Different approaches to influenza vaccination.
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Adolescent↗
Biomedical subjects
Marie Paule Kieny
Publications and source records attributed to Marie Paule Kieny.
A review of human vaccine research and development: malaria.
The last several years have seen significant progress in the development of vaccines against malaria. Most recently, proof-of-concept of vaccine-induced protection from malaria infection and disease was demonstrated in African children. Pursued by various groups and on many fronts, several other candidate vaccines are in early clinical trials. Yet, despite the optimism and promise, an effective malaria vaccine is not yet available, in part because of the lack of understanding of the types of immune responses needed for protection, added to the difficulty of identifying, selecting and producing the appropriate protective antigens from a parasite with a genome of well over five thousand genes and to the frequent need to enhance the immunogenicity of purified antigens through the use of novel adjuvants or delivery systems. Insufficient clinical trial capacity and normative research functions such as local ethical committee reviews also contribute to slow down the development process. This article attempts to summarize the state of the art of malaria vaccine development.
Animals↗
Report of the second meeting on the development of influenza vaccines that induce broad-spectrum and long-lasting immune responses, World Health Organization, Geneva, Switzerland, 6-7 December 2005.
New influenza vaccines that induce broad-spectrum and long-lasting immune responses and provide protection against divergent influenza viruses could overcome problems with the current vaccination strategy, based on annual intervention, better suit the needs of developing countries and contribute to epidemic and potential pandemic control. The World Health Organization held a consultation to review the current status of research in the area of influenza vaccines and to establish a research agenda for the development of such influenza vaccine. The main conclusions and recommendations from this consultation are presented below.
Humans↗
A review of vaccine research and development: meningococcal disease.
This paper reviews the current status of research and development of vaccines against meningococcal disease due to Neisseria meningitidis, a major cause of severe meningitis and septicemia with epidemic potential. While five serogroups (A, B, C, Y, and W135) are responsible for most of the disease, Group A remains unique in its ability to cause large scale epidemics mainly in Africa but also in Asia. The majority of cases in Europe and America are due to Groups B and C. The successful experience with Hib and pneumococcal conjugate vaccines has paved the way for the development of polysaccharide conjugate vaccines for the prevention of meningococcal disease. Widespread vaccination with Group C conjugate vaccines now in use in several European countries indicates that these vaccines are immunogenic, induce immunological memory, reduce colonization and provide herd immunity to the general population. A monovalent group A conjugate vaccine being developed at an affordable price, offers hope for the elimination of large epidemics in African countries. Multivalent (A, C, Y, W) conjugate vaccines are being developed, and one has already been licensed. However, effective global prevention of meningococcal disease will not be achievable without the development of a vaccine against Group B meningitis, for which outer membrane protein vaccines are under development.
Animals↗
A review of vaccine research and development: the human immunodeficiency virus (HIV).
Since the discovery of AIDS in 1981, the global spread of HIV has reached pandemic proportions, representing a global developmental and public health threat. The development of a safe, globally effective and affordable HIV vaccine offers the best hope for the future control of the pandemic. Significant progress has been made over the past years in the areas of basic virology, immunology, pathogenesis of HIV/AIDS and the development of antiretroviral drugs. However, the development of an HIV vaccine faces formidable scientific challenges related to the high genetic variability of the virus, the lack of immune correlates of protection, limitations with the existing animal models and logistical problems associated with the conduct of multiple clinical trials. More than 35 vaccine candidates have been tested in Phase I/II clinical trials, involving more than 10,000 volunteers, and two Phase III trials have been completed, themselves involving more than 7500 volunteers. Multiple vaccine concepts and vaccination strategies have been tested, including DNA vaccines, subunit vaccines, live vectored recombinant vaccines and various prime-boost vaccine combinations. This article reviews the state of the art in HIV vaccine development, summarizes the results obtained so far and discusses the challenges to be met in the development of the various vaccine candidates.
AIDS Vaccines↗
Development and evaluation of influenza pandemic vaccines.
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Adjuvants, Immunologic↗
Development of vaccines against influenza H5.
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Animals↗
Entry of hepatitis C virus pseudotypes into primary human hepatocytes by clathrin-dependent endocytosis.
Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide. Studies of the early steps of HCV infection have been hampered by the lack of convenient in vitro or in vivo models. Although several cell-surface molecules that mediate the binding of HCV envelope proteins to target cells have been identified, mechanisms of viral entry into human hepatocytes are still poorly understood. Vesicular stomatitis virus/HCV pseudotyped viruses expressing the HCV envelope glycoproteins on the viral envelope were generated and it was found that their entry into human hepatocytes required co-expression of E1 and E2 on the pseudotype surface. Neutralization of pseudotype infection by anti-HCV antibodies suggested that cellular entry was mediated by HCV envelope glycoproteins and by previously characterized cell-surface molecules, including CD81. An entry assay based on the release of a fluorochrome from labelled HCV pseudotypes provided evidence for a pH-dependent fusion of the pseudotype envelope with a cellular compartment. By using a panel of endocytosis inhibitors, it is postulated that penetration of HCV into primary cultures of hepatocytes takes place by clathrin-mediated endocytosis.
