CONTROL OF VIRAL DISEASES BY IMMUNIZATION Part 2

Delivery and Formulation • At present, vaccines are delivered by a limited number of methods, including the: • traditional hypodermic needle injection, • oral administration, • and the “air gun” injection of liquid vaccines under high pressure through the layers of skin. • Subcutaneous or scarification (smallpox) • Other methods under consideration include new emulsions, artificial particles, and direct injection of fine powders through the skin.

Delivery and Formulation • Oral delivery of vaccines can be effective in stimulating Ig. A antibodies at mucosal surfaces of the intestine and in inducing a more systemic response. • Genetically engineered edible plants that synthesize immunogenic viral proteins represent an attractive approach to designing potent and cost-effective oral vaccines. • Transgenic plants expressing viral antigens can be developed, or plant viruses with genomes encoding immunogenic proteins can be used to infect food plants.

Delivery and Formulation • Early experiments are promising: when such a plant is eaten, antibodies to the viral structural protein can be demonstrated in the animal’s serum. • Oral vaccination, by whatever methodology, is not always possible, because the enzymes of the oral cavity, coupled with the high acidity of the alimentary tract, destroy many vaccines.

Adjuvants • Inactivated virus particles or purified proteins often do not induce the same immune response as replication-competent, attenuated preparations, unless mixed with a substance that stimulates the early inflammatory response. • Such immunostimulants are called adjuvants • Vaccine researchers can optimize a vaccine by using different combinations of adjuvant and immunogen to induce a protective immune response. • Adjuvants act by stimulating early intrinsic and innate defense signals, which then form subsequent adaptive responses.

Adjuvants • Adjuvants vary in composition, from lipid vesicles to mixtures of aluminum salts. • Some adjuvants, like alum (microparticulate aluminum hydroxide gel), are widely used for human vaccines such as the papillomavirus, hepatitis A, and hepatitis B vaccines.

Vaccine for every Virus • Developing effective vaccines to some viruses is proving very difficult, • e. g. , influenza, common cold viruses, HIV-1, herpes, and more. • Common problems include the existence of many serotypes, antigenic drift and shift.

Examples of virus vaccines

Vaccination Schedule in Palestine DTP: Diphtheria, tetanus, pertussis; Polio: OPV, IPV; MMR: measles, mumps and rubella; Hib: Haemophilus influenzae type b; BCG: Bacillus Calmette–Guérin

Protection from Infection or Protection from Disease? • There are different possible outcomes following vaccine administration: 1. In some cases, the antibody and memory T cells established by vaccination are maintained for long periods, • their mobilization will be sufficient to stop a subsequent infection before the virus can spread beyond the site of entry. • Disease is prevented because the virus cannot reproduce or spread. 2. In other cases, virus reproduction and spread may not be blocked immediately.

Protection from Infection or Protection from Disease? • Such infections can only be cleared by the coordinated action of vaccine-induced immune effectors and infectioninduced immune responses (e. g. , interferon production). • In this case, disease may not be prevented, but its onset can be delayed or its severity lessened. 3. In a third, less optimal outcome, the virus will not be eliminated • because the host’s response to the vaccine or to subsequent infection (or both) is inadequate. • Consequently, disease is not prevented and vaccination may confer only a modest delay in the appearance of disease.

$Passive immunization • Normal pooled human immunoglobulin (Ig) fraction. • Heat treated to destroy$

Passive immunization • Normal pooled human immunoglobulin (Ig) fraction. • Heat treated to destroy viruses. • Considered as safe. • Examples of use: • Prevention of hepatitis A. • Prevention or modification of measles in the immunocompromised who have been in contact with a case. • HBV Ig is coadministered with the vaccine to provide rapid protection after say a needle-stick injury. • Rabies Ig immediately after exposure. • Varicella Zoster Ig to the immunosuppressed and leukemic.

ANTIVIRAL CHEMOTHERAPY

Introduction • Public health measures and vaccines can control some viral infections effectively. • For those that cannot, we must rely on antiviral drugs. • Unfortunately, despite more than 50 years of research, our armamentarium of such drugs remains surprisingly small.

