Trends in vaccinology

Transcription

1 Trends in vaccinology Mathieu Peeters, MD Joint Conference of European Human Pharmacological Societies and Joint Conference of European Human Pharmacological Societies and 20th Anniversary of AGAH March 31 - April 01, 2011 Berlin, Germany

2 Edward JENNER: 1796 Observed protection from Smallpox in milkmaids exposed to cowpox injected an 8 year old boy with pus from a milkmaid s cowpox lesion Protection against human smallpox

3 Many new vaccines since Jenner cervical cancer rotavirus conjug pneumococcal HA/HB DTP Pa combo hepatitis A Hib hepatitis B pneumococcus meningococcus rubella mumps measles OPV (polio Sabin) IPV (polio Salk) yellow fever influenza cholera pertussis tetanus tuberculosis rabies diphtheria typhoid

4 What have vaccines achieved so far?!" #

5 18 th Century Attenuated & Inactivated vaccines history Animal virus (vaccinia) 19 th Century 20 th Century Physical attenuation (Rabies, Anthrax) Passage in animals, eggs, in vitro (Yellow fever, BCG) Toxoids (Diptheria, Tetanus) Killed whole organisms (thypoid, cholera, Whole-cell pertussis, IPV, hepatitis) Extracts (Flu, Anthrax, Rabies) Passage in cell culture in vitro (Measles, OPV, Varicella, Mumps Rubella, Live flu) Polysaccharides (Pneumo, Typhoid) Conj. Polysaccharides (pneumo, Hib, meningo) Proteins (Acellular Pertussis, Hep B) Peptides Adapted from : Plotkin et al. Clinical and vaccine immunology 2009, vol 16,

6 Live Attenuated Vaccines Developing an attenuated strain!"# " $%!" &!#'"& ( ("%%!#!""#!" "!#"$!"#!"%!!

7 Live attenuated vaccines Extremely effective Best way to stimulate all the components of immunity that infection with the pathogenic organism does, Some pathogens considered too risky even in attenuated form Immune responses elicited by wild-type infection are not necessarily effective for clearing a pathogen after an infection. Risk of reversion to virulent form

8 Inactivated Vaccines $)%*##"! %#"%# "+( (!#"!"*"$$!" % $&!( (%"$!""#! "!" ""& & #%)#

9 Inactivated Vaccines Generally used for pathogens for which a humoral immune response is considered the primary protective immune response Inadequate for inducing the appropriate forms of cellular immunity needed for certain diseases.

10 Subunit Vaccines Recombinant vaccines e.g. Hepatitis B Surface Antigen

11 Subunit Vaccines Recombinant subunit vaccines

12 Subunit Vaccines Free of infectious particles ( plasma-derived vaccines) Once a suitable Master Working Cell Bank has been established, the antigens can be produced efficiently, economically and on a large scale. The use of highly purified antigens has decreased the risk of vaccine toxicity but, as a consequence, the immunogenicity of some of these vaccine antigens is suboptimal.

13 Vaccinology : an evolving science Vaccine development has historically progressed by trial and error Shift towards knowledge based R&D Pathogen Immune system Immune response Target population Modern approaches to develop new or improved vaccines

14 New technologies available New adjuvants Target antigen Conjugates (carrier + peptide, carrier + PS,...) Gene based vaccines DNA vaccines Live vectored (virus/bact) vaccines Virus like particles Immunisation routes Intradermal Mucosal (oral, nasal, )...

15 Vaccine adjuvants Latin adjuvare : to help An adjuvant can be an immunostimulant and/or a vaccine delivery system Vaccine delivery system : transports the antigen Immunostimulant : compound that acts directly or indirectly on the immunocompetent cells to increase the immune response to a given antigen It is designed to increase the specific immune response (intensity, quality and breadth)

16 Gaston Ramon : Adjuvant Innovation In 1925, Ramon was first to recognize that a variety of substances could increase antigen-specific antibody production when added to diphtheria and tetanus toxoids prior to vaccination. Aluminum salt is the most Aluminum salt is the most widely used adjuvant

17 Why Do We Need Better Adjuvants? To increase the magnitude of the immune response To bypass weakened immunity Immunosenescence Immunosuppression To increase production capacity by reducing antigen content/dose To induce long-term protection Long-term persistence of protection Immunological memory Antibody level Vaccine with Adjuvant System Time

