Collaborative Multidisciplinary Workshop Report: Progress toward a<i>Chlamydia pneumoniae</i>Vaccine

Chlamydia pneumoniae is recognized as a significant human pathogen [1]. It is a common cause of community-acquired pneumonia and of upper respiratory tract disease, including bronchitis and sinusitis. Infection has also been associated with other respiratory tract diseases, such as asthmatic bronchitis, adult-onset asthma, and chronic obstructive pulmonary disease. However, it is the strong association between C. pneumoniae infection and atherosclerosis that has drawn most attention to the pathogen, and although the association has not been proven to be causal, it is becoming recognized as potentially highly important. Given our knowledge of the role of C. pneumoniae as a human pathogen, an effective vaccine against C. pneumoniae would be of significant public health benefit. However, C. pneumoniae vaccines are only at the earliest stages of development. The Vaccine Development and Field Trials Workshop Group was convened to consider the feasibility of conducting clinical trials for a C. pneumoniae vaccine and to identify research activities necessary to support the testing and licensing of a vaccine. The workshop group chose to address these issues by considering two questions: (1) What information is necessary to develop a safe vaccine and to initiate vaccine trials, and (2) how could the disciplines represented by other meeting workshop groups contribute to the process of implementing vaccine trials? Before discussing our group's consideration of these questions, it may be useful to consider the steps involved in developing a candidate vaccine, from basic research to licensure, since the process is not always clear to those working outside the industrial or regulatory environments. The following discussion necessarily simplifies a complex process. For a comprehensive overview of the process, both in general and for specific products, refer to [2–5]. In very broad terms, the stages of vaccine development include antigen discovery, antigen formulation, scale-up, testing (safety, consistency, immunogenicity), clinical trials to show safety and efficacy, licensure and recommendation, and post-marketing surveillance for continued safety and efficacy. Antigen discovery is the identification of candidate vaccine antigens, usually proteins but possibly other molecules, such as polysaccharides. Antigens may be whole organisms (e.g., poliovirus), significant subunits of the whole organism, such as virus capsids (e.g., split influenza virus vaccines), or purified molecules (e.g., tetanus toxin, pneumococcal capsular polysaccharides). Antigens obviously need to elicit a protective and durable immune response, but nonimmunological factors, such as the stability of the antigen, its solubility, or ease of purification, may also influence the choice of antigens to carry forward into a licensed product. Antigen formulation is directed to identifying a means of safely and effectively delivering the antigen. Even when a protective antigen is known, it is not always a straightforward process to use it in a vaccine to elicit a protective immune response. Methods of antigen delivery include live attenuated organisms (e.g., poliovirus), inactivated whole organisms (e.g., hepatitis A virus), inactivated toxins (e.g., tetanus toxoid), defined antigens delivered with an adjuvant (e.g., diphtheria toxoid with the adjuvant alum), or the use of viral vectors or DNA to deliver genes encoding selected antigens (e.g., the use of poxvirus vectors to deliver human immunodeficiency virus antigens). Scale-up is the process of taking antigen production and formulation from the laboratory bench to a process that can reproducibly and economically produce hundreds of thousands of doses. The complexity of this process should not be underestimated. Biological, chemical, physical, and engineering problems associated not only with the production of an antigen but also with its subsequent purification must be solved. Viable solutions range from multiple repetitions of a successful small-scale process (e.g., the manufacture of influenza vaccine in eggs) to the development of appropriately scaled single-step processes (e.g., the growth of poliovirus on Vero cells in 1000-L bioreactors for the production of the inactivated poliovirus vaccine). Testing covers a multitude of processes designed to ensure that a product is potent, consistent in quality, and safe before it is put into clinical trials. In the later stages of preclinical development, and certainly by the time that a product enters clinical trials, testing is an integral part of the quality-assurance and quality-control processes that are fundamental to the manufacture of biological products. Examples of necessary variables to be tested include toxicity in small animals, lot-to-lot variation in antigen purity or immunogenicity, successful inactivation of virus in inactivated vaccines, stability of formulated product during storage, and immunogenicity or protective efficacy in an appropriate animal model. Above all, it is essential to provide adequate assurance that a product is safe before it can be considered for administration to humans. From the perspective of many with scientific or clinical backgrounds, testing is arguably the least interesting stage of vaccine development; however, inadequate attention to testing will usually be fatal to the development of a vaccine. Clinical trials are the process by which a defined product is tested for safety and efficacy in humans. Entry of a product into clinical trials requires an Investigational New Drug application to the Food and Drug Administration (FDA) in the United States or a similar application to an equivalent administrative body in other countries. The application includes a description of the product, its intended use, all data relating to its safety, purity, and potency, and the clinical trial