Major limitation in antiviral drug development 1. The requirement for a high degree of safety. • This restriction can be difficult to overcome because of the dependence of viruses on cellular functions: a compound that blocks a pathway that is critical for the virus can also have deleterious eﬀects on the host cell. 2. The antiviral compounds must be extremely potent: • even modest reproduction in the presence of an inhibitor provides the opportunity for resistant mutants to prosper. • Achieving sufficient potency to block viral reproduction completely is remarkably difficult. 3. Other limitations can be imposed by the difficulty in propagating some medically important viruses in the laboratory

Therapeutic index • Antivirals should inhibit virus-directed events rather than normal cellular activities. • This is usually expressed by therapeutic index (T. I. ), which can be defined as the ratio: • TD 50 is the dose of drug that causes a toxic response in 50% of the population • ED 50 is the dose of drug that is therapeutically effective in 50% of the population. • In general, only those agents displaying a T. I. of at least 10 and preferably 100 -1000 are worth pursuing further.

Therapeutic index

Strategies for development of antiviral agents • Binding to the free virus particle, this could stop virus infection early. • Interference with virus adsorption or attachment to the receptor binding site on the cell. e. g. , the use of soluble CD 4 molecules to prevent HIV infection. • Inhibition of virus uncoating and release of nucleic acid. • Inhibition of viral nucleic acid transcription and replication. e. g. , certain viruses have their own enzymes such as, influenza (RNA transcriptase), herpes (DNA polymerase, retroviral reverse transcriptase.

Examples of antiviral drugs different steps in virus multiplication • Viral adsorption • In case of HIV-1, its primary receptor is CD 4 Tcell antigen, to which viral glycoprotein “gp 120” binds. • Soluble CD 4 is injected thus preventing the virus from binding to T-cells. • Another approach is the prevention of soluble or analogues to “gp 120” that should attach to cellular CD 4 preventing HIV from binding to cells. • Sulfated polysaccharides such as dextran sulfate and heparin inhibit HIV adsorption to target cells.

Examples of antiviral drugs different steps in virus multiplication

Examples of antiviral drugs different steps in virus multiplication • Amantadine • Against influenza A virus • Amantadine blocks a viral ion channel (M 2 protein) and • Prevents the virus from infecting cells. • It should be given early in the infection( first day). • Resistant strains have developed

Examples of antiviral drugs different steps in virus multiplication • Oseltamivir (Tamiflue) and Zanamivir (Relenza) • Neuraminidase inhibitors • They prevent the release of influenza virus from infected cells. • Acyclovir • Inhibits herpesvirus DNA polymerase, thus virus DNA replication is inhibited • Idoxuridine (IDU) and Trifluorothymidine (F 3 T) • They are analogues of thymidine, they are incorporated into nucleic acid (DNA), mismatching occurs during both transcription and replication of substituted DNA

Examples of antiviral drugs different steps in virus multiplication • Zidovudine (Azidothymidine) • Against HIV-1 • The molecule has to be phosphorylated intracellularly to produce the active antiviral drug. • The triphosphate is a very potent inhibitor of viral reverse transcriptase enzyme and prevents nucleotide chain elongation. • Lamivudine • Reverse transcriptase inhibitor, for both HIV and HBV treatment.

Examples of antiviral drugs different steps in virus multiplication • Istatin-ß-thiosemicarbazone (IBT) • Inhibits the translation of late m. RNA of poxvirus. • Rifampin • Inhibits poxvirus morphogenesis, the drug seems to inhibit the association of a protein viral component to the progeny virus particles. • Saquinavir • Inhibits viral protease, many viral proteins are synthesized in the form of precursors that must be cleaved to yield functional proteins, e. g. , in the case of HIV. • These cleavages are affected by highly specific virusencoded proteases that are the prime targets for interference with virus multiplication.

Examples of antiviral drugs different steps in virus multiplication • Ribozymes • May be used to cut RNA and DNA at sites that will disable them. • Interferon alpha • Is used for the treatment of HCV and HBV.

Examples of antiviral drugs different steps in virus multiplication • Drug-resistant strains of many viruses have been isolated. • Combination of two or more drugs are used to overcome resistance problem. • Some virus genomes generate proteins that mimic those used by the human immune system, confusing the immune system response, researchers are now searching for antivirals that can recognize these intruder proteins and disable them.