Opportunities to Prevent and Mitigate the Impact of Chronic Diseases Caused by Infectious Agents
The ultimate goal in identifying connections between infectious agents and chronic diseases is to find better ways to cure, or even prevent, those diseases. Various therapeutic approaches may prove fruitful and deserve continued attention. Several of these areas were explored during the workshop, along with ways to most effectively move therapeutic methods from the laboratory into widespread practice. Discussion was somewhat limited, however, by time constraints and the availability of speakers.
Among therapeutic possibilities, vaccines hold a special attraction, given their unique record of totally eliminating or eradicating several target diseases. Recent advances in molecular biology and genetics have provided powerful new methods for vaccine development. Of particular importance is the possibility offered by the new sciences of genomics and proteomics to detect the relevant antigens and to identify specific aspects of immunity that should be enhanced by the vaccine. There also have been important advances made in understanding the processes of acquired immunity and the pathogenesis of various diseases (including the interplay between microbe and host). Collectively, these efforts may point the way to the eventual development of effective means to control at least some chronic diseases.
To underpin scientific efforts, sound planning and program management is a must. In order to most effectively develop and implement new prevention and intervention efforts—encompassing vaccines and a host of other means—there will need to be in place an overarching strategy to guide efforts across a range of fronts. This strategy will rely heavily on collaborations to enhance the productiv-
ity of independent investigators, to integrate rigorously executed laboratory techniques into well-designed epidemiologic studies and surveillance systems, and to complement short-term studies with long-term follow-up. It also will be necessary to develop funding mechanisms that recognize the value of such crosscutting efforts.
Helena Mäkelä described the recent advances that are raising promise for the development of vaccines to fight chronic diseases, either by preventing acute infection or by curing established persistent infection. The possibility of developing a vaccine to fight cardiovascular disease, one of the major killers in the United States and worldwide, served as an example. The vaccine would target Chlamydia pneumoniae, which has been linked to atherosclerosis by several lines of evidence, though its causative role has not been conclusively established. Among efforts to date, researchers have developed an experimental model of C. pneumoniae in the mouse, and work with this system is yielding fundamental lessons. Also, a number of candidate vaccines have been prepared and tested for prevention of acute infection, and several of them have proved to afford at least partial protection.
Siobhán O’Conner presented a blueprint for the strategic approach that will be needed to integrate laboratory research, epidemiology, and surveillance. This blueprint is based on several basic tenets that stress the importance of standardized or comparable case definitions—for the infection as well as the outcome—and universally high standards of specificity, sensitivity, and reproducibility of laboratory assays. As the field advances, a number of crosscutting issues also will require continuous attention. One such issue will be the need to provide adequate medical education (both academic training and continuing education) so that health professionals will be able to capitalize on the benefits afforded by confirmed and newly discovered links between infectious agents and chronic diseases, while at the same time protecting the well-being of their patients. O’Connor concluded that although the links between microbial infections and chronic diseases can be complex and multifactorial, they can be characterized—and beneficial interventions against infection can be designed.
DEVELOPING VACCINES FOR PREVENTION OF CHRONIC DISEASE
P. Helena Mäkelä, M.D., Ph.D.*
National Public Health Institute, Helsinki, Finland
The potential of vaccination as an intervention is undeniable. Vaccines have
the unique record of totally eliminating or eradicating their target disease—smallpox in the recent past, polio likely to happen in the near future.
The important point is that vaccination has a target separate and different from the human body, thus making it possible to destroy the microbe without harm to the host. Vaccination is an exciting novel concept for intervention in chronic diseases arising from the realization of a link of many chronic conditions with infectious agents.
A second aspect that sets vaccination apart from other interventions is that it is based on acquired immunity, the powerful defense system of the mammalian body. It provides a very sophisticated machinery for defense against the target microbe; what vaccination needs to do is to enhance its activity and direct it to the specified target.
