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#live attenuated vaccines

3 public questions tagged with this topic.

Vaccine

Live attenuated vaccines are weakened by:

Live attenuated vaccines are weakened by serial passaging in non natural host cell cultures, tissues or under suboptimal temperature forcing accumulation of adaptive mutations and deletion of virulence genes. Method pioneered by Louis Pasteur for anthrax and rabies via passage in animals. For viral vaccines, poliovirus Sabin strains passaged in monkey kidney and mouse spinal cord selecting neurovirulence attenuating mutations in 5'UTR internal ribosome entry site reducing replication in neurons while retaining replication in gut. Measles Edmonston strain passaged in primary human kidney cells, chick embryo fibroblasts adaptation to avian receptors reducing human pathogenicity. BCG created by 230 serial passages of Mycobacterium bovis on potato bile glycerin medium 1908-1921 resulting loss of RD1 region encoding ESX-1 secretion system essential for virulence. Alternative modern strategies include cold adaptation growing influenza at 25°C selecting viruses replicating in cooler upper respiratory tract not warm lower lung, generation of reassortants, or reverse genetics deleting virulence genes like HSV ICP34.5. Attenuated microbe replicates limitedly presenting native antigens via both MHC pathways, inducing strong cellular immunity. Reversion monitored by sequencing.

Ref: Pasteur attenuation principle; Plotkin live vaccine passage; WHO Live attenuated methods.

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Immunological Applications

Live attenuated vaccines differ from inactivated vaccines because they:

Live attenuated vaccines developed through classical virology approach reducing pathogenicity while retaining replicative capacity that mimics natural infection without causing severe disease. Attenuation strategies include serial passage in heterologous host cells like chick embryo fibroblasts, embryonated eggs, or at subphysiologic temperature 25 to 33 degrees cold adaptation accumulating adaptive mutations in polymerase genes L and P reducing transcription efficiency in human cells at 37 degrees, plus mutations in surface glycoprotein cleavage sites reducing fusogenicity and in interferon antagonism proteins NS1 and V impairing immune evasion. Resulting strain enters mucosal epithelia via natural route intranasal or oral, expresses entire antigen repertoire including conformational fusion protein prefusion state, matrix and nucleoprotein providing CD8 epitopes conserved across strains that are destroyed by formalin inactivation crosslinking fusion peptide, and replicates limitedly to titers 10^3 to 10^4 increasing antigen dose tenfold from inoculum. This mechanistic insight supports diagnostic and therapeutic applications while reinforcing core immunological and cell biology principles taught in advanced curricula.

Ref: Plotkin Vaccines 7th ed live attenuated replication PAMP; Abbas Cellular Molecular Immunology Sabin polio reversion risk.

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Immunological Applications

Live attenuated vaccines differ from inactivated vaccines because they:

Live attenuated vaccines comprise pathogens weakened laboratory passage serial passage heterologous hosts chick embryo fibroblasts 100 times cold adaptation growth 25C restrictive temperature-sensitive polymerase mutations or targeted deletions removing virulence determinants NS1 influenza inhibiting interferon thymidine kinase herpes limiting replication neurons capsule genes retaining ability infect host cells particularly epithelial dendritic cells transcribe viral genes under cellular Pol II produce antigens near wild-type assemble virions replicate transiently low levels limited host innate immunity without clinical disease impaired antagonism interferon. Intracellular replication triggers cytosolic dsRNA sensors RIG-I recognizing 5 triphosphate RNA MDA5 long dsRNA inducing MAVS aggregation activating IRF3 NF-kB generating antiviral state type I IFN beta inflammasome NLRP3 caspase-1 cleaving IL1beta providing potent intrinsic adjuvant mimicking natural infection. Antigen synthesized endogenously enters ER translocon SEC61 loading TAP nascent MHC I heavy beta2 microglobulin presenting CD8 CTL critical intracellular bacteria TB viruses CMV while exogenous release stimulates MHC II. Mucosal IgA induced administered orally oral polio Sabin or intranasally live attenuated influenza FluMist homing lamina propria plasma secreting secretory IgA. In contrast inactivated vaccines killed chemical treatment formalin 0.02 percent 28 days crosslinking proteins beta-propiolactone alkylating nucleic acids heat 56C denaturing

Ref: Plotkin Vaccines 8th ed Live Attenuated vs Inactivated Comparison; CDC Vaccine Types Replication Immunity Mechanisms; Janeway Live Vaccine Cellular MHC I Chapter 12.

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