Lecture 11: virus vaccines and antiviral drugs

Virus Vaccines and Antiviral Drugs

Learning Outcomes

• Students should be able to describe virus vaccines and their functions.
• Students should be able to describe the types of antiviral drugs and their functions.

Live Attenuated Vaccines

• These vaccines contain a mutant strain derived from a wild-type virulent strain, but are antigenically identical to the wild-type strain.
• Advantages include: increasing amount of virus antigen as the virus replicates, and inducing a wide range of immune responses, especially involving B cells, CD4 T cells, and CD8 T cells
• Examples of live attenuated vaccines:
  • Sabin poliovirus vaccine
  • Mumps, Measles, Rubella (MMR) vaccine
  • Rotavirus vaccines, which 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.
• Drawbacks:
  • Reversion to virulence (as seen with the Sabin polio vaccine).
  • Recombinants between the vaccine strains and wild-type strains can occur.
  • Extensive quality control tests are required.

Inactivated Virus Vaccines

• Inactivated virus vaccines are chemically inactivated by formaldehyde or β-propiolactone. E
• The Salk poliovirus is an example, incubated in formalin at 37°C for 10 days.
• Other examples: Hep A, foot and mouth disease virus, influenza virus.
• These induce mostly humoral immune response or antibody response.

Subunit Vaccines

• Contain purified virus components, such as surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) of influenza A virus.
• Example: Influvac Tetra, which is a vaccine containing 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.
• A disadvantage is that they are poorer immunogens than live attenuated and inactivated vaccines.

Virus-Like Particles (Recombinant Vaccines)

• VLPs resemble virions but are devoid of nucleic acids, making them safer because they cannot replicate.
  • HBV surface glycoprotein produced in yeast cells as a vaccine.
  • HPV capsid protein produced in insect or yeast cells, can generate neutralizing antibodies.

Chemical Types of Antiviral Drugs

• Nucleoside analogues: vidarabine, aciclovir, ganciclovir.
• Antisense oligonucleotides: fomivirsen (5'-GCG TTT GCT CTT CTT CTT GCG-3'), which binds to the mRNA and blocks translation of viral mRNA of a key CMV gene UL123 to inhibits translation of viral mRNA of a key CMV gene UL123 that encodes the CMV protein IE2.
• Peptide analogues: Protease inhibitors like saquinavir, ritonavir, indinavir, nelfinavir.
• Triazole carboxamide: Ribavirin.
• Tricyclic amine: Amantadine, Rimantadine.
• Proteins: Interferons and monoclonal antibodies.

Attachment (Antiviral Drug Mechanism)

• An agent mimics the viral Ag protein (VAP) and binds to the cellular receptor.
  • Binding of anti-receptor antibodies
  • Synthetic ligands, e.g. synthetic peptides resembling the receptor-binding domain of the VAP itself.

Penetration / Uncoating (Antiviral Drug Mechanism)

• Uncoating of capsid intracellularly and by intracellular enzymes is necessary for viral replication.
  • Amantadine: blocks NA of influenza viruses; influenza A viruses develop resistance to it.
  • Oseltamivir (Tamiflu): neuraminidase inhibitor, a competitive inhibitor of influenza's neuraminidase enzyme.
  • Rimantadine: blocks the ion channels formed by the influenza M2 protein on the viral envelope, causing unsuccessful uncoating of the viral capsid and preventing the viral genome's release into the cell nucleus.

Genome Replication

• Nucleoside/nucleotide analogues: Structurally similar to nucleotides and inhibit viral polymerase, reverse transcriptase/
  • Pro-drugs are metabolized by cellular enzymes in order to become active.
  • Analogues create competition, and inhibit viral polymerases, including reverse transcriptase
  • Problems: toxicity and side-effects.

Ribavirin

• This a guanosine analogue.
• It fights several RNA virus infections, specifically persistent infection with HCV and RSV.
• Ribavirin inhibits viral RNA synthesis and mRNA capping.

Remdesivir

• Mimics adenosine monophosphate.
• Remdesivir inhibits the RNA-dependent RNA polymerase (RdRp) of Ebola viruses.
• Approved by FDA for treating COVID-19 but WHO issued a conditional recommendation against its use in hospitalized patients on 20 November 2020.
• Remdesivir usage now includes treating COVID-19 in hospitalized patients and mild to moderate COVID-19 in non-hospitalized patients at risk of death and severe disease symptoms.