design. The identification of the group or groups who would benefit from vaccination is critical to this stage, as it will determine the intended use of the product. If several different target groups have been identified (e.g., hepatitis A for children as opposed to adult travelers), then different and appropriately designed clinical trials will be required, and manufacturers and regulatory agencies may well treat these as separate products even if the antigen and formulation are very similar. Clinical trials of a vaccine usually comprise three phases: phase I to demonstrate safety and required dose; phase II to demonstrate immunogenicity; and phase III to demonstrate efficacy. In practice, phases may overlap and reiterate; for example, vaccines intended for young children are first tested in healthy adults and older children. The demonstration of safety is a principal concern at all stages. The clinical trial process culminates with a Biologics License Application (BLA), which covers how and where the product is to be made and tested, evidence that lot-to-lot variation of a product is within acceptable limits, the results of the clinical trials, and the proposed indications for which the product would be used (e.g., for the prevention of hepatitis A infection in adults). The BLA replaces what were formerly two separate applications, a Product License Application covering the product and an Establishment License Application covering the product manufacturer. The granting of a license allows a product to be marketed, but its use would also depend upon the guidelines and recommendations of bodies such as the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention, the American Academy of Pediatrics, the American College of Physicians, and the American Academy of Family Physicians. For example, inactivated poliovirus vaccine (IPV) has been licensed in the United States for many years, but its use was relatively limited historically since the live attenuated oral poliovirus vaccine (OPV) subsequently was recommended for routine childhood immunization. In 1997, a sequential IPV-OPV regimen was added as an option, with recommendations for this as the preferred regimen beginning in 1999 [6, 7]. As of 1 January 2000, the IPV-only regimen is recommended for doses for childhood poliomyelitis immunization [8]. Formal recommendations have profound effects on vaccine usage in clinical practice. It is important to realize granting a license and launching a vaccine onto the market does not end the development process. For example, monitoring of vaccinees for adverse events may reveal safety issues that are too infrequent to be detected during clinical trials. The manufacturer may choose to improve the production process, to change the product formulation, or to continue clinical testing in target populations not covered by the existing license or recommendations. Regulatory agencies may request changes to the product or its use. The recent report of possible increased association of intussusception with rotavirus vaccine exemplifies the importance of postmarketing surveillance and the rapidity of changes that occur for vaccine recommendations [9, 10]. Depending on the magnitude and significance of the proposed change, some level of regulatory approval will be required, up to and including an entirely new license application. In considering what would be needed to take a candidate C. pneumoniae vaccine through the vaccine-development process, the workshop group recognized that although considerable progress toward developing a C. pneumoniae vaccine has been made in the last 1–2 years, a true candidate vaccine does not yet exist. The development of a candidate vaccine requires the determination of both protective antigens and a safe, effective, formulation of those antigens. Several laboratories are working to identify protective antigens (e.g. [11]), although much of the information is as yet unpublished. Conversely, antigen formulation remains an area in which much information is still needed, including what constitutes a protective immune response to C. pneumoniae in humans, how to express recombinant antigens efficiently, and how to formulate them to elicit a protective response in humans. The processes of scale-up and testing were discussed only briefly by the workshop group. These are principally industrial processes, and much of the relevant expertise lies with the potential manufacturers of a vaccine. Specific potential issues of scale-up and testing are best addressed by the manufacturers and regulatory agencies after candidate antigens have been identified, rather than by the general academic and clinical community. In contrast, there was extensive discussion by the workshop group of the information required to facilitate the conduct of clinical trials. It is still unclear which target groups are the most appropriate for vaccination, whether vaccination should be considered for prophylactic or therapeutic use, or what might be an acceptable measure of vaccine efficacy. In particular, when planning the BLA and the granting of a license, the indications (i.e., target groups and diseases) requested and the order in which they are requested will greatly influence the design of clinical trials. While it is the association with cardiovascular disease that is currently driving much of the interest in a C. pneumoniae vaccine, there also would be value in a vaccine against chlamydial respiratory tract infections (RTI). Current FDA guidelines restrict vaccine licensure to uses for indications for which there is proven efficacy in humans. The vaccine industry has a wealth of experience in developing RTI vaccines, and clinical trials for RTI indications can be conducted much more quickly than those for cardiovascular indications, such as the prevention of atherosclerosis; therefore, the first trials conducted and the first product to be licensed will probably be for RTI