Recent advances of molecular biology and genetics have provided vaccine development with very powerful methods of research. These include the possibilities offered by genomics and proteomics to detect the relevant antigens to include in the vaccine and to identify the branches of immunity that should be enhanced by the new vaccines. At least equally important are the advances recently made and to be made in understanding the processes of acquired immunity on one hand and of pathogenesis of the diseases—an interplay between the microbe and host—on the other. Also to be included here are new means of producing the desired vaccine antigens in a heterologous host, e.g., E. coli or yeast, thus bypassing difficulties of growing a fastidious microbe or purifying a specific protein. An even more sophisticated form of vaccination is administration, instead of a vaccine antigen, its gene inserted in the genome of a viral or bacterial vector or a naked piece of nucleic acid, relying on its expression in the vaccinated individual. The advances in immunology suggest possibilities of developing novel adjuvants to enhance or suppress selected responses. Increasing knowledge of mucosal immunity may allow the development of more specific vaccines according to the site of the microbial invasion to be prevented.
However, many problems and questions immediately arise:
How certain is the link of a chronic disease to the microbe suspected as the culprit? A major barrier to vaccine development is not knowing how great an investment is needed before a vaccine is on the market. Obviously the industry will want to closely assess all information about the link when making decisions of starting the development process or of continuing it throughout. The public sector might be less sensitive to this kind of uncertainty, but it does not as a rule have the capacity and know-how to carry out the full process of modern vaccine development. On the other hand, on the competitive market, early start of the development would be an important advantage.
What is known of the pathogenesis of the chronic disease and the infection behind it? Important questions with immediate relevance to vaccine development are whether or not the chronic disease is dependent on the continued pres-
ence and persistence, of the microbe (as seems to be the case with gastric ulcer associated with Helicobacter pylori infection) or mediated by a process once set in motion or fully carried out by the microbe that then disappears (the latter may be the case with juvenile diabetes due to destruction of islet cells associated with a viral infection).
How does acquired immunity affect the condition? In case of persistent infection we would need to know the characteristics of the immunity that allows the infection to persist—which component is missing and why, how could we change the situation to convert the persistence-associated immunity to a protective immunity? Would it be possible to affect this during the persistent state so that the persistence could be cured? For vaccine development, the characteristics of protective immunity for each infection would need to be known. Questions that can be asked to help this characterization include the role of antibodies (if yes, to which antigens? is high affinity essential? would some isotype be specifically needed?) and the role of T cells (and further, whether it is the CD4+ cells stimulated by antigenic peptide bound to the MCH class II molecules on the surface of antigen-presenting cells or the CD8+ cells stimulated by peptide bound to class I molecules, and whether it should be a Th 1- or Th 2-type response, each associated with its separate sets of cytokines).
Do we have an experimental animal model? The use of such a model is normally an essential part of vaccine development that helps to convert the theoretical findings at the laboratory bench to a form on which we can predict what can be expected of the vaccine’s performance in humans. The better the model, the more we can learn about the candidate vaccine, and more importantly, about the pathogenesis of the infection, the disease, and the immunity. Nevertheless, it is also true that no animal experiments can replace final clinical trials in which the vaccine is evaluated in its real target population.
Of the problems listed, the question of persistent infection requires special attention as a feature not considered in the context of conventional vaccines. Again, there are more open questions than facts. In order to persist, the microbe will have to hide from both innate host defenses and the effector mechanisms of acquired immunity. This raises a series of questions. Where exactly does this take place? How can we identify—diagnose—a persistent infection? What are the host factors that induce persistence and/or allow it to continue? What about the microbe? Is it dormant, with only a few genes active? If so, which ones are they and what are their products (which might be the sought-after vaccine antigens)? The intracellular space is protected from antibodies, and indeed utilized by most persisting microbes. But then we need to ask in which cells, in which part of the body (e.g., Herpes viruses in the nuclei of the neurons in sensoric ganglia), and in which compartment of the cells? Intracellular bacteria most often enter via phagocytic vacuoles, but can then further modify their microenvironment by regulating the acidification of the vacuolar fluid, fusion with lysosomal granules, etc.