Aciclovir or Acyclovir

• This a guanosine analogue.
• Inhibits virus DNA synthesis with no side-effects on cell DNA synthesis.
• Treats HSV-1, HSV-2 and varicella-zoster virus infections (chicken pox, shingles).

Ganciclovir

• Similar to aciclovir, but has a lower selective index (lower SI and increased lethal dose (LD)).
• Ganciclovir can reduce RBC levels due to damage to bone marrow cells.
• Treats CMV infection, especially pneumonia and retinitis in immunocompromised patients.

Cidofovir

• This treatment is effective against the small pox virus.
• Is a topical or injectable antiviral medication used primarily as a treatment for cytomegalovirus (CMV) retinitis in people with AIDS.
• Has efficacy in the treatment of aciclovir-resistant HSV infections.
• Anti-smallpox medication (Brincidofovir is a cidofovir derivative with much higher activity against smallpox).
• Administered with Probenecid to decrease side effects to the kidney as toxicity targets the kidney.
• Must be hydrated with normal saline (1L).

Azidothymidine (AZT)

• AZT is a thymidine analogue.
• It inhibits HIV reverse transcriptase.
• AZT attaches to the growing DNA strand, terminating reverse transcription by RT.
• It may interfere with cell DNA polymerase activity and cause bone marrow damage.

Lamivudine (3TC)

• 3TC is a cystidine analogue that that inhibits the reverse transcriptase of HIV and HBV.
• This drug controls the virus infection, but does not fully eliminate.
• Lamivudine is used in combination with alpha-interferon in HBV treatment.

Interferon (IFN)

• IFN alpha/beta inhibits vRNA (viral RNA) synthesis and replication.
• This treatment is also used in synthesis of viral protein.
• IFN is used in in combination with antiviral drug to treat chronic HBV.
• treatment for HCV involves PEG-IFN plus ribavirin in chronic cases.

Antisense Oligonucleotides

• These are very specific drugs that form complementation with mRNA.
• They can cause Degradation of mRNA and prevent viral protein expression.
• Antisense molecules are extremely specific.
• For Example, Fomivirsen (brand name Vitravene, 21-nucleotides).
• Fomivirsen is complementary to the mRNA of CMV E2.

Nucleoside Analogues and Non-Nucleoside Inhibitors

• Highly active anti-retroviral therapy (HAART) is used in HIV infection when CD4 cell counts are less than 350 cells/mm³.
• HAART combines two reverse transcriptase inhibitors (nucleoside analogues) and a protease inhibitor.
• Protease inhibitors are used to treat the first line. First-line medication consists of 2 nucleoside analogues from the NRTI group and 1 non-nucleoside drug from the NNRTI group.
• The Malaysia Ministry of Health provides a supply of these medications if patients are successfully treated on the first-line treatment.
• Second-line treatment consists of 2 NRTIs and 2 PIs, with the patient required to purchase one of the PI drugs, and the remaining medications 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).
• Lapses from their medicine routine increase patients risk of drug-resistant strains of HIV emerging.

Antiretroviral Drugs Available in the Ministry of Health, Malaysia

• NRTI (Nucleoside Reverse Transcriptase Inhibitor): Stavudine, Lamivudine (3TC ®), Zidovudine (Retrovir ®), Didanosine (Dinex EC ®), Tenofovir (Tenvir ®), Abacavir (Ziagen ®).
• NNRTI (Non-nucleoside Reverse Transcriptase Inhibitor): Nevirapine (Hirapine ®), Efavirenz (Stocrin ®).
• PI (Protease Inhibitor): Indinavir (Crixivan ®), Ritonavir (Norvir ®), Lopinavir (Kaletra ®), Darunavir (Prezista ®).

Pre-Exposure Prophylaxis (PrEP)

• For people at risk of getting HIV from sex or injection drug use
• Two medications are 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.
  • DescovyⓇ (emtricitabine 200 mg & tenofovir alafenamide 25 mg) is for people at risk through sex, excluding people assigned female because of lack of data on efficacy. -PrEP reduces risk of getting HIV from sex by about 99% when taken well. -PrEP reduces risk of getting HIV for injection drug use by 74% when taken as prescribed. -PrEP is 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.

Explore the differences between live attenuated and inactivated vaccines, focusing on their mechanisms, advantages, and risks. Compare subunit vaccines and virus-like particles regarding safety and immunogenicity. Understand the importance of quality control in vaccine production.