indications. However, trials and postmarketing surveillance conducted for a C. pneumoniae RTI vaccine could, if properly designed, also yield much information of relevance to the role of C. pneumoniae in atherosclerosis. This information could result in additional indications for approved C. pneumoniae vaccines, or it could drive the development of improved C. pneumoniae vaccines with better effectiveness against atherosclerosis. A dilemma might arise if a future C. pneumoniae vaccine licensed only for RTI indications had a solid but unproven scientific foundation supporting a role for C. pneumoniae in atherosclerosis. The dilemma could involve regulatory, licensing, and recommending bodies; clinicians; the public; and health care insurers. The perception by the medical and lay communities of additional benefit for the prevention of atherosclerosis may result in increased demand for use of the vaccine, even without clinical trials to substantiate benefit for prevention of atherosclerosis. While the perceived benefit for prevention of RTI may not be sufficient for recommending agencies to recommend routine C. pneumoniae vaccination or to drive public demand for vaccination, the belief by the general public that C. pneumoniae is associated with atherosclerosis may drive the off-label use of a C. pneumoniae vaccine. This situation is different than the public perception of most vaccines, which are licensed for the prevention of acute infectious illness. However, it is similar to, but still distinct from, the public perception of the benefits of hepatitis B vaccination. While the benefit in prevention of acute hepatitis B is significant and was established prior to licensure, the decreased risk of hepatocellular carcinoma is a significant benefit that was demonstrated only by postmarketing studies and may not yet be fully comprehended by the public [12]. In the light of these discussions and in the hope of stimulating further research, the workshop group formulated a number of questions that might help to focus studies intended to promote the development of a C. pneumoniae vaccine. These are presented and discussed in the following to the considered by of the other workshop of the most important issues discussed was whether a C. pneumoniae vaccine should be considered for prophylactic or therapeutic use. The best data that children to to C. pneumoniae in significant at of which means that a prophylactic vaccine would need to be to children. However, it is from clear what the target for vaccination should be or even whether children comprise a target If at of is a result of infection following into information is needed in groups that might be before such as children in care or similar environments. in care for example, may vaccination of as opposed to or which would the development and clinical testing of vaccine. The of the appropriate for vaccination is an important but a more fundamental is whether there are sufficient benefits to children to vaccination. Current information that chlamydial RTI in children are and there may be for the use of a vaccine for this information is required to the of chlamydial RTI in children and the associated children the infection to or and if they with what have to take time from to care for the of infection more in children with respiratory tract diseases, such as to these and other questions will be important in whether a C. pneumoniae vaccine can be for children on the of the medical of medical or of to and in for children. For two the prevention of future atherosclerosis is to provide a for C. pneumoniae vaccination in children. a role for C. pneumoniae in the development of atherosclerosis is not yet and more clinical trials to demonstrate prevention of atherosclerosis in humans, which would be necessary FDA to licensure for this would take to If children are not to be a vaccine target what of The is whether a vaccine would be prophylactic the prevention of in who have had an infection but or therapeutic the of chronic improved of the of C. pneumoniae infection in adults is required to provide an What is the of chronic infection in the general or selected target What is the of infection chronic and are multiple infections required before infection established to be considered chronic infection infection or or is it by of with of occur (e.g., acute RTI in the of chronic infection of and if what is the clinical For these target groups for vaccination need to be identified more The are probably a target in that C. pneumoniae occur in this and the of respiratory tract disease can be this group may be to drive the development of a vaccine of the relatively limited number of who from C. potential target groups need to be identified and with respiratory tract disease, such as chronic bronchitis, asthma, or chronic obstructive pulmonary disease, might also benefit from vaccination, as might those who are recommended to influenza vaccine. The benefits to these groups also need to be A vaccine that does not but does disease, such as may be all that is required to use in some of these target however, this is to determine from the is even information to which groups might benefit from a vaccine for C. cardiovascular disease, but data is needed since this is the that is interest in vaccine development. It should be possible to some from the trials for C. As it may also be possible to useful information from the postmarketing surveillance of a vaccine for RTI indications, which for will be and before a vaccine for C. cardiovascular disease. It was the of the workshop group that the of data was to be the that the of vaccine development. The design of phase III trials at least will an improved of the of C. pneumoniae infection and disease. However, it was recognized that studies are limited by the of a for the of C. pneumoniae In of clinical studies for candidate C. pneumoniae vaccines, there is a and need for and for acute and chronic C. pneumoniae The of such