History of Vaccines (lịch sử vacxin)

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Leading cause of death in human population: INFECTION. Most important contributions to public health in last 100 yrs: SANITATION. VACCINATION. Earliest contributions: JENNER – smallpox vaccine. PASTEUR – rabies vaccine. Greatest Triumphs: Global eradication of smallpox (1980). Future global eradication of polio.

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Nội dung Text: History of Vaccines (lịch sử vacxin)

History of Vaccines  Leading cause of death in human population  INFECTION  Most important contributions to public health in last 100 yrs  SANITATION  VACCINATION  Earliest contributions  JENNER – smallpox vaccine  PASTEUR – rabies vaccine  Greatest Triumphs  Global eradication of smallpox (1980)  Future global eradication of polio
History • Although early in history the basis of disease was not known, the presence of a life-long immunity to disease was understood as early as the 4th century. • The first documentation of “immunization” was the process of variolation – the removal of pus from smallpox lesions and the subsequent scratching of an uninfected person in the 10th century in India • In 1796, Edward Jenner observed that milk maids exposed to cowpox (vaccinia virus) did not acquire smallpox – he predicted that deliberately infecting an individual with vaccinia would protect against smallpox (variola virus) – Sarah Nelmes donated fluid from her cowpox-infected hands, which was inoculated into James Phipps – produced a lesion similar to cowpox – later challenged James Phipps with fluid from a smallpox lesion, but no subsequent smallpox developed – this was the first recorded incidence of “vaccination”. • Jenner would be imprisoned for this type of experiment today, but the James Phipps vaccination led to the development of the smallpox vaccine and the eradication of naturally occurring infections worldwide.
Immune mechanisms to eliminate virus or virus-infected cells  Humoral & cell-mediated immune responses important for antiviral immunity  Must eliminate both virus & virus-infected cells  Failure to resolve infection leads to;  Persistent infection  Late Complications  Humoral immune response acts primarily on extracellular virions/bacteria  Cell-mediated immune responses (T cells) target virus-infected cells
Primary and Secondary Antibody Responses
Virus-specific T Cell Responses ~ CD4 and CD8 T Cells Antiviral CD8+ and CD4+ T-cell responses. The three phases of the T-cell immune response (expansion, contraction and memory) are indicated. Antigen-specific T cells clonally expand during the first phase in the presence of antigen. Soon after the virus is cleared, the contraction phase ensues and the number of antigen-specific T cells decreases due to apoptosis. After the contraction phase, the number of virus-specific T cells stabilizes and can be maintained for great lengths of time (the memory phase). Note that, typically, the magnitude of the CD4+ T-cell response is lower than that of the CD8+ T-cell response, and the contraction phase can be less pronounced than that of CD8+ T cells. The number of memory CD4+ T cells might decline slowly over time.
Humoral Immune Response  Not all immunogens elicit protective immunity  Best targets usually viral attachment proteins  Capsid proteins of non-enveloped viruses  Envelope glycoproteins of enveloped viruses  Antibody may neutralize free virus particles  Antibody binds virus particles  Blocks binding to cell-surface receptors  Destabilizes virus particles  Antibody opsonizes free virus particles  Antibody binds virus particles  Promotes uptake & clearance by macrophages (Fc receptors)  Antibody prevents spread of extracellular virus to other cells  Most important in viremic infections
Targets for Antiviral Antibodies • Antiviral antibodies can impact viral infection in multiple ways. The antiviral activities of antibodies. a | Activities against free virus (an enveloped virus is shown). Neutralizing antibodies probably act primarily by binding to the envelope protein (Env) at the surface of the virus and blocking infection (neutralization). They can also trigger effector systems that can lead to viral clearance, as discussed in the text. b | Activities against infected cells. These activities can be mediated by both neutralizing and non-neutralizing antibodies. Neutralizing antibodies bind to the same proteins on infected cells as on free virus. Non-neutralizing antibodies bind to viral proteins that are expressed on infected cells but not, to a significant degree, on free virus particles. Examples include altered forms of Env protein and certain non-structural (NS) proteins, such as NS1 of dengue virus. The binding of neutralizing and/or non- neutralizing antibodies to infected cells can lead to clearance of such cells or the inhibition of virus propagation as shown.