Animals↗
A review of vaccine research and development: human enteric infections.
Worldwide, enteric infections rank third among all causes of disease burden, being responsible for some 1.7-2.5 million deaths per year, mostly in young children and infants in developing countries. The main infectious agents responsible for human enteric infections include several viruses (enteric adenoviruses, astroviruses, human caliciviruses (HuCV), rotaviruses (RV)) and several bacterial agents, such as Campylobacter jejuni, a variety of pathogenic Escherichia coli strains including enterotoxigenic E. coli (ETEC), several Shigella species, various Salmonella strains including S. typhi and S. paratyphi, the agents of typhoid fever, and Vibrio cholerae, the agent of cholera. While effective vaccines are available at present against typhoid fever and cholera, no vaccine is available against illnesses caused by HuCV, Campylobacter, ETEC or the Shigellae. Rotavirus vaccines have had more success, although RV disease prevention suffered a major setback in 1999 with the withdrawal of a live simian-human reassortant RV vaccine less than a year after its introduction. New live oral RV vaccines have now been developed and are or should presently be ready for licensure. This article reviews the state of the art in vaccine R&D against human viral and bacterial enteric infections of public health importance.
Biomedical Research↗
Human vaccine research and development: an overview.
One-fifth of global mortality, especially in children under the age of five is due to infectious diseases. Vaccines are effective at combating these diseases, as shown by the success of smallpox eradication, the impressive progress towards polio eradication, the significant achievements in measles mortality reduction and many others. New safe and effective vaccines must be developed for a variety of infections of public health importance against which no effective preventive intervention measure is either available or practical. In addition, appropriate mechanisms should be put in place to ensure access for all children to the needed vaccines. To meet these challenges, a new paradigm needs to be built among all stakeholders of immunization, including countries, industry, research institutions, foundations and international agencies like the World Health Organization (WHO) and the United Nations Children Fund (UNICEF). Importantly, developing countries should be empowered to participate actively in the development and introduction of new vaccines according to their national priorities.
Global Health↗
A review of vaccine research and development: human acute respiratory infections.
Worldwide, acute respiratory infections (ARIs) constitute the leading cause of acute illnesses, being responsible for nearly 4 million deaths every year, mostly in young children and infants in developing countries. The main infectious agents responsible for ARIs include influenza virus, respiratory syncytial virus (RSV), parainfluenza virus type 3 (PIV-3), Streptococcus pneumoniae and Haemophilus influenzae. While effective vaccines against influenza, H. influenzae type b (Hib) and S. pneumoniae infections have been available for several years, no vaccine is available at present against illnesses caused by RSV, PIV-3, metapneumovirus or any of the three novel coronaviruses. In addition, the threat constituted by the multiple outbreaks of avian influenza during the last few years is urgently calling for the development of new influenza vaccines with broader spectrum of efficacy, which could provide immunity against an avian influenza virus pandemic. This article reviews the state of the art in vaccine R&D against ARIs and attempts to address these basic public health questions.
Acute Disease↗
Hepatitis C virus core, NS3, NS5A, NS5B proteins induce apoptosis in mature dendritic cells.
Although reasons for hepatitis C virus (HCV) persistence are still unknown, specific cellular immune responses appear to influence the pathogenesis and outcome of the infection. Apoptosis of cells infected by viruses may appear suicidal to the viruses that induce programmed cell death of its host. However, apoptosis has been suggested to be a response to virus infection as a mean of facilitating virus dissemination. Annexin V-propidium iodide staining and DNA fragmentation, were used to show that expression of the core, NS3, NS5A, or NS5B protein induces apoptosis in mature dendritic cells. In addition, immunoblotting was used to demonstrate that expression level of p21waf1/cip1 protein decreased in cells expressing one of these HCV proteins. No expression of p53 could be detected and expression of Akt was independent of HCV proteins expression. These results suggest that the effect of these HCV proteins on HCV associated pathogenesis may be linked (at least partially) to its ability to modulate apoptosis pathways in mature dendritic cells.
Apoptosis↗
Comparative immunogenicity analysis of modified vaccinia Ankara vectors expressing native or modified forms of hepatitis C virus E1 and E2 glycoproteins.
We have evaluated in C57/Bl6 and HLA-A2.1 transgenic mice the immunogenicity of three MVA vectors expressing either native HCV E1E2 polyprotein, truncated and secreted E1 (E'1(311)) and E2 (E'2(661)) proteins, or a chimeric E1E2 heterodimer presented at the plasma membrane. Immunization induced mainly a Th1 response in HLA-A2.1 transgenic mice while a Th2-type response was detected in C57/Bl6 mice. Comparison of the three vectors shows an increase in the humoral response when antigens are secreted or membrane bound, and slightly in the cellular response when antigens are exposed on the cell surface.
