Lecture 11: Virus Vaccines & Antiviral Drugs - PDF

Lecture 11: Virus vaccines and antiviral drugs Yap Wei Boon, Ph.D (Assoc. Prof.) Email: [email protected]  Learning outcomes In the end of the lecture, students are able to: describe virus vaccines and their functions; describe the types of antiviral drugs and their f...

Lecture 11: Virus vaccines and antiviral drugs Yap Wei Boon, Ph.D (Assoc. Prof.) Email: [email protected]  Learning outcomes In the end of the lecture, students are able to: describe virus vaccines and their functions; describe the types of antiviral drugs and their functions. ANTIVIRAL VACCINES Loading…  Live attenuated vaccines Contain a mutant strain derived from a wild-type virulent strain. Antigenically identical to the wild-type. -- Advantages: (1) increasing amount of virus antigen as the ability virus replicates. (2) induce wide range of immune for body responses especially B cell, CD4 T cell and CD8 T cell to stimulate responses. antibody for pathogen Cantibodyresponse)  Examples. ◦ Sabin poliovirus vaccine ◦ Mumps, Measles, Rubella (MMR) vaccine ◦ Rotavirus vaccines (rotarix, rotateq): prevent 15–34% of severe diarrhea in the developing world and 37–96% of the risk of death among young children due to severe diarrhea. Loading… Drawback: (1) reversion to virulence (Sabin polio vaccine), (2) recombinants between the vaccine strains and wild type strains, (3) requires extensive quality control tests. oral vaccine cause complication but , manageable (life activated) drawbacks : symptoms similar like polio (the vaccine mutate in the body)  pathogen not living anymore Inactivated virus vaccines Chemically inactivated by formaldehyde or β- propiolactone. Chemical (to kill) ~ Eg. Salk poliovirus (incubated in formalin at 37ºC for 10 days) - Others: Hep A, foot and mouth disease virus, influenza virus. Induce mostly humoral immune response(antibody response).  ↓ immunogenic , antigenic Subunit vaccines Purified virus components. Eg. surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) of influenza A virus. ◦ Influvac Tetra [15 ug of HA H1N1, H3N2, B(Phuket), B(Austria)] - For use in adults and children from 6 months of age Advantages: fewer side effects especially in children. Disadvantages: poorer immunogenic than live attenuated and inactivated vaccines.  not infectious but able to stimulate immune response IMPOSTER !! , Cimmunogenic) Virus-like particles (recombinant vaccines) VLP resemble virions but are devoid of nucleic acids (cannot replicate), therefore safer. Eg. 1: HBV surface glycoprotein which is produced in yeast cells and used as vaccine. Eg. 2: HPV capsid protein produced in insect cells or yeast cells is able to generate neutralizing antibodies. They look similar but not exactly identical , have about the same immunogenicity as the real virus. (safer but still immunogenic) ANTIVIRAL DRUGS Chemical Types Of Antiviral Drugs Chemical Type Example Of Drugs Nucleoside analogue vidarabine, aciclovir, ganciclovir Antisense oligonucleotides formivirsen (5'-GCG TTT GCT CTT CTT CTT GCG-3’) bind to the mRNA and hence blocks translation of viral mRNA of a key CMV gene UL123, which encodes the CMV protein IE2. Peptide analogue Protease inhibitors: saquinavir, ritonavir, indinavir, nelfinavir Triazole carboxamide Ribavirin Tricyclic amine Amantadine Rimantadine Proteins Interferons, monoclonal antibodies  Attachment Agent mimics the viral Ag protein (VAP) & binds to the cellular receptor anti-receptor antibodies synthetic ligands, e.g. synthetic peptides resembling the Loading… receptor-binding domain of the VAP itself.  Penetration / Uncoating Uncoating of capsid intracellularly and by intracellular enzymes Amantadine (blocks NA of influenza viruses)- influenza A virusa replicate viruses develop resistance. X release RNA Oseltamivir (Tamiflu) - neuraminidase inhibitor, a competitive S inhibitor of influenza's neuraminidase enzyme. more frequently Rimantadine (blocks the ion channels formed by the influenza used in Malaysia Me2 protein) on the viral envelope) - unsuccessful uncoating of -- viral capsid to release viral genome into the cell nucleus for very viral genome synthesis. important  Genome Replication Nucleoside/nucleotide analogues. - ~ similar to nucleotide Pro-drugs are metabolized by cellular enzymes in order to become nucleotide analogues active. create competition (nucleotide us > - Structurally similar to nucleotides inhibit viral polymerase including reverse transcriptase. (stop - longation Problems: toxicity and side-effects.  ↳ do elegation ↓ Xfurther Xewviru RNA/DNA by degrad a host cell  Ribavirin Guanosine analogue. Used to fight several RNA virus infections, especially persistent infection with HCV, RSV. Inhibits viral RNA synthesis and mRNA capping.  