- Email: [email protected]
Therapeutic strategies for infectious diseases: Vaccines and anti-infective agents
Drug Discovery Today: Therapeutic Strategies
Vol. 3, No. 2 2006
Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Editorial
EDITORIAL
Therapeutic strategies for infectious diseases: Vaccines and anti-infective agents Paul-Henri Lambert1, Gary Woodnutt2 1 2
Centre of Vaccinology, CMU, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. Email: [email protected] CovX Research LLC, 9381 Judicial Drive, Suite 200, San Diego, CA 92121, USA. Email: [email protected]
Overall, the use of vaccines and anti-infective therapies in concert have drastically reduced the burden of morbidity and mortality associated with infectious disease. The effects have been so successful that many companies have reduced efforts focused on infection and moved on to potentially more demanding and valuable therapeutic areas. Although current anti-infective agents are generally still efficacious, their effectiveness is eroding because of the development and spread of resistance in common pathogens as well as the increase in
prevalence of previously rare, or unknown, organisms that are intrinsically more resistant to current therapies. As a result there has been renewed interest in the discovery and development of novel infection interventions. Vaccines were long considered as a poor parent of the drug industry and, despite their immense public health value, their economic appeal was modest. However, we are now entering a new era in vaccinology. New vaccines have appeared and several others are close to licensure, which
Box 1. Section Editors Paul-Henri Lambert Paul-Henri Lambert graduated as an MD from the University of Liege. He then trained in immunopathology with Frank Dixon at Scripps before heading a research unit at the University of Geneva where he became a professor in 1984. His research led to the deciphering of immunological mechanisms involved in autoimmune and immune complex-mediated diseases and in the pathogenesis of malaria. He then became involved in the development of new strategies to optimise vaccine immunogenicity. For over 20 years, PH Lambert has also been involved with the World Health Organisation, heading global vaccine research and training programmes where he is now chairing the WHO Global Adisory Committee for Vaccine Safety. He remains associated to the Centre of Vaccinology at the University of Geneva as a retired professor. He has authored over 415 publications, is a member of several international scientific boards, foreign member of the Royal Academy of Medicine in Belgium and Fellow of the American Association for the Advancement of Science.
1740-6773/$ ß 2006 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2006.05.002
Gary Woodnutt Gary Woodnutt is currently Vice President of Biology in a San Diego biotechnology Company, CovX, specializing in novel protein therapeutic approaches to oncology and metabolic diseases. He obtained his bachelors degree in Biochemistry and Physiology from Leeds University and his PhD from Reading University. He joined Beecham Pharmaceuticals in 1980 working on anti-microbial development and market support for Augmentin and worked extensively in the Discovery of novel anti-infectives for GlaxoSmithKline until 2002. His major scientific interests have centered on the pharmacodynamics of anti-bacterial compounds and in particular improving the ability of animal models to predict clinical response in human. He serves on the editorial board of Antimicrobial Agents and Chemotherapy.
111
Drug Discovery Today: Therapeutic Strategies | Editorial
have a potential for significantly changing the health technologies panorama. In this issue, we have selected a few examples of emerging vaccines that will have a profound impact not only on the related disease burden but also on overall antibiotic usage. For a long time, most vaccine doses were used during childhood and were mainly targeting classical children disease, for example, measles, mumps, rubella, polio, whooping cough (Pertussis), tetanus or diphtheria. Their use was more recently extended to prevention of infant meningitis (Haemophilus type b) and to protection against Hepatitis B. Today we are witnessing the emergence of two groups of new vaccines that could have a considerable impact. First, we have or will soon have access to vaccines that complement the available childhood prophylactic tools and would allow control of prevalent diarrhoeal diseases caused by rotavirus or the prevention of bacterial acute respiratory or invasive diseases as well as otitis media resulting from pneumococcal or meningococcal infection. The impact of pneumococcal conjugate vaccines on the use of antibiotics in infancy might be of crucial importance for controlling the emergence of antibiotic resistance. Second, new vaccines against diseases that represent significant health targets in adults or elderly are now becoming available. For example, HPV vaccines will contribute to the prevention of cervical cancer, and hepatitis C vaccines will limit the huge burden of chronic liver diseases whereas Zoster vaccines will decrease the incidence of ‘shingles’ in the elderly. It can also be expected that a new generation of influenza vaccines, including pandemic vaccines and adjuvant-containing vaccines, will soon become available. Their importance will be particularly emphasized in the context of progressing avian influenza epidemics. They should have an increased low-dose efficacy and an improved immunogenicity in infants and elderly. Finally, other vaccines are still on the drawing board but recent progress towards clinical development is more than promising. This is the case for new TB vaccines to be used either as replacement for BCG or to boost immune responses in individuals already primed through exposure to BCG or to other mycobacteria. Malaria vaccines are also on a moving trend and there is a first proof of evidence that some degree of protection can be achieved with appropriately formulated vaccines. Unfortunately, the solution to the difficult challenge of developing HIV vaccines appears remote. Similarly, vaccines for some other ‘tricky’ viral infections, for example, RSV or CMV, are still badly needed. Outside of vaccines there is also increased interest in the discovery and development of new anti-infective therapies.
