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 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 4 th 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 10 th 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 Primary and Secondary Antibody Responses Responses Virus-specific T Cell Responses ~ Virus-specific T Cell Responses ~ CD4 and CD8 T Cells 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 • 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. Targets for Antiviral Antibodies Targets for Antiviral Antibodies . Triumphs  Global eradication of smallpox (1980)  Future global eradication of polio History History • Although early in history the basis of disease was not known, the presence of a life-long immunity. culture passage  Many new types of vaccines now being developed:  SUBUNIT VACCINES (not technically gene therapy)  HYBRID VIRUS VACCINES  REPLICON VACCINES  DNA VACCINES . 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