vaccine strategies

There are two methods of prophylaxis available in the United States to control the incidence of influenza; chemoprophylaxis, or therapy with antiviral drugs, and immunoprophylaxis, or vaccination with an inactivated flu virus.

Chemoprophylaxis

Amantadine hydrochloride and rimantadine hydrochloride are related drugs which interfere with the viral cycle of influenza type A. For information concerning amantadine and rimantadine drug therapy, link to the drug therapy page.

Chemoprophylaxis with amantadine or rimantadine is recommended as a supplement to vaccination for individuals at high risk for severe illness. Administration of the drugs does not interfere with the immune response to vaccination. Amantadine and rimantadine are especially recommended for high risk individuals who cannot be vaccinated, such as those who are immunosuppressed or allergic to vaccine components. Amantadine and rimantadine have been demonstrated to cause minor side affects such as nausea, lightheadedness, and anxiety in a small percentage of recipients.
Immunoprophylaxis

A. Inactivated influenza vaccine

All currently available and licensed vaccines in the United States are composed of inactivated virus. These vaccines generally exhibit a 70-90% efficacy in reducing the incidence of clinical illness in healthy subjects when the circulating strains of virus match that of the vaccine strain. Vaccination is highly recommended for individuals who may experience increased health complications upon infection. The vaccination of at least 60% of persons at risk for severe influenza-related illness is a national health objective for the year 2000. The United States Centers for Disease Control and Prevention defined high risk groups for influenza in a 1998 press release as:

 
Images from National Foundation for Infectious Diseases
Persons >65 years of age
Residents of nursing homes and chronic-care facilities
Adults and children who have chronic disorders of the pulmonary or cardiovascular systems, including children with asthma
Adults and children who have required regular medical follow-up or hospitalization during the preceding year because of chronic metabolic diseases (including diabetes), renal dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications)
Children and teenagers (6 months - 18 years) who are receiving long-term aspirin therapy and, therefore, might be at risk for developing Reye syndrome after the flu
Women who will be in the second or third trimester of pregnancy during the flu season
Vaccine Preparation: Inactivated vaccines are available in three forms; whole-virus, split-virus, and subunit virus vaccines. Whole virus vaccines are produced by injecting flu virus into chicken eggs and harvesting the chick embryo allantoic fluids 2-3 days later. The virus subsequently undergoes zonal gradient centrifugation and inactivation by formalin or B-propiolactone. Split virus vaccines, which are prepared by treatment with ethyl ethers or detergents contain essentially all viral structure proteins and portions of the viral membrane. Subunit vaccines are solubilized with detergents and furthered purified of surface glycoproteins. They contain hemagglutinin monomers and residual structural proteins. Split and subunit virus vaccines are generally less toxic than whole virus vaccines, and are recommended for use in child immunizations. Inactivated vaccines must be administered via injection.

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Strain Composition: Inactivated vaccines are produced annually in order to target the specific HA and NA surface antigens of influenza strains predicted to circulate in the coming flu season. In February of each year the World Health Organization Influenza Surveillance System releases the names of three such strains. These strains are recommended by WHO to be used as the basis for the creation of a tripartite vaccine. The three viral strains projected for the 1998-1999 flu season were:
 A/Sydney/5/97(H3N2)-like virus

 A/Beijing/262/95(H1N1)-like virus

 B/Beijing/184/93-like virus
Immune ResponseThe immune response to the inactivated influenza vaccine is elicited approximately seven days post intramuscular vaccination. At this time a high titer of circulating antibodies to viral HA can be detected. The formation of IgG antibodies is induced in the upper and lower respiratory tract. A cytotoxic T lymphocyte response is also detectable. The inactivated influenza vaccine does not elicit mucosal immunity.

Adverse Effects: Adverse effects to the inactivated vaccine include both local and systemic reactions. Local reactions include erythema, tenderness and itching at the injection site. Systemic reactions are rare, and include incidences of brief, sustained fever, myalgia, arthralgia, headache, and malaise.

B. Live attenuated vaccine

Live attenuated vaccines are being widely tested in the United States; they represent the most anticipated candidates for the second generation of influenza vaccines. Live attenuated vaccines are advantageous because of their ability to replicate within the host, thus eliciting strong humoral and cell mediated responses and often eliminating the need for booster administrations. Attenuated virus vaccines do not cause clinical illness and have been experimentally determined to be safe and genetically stable.

Reassortment Vaccines: Genetic reassortment viruses serve as the basis for current live influenza vaccines. Reassortment is achieved through the simultaneous infection of a cell with two genetically dissimilar strains of virus. This process exploits the segmented genome of influenza; during the dual infection, different segments of RNA from each virus can be donated to produce reassorted progeny. Generally, one donating strain possesses the wildtype HA and NA-coding genes projected to circulate in the upcoming flu season. The other donating strain (termed "master strain") possesses genes which confer attenuation. Viruses expressing both desired characteristics are selected by antibody assays.

Attenuation: Attenuation is achieved through the multiple passaging of virus under conditions which make them non-pathological to humans. Current live attenuated influenza vaccine candidates are attenuated via cold adaptation, in which the virus is grown at progressively lower temperatures. Through this process viruses are produced which a) can thrive in the cooler distal ends of the respiratory tract (thereby eliciting mucosal immunity) and b) cannot survive in the lower respiratory and thus cannot cause a systemic/ pathological infection. Live attenuated vaccines are also advantageous as they can be administered orally or intransally.

 

C. Experimental Vaccines

Some experimental vaccines for influenza currently being tested include:

Polynucleotide Immunization: The intramuscular injection of polynucleotides, or "naked" DNA coding for influenza proteins has been demonstrated to elicit both humoral and cell-mediated immune responses in animal models. These DNA vaccines express HA and internal proteins and are much more efficient than the inactivated influenza vaccine. The production of antigens in their native forms improves the presentation of the antigens to the host immune system. Unlike live attenuated vaccines, DNA vaccines are not infectious and carry no threat to producing the influenza pathology.

Poxvirus Recombinants: Recombinant canarypox or vaccinia virus can be made to express influenza virus proteins during infection. Again, presentation of influenza antigens through virus vectors is non-infectious, and has no potential for reversion to virulence. Pox recombinant virus vaccines are useful as they can be made to express multiple foreign antigens. Recombinant vaccinia viruses have been shown to elicit a strong cytolytic T lymphocyte response in mouse models. Unfortunately, major side affects are associated with the current use of the vaccinia virus vectors, such as the progressive vaccinia infection in immunocompromised individuals and encephalitis or encephalopathy in infants. A modified strain (NYVAC) has been developed which is highly attenuated in immunocompromised animals.

Synthetic Peptides: Oligopeptides corresponding to the antigenic components of the HA protein have been developed. These peptides are conjugated to tetanus toxoid which acts as a protein carrier during immunization. Due to difficulty in presenting the peptides in appropriate configurations, some peptides have been demonstrated to be marginally immunogenic.

Adjuvants: Adjuvants are substances used to increase the immunogenicity of a given vaccine. Several experimental adjuvants for the inactivated influenza vaccine are presently being tested in preclinical studies: immune stimulatory compounds (ISCOMS), liposomes, muramylpeptide derivatives, and a monoclonal anti-HA antibody adsorbed to alum.