112
www.drugdiscoverytoday.com
Vol. 3, No. 2 2006
Importantly the focus of anti-infective research has shifted in recent times to concentrate more on maintaining activity against those organisms that are difficult to treat. New agents are now expected to work through novel modes of action or at least have activity against organisms that have established resistance mechanisms. Significant improvements in therapy have been derived from combining agents with complimentary modes of action and have been successfully applied to the treatment of viral infections in particular. The use of combination therapies is probable to continue to expand in the future in part owing to increased understanding of the properties of current therapies enabling well informed decisions on appropriate dosage. Approaches that specifically target resistance mechanisms with the promise of rejuvenating current therapies add to the spectrum of possible combination therapies. However, the diversity of potential targets continues to increase and the promise of finding individual compounds that will have a broad enough activity is still to be fulfilled. Single agent therapies are still being actively pursued with strategies encompassing the synthesis of molecules directed towards well-validated targets; new target screening and investigation of new modalities such as gene therapy. Targeting areas that have no historical precedent whereas potentially the most important strategy for future anti-infectives is not a short-term solution and it will be some years before many of these targets produce marketed drugs (if at all). In some cases changes in treatment modality will require fundamental alteration of anti-infective treatment practices, with associated education, and can also lead to modification of previously accepted clinical trial designs which can lead to slower adoption of these interventions. Derivitisation of current therapeutic agents and/or discovering new compounds that work against proven targets is producing more immediate therapies. In some cases these ‘new’ drugs provide only slight improvement over current standards and it remains to be seen how long lived they will be. An increased number of therapeutic and prophylactic options will allow us to compare directly the potential benefits of each agent and therefore help with selecting appropriate clinical dosing strategies. However, organisms will continue to evolve and we will need to be vigilant to ensure that we have adequate responses to these inevitable changes. With best wishes, Paul-Henri Lambert Gary Woodnutt
Vol. 3, No. 2 2006
Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Editorial
EDITORIAL
Therapeutic strategies for infectious diseases: Vaccines and anti-infective agents Paul-Henri Lambert1, Gary Woodnutt2 1 2
Centre of Vaccinology, CMU, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. Email: [email protected] CovX Research LLC, 9381 Judicial Drive, Suite 200, San Diego, CA 92121, USA. Email: [email protected]
Overall, the use of vaccines and anti-infective therapies in concert have drastically reduced the burden of morbidity and mortality associated with infectious disease. The effects have been so successful that many companies have reduced efforts focused on infection and moved on to potentially more demanding and valuable therapeutic areas. Although current anti-infective agents are generally still efficacious, their effectiveness is eroding because of the development and spread of resistance in common pathogens as well as the increase in
prevalence of previously rare, or unknown, organisms that are intrinsically more resistant to current therapies. As a result there has been renewed interest in the discovery and development of novel infection interventions. Vaccines were long considered as a poor parent of the drug industry and, despite their immense public health value, their economic appeal was modest. However, we are now entering a new era in vaccinology. New vaccines have appeared and several others are close to licensure, which
Box 1. Section Editors Paul-Henri Lambert Paul-Henri Lambert graduated as an MD from the University of Liege. He then trained in immunopathology with Frank Dixon at Scripps before heading a research unit at the University of Geneva where he became a professor in 1984. His research led to the deciphering of immunological mechanisms involved in autoimmune and immune complex-mediated diseases and in the pathogenesis of malaria. He then became involved in the development of new strategies to optimise vaccine immunogenicity. For over 20 years, PH Lambert has also been involved with the World Health Organisation, heading global vaccine research and training programmes where he is now chairing the WHO Global Adisory Committee for Vaccine Safety. He remains associated to the Centre of Vaccinology at the University of Geneva as a retired professor. He has authored over 415 publications, is a member of several international scientific boards, foreign member of the Royal Academy of Medicine in Belgium and Fellow of the American Association for the Advancement of Science.