Strategies for Vaccination to Prevent Chronic Disease Associated with an Infectious Agent
The many varieties in which microbes may lead to chronic conditions suggest that different strategies of vaccination will be needed. These can be classified as one of two basic types: one, preventing the primary acute infection, and two, curing the persistent infection.
Prevention of acute infection has many advantages. It would not differ from the established concept of vaccination. Vaccine development would be straightforward up to and including the clinical efficacy trial, in which the prevention of the acute infection would be the outcome measured. Thus, one would not need to worry about the pathogenesis of the chronic disease. The success of this approach has indeed been demonstrated for the hepatitis B vaccine (reduction of chronic hepatitis and liver cancer in 10 years following vaccination in infancy [Lee and Ko, 1997]). This vaccine is now recommended by the World Health Organization for use in the infant immunization program all over the world. An effective vaccination program reaching a high coverage rate would also be likely to reduce the transmission of the infectious agent and thereby lead to herd immunity further enhancing the overall effect of the program. Vaccination of this type would seem very attractive for prevention of infections that lead to the chronic disease relatively early in life, e.g., for juvenile diabetes, if the connection to the infectious agent is established and a vaccine available.
For a vaccine of this type to succeed it would need to be highly efficacious, leading to full elimination of the infective agent and continued protection from eventual new encounters. Specifically it should not allow persistence to develop, and demonstration of this effect should be included in the final tests for vaccine licensure. From a programmatic point of view this type of vaccine should be administered before the infection is normally acquired, which usually means early in infancy. This would not cause problems as such since most vaccinations now take place within the infant immunization program, assuring an effective infrastructure for vaccine delivery and good access to a high proportion of all children born. However, the vaccine should be effective enough to provide protection up to an advanced age—preferably through life, a fairly strict requirement. Furthermore, the main problem may lie in motivating the inclusion of one more vaccine among the injections given to infants, if the intended benefits—prevention of a chronic disease—will only be seen decades later.
The second alternative, curing an already established persistent infection, would be an answer to the programmatic problem just described. The vaccine could be given later in life, at a time when individuals start to worry about the dangers of various chronic conditions affecting higher age groups. Motivation for vaccination would be especially high among those who have already experienced symptoms of the chronic disease. On the other hand, so far there is no established infrastructure or system for reaching the adults who should be vaccinated, al-
though one is currently needed for efficient delivery of the annual influenza vaccine. However, the development of a vaccine capable of curing an established persistent infection is a formidable challenge, and no such vaccine exists as a model.
The Example of Cardiovascular Disease
The role of Chlamydia pneumoniae in atherosclerosis is supported by several lines of evidence but has not been conclusively established (Saikku, 1999; Grayston, 2000; O’Connor et al., 2001). This is a definite handicap for serious investment in vaccine development. On the other hand, the disease is so prevalent and well known as the major cause of death for those aged 40 years and above that the potential market for a vaccine would be very lucrative. Therefore, let us examine how a vaccine could be developed and used.
C. pneumoniae is an obligate intracellular gram-negative bacterium. It has a small genome of approximately 1.2 million nucleotides fully sequenced. Its primary mode of transmission is via the respiratory route from man to man, and the respiratory infection that develops is usually mild but can also progress to pneumonia. The first infection occurs in childhood and in early adolescence, repeated infections are common. Fifty to seventy percent of adults are seropositive. There is little accurate information about acquired immunity in man; antibody responses are easily demonstrated to several antigens, and the same is true of T-cell responses. However, the immunity following infection does not prevent repeated infections and allows the development of persistent infection. It is not clear whether or not the immunity itself plays a critical role in the pathogenesis of the cardiovascular disease.
There is quite a bit of evidence for persistence of C. pneumoniae after infection: it has been identified in peripheral blood mononuclear cells and in vascular plaques of individuals with other osclerotic disease. The role and mechanisms of action of the persistent bacteria in the pathogenesis of cardiovascular disease is open—potential mechanisms suggested include local reactivation of the bacteria with resulting local inflammation, activation of the blood coagulation system, and induction of various cytokines either directly by the bacteria or their components (especially lipopolysaccharide) or in conjunction with immune cells and/or antibodies.
