History of Vaccines (lịch sử vacxin) docx

Immune mechanisms to eliminate virus or virus-infected cells  Humoral & cell-mediated immune responses important for antiviral immunity  Must eliminate both virus & virus-infected cell

History of Vaccines

 INFECTION

health in last 100 yrs

 SANITATION

 VACCINATION

 JENNER – smallpox vaccine

 PASTEUR – rabies vaccine

 Global eradication of smallpox (1980)

 Future global eradication of polio

• 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

• 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 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

Non-Targets for Antiviral Antibodies

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

 AVIRULENT – does not cause human disease (often other species)

 ATTENUATED – deliberately manipulated to become benign

 Progresses through normal host response

 Humoral, cellular & memory immune responses develop

 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

Route of administration Natural or injection Injection

Side effects Occasional mild

symptoms Occasional sore arm

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

Subunit Protein Vaccines

 Genes for immunogenic proteins cloned into bacterial & eukaryotic expression vectors which produce protein in vitro:

 Identifying appropriate subunit or peptide immunogen to elicit protective antibody & ideally CTL

 Present antigen in correct conformation

 Examples include:

 HBV surface antigen (in use)

 HIV gp120

 Influenza virus hemagglutinin

 Papillomavirus virus-like particles (VLP; in use)

 With viruses, single proteins can make particles that bud from cells (VLP) that can use class I and class II pathways

Hybrid Virus & Replicon Vaccines

 Genes from infectious agents that cannot be attenuated inserted into “safe” viruses:

 CHIMERIC VIRUSES: Combined genomes from related virulent & attenuated viruses

 YFV 17D-based vaccines for dengue, West Nile & Japanese

encephalitis virus

 VIRUS VECTORS: Attenuated virus engineered to express

immunogenic gene from pathogenic virus

 Canarypox, retrovirus & alphavirus vectors

 Replicons - virus particles capable of only one round of infection

 Essential gene(s) deleted from genome

 Added back in trans to make virus particles in cell culture

Chimeric RNA virus (Acambis “Chimeravax”)

cDNA clone of 17D Yellow fever virus vaccine with C, prM and E of Dengue, Japanese encephalitis or West Nile virus substituted

Viral Immunogens

Structural

Genomic

Foreign protein

26S Genomic

Alphavirus Replicon Vectors

26S Genomic

DNA Vaccines

 Great potential for immunization against infectious agents requiring T cell &

antibody responses

 Gene of protein eliciting immune response cloned into eukaryotic expression vector

 Naked DNA injected into muscle or skin

 DNA taken up by cells & gene expressed

 Protein produced and presented to immune system

 Very easy to design & produce

 Extremely safe, no possibility of reversion to virulence

 Have many similar drawbacks to other non-living vaccines (limited immunogenicity, require adjuvants)

 However, bacterial DNA (plasmid amplified in bacteria) is a natural adjuvant for like receptor 9, an innate immunity stimulating molecule

Immunogen determines route of presentation e.g., class I (cytoplasmic) vs class II (secreted)

Clinical trials for plasmid-based cancer vaccines

Gene Therapy Adjuvants

Adjuvant can be protein delivered with live or killed vaccine

For gene therapy, adjuvant can be delivered by a vector:

VirusRepliconBacteriumPlasmid

Or, adjuvant can be the nucleic acid itself delivered with another vaccine (usually killed vaccine)

Adjuvant protein and/or nucleic acid is utilized to increase the response of host cells such that immunization with vaccine resembles or is more stimulating than natural agent infection Examples:

Mip3-alpha – chemokine attracting immature dendritic cellsIFN-gamma – cytokine skewing towards TH1 immunity

IL-12 – cytokine promoting TH1 and mucosal antibodyCpG DNA – elicits cytokine response like pathogen Virus RNA – elicits cytokine response like pathogenCD86 - co-stimulatory molecule can be supplied, required for nạve T cell activation

Ubiquitin – proteasome targeting molecule, enhances Ag processing

26S Genomic

Cytokine (e.g.,IFN-g, IL-12)

Virus Vaccines Licensed in U.S.

Universal childhood vaccines

 Influenza A & B virus Elderly Parenteral, annual, killed

 Hepatitis A virus Travelers Parenteral, killed

 Japanese encephalitis virus Travelers Parenteral, killed

 Yellow fever virus Travelers Parenteral, live

 Rabies High-risk Prophylactic &

therapeutic , killed

 Smallpox High-risk Intradermal, live

 Rotavirus Children Live, cow virus

 Human Papilloma virus (3 dose) Females Intramuscular, Recombinant

Virus-Like Particle (no DNA)

Virus Vaccines Licensed in U.S.

Bacteria as vaccines/vectors

Killed/Subunit – DTaP , anthrax, meningococcal meningitis,

Live attenuated – Mycobacterium bovis cow bacterium (BCG), Salmonella

typhimurium Ty21a, CVD, Vibrio cholera 103-HgR

Expression of heterologous antigen – S typhimurium, Listeria

monocytogenes, Bacillus anthracis

Plasmid delivery – Shigella sp., Listeria sp Some intracellular bacteria

target dendritic cells and can deliver plasmids to the APCs

Advantages: can give orally for mucosal immunity, sometimes long

term antigen expression

Disadvantages: much more complex than viruses, attenuation

mechanisms less well understood and may have unexpected long

term consequences for vaccinees