually dependent. Biomedical progress is cyclical, not linear, with revisions and updating perpetually necessary in all interconnected areas. Basic scientific research on all aspects of the HPVs remains essential. To move forward, we must not become complacent that enough has already been achieved. Professionals together with the student generation must proceed with the motivation that global efforts and entrepreneurship can continue to make dramatic advances and replace today’s best achievements. All stakeholders need to be mindful that research is an ongoing process of discovery and updating of priorities. Progress requires steady commitment and engagement. In the research and development community, as our understanding of fundamental principles of health and disease grows, we must identify all possible applicability to health care delivery and translate those scientific achievements into improved clinical capabilities. Effective public health policies, univerally available medical care, unsensationalized and factual education about HPV, and relentless advocacy for prevention, screening and treatment are current priorities of the highest order because they comprise proven deliverables. The details will necessarily differ by culture and society, and most of all across the spectrum from affluence to poverty. We must be advocates who can present compelling rationales for implementation of what is attainable today and for assuring the financial resources and public health infrastructures are available for making much more possible in the coming years. We need penetrance of this message to all global coordinates. We will be inspired by the greatest that we can achieve but will be judged by the least that we end up achieving. In a practical sense, we need expatriot students, scholars and health care workers with firsthand appreciation of HPV to identify and engage professional colleagues in their home countries to define the demonstration projects and provide guidance and driving force. We as a community cannot succeed if the effort is limited to passive receipt of services. We must have the will to create anew and find the regional relevance and value as part of the larger process of self-identity and purpose. Pragmatically, regional manufacture of products is essential, whenever possible, to contribute a direct benefit to the local economies.
There must be an ongoing efforts to achieve widespread – optimally universal – implementation of anti-HPV capabilities in the most affluent societies, wherein safety, efficacy and social value are demonstrated, and frankly, to assure the commercial success of vaccines and molecular screening strategies, and coordinately to balance those achievements with delivery of comparable products and services to the vast and diverse regions of the world where the toll of HPV diseases is most extreme, but where limited resources are over-extended and setting health care and other economic priorities are unimaginably difficult. To this end, major international governmental organizations such as the Global Alliance for Vaccines and Immunisation (GAVI) as a partnership of donor nations, non-governmental organizations, and corporate suppliers are developing and implementing plans that include tiered pricing based on economic abilities of the recipient nations, to expand and support vaccination and molecular-based screening. Such efforts would be dependent, as always, on public education, appreciation of the consequences of not addressing critical needs for HPV management, and on funding of the essential clinical infrastructures. 9. The chapters ahead The closely coordinated and intensively reviewed chapters comprising this up-to-the-moment Monograph introduce the progress in basic research, clinical capability and public health delivery of vaccines and diagnostic screening that have been realized over the 4 years since the previous edition of “Vaccine”. They importantly focus on the remaining challenges in very diverse but nonetheless representative geographic and ethnic regions of the world: (a) Central and Eastern Europe and Central Asia, (b) North Africa and the Extended Middle East, (c) Israel, and (d) Sub-Saharan Africa, thus greatly expanding on the previous attention dedicated to the Caribbean, Central and South American, and Asia Pacific regions. The availability of the series of Monographs in a wide range of world languages further expands their practical utility. Herein we celebrate that the many new achievements elicit a measure of gratification, generate realistic hope, and above all strengthen our resolve to deliver the essential future efforts. This article forms part of a special supplement entitled “Comprehensive Control of HPV Infections and Related Diseases” Vaccine Volume 30, Supplement 5, 2012. Disclosed potential conflict of interest The author has disclosed no potential conflicts of interest and no financial or consulting relations with any company. Thomas R. Broker ∗ University of Alabama at Birmingham, Biochemistry and Molecular Genetics, Birmingham, AL, USA ∗ Tel.:
+1 205 975 8200; fax: +1 205 975 6075. E-mail address: [email protected] 12 June 2012