An experimental model of C. pneumoniae infection has been developed in the mouse (Kaukoranta-Tolvanen et al., 1993; Penttilä et al., 1998). The acute infection resulting from intranasal inoculation of moderate doses of C. pneumoniae (105–106 inclusion forming units [IFUs]) resembles the human infection in many ways. It is a pneumonia that is symptomatically mild. The bacteria are seen in the lungs inside epithelial cells and macrophages; their numbers stay high for 1–2 weeks and then decrease to undetectable (culture-negative) in 3–4 weeks. An immune response can be seen in antibody production and T-cell
responses. Most importantly, the infection results in partial protection seen on reinfection when a similar intranasal inoculation results in a lower peak level of IFUs and their disappearance in 1–2 weeks.
The role of different branches of the immune system has been studied in the mouse model using gene-deleted mice as well as mice injected with antibodies to deplete specific immune cells or interferon (Penttilä et al., 1999; Rottenberg et al., 1999). These experiments have shown that the cure of the acute infection did not require antibodies or either CD4+ of CD8+ T-cells; however, in more severely deleted mice lacking both types of T cells cultivable bacteria continued to be present in the lungs in relatively high numbers. Interferon gamma (INF-γ) was identified as an important mediator. The protective immunity seen on reinfection would be more relevant from the vaccine development point of view. The experimental findings pointed at the central role of CD8+ cells in this protection: if they were depleted, the reinfection proceeded at the same kinetics as the primary infection. IFN-γ appeared to be a mediator of cure also in this phase. In summary, consistent with the intracellular multiplication of C. pneumoniae, T cells, and, especially CD8+ T cells, seem to have a key position in protective immunity.
A number of candidate vaccines have been prepared and tested for prevention of the acute infection (Penttilä et al., 2000; Svanholm et al., 2000; Murdin et al., 2000). Killed C. pneumoniae particles (EB, the infectious elementary bodies) afforded partial protection that was less strong than seen during recovery from a previous infection. Several C. pneumoniae genes given in the form of naked DNA vaccines have likewise provided partial protection but again less strong than seen in reinfection. The immune response to the products of the respective C. pneumoniae genes were easily measurable as both antibody and T-cell responses, including cytotoxic CD8+ lymphocytes (CTL). In the same approach, several other genes have failed to induce protection.
The key determinants of protection in the acute infection model are still not known. The prominent role of the intracellular life of C. pneumoniae is consistent with the importance of CD8+ cells in protective immunity. The vaccines that so far have given positive signals of protection have stimulated CD8+ cells. Then why only incomplete protection? Is it due to us not having identified the right antigen(s)? Quite possibly so: most of the C. pneumoniae gene products likely remain within the body of the gram-negative bacterium, which further resides within the intracellular vesicle known as inclusion body. Therefore only few proteins would be likely to reach the cytoplasm of the host cell, a primary requirement in order to be processed, associated with the nascent MHC class I molecules and presented by these on the cell surface essential for recognition by immune CTLs. These proteins would most likely be protein(s) purposely exported by the bacteria to interact with the host cell components and subvert these to the benefit of the microbe. In other gram-negative bacteria, such proteins are typically secreted by a specific “Type III Secretion” machinery, and evidence is accumulat-
ing for the importance of the Type III system also in Chlamydiae (Fields and Hackstadt, 2000; Bavoil et al., 2000).
In addition to hiding from the immune system by their intracellular lifestyle, Chlamydiae have also developed a sophisticated mechanism for thwarting the MHC-based immune recognition. This takes place by downregulation of the transcription of both MHC class I and class II molecules; the downregulation is mediated by specific degradation by C. pneumoniae-coded proteins of host cell factors promoting the transcription (Zhong et al., 1999, 2000). This is an entirely novel mechanism of immune evasion by pathogenic microbes, and certainly presents a formidable challenge for vaccine development.
