Study Notes on COVID Vaccine Development and Immunology

COVID Vaccine Development

• Prevention of Acquisition

  • Early COVID vaccines were effective at preventing acquisition when matched well with the virus.

  • Current vaccines do not prevent acquisition due to increased genetic diversity in the virus.

• Genetic Diversity of the Virus

  • COVID-19 exhibits greater genetic diversity than any other known pathogen.

  • Important to illustrate this concept through examples of HIV and SARS-CoV-2.

  • Greater diversity can lead to challenges in vaccine effectiveness and immune response.

• Immunogenic Properties of the Virus

  • The envelope of HIV is less immunogenic than other virus envelopes.

  • Cause: Presence of a glycan shield that protects surface proteins from immune recognition.

  • The virus employs multiple diversionary strategies to evade immune responses.

  • There are diversionary antibodies whose identification is complex.

  • Lack of systematic methods to differentiate between inhibitory and non-inhibitory antibodies.

• Ball Virus Structure

  • HIV is classified as a ball virus with fewer surface trimers compared to most viruses.

  • This results in lower crosslinking capabilities.

  • The implication of having only single-arm binding leads to the necessity of higher avidity antibodies.

  • Current status in finding human cures is zero out of seventy-seven million cases.

• Comparative Genetic Analysis

  • HIV and SARS-CoV-2 show significant differences in genetic variability.

  • HIV has greater amino acid sequence variability among its strains than COVID-19.

  • Illustrations depicting the diversity in HIV envelope and the impact of the glycan shield.

• Antibody Binding Dynamics

  • Distance between HIV trimers complicates crosslinking and diminishes antibody efficacy.

  • Inter-spike crosslinking is uncommon due to low density of viral spikes versus other viruses such as influenza.

• HIV Vaccine Development History

  • Early attempts involved recombinant DNA technology to create vaccines.

  • Resulting vaccines were largely unsuccessful due to differences between monomeric and trimeric structures of the envelope.

  • Attempts to improve vaccines involved T cell-based approaches based on conserved epitopes, which also failed.

  • The RV144 trial had partial successes but exhibited immunodominance towards variable regions rather than conserved regions.

• Immunodominance Issues

  • Immunodominance: The phenomenon where immune responses target variable rather than conserved regions, limiting broad immunity.

  • Proteasomal processing of epitopes can favor variable region responses over conserved ones.

  • Efforts at creating mosaic proteins to cover all strains of HIV have not yet been successful.

• Passive Immunization and Neutralizing Antibodies

  • Passive immunization has shown effectiveness, leading to discoveries of sites of vulnerability on the virus.

  • Efforts to induce broadly neutralizing antibodies (bnAbs) are critical.

  • Germline priming and lineage design strategies are used to create bnAbs through sequential immunizations.

• Recent Trials and Findings

  • AMP trial: Included 4,600 volunteers receiving IV infusions of a CD4 binding site antibody (BRCA1).

  • Administered every two months for ten doses over approximately eighty weeks.

  • Results indicated efficacy with challenges on the amount of antibody required.

  • Needed more neutralizing antibodies in vivo than anticipated, demonstrating that 30 micrograms/ml of antibody was vital for effectiveness.

  • Efficacy rates reached up to seventy percent in some settings based on antibody levels.

• Preventive Titer Calculation

  • A model was established to determine the levels of neutralization needed for 95% efficacy.

  • The threshold was identified and termed preventive titer eighty, representing a combination of serum titer and IC80 of the virus.