Antiviral Vaccines and Their History

Antiviral Vaccines

• Vaccination is the most effective means to prevent viral infections
• Serious adverse effects must be investigated, however they are very rare.
• If a vaccine is not 100% safe/effective, it raises ethical concerns
• Vaccination has significantly decreased diseases like smallpox, polio, measles, mumps, rubella, and congenital rubella syndrome.

Antiviral Vaccines - History

• Early vaccine technology was crude but effective
• Chinese doctors used powdered smallpox scabs for early immunization
• Lady Montagu introduced variolation to England
• Jenner's work with cowpox was a milestone in smallpox prevention
• Pasteur and collaborators developed an early rabies vaccine
• Milestones in antiviral vaccine development include early use of smallpox scabs, variolation, cowpox, and later, developments in viral culture technologies, including cell culture and embryonated eggs, which revolutionized vaccine development.
• The use of primary cell culture and immortalized cell lines accelerated vaccine development during the 1950s and 1960s. This led to the development of vaccines for diseases like polio, measles, mumps, and rubella
• Crude vaccines from natural products worked well, but due to limitations, serious side effects occurred. Fear of epidemics often motivated vaccination.

Antiviral Vaccines - Classical Categories

• Current antiviral vaccines fall into categories like live wild-type, live attenuated, inactivated, subunit, and viral-like particles (VLPs)
• Live attenuated viruses are generally very effective due to serial passage and in vitro cultivation of viruses reducing their pathogenicity.
• Live wild-type viruses replicate poorly in unexpected hosts, but share immunogenic determinants with related viruses such as vaccinia virus
• Inactivated viruses are treated with chemicals like formaldehyde or organic solvents to inactivate them.
• Subunit vaccines consist of purified viral proteins, offering simplicity and stability. These vaccines typically have less efficacy than live vaccines, so boosters are often required.
• Viral-like particles (VLPs) are often more effective than single purified proteins.

Antiviral Vaccines - Newer Categories

• Chimeric vaccines are live, genetically modified organisms that express targeted viral proteins. These can deliver antigens to specific locations in the body.
• RNA and DNA vaccines introduce mRNA or DNA plasmids encoding viral proteins for transient expression in host cells.
• Nanoparticle vaccines (including VLPs) use synthetic nanoparticles to display viral antigens and can be combined with adjuvants.

Antiviral Vaccines - Safety

• Current vaccines are the safest ever marketed but not 100% safe.
• The history of vaccine developments has seen unfortunate incidents due to incomplete knowledge, but new surveillance methods enhance safety.
• Certain significant adverse events have been documented in the past.

Antiviral Vaccines - Herd Immunity

• Herd immunity results from high rates of vaccination in a population, effectively limiting the spread of a viral pathogen.
• Unvaccinated individuals are protected by reaching a threshold of "dead-end hosts".
• Community immunity levels can change due to vaccination rates and viral diversity.

Antiviral Vaccines - Ethical Issues

• Individuals refusing vaccination raise ethical questions about managing infected individuals and preventing further spread.
• Non-vaccinated individuals should not be excluded from essential services.
• Communities should prioritize protection of vulnerable members.
• Vaccination programs should consider the healthcare burdens associated with vaccine-preventable diseases and ensure equitable compensation for vaccine-related adverse events.

Antiviral Drugs

• The discovery and use of antiviral compounds is relatively recent, starting in the 1960s.
• Viral replication within human cells poses challenges to drug discovery.
• Broad-spectrum antivirals face limitations because of the large number of viruses, leading to less interest, as available vaccines also reduce the drive to develop new antiviral compounds.
• Discovering and obtaining antiviral drugs include methods like serendipity, modifying known compounds, high-throughput screening assays, and rational design strategies (including use of 3D structures of viral proteins)

Antiviral Drugs - Mechanism of Action

• Antivirals generally target specific steps of the virus life cycle such as attachment, entry, uncoating, viral gene expression, genome replication, assembly, maturation, and release.

Antiviral Drugs - Specific Targets

• Drugs are developed targeting viral enzymes for attachment, entry, uncoating, genome replication, etc
• Examples of viral targets in HIV are receptors, reverse transcriptase, protease, integrase

Antiviral Drugs - Therapeutic Index (TI)

• TI is the ratio of TD50 (toxic dose in 50% of population) to ED50 (effective dose in 50% of population).
• A higher TI is preferred as it signals less toxicity for a given therapeutic effect.

Antiviral Drugs - Attachment/Entry Inhibition

• Drugs can directly bind to virions or virus receptors / co-receptors, blocking fusion.
• Examples include Maraviroc blocking HIV-1 co-receptor CCR5 and Enfuvirtide binding to HIV to block conformational changes

Antiviral Drugs - Uncoating Inhibition

• Drugs can block ion channels in the virion envelope to prevent the interior acidification needed for viral release.
• Amantadine is an example of this type.

Antiviral Drugs - Nucleic Acid Synthesis Inhibitors

• Nucleoside analogues are incorporated into the growing viral genome, which prematurely terminates viral genome replication
• Acyclovir is an example that's phosphorylated by viral kinases
• AZT is a nucleoside analogue with an altered sugar moiety to cause termination in DNA synthesis.
• Non-nucleoside RT inhibitors (NNRTIs) like Nevirapine inhibit viral enzymes that are needed for genome replication.

Antiviral Drugs - Integrase Inhibitors

• Integrase inhibitors like Raltegravir block viral DNA insertion into the host chromosome.
• These are often part of combination therapies.

Antiviral Drugs - Protease Inhibitors

• Protease inhibitors interfere with virus assembly and maturation.
• Ritonavir is an example of a peptidomimetic protease inhibitor.

Antiviral Drugs - Neuraminidase Inhibitors

• Neuraminidase inhibitors block the release of influenza viruses from infected cells.
• Examples are Zanamivir (Relenza) and Oseltamivir (Tamiflu).

Antiviral Drugs - HIV Targets

• HAART (Highly Active Antiretroviral Therapy) often targets multiple steps in the replication cycle.

Antiviral Drugs - SARS-CoV-2 Targets

• Several drugs are under clinical trials for SARS-CoV-2 targeting multiple steps in virus replication.

Antiviral Drugs - Future

• Active research in understanding and targeting viruses is ongoing.
• New viral targets lead to new drug development.
• Successes against some viruses (HIV, influenza, herpes) provide hope for success against other viruses.

Final Exam

• The final exam covers lectures 5 through 12 and some content from earlier lectures.
• The format is similar to the midterm, including multiple-choice, fill-in-the-blank, and short answer questions, including application questions.