Animals↗
Research and development of new vaccines against infectious diseases.
Infectious diseases are responsible for approximately 25% of global mortality, especially in children aged younger than 5 years. Much of the burden of infectious diseases could be alleviated if appropriate mechanisms could be put in place to ensure access for all children to basic vaccines, regardless of geographical location or economic status. In addition, new safe and effective vaccines should be developed for a variety of infections against which no effective preventive intervention measure is either available or practical. The public, private, and philanthropic sectors need to join forces to ensure that these new or improved vaccines are fully developed and become accessible to the populations in need as quickly as possible.
Biotechnology↗
Recombinant CD63/ME491/neuroglandular/NKI/C-3 antigen inhibits growth of established tumors in transgenic mice.
Attempts to vaccinate against tumors can be hindered by the induction of immunological tolerance to the target Ag as a result of Ag expression on normal tissues. In this study, we find that transgenic mice expressing the melanoma-associated Ag CD63/ME491/neuroglandular/NKI/C-3 on their normal tissues do, in fact, exhibit immunological tolerance to the Ag, recapitulating the conditions in cancer patients. In these mice, growth of murine melanoma cells expressing the Ag after gene transfer was inhibited by immunization with Ag-expressing recombinant vaccinia virus combined with IL-2, but not by immunization with the protein alone, anti-idiotypic Abs, or irradiated tumor cells. The effect of the recombinant virus was demonstrated both for nonestablished and established tumors. Infiltration with both CD4(+) and CD8(+) T lymphocytes was significantly more extensive in tumors from experimental mice than in tumors from control mice. MHC class I-positive, but not class I-negative, tumors were inhibited by the vaccine, suggesting that MHC class I-restricted T lymphocytes play a role in the antitumor effects. Abs did not appear to be involved in the vaccine effects. CD63 was immunogenic in 2 of 13 melanoma patients, pointing to the potential of this Ag, combined with IL-2, as a vaccine for melanoma patients.
Animals↗
Third meeting on Novel Adjuvants Currently in or Close to Clinical Testing World Health Organization--Organisation Mondiale de la Santé, Fondation Mérieux, Annecy, France, 7-9 January 2002.
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Adjuvants, Immunologic↗
Immunization safety priority project at the World Health Organization.
In 1999, the World Health Organization's (WHO) Department of Vaccines and Biologicals launched the Immunization Safety Priority Project with the aim of establishing a comprehensive system to ensure the safety of all immunizations given in national immunization programs. Countries are the primary focus of the project. WHO has a role, not only because of its technical and normative role, but also because of its privileged relationship with country authorities and other partners, and its global vision and mandate. The four major areas of focus in the project are to (1) promote and coordinate research and development of safer and simpler delivery systems; (2) ensure vaccine safety, from vaccine development all the way through clinical trials and vaccine distribution until use; (3) broaden access to safer and more efficient systems for vaccine delivery and management of sharps waste; and (4) establish efficient mechanisms to detect serious or potentially serious adverse events following immunization, and enable prompt and effective response. The project emphasizes the importance of advocating safety and building capacity at national levels.
Advisory Committees↗
Hepatitis C virus IRES efficiency is unaffected by the genomic RNA 3'NTR even in the presence of viral structural or non-structural proteins.
Hepatitis C virus (HCV) translation is mediated by an IRES structure. Instead of a poly(A) tail, the 3' end of the genome contains a tripartite 3'NTR composed of a non-conserved region, a polypyrimidine tract and a highly conserved stretch of 98 nt, termed the 3'X region. Using a set of bicistronic recombinant DNA constructs expressing two reporter genes separated by the HCV IRES, it was determined whether the HCV 3'NTR sequence, in the presence or absence of HCV proteins, played a role in the efficiency of HCV IRES-dependent translation ex vivo. Bicistronic expression cassettes were transfected into hepatic and non-hepatic cell lines. These results show that neither the entire 3'NTR nor the 3'X sequence alters IRES-dependent translation efficiency, whatever the cell line tested. A potential effect of the 3'NTR on IRES-dependent translation in the presence of HCV proteins was investigated further. Neither non-structural nor structural HCV proteins had any effect on the efficiency of IRES in this system. In addition, in order to mimic HCV genome organization, monocistronic expression cassettes containing the IRES and a Core-DsRed fusion gene were constructed with or without the 3'NTR. In this context, no effect of the 3'NTR on IRES translation efficiency was observed, even in the presence of HCV proteins. These data demonstrate that HCV translation is not modulated by the viral genomic 3'NTR sequence, even in the presence of HCV structural or non-structural proteins.
3' Untranslated Regions↗