The immune recognition and subsequent killing of the infected cells is not necessarily uniform for all cells; thus the infection may proceed or become persistent in only a part of the initially infected cells. Then we are faced with the likely possibility that antigen presentation in the persistently infected cells will differ from that seen during the acute phase. Very likely, therefore, a vaccine capable of preventing and curing the persistent infection will be different from the one preventing the acute infection. The mouse model may be suitable for studying the persistent infection, too. C. pneumoniae-specific DNA can be detected by PCR for at least 2 months after cultures have turned negative, and the dormant infection can be reactivated by immunosuppressive treatment of the mice (Malinverni et al., 1995; Laitinen et al., 1996). Our experience with both methods of detection suggests that persistence develops in part of the animals only, a further point of resemblance to the human C. pneumoniae infection. Persistent infection can also be detected in vitro in cell cultures of C. pneumoniae (Byrne et al., 2001; Pantoja et al., 2001). Such a mode of growth can be induced by treatment of the culture with IFN-γ or sublethal doses of antibiotics or by depletion of tryptophan. The morphology of the inclusion bodies in which C. pneumoniae normally multiply and mature to the infectious EB forms changes and no EBs are seen.
Crucial questions on the path to the development of a vaccine aimed at curing the persistent C. pneumoniae infection then include:
Which C. pneumoniae proteins are produced during persistence?
Which of them reach the cytoplasm?
Are these processed for MHC class I presentation?
Are the processed epitopes presented on the cell surface or is the C. pneumoniae-mediated downregulation of MHC class I complete?
Is the recognition by CD8+ cells efficient, leading to immunization?
Is the recognition by specific CTLs efficient, leading to cell lysis or killing?
Are there infected cells escaping the CTLs?
If we are lucky, answers to these questions as well as the large amount of work devoted to developing vaccines for other Chlamydiae (C. trachomatis, C. psittaci) may lead to the development of the desired vaccine for prevention of C. pneumoniae-associated cardiovascular disease (Igietseme et al., 2002). However, other questions remain. We would need to define how the vaccine will be used, the main alternative being incorporation in the infant immunization program or recommended to all at a certain age. If the former, who will pay for the cost of vaccination to prevent a disease perhaps 50 years later? If the latter, will the target be all individuals or only males, and at which age, 30 or 40 or 50 years?
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TOWARD A STRATEGIC APPROACH: INTEGRATING EPIDEMIOLOGY, LABORATORY RESEARCH, AND SURVEILLANCE; SETTING PRIORITIES
Siobhán O’Connor, M.D., M.P.H.
Assistant to the Director of the National Center for Infectious Diseases
[For Infectious Causes of Chronic Diseases]
Centers for Disease Control and Prevention, Atlanta, GA
Evidence that microbes are at the root of chronic conditions such as peptic ulcer disease, Whipple’s disease, hepatocellular carcinoma, and cervical cancer has transformed medicine. These examples underscore the plausibility that infectious agents might be linked to numerous other non-communicable chronic conditions. Indeed, research into speculative and as yet to be proposed associations can no longer be viewed as “fishing expeditions,” despite the investigative challenges. Strategies that use collaborations to enhance the productivity of independent investigators, integrate rigorously executed laboratory techniques into well-designed epidemiologic studies and surveillance systems, and complement short-term studies with long-term follow-up can overcome the hurdles to create new prevention and intervention opportunities. Balancing research on potential infectious links for common chronic conditions, in which the contribution of microbes to overall burden could be minor, with that on less common diseases, perhaps likely to have a primary infectious cause, could benefit many.
Certain basic tenets, however, are crucial to successfully defining, characterizing, and mitigating the burden of chronic diseases that is induced by infectious diseases. Widespread use of standardized or comparable case definitions—for the
infection and the outcome—is needed for comparisons across studies and conclusions on causality. So, too, are universally high standards of specificity, sensitivity, and reproducibility in laboratory assays, applied to appropriate specimens and controls. Minimum performance criteria are feasible, even when investigator creativity enters uncharted territory or population and exposure differences impact reproducibility. Peer review journals can reinforce these standards if publication depends upon the use of sound epidemiologic design and laboratory assays capable of supporting the conclusions.