Cancer Vaccines Tumors can be destroyed by cytotoxic T cells or antibody- dependent cytotoxic mechanisms if the immune system can identify the tumor as “nonself” This is difficult with uninfected cells since the immune response is generally tolerized toward “self” antigens However, some tumor-specific antigens are expressed by cancer cells either in a unique context or are antigens that were expressed prior to but not after the tolerization process. This is generally because tumor cells are less differentiated than normal cells. In addition, tolerance can be broken by especially immunogenic vaccines The “holy grail” of tumor vaccines is an antigen that is expressed only by the tumor cells, to which the host is not tolerized
Gene Therapy Vaccines: Introduction of nucleic acids  Subdivided into groups:  NON-LIVING VACCINES (inactivated/subunit/killed) – Don’t infect but contain nucleic acids (adjuvant effects)  LIVE VACCINES – Modified virus or bacterium or replicating vector expressing heterologous immunogen  DNA VACCINES – Plasmid DNA injected, expresses immunogen  ADJUVANTS – Nucleic acid-based vectors that non- specifically stimulate host responses to co-administered immunogen
Non-Living Virus Vaccines  No risk of infection by viral agent  Generally safe, except in people with allergic reactions  Large amount of antigen elicits protective antibody response  Produced in several ways:  Chemical inactivation (e.g., formalin) of virus  Heat inactivation of virus  Purification of components or subunits of viral agent from infected cells  Typically administered with ADJUVANT  Boosts immunogenicity  Influences type of response (TH1 versus TH2, secretory IgA)  Used when wild-type virus:  Cannot be attenuated  Causes recurrent infection  Has oncogenic potential
Live Virus Vaccines  Preparations of viruses limited in ability to cause disease  AVIRULENT – does not cause human disease (often other species)  ATTENUATED – deliberately manipulated to become benign  Immunization resembles natural infection  Progresses through normal host response  Humoral, cellular & memory immune responses develop  Immunity generally long-lived  BUT, can revert to virulent form in host  May still be poorly immunogenic  May still be dangerous in immunocompromised individuals  Pregnant women  Infants  Immunosuppressed (chemotherapy, HIV etc.)
Live Virus Vaccines  Live virus vaccines are attenuated because:  They are mutants of wild-type virus  They are related viruses with non-human host that share epitopes  They are genetically-engineered to lack virulence properties  Attenuated mutant viruses include:  HOST RANGE MUTANTS: Grown in embryonated eggs or tissue culture cells  TEMPERATURE-SENSITIVE MUTANTS: Grown at non-physiological temperatures  IMMUNE-SENSITIVE MUTANTS: Grown away from selective pressures of host immune response  TROPISM-ALTERED MUTANTS: Replicate at benign site, but not target organ (e.g. Sabin polio vaccine in GI tract but not CNS)  Live-attenuated virus vaccines licensed for measles, mumps, rubella, VZV, yellow fever & polio
Blind Passage: Most live attenuated virus and bacterial vaccines
Live Versus Non-Living Vaccines Property Live Non-Living Route of administration Natural or injection Injection Cost Low High Number of doses Single Multiple Need for adjunvant No Yes Duration of immunity Long-term Short-term Antibody response IgG, IgA IgG Cell-mediated response Good Poor Heat lability of vaccine Yes No Interference Occasional None Side effects Occasional mild Occasional sore arm symptoms Local versus systemic Both Local Reversion to virulence Occasionally None
The Future of Vaccines  Molecular biology now applied to vaccine design  New live vaccines genetically engineered to inactivate/delete virulence genes  Replaces random attenuation by cell culture passage  Many new types of vaccines now being developed:  SUBUNIT VACCINES (not technically gene therapy)  HYBRID VIRUS VACCINES  REPLICON VACCINES  DNA VACCINES