18 Why Do We Need Better Adjuvants? Adjuvant s activate different arms of the immune system and enhance the immune response humoral cellular immunity Extracellular targets Infected cells However, need to keep an appropriate balance between immunogenicity and reactogenicity

19 Gene-Based Vaccines Recombinant plasmid DNA Mammalian expression vectors - express antigen gene(s) in transfected cells after intramuscular or intradermal delivery Recombinant live virus vectors Attenuated virus vector (e.g. Adenovirus) undergoes transient replication Attenuated virus vector (e.g. Adenovirus) undergoes transient replication after injection - expression of antigen gene(s)

20 DNA vaccines Direct transfection of APC apoptosis, secreted, VLP Transfection of muscle cells or keratynocytes Adapted from:

21 Key advantages of DNA vaccines Induce both humoral and cellular immune responses (incl. CTL) similar to live attenuated platforms Safe Unable to revert into virulent forms, unlike live vaccines No significant adverse events in clinical trials Stability Storage at room temperature No cold chain requirement Long shelf-life Easy distributable in developing countries Ease of manufacturing Rapid production and formulation Relatively inexpensive Large scale production

22 Potential concerns Efficacy First-generation DNA plasmids elicited low levels of T and B cell memory Safety DNA integration Autoimmunity against patient DNA

23 Viral vector Live vector protein CD8 CD4 B CTL APC T helper

24 Potential advantages of virus derived vectors High-level production of protein antigens directly within the cells of the immunized host Possibility of efficient delivery of antigen directly to the components of the immune system Potential adjuvant effects of the viral delivery system Potential to be administered via different routes; also intradermal, intranasal, intra-rectal, intra-vaginal (and induce mucosal immune response) Potential issue Pre-existing immunity against the vector

25 Virus Like Particles (VLP) Multiprotein structure that mimic the oganization and conformation of authentic native viruses but lack the viral genome Virus VLP

26 Virus Like Particles (VLP) Insertion of gene in virus Initial stock of recombinant virus Inoculation in fresh cell culture Virus enters cell. Its genome moves into the nucleus Production of proteins, assembly into pentamers Cells collected and disrupted Highly purified VLP

27 Potential advantages of VLP No requirement for inactivation or attenuation Epitopes might be altered by inactivation Conformational epitopes more similar to the native virus Improved immune system response Main challenge = bioengineering issues

28 Alternative Delivery Samir Mitragotri NATURE REVIEWS IMMUNOLOGY VOLUME 5 DECEMBER 2005

29 Cutaneous immunization Samir Mitragotri NATURE REVIEWS IMMUNOLOGY VOLUME 5 DECEMBER 2005

30 Advantages and limitations of needle-free delivery Samir Mitragotri NATURE REVIEWS IMMUNOLOGY VOLUME 5 DECEMBER 2005 and industrial feasibility, patient acceptance

31 THERAPEUTIC VACCINES Cancer: contain novel cellular antigens, vaccine with proteins/peptides expressed by cancer Tolerization to auto-antigens in auto-immune diseases (MS, diabetes) Drug addiction (cocaine, nicotine): Ab that removes drugs from body Alzheimer: immunization against amyloid Contraception: immunization against hormones

32 Advances in Molecular biology Discovery of tumor Associated Antigens Cancer cells have altered gene expression profile different from normal cells: tumor associated antigens exist!! Differences between normal and tumor cells are potential targets for Differences between normal and tumor cells are potential targets for immunotherapy

33 Antigen specific cancer immunotherapy Helper T-Cells Antibody production Naive CD8 + Lymphocyte Naive CD4 + Lymphocyte Cytolytic T-cells injection site (A) Draining Lymph Node (B) Tumor (C)

34 Conclusions Many opportunities access to new technologies through research and collaborations progress in fundamental immunology development of support technologies better understanding of molecules (eg. physical chemistry) better understanding of biological systems (eg. omics) Pave the way towards new vaccine targets in infectious disease, immunotherapy, allergy, life-style, autoimmunity,...

35 Conclusions. but also many challenges Predicting immune correlates of protection Improving T cell responses Delivery systems, vectors, adjuvants, combination prime- boost strategies Vaccines for the elderly Vaccines for the very young Cold chain and supply