Building on the Basics
From these basics, integration and complementation of laboratory elements with epidemiologic studies and surveillance systems can clarify new and suspected associations. However, this will require greater investment in:
Pathogen discovery activities that: identify novel agents, define which species of known agents impart chronic sequelae, and detect agents in alternative tissues;
Development of new and improved laboratory technologies to advance pathogen discovery and the detection of known agents;
Expansion of viral screening methodology; and
Continued development of improved, more sensitive and specific laboratory diagnostic assays that can identify an infectious root of disease at the site of pathology or a distant site, and distinguish active from latent or past infection.
Demonstrated in HIV/AIDS, human herpesvirus 8-associated Kaposi’s sarcoma and Chlamydia trachomatis-related reactive arthritis, among others, observational and applied (laboratory) epidemiology remain powerful tools by which to recognize infection-chronic disease associations. Therefore, just as vital will be a parallel investment in epidemiology that emphasizes:
Linking of databases—for infection-chronic disease associations, infectious diseases, and chronic syndromes—designed or modified to be compatible;
Observational epidemiology to identify clusters and trends;
Application of validated pathogen discovery technology to further describe the epidemiology of infections and identify potential infection-chronic disease links;
Achieving balance between cross-sectional studies and longitudinal cohorts of individuals affected and unaffected by a chronic disease, including those infected and uninfected;
Longitudinal follow-up of infectious exposures through surveillance systems (e.g., state-based FoodNet surveillance) and cohorts of recently infected people; and
Banking specimens for analysis with future technology and to study newly proposed etiologic associations.
As these options are considered, it will be important to plan, prioritize, and invest in research that addresses certain key issues, including studies that:
Define temporal relationships between infection and disease, the stage of infection that determines chronic outcome (e.g., first infection, re-infection, persistent infection, co-infections, or a subsequent cross-reacting infection);
Clarify the stage at which infection must be prevented or treated to minimize or eliminate chronic sequelae—intervention should decrease the chronic disease burden;
Support multi-center/multi-investigator collaborations that pool findings with comparable case-definitions, study designs, and validated laboratory assays to increase the power and statistical significance of results;
Initiate or expand existing multi-national and multi-racial/ethnic studies that can identify groups at high risk for infection-related chronic sequelae (because of genetic, environmental, cultural, or multifactorial predisposition); and
As appropriate, expand cohorts and specimen sampling in established systems (e.g., NHANES) in order to study less common conditions and high risk populations OR establish new networks, building on systems such as managed care organizations.
Complementary to these issues will be questions of etiopathogenesis. By what process(es) does infection influence chronic sequelae? For some associations, it will be important to first identify the links and potential interventions, later elucidating the pathway from infection to disease. In other situations, understanding mechanisms of pathogenesis can spur research to consider microbial roots of disease. This is certain to be a dynamic area in which a balanced approach may be the most productive.
Strategies that build on fundamentals of sound science are likely to identify and clarify additional infectious disease-chronic disease links, confirming this arena to be both our challenge and our future. Some investments of today may yield early answers, while other returns may take years. That is the nature of the unknown and of chronic conditions. However, the potential benefits of these investments to populations and to individuals are great—greatest if investment begins now. As the field expands two additional, crosscutting issues call for continuous consideration:
To capitalize on the benefits afforded by confirmed and newly discovered infection-chronic disease links, medical education (training and continuing education) must improve recognition of known and potential links, the attendant intervention opportunities, and the cautions against inappropriate therapies; and
The potential changes that population migrations and individual travel impart on the distribution and character of even established associations create an ongoing need for surveillance.
Although the links between infectious diseases and chronic diseases can be complex and multifactorial, they can be characterized, and beneficial interventions against infection designed. Most fruitful is an approach that increases investments in the laboratory, epidemiology, and surveillance, emphasizing integration of these elements and collaborations that can increase the yield of research and medical science.