CH 105 - Chemistry and Society

Influenza Treatment:  Drugs and Vaccines

04/18/2008

Drugs

Developing drugs to treat viral infections is difficult, since many of the proteins used for viral replication are host proteins. However, viral specific proteins encoded by the viral genome and needed for virus propagation are available targets for new drus.

Amantidine and Rimantadine: Works on type A influenza.  They inhibit the M2 protein (ion channel in membrane), which somehow inhibits viral replication.

  amantidine

Structures of amantidine and rimantadine

Oseltamivir (Tamiflu) and zanamivir (Relenza)  (structure) These work on both influenza A and B. They inhibit neuraminidase, whose activity is necessary for viral release from infected cells.

All these drugs can decrease flu symptom duration by one day if taken within two days of symptom appearance.   Amantidine and Tamiflu have been shown to be effective in preventing flu. 

Relenza (taken as an inhalant) appears to work best in treatment of non-complicated flu cases less than 2 days old.  The H5N1 virus appears to be resistant to Amantidine and Rimantadine, but not Tamiful or Relenza.

Jmol Model:Neuraminidase:Relenza Complex (also bound to a sugar called NAG)

Vaccine Development

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Prevention by Vaccination.  Credit:  http://virology-online.com/viruses/Influenza4.htm

Vaccines against influenza have been around for 50 years. Despite this, the efficacy of influenza vaccines is still questioned, and the ability of vaccines to limit epidemic infection has not been proven.

1. Immunity to Influenza - the results of challenge studies indicated that immunity is induced by the host responses to the virus haemagglutinin (HA) and to neuraminidase (NA). Antibody against HA is the most important component in the protection against influenza viruses. In addition to conferring relative protection against infection, serum HI is reported both to reduce the severity of infection and decrease virus spreading in infected persons. Serum anti-neuraminidase Ab has also been shown to contribute protection against influenza infection. A generally held view is that serum HI antibody is more important in determining immunity than anti-neuraminidase antibody. It is clear that an influenza vaccine must contain both HA and NA antigens in a form which will stimulate the production of neutralizing antibody, local IgA antibody and possibly cellular immunity.

2. Types of vaccine

  1. Whole virus vaccines - whole inactivated virus vaccines were the first influenza vaccines to be produced. The currently circulating strain of influenza is inoculated into embryonated eggs, harvested 2-3 days later and inactivated. this vaccine confers protection in 60-90% of vaccinees and the protection lasts for 1-5 years, depending on the vaccine strain and the age of the vaccinee. However, the subsequent infecting virus may show slow antigenic drift and the vaccine induced antibody will be less effective in conferring protection against the new strains.
     
  2. Split virus vaccines - Because of the high incidence of reactions seen in vaccinees given whole, inactivated virus vaccine, attempts have been made to produce a vaccine which is less reactogenic but conserving immunogenicity. Split vaccines were prepared inactivated particles disrupted with detergents. These vaccines have been shown to induce fewer side effects in the vaccinees and are just are immunogenic as whole virus vaccine. Whole virus vaccine should not be used in children.
     
  3. Subunit virus vaccines - subunit vaccines have been prepared which contained only the HA and NA antigens. These are used in aqueous suspension or may be absorbed to carriers such as alhydrogel. Volunteers given subunit vaccines experienced fewer reactions than those given whole virus vaccines and those given aqueous vaccine experienced fewer reactions than those given the absorbed subunit vaccine. therefore, the best vaccines available at present are the aqueous subunit vaccines, although some authorities have questioned the effectiveness of subunit vaccines.
     
  4. Live attenuated vaccines - there is experimental evidence that immunization with live, attenuated influenza virus vaccines induce a solid immunity than do inactivated vaccines. Normal methods for attenuation, such as repeated passages and temperature adaptation require a long period to complete, and probably too long for the vaccine to become available for immunization against the current influenza strain. To circumvent this problem , already attenuated strains have been mixed with wild-type virus to produce recombinants which contain the RNA fragments which code for wild-type HA and NA, and all the other genetic material form the attenuated strain. These recombinants can be produced relatively quickly. When given intranasally, produced few side effects.

Although research to develop live attenuated vaccines has been pursued for 20 years, basic problems remains particularly in the area of purification. The vaccine must also be shown to be attenuated and safe. It is estimated that if the safeguards are to be satisfied, 2 years would be needed for the development of an attenuated vaccine. This makes their development impractical , since by the time the vaccine virus can be made available, the epidemic strain against which the vaccine has been prepared would have disappeared. For an attenuated vaccine to be a practical proposition, the development time must be down to 6-9 months.

3. Recommendations - At present, no live attenuated vaccine is available for general use. The vaccines that are currently available are produced from virus grown in embryonated eggs. The aqueous subunit vaccine is the most acceptable formulation. These vaccines produce few reactions and confer protection in 60-90% of vaccinees. Vaccination is recommended for the elderly and individuals at risk for severe infection. In addition, key personnel n industry and social and medical services. It is highly debatable whether the vaccine should be given to the general population. Influenza immunization is strongly recommended for adults and children with any of the following:

1. Chronic respiratory disease
2. Chronic heart disease
3. Chronic renal failure
4. Diabetes mellitus and other endocrine disorders
5. Immunosuppresion due to disease or treatment

Immunization is also recommended for residents of nursing homes and old peoples' homes and other long stay facilities where rapid spread is likely to follow. Two types of vaccines are available in the UK; "split virus vaccines", and "surface antigen" vaccine which contains highly purified HA and NA antigens prepared from disrupted virus particles. Both vaccines are suitable for use in children.
 

 
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Vaccine Production

credit:  http://www.bioteach.ubc.ca/TeachingResources/MicrobiologyImmunology/FluVirusAntlerCBoyleE.ppt#292,22,Live Vaccines

An example of an attenuated vaccine produced through genetic reassortment is FluMist. The Master strain virus was selected so it grows optimallly at 25oC but not at body temperature at 37oC.  The mist is sprayed in the nose where the temperature is not 37oC.  There is can illicit an immune response that is systemic throughout the whole body.

  • Subunit vaccines:  Use only purified H protein or N protein to immunize patients.  Protein Sciences Corporation is developing FluBl�k�, a influenza vaccine produced in cells in culture
  • DNA vaccines: inject DNA encoding H or N protein, with goal that patient produces the H or N protein.  Vical Inc has produced DNA vaccines against the Ebola virus. 
  • Government Plan for the next influenza pandemic

The problem with any vaccine is that during a pandemic, the amount of vaccine required would greatly exceed the demand.  In addition, multiple vaccinations to boost the immune system might be required.  Scientist are trying to develop new adjuvants that can make a single dose of a vaccine more immunogenic.  Adjuvants works by costimulating the immune system allowing a greater response, in this case, development of antibody and immune cells to the injected antigen.  A potentially significant breakthrough has recently (March 2008) been reported by Iomai, a biotechnology firm.  They have developed a skin patch that contains a proprietary adjuvant.  It is absorbed into the skin into Langerhan cells.  These take up the adjuvant and migrate to the lymph nodes where the immune response to the influenza virus, delivered by a vaccine (produced by Solvay) at the same site, takes place.  They reported that the patch allowed a robust immune response against a single dose of an avian flu vaccine instead of multiple doses, leaving more vaccine available for others. 

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