it to and currently data and problems for the design of future studies and clinical trials. to identify infection would be preferred for use in clinical trials since of can be and However, that would monitoring of the immunogenicity and efficacy of a vaccine would be In practice, this would include not only but of C. pneumoniae immune and for the of C. pneumoniae in clinical such as cells or If C. pneumoniae vaccines are with an to cardiovascular disease, it will be important to determine the between C. pneumoniae infection and other identified risk for such as and Given the need for and of including the need to between acute and chronic it would be of interest to if C. pneumoniae infection has distinct and effects for example, and whether these effects are specific to use as a of acute or chronic infection it is important to if in may be a risk for C. pneumoniae and of C. pneumoniae RTI and cardiovascular disease are currently and are of use in the antigen discovery process. As protective antigens are it would also be useful if of in these could be to provide a for a vaccine formulation and for monitoring immune to vaccination in humans. The of clear of means that the efficacy of a vaccine be proven phase III clinical trials are The existing are of Given the recognized role of in chlamydial disease and the to demonstrate that a product is safe before it can be to humans, it would be useful to develop a small animal of a would be to determine the role of specific antigens in a for those antigens that elicit an adverse immune response from a vaccine. It would also be to determine the if between protective and immune whether protective are different in from or whether an protective response might would be of considerable value in a vaccine. the between protective and and which antigens can elicit of response would greatly facilitate discussions on product safety between manufacturers and The trials of the efficacy of for the of cardiovascular disease a highly for trials of a therapeutic vaccine intended to treat C. atherosclerosis. In particular, they provide a for the design of vaccine trials and for the of appropriate clinical end In the that is to be effective for prevention of the trials will also the level of efficacy to be from a vaccine intended for use in an equivalent target The of both effective and a vaccine will certainly to the design and testing of both vaccines and The most would be to infection with and then to but should not be For example, it may be possible to the or of or the need for by a vaccine with an A vaccine could also provide a to problems that may arise with the use of such as the development of or of adverse although it should be that is not a with C. pneumoniae at and the tested for the of cardiovascular disease to be well was workshop group for clinical however, there are many important questions to vaccine development that could potentially be by some in studies of human immune to C. pneumoniae The to of human to C. pneumoniae antigens would be useful in conducting the necessary in of and in monitoring the immunogenicity of a vaccine. of in both and may it possible to studies from small into humans. It will be important to determine whether or to proposed vaccine antigens, whether these are or and whether during phase trials It would also be of interest to determine the of to defined antigens and the significance of of to such antigens. The of should also be addressed in human studies if a workshop group made an interesting and important to the that although trials of a vaccine had been of following in were The of Chlamydia vaccination to the human but such has been only in It would certainly facilitate development and safety testing of a C. pneumoniae vaccine if it could be that chlamydial vaccines are to to adverse events in than is the workshop group was of the that a vaccine effective against C. pneumoniae infection would be of value for the prevention of respiratory tract disease. If C. pneumoniae infection is proven to be a cause of an effective vaccine would also be of value for the and possible prevention of C. pneumoniae cardiovascular disease. Development of a vaccine is but our to conduct appropriate clinical trials may be limited by the of adequate data potential target groups and the need for a of infection and Vaccine manufacturers and may be to address some of these but public agencies should and the process by supporting research in these studies have a strong association between C. pneumoniae infection and atherosclerosis. and studies will improve our of the of C. pneumoniae in cardiovascular disease and will help to demonstrate the of a role for C. pneumoniae in the development of atherosclerosis. The of results with demonstrated will many to that C. pneumoniae is a for atherosclerosis. A proven benefit from clinical trials will the evidence However, the demonstration that a vaccine for C. pneumoniae is effective in the or prevention of cardiovascular disease is the best evidence for of since a vaccine is a specific that is to other risk factors, processes, or other potentially involved in cardiovascular disease and the processes the development of the of the development and use of an effective vaccine for C. pneumoniae would provide the best and to the role of C. pneumoniae in cardiovascular disease in humans. the of the workshop group made the following is a and need for and for acute and chronic C. pneumoniae intended to identify protective antigens and of delivering those antigens to elicit a protective response in should be In order to provide a for vaccine and for monitoring to vaccination in humans, studies of the of chlamydial infection of and of human immune to C. pneumoniae infection are This should include a determination of what constitutes a protective immune response to C. pneumoniae in humans. studies to identify and target groups for vaccination are

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