Mucosal surfaces of respiratory tract and GI tract. Rhino; myxo; corona; parainfluenza; respiratory syncytial; rota
Infection at mucosal surfaces followed by spread systemically via blood and/or neurones to target organs: picorna; measles; mumps; HSV; varicella; hepatitis A and B
Direct infection of blood stream via needle or bites and then spread to target organs: hepatitis B; alpha; flavi; bunya; rhabdo
Local immunity via IgA very important in 1 and 2.
There is little point in having a good neutralizing humoral antibody in the circulation when the virus replicates, for example, in the upper respiratory tract. Clearly, here secreted antibodies are important. Although in the case of influenza serum antibodies may be important www.freelivedoctor.com
Last US natural (non-vaccine associated) case was 15 years ago
2 does injectable (Salk) vaccine
2 doses oral
Vaccine cases 1 in 3 million does
New strategy will prevent about 5 of the 10 vaccine-associated cases (the five found in vaccinees)
Cost $20 million
Savings from eradication $230 million
New Recommendations To eliminate the risk for Vaccine-Associated Paralytic Poliomyelitis, the ACIP recommended an all-inactivated poliovirus vaccine (IPV) schedule for routine childhood polio vaccination in the United States. As of January 1, 2000 , all children should receive four doses of IPV at ages 2 months, 4 months, 6-18 months, and 4-6 years. www.freelivedoctor.com
Use monoclonal antibodies to select for virus with altered surface receptor
Use mutagen and grow virus at 32 degrees . Selects for temperature-sensitive virus. Grows in upper respiratory tract but not lower
‘ flu (new vaccine)
respiratory syncytial virus
New Methods Recent ‘flu vaccine from Aviron Passage progressively at cold temperatures TS mutant in internal proteins Can be re-assorted to so that coat is the strain that is this years flu strain www.freelivedoctor.com
DNA resists temperature extremes so storage and transport are straight forward
DNA sequence can be changed easily in the laboratory. This means that we can respond to changes in the infectious agent
By using the plasmid in the vaccinee to code for antigen synthesis, the antigenic protein(s) that are produced are processed (post-translationally modified) in the same way as the proteins of the virus against which protection is to be produced. This makes a far better antigen than purifying that protein and using it as an immunogen.
Mixtures of plasmids could be used that encode many protein fragments from a virus/viruses so that a broad spectrum vaccine could be produced
The plasmid does not replicate and encodes only the proteins of interest
No protein component so there will be no immune response against the vector itself
Because of the way the antigen is presented, there is a CTL response that may be directed against any antigen in the pathogen. A CTL response also offers protection against diseases caused by certain obligate intracellular pathogens (e.g. Mycobacterium tuberculosis)
For a vaccine what are the measures of protection?
Can we overcome polymorphism?
What are the key antigens?
Attenuated or killed or neither?
Mucosal immunity critical?
Prevent infection or prevent disease?
How does HIV kill cells anyway?
Towards an anti-HIV Vaccine www.freelivedoctor.com What should vaccine elicit? Humoral response neutralizing antibody kill free virus Cellular response kill infected cells problem of cell-cell infection
Towards an anti-HIV Vaccine www.freelivedoctor.com Early faith in neutralizing antibodies backed by chimpanzee experiments HIV high levels of neutralizing antibody Can resist subsequent challenge by virus injected I.V. !!!! But not via rectum or vagina But chimps do not get AIDS
Animals challenged with small doses of virus at moment that antibody levels high (virus --not infected cells!)
Challenge virus same strain as that used to induce antibody
No vaccine made from one virus strain has protected chimps from another virus strain
Protection in man may not result from neutralizing antibodies at all
Ability to raise neutralizing antibodies in monkeys does not correlate with protection
Cell-mediated immunity is the key
This is also key in humans
HIV-exposed but not infected people shows signs of a cell-mediated response
Towards an anti-HIV Vaccine Since 1986: > 15 SUBUNIT VACCINES Based on gp160/gp120 All safe None effective Low levels of strain-specific antibodies that quickly disappear Only ephemeral effects of cell-mediated immunity All done with gp160/gp120 of syncytium-inducing virus None tested on large groups of high risk people www.freelivedoctor.com