MGY378 28: Live vaccines

vaccine

• biological product that induces an immune response that confers protection against infection/ disease when you are subsequently exposed to pathogen

• contains antigens (proteins, polysaccharides) from the pathogen

correlates of protection

• Mechanistic CoPs (causal):

  • Directly responsible for protection

    • ex: anti-toxin abs for tetanus vaccine

• Non-mechanistic CoPs (surrogate):

  • Correlate statistically with protection but aren't the actual cause

  • ex: anti-S IgG levels for HBV

live vaccines

• attenuated - infect and reproduce but don’t cause disease

• recombinant - infect cells but do not cause disease

  • infected cells express target immunogenic proteins

• stimulates production of antibody and cell-mediated immunity

non-live vaccines

• do not cause infection

• chemically inactivated WT virions

  • formalin-inactivated

• purified proteins

• stimulate production of antibodies against viral proteins or purified protein

list of live vaccines

• vaccinia

• measles vax

• polio vax

• ebola vax

smallpox

• variola

• systemic febrile illness with rash

• 4 forms of smallpox

  • ordinary

  • vax-modified

  • flat

  • hemorrhagic - 25% case fatality

• 10-14 day incubation → easy spread

• highly contagious

variola

• poxvirus

• large DNA genome >180 kb

• enveloped

• brick-shaped

• replicates in cytoplasm unlike other DNA viruses

• transmission: airborne, droplet, contact, fomites

variolation

Scab from smallpox patient delivered to healthy person by scratching it into the arm

vaccinia

• milkmaids who had cowpox (vaccinia) were protected from smallpox

• Edward Jenner inoculates boy with cowpox, gives smallpox → protected against smallpox

• cowpox = attenuated ver of smallpox

  • live vax

Horse Grease disease

• Horsepox virus HPXV

• indistinguishable from vaccinia/ cowpox infections

• nodules similar to parapoxVs/ bovine herpesV 2 (mamillitis)

Beaugency lymph

• lymph from cows from Beaugency, France

• for smallpox vaccines, originally propagated in animals

HPXV vs Vaccinia

HPXV

• Plaque assay: smaller plaques than cowpox & Vaccinia, no secondary plaques

• thus less virulent than cowpox & vaccinia

no clear advantage over using either HPXV or VACV as vaccine in balb/c mice

VACV-HPXV recombinants

• possible evolution - poxV can swap DNA w/ ea o

• Maybe a version of the vax was a hybrid of cow and horsepox

14L locus in Dryvax clone DPP17

• smallpox VACV vaccine

• encodes block of seq & frameshift mutation that resembles homologous locus in HPXV

• recombination?

measles

• airborne

• only reservoir is humans

• R₀ = 14-18

• deafness/ brain damage

• 1-5% case fatality

• 1/10 000 cases SSPE

SSPE

= subacute sclerosing pan-encephalitis

• brain inflammation

• fatal

• occurs 5-10 yrs after recovery

measles vax

• Edmonston strain

• later vers passaged 40X in chicken embryos to attenuate

• 2 doses = 99% efficacy

• herd immunity = 85-95%

polio

• picornavirus

• 7-35 day incubation period

• 10% severe disease

  • neck stiffness, paralysis

• fecal-oral transmission

Salk polio vaccine (IPV)

• inactivated (killed, non-live) polio vaccine

• WT type 1 & 3 polio inactivated with formalin (crosslinks proteins)

  • can still present ag to immune system

• injected → ab production

• humoural protection

  • cannot go to CNS

Sabin polio vaccine (OPV)

• oral polio vaccine

• live, attenuated

• WT type 3 virus from fatal paralytic case

• passaged:

  • 21X in monkeys

  • 47X in monkey cell culture

OPV attenuation

key mutation in 5’UTR affecting IRES (internal ribosomal entry site) → poor replication

can still stimulate ab production and cell-mediated imm response

OPV protection

• infects cells within intestine → progeny virus excreted in stool

• if progeny go to CNS, poor replication (no symptoms)

• a WT infection later on neutralized by mucosal antibodies that are already there due to OPV

Vaccine-derived polio type 2

• caused by OPV

• the 5’UTR key mutation can sometimes revert

• this is why Canada uses IPV

• 3rd world countries still use OPV - may be exposed during travel

Ebola vaccine

• VSV (infects cattle)

• removed glycoprotein, replaced with ebolaV glycoprotein

  • present to imm sys

• efficacy = 95-100%

• Ring vaccination strategy

  • Vaccinate all the people who have had contact with case 1

live vax challenges

• requires cold chain

• needle-based administration

  • logistically challenging, risk of needle reuse, hard for kids

• herd immunity for immunocompromised/ pregnant

• hard to develop