1740-6773/$ ß 2006 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2006.05.002
Gary Woodnutt Gary Woodnutt is currently Vice President of Biology in a San Diego biotechnology Company, CovX, specializing in novel protein therapeutic approaches to oncology and metabolic diseases. He obtained his bachelors degree in Biochemistry and Physiology from Leeds University and his PhD from Reading University. He joined Beecham Pharmaceuticals in 1980 working on anti-microbial development and market support for Augmentin and worked extensively in the Discovery of novel anti-infectives for GlaxoSmithKline until 2002. His major scientific interests have centered on the pharmacodynamics of anti-bacterial compounds and in particular improving the ability of animal models to predict clinical response in human. He serves on the editorial board of Antimicrobial Agents and Chemotherapy.
111
Drug Discovery Today: Therapeutic Strategies | Editorial
have a potential for significantly changing the health technologies panorama. In this issue, we have selected a few examples of emerging vaccines that will have a profound impact not only on the related disease burden but also on overall antibiotic usage. For a long time, most vaccine doses were used during childhood and were mainly targeting classical children disease, for example, measles, mumps, rubella, polio, whooping cough (Pertussis), tetanus or diphtheria. Their use was more recently extended to prevention of infant meningitis (Haemophilus type b) and to protection against Hepatitis B. Today we are witnessing the emergence of two groups of new vaccines that could have a considerable impact. First, we have or will soon have access to vaccines that complement the available childhood prophylactic tools and would allow control of prevalent diarrhoeal diseases caused by rotavirus or the prevention of bacterial acute respiratory or invasive diseases as well as otitis media resulting from pneumococcal or meningococcal infection. The impact of pneumococcal conjugate vaccines on the use of antibiotics in infancy might be of crucial importance for controlling the emergence of antibiotic resistance. Second, new vaccines against diseases that represent significant health targets in adults or elderly are now becoming available. For example, HPV vaccines will contribute to the prevention of cervical cancer, and hepatitis C vaccines will limit the huge burden of chronic liver diseases whereas Zoster vaccines will decrease the incidence of ‘shingles’ in the elderly. It can also be expected that a new generation of influenza vaccines, including pandemic vaccines and adjuvant-containing vaccines, will soon become available. Their importance will be particularly emphasized in the context of progressing avian influenza epidemics. They should have an increased low-dose efficacy and an improved immunogenicity in infants and elderly. Finally, other vaccines are still on the drawing board but recent progress towards clinical development is more than promising. This is the case for new TB vaccines to be used either as replacement for BCG or to boost immune responses in individuals already primed through exposure to BCG or to other mycobacteria. Malaria vaccines are also on a moving trend and there is a first proof of evidence that some degree of protection can be achieved with appropriately formulated vaccines. Unfortunately, the solution to the difficult challenge of developing HIV vaccines appears remote. Similarly, vaccines for some other ‘tricky’ viral infections, for example, RSV or CMV, are still badly needed. Outside of vaccines there is also increased interest in the discovery and development of new anti-infective therapies.
112
www.drugdiscoverytoday.com
Vol. 3, No. 2 2006
Importantly the focus of anti-infective research has shifted in recent times to concentrate more on maintaining activity against those organisms that are difficult to treat. New agents are now expected to work through novel modes of action or at least have activity against organisms that have established resistance mechanisms. Significant improvements in therapy have been derived from combining agents with complimentary modes of action and have been successfully applied to the treatment of viral infections in particular. The use of combination therapies is probable to continue to expand in the future in part owing to increased understanding of the properties of current therapies enabling well informed decisions on appropriate dosage. Approaches that specifically target resistance mechanisms with the promise of rejuvenating current therapies add to the spectrum of possible combination therapies. However, the diversity of potential targets continues to increase and the promise of finding individual compounds that will have a broad enough activity is still to be fulfilled. Single agent therapies are still being actively pursued with strategies encompassing the synthesis of molecules directed towards well-validated targets; new target screening and investigation of new modalities such as gene therapy. Targeting areas that have no historical precedent whereas potentially the most important strategy for future anti-infectives is not a short-term solution and it will be some years before many of these targets produce marketed drugs (if at all). In some cases changes in treatment modality will require fundamental alteration of anti-infective treatment practices, with associated education, and can also lead to modification of previously accepted clinical trial designs which can lead to slower adoption of these interventions. Derivitisation of current therapeutic agents and/or discovering new compounds that work against proven targets is producing more immediate therapies. In some cases these ‘new’ drugs provide only slight improvement over current standards and it remains to be seen how long lived they will be. An increased number of therapeutic and prophylactic options will allow us to compare directly the potential benefits of each agent and therefore help with selecting appropriate clinical dosing strategies. However, organisms will continue to evolve and we will need to be vigilant to ensure that we have adequate responses to these inevitable changes. With best wishes, Paul-Henri Lambert Gary Woodnutt