Remdesivir Mimics adenosine monophosphate. Inhibits the RNA-dependent RNA polymerase (RdRp) of Ebola viruses. Approved by FDA for treating COVID-19 but WHO used to issue a conditional recommendation against the use of remdesivir in hospitalized patients (20 November 2020). However, it is now used to treat hospitalized COVID-19 patients, and mild to moderate COVID-19 in non-hospitalized patients who are at risk of death and severe disease symptoms. Intravenous remdesivir is approved by the Food and Drug  treet -general drug to chicpox , shingles , HSV. 1 , HSV-2 Aciclovir or Acyclovir - Guanosine analogue. Inhibits virus DNA synthesis with no side-effects on cell DNA synthesis. Used to treat HSV-1, HSV-2 and varicella-zoster virus infections. S chicken pox  Ganciclovir effective dose (ED) g similar to aciclovir but has a lower SI. & lethal dose (LD) :· ↓ SI , PLD higher toxicity Reduced RBC level due to damage to bone marrow cells. Used to treat CMV infection, especially pneumonia and retinitis in immunocompromised patients.  Cidofovir effective against small Pox ~ - - toxicity especially to kidney Cidofovir (Vistide) ◦ topical or injectable antiviral medication primarily used as a treatment for cytomegalovirus (CMV) retinitis in people with AIDS. Efficacy in the treatment of aciclovir-resistant HSV infections. Anti-smallpox (Brincidofovir, a cidofovir derivative with much higher activity against smallpox). to patients receiving Administered with probenecid which decreases side cidofovir effects to the kidney. & Hydration with normal saline (1L) must be administered  to patients receiving cidofovir. Azidothymidine (AZT) Thymidine analogue. Inhibits HIV reverse transcriptase. Attaches to the growing DNA strand, hence terminating reverse transcription by RT. May interfere with cell DNA polymerase activity and cause damage to bone marrow.  Lamivudine (3TC) Cystidine analogue that inhibits RT of HIV and HBV. Control the virus infections but does not eliminate the infections. In HBV treatment, it is used in combination of α- interferon  INTERFERON (IFN) IFN alpha/beta : inhibit vRNA synthesis and replication and viral proteins synthesis. Used in treatment for chronic HBV (in combination with antiviral drugs). HCV treatment with PEG-IFN plus ribavirin chronic HCV.  Antisense Oligonucleotides Very specific and form complementation with mRNA. Degradation of mRNA and prevent viral protein expression. Antisense molecules are extremely specific. Eg. Fomivirsen (brand name Vitravene, 21-nucleotides) complementary to the mRNA of CMV E2.  · Combination of nucleoside analogues and non-nucleoside inhibitors Highly active anti-retroviral therapy (HAART) in HIV infection (CD4 cell counts are less than 350cells/mm³). Two reverse transcriptase inhibitors (nucleoside analogues) and a protease inhibitor. inhibitor nucleotide reverse transcriptase ❑ The first line treatment consists of 2 drugs from the NRTI group (nucleoside chemical that acts like analogue - analogues) and 1 drug from the NNRTI (non-nucleoside) group. This set of - medications will be supplied by the Malaysia Ministry of Health for life if patients are successfully treated on the first line treatment. protease inhibitors ❑ Second-line treatment consists of 2 NRTIs and 2 PIs, but one of the PI drugs will - have to be purchased by the patient, whilst the remaining medications will be supplied by the Malaysia Ministry of Health. HAART effects is monitored by measuring HIV load in the patient’s blood (5-50 copies/ml, some patients may have < 5 copies/ml). If patients lapse from their medicine routine they increase risk of drug-resistant strains of HIV emerging. Antiretroviral Drugs Available in the Ministry of Health, Malaysia NRTI (Nucleoside Reverse Transcriptase NNRTI (Non-nucleoside Reverse PI (Protease Inhibitor) Inhibitor) Transcriptase Inhibitor) -navir Stavudine Nevirapine (Hirapine ®) Indinavir (Crixivan ®) - Efavirenz (Stocrin ®) Lamivudine (3TC ®) Ritonavir (Norvir ®) - Zidovudine (Retrovir ®) Lopinavir (Kaletra ®) - Darunavir (Prezista ®) Didanosine (Dinex EC ®) - Tenofovir (Tenvir ®) Abacavir (Ziagen ®)  Pre-exposure prophylaxis (PrEP) For people at risk of getting HIV from sex or injection drug use. There are two medications approved for use as PrEP: Truvada® (tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg) - is for all people at risk through sex or injection drug use. given & Descovy® (emtricitabine 200 mg & tenofovir alafenamide 25 mostly to male mg)- is for people at risk through sex, except for people assigned female at birth who are at risk of getting HIV from vaginal sex as it effectiveness is not fully studied.  PrEP reduces the risk of getting HIV from sex by about 99% when taken as prescribed. Although there is less information about how effective PrEP is among people who inject drugs, we do know that PrEP reduces the risk of getting HIV by at least 74% when taken as prescribed. PrEP is much less effective when it is not taken as prescribed. **PrEP provides protection from HIV, but does not protect against other STDs. Condoms can help prevent other STDs that can be transmitted through genital fluids, such as gonorrhea and chlamydia. ~THANK YOU~ Loading…