Vaccines and Biopharma 101: Cheat Sheet Edition

The race to the COVID-19 vaccine may have piqued your interest. Here is an introductory, survival guide of what vaccine development entails!

"What are Viruses?"

A virus is an infectious microorganism that consists of genetic material (RNA or DNA, single or double stranded) encapsulated in a capsid (protein coat) and sometimes, an additional lipid envelope layer. They are obligate intracellular parasites, meaning they cannot reproduce independently. Viruses rely on host cell machinery, such as protein-translating ribosomes, to make virions (viral progeny). 

Viruses, like living things, have the ability to evolve and adapt through mutations due to chance, natural selection and error-prone replication machinery. Hence, different Coronavirus strains are debated to have surfaced. 

Nevertheless, viruses are non-living since they are acellular, have no organelles and depend on a host cell for reproduction. Viruses either have RNA or DNA, but not both, so there is no central dogma (DNA to RNA to protein). For this reason, viruses depend on a host cell that can transcribe and translate their genome. Moreover, the lack of cells and organelles eliminates the requirement for hallmarks of life, such as metabolism and homeostasis regulation, in viruses. 

Since viruses are ‘non-living’, they technically cannot be ‘killed’. However, our immune system has mechanisms to prevent viruses from taking over host cells, including:

• killing virus-infected host cells

• neutralizing free virus particles with antibodies before they can infect more host cells

• halting hijacked cell machinery so viruses can no longer reproduce

Viruses may, in turn, outsmart and evade these immune mechanisms. For instance, HIV often conveniently infects CD4+ Helper T cells, which are essential for activating B cells to make antigen-specific antibodies, crucial for memory upon secondary exposure to the pathogen (disease-causing antigen). 

"What are Vaccines?"

A vaccine is a substance that stimulates the immune system to recognize and eliminate with enough specificity the pathogen of interest. The name ‘vaccine’ historically comes from latin root ‘vacca’, meaning cow. In 1796, Edward Jenner  discovered that infection of a relatively mild cowpox virus successfully conferred immunity against the deadly smallpox virus. 

"How does the immune system respond to vaccines?"

"How does the Biopharma industry develop vaccines?"

The COVID-19 pandemic has jumpstarted ‘Operation Warp Speed’ in the pharmaceutical industry. Normally taking more than 10-12 years, drug/vaccine development for COVID-19 has accelerated to record-breaking timing, anticipating vaccine approval in approximately 1 year. Over 120 drug candidates are currently undergoing review and development in order to treat COVID-19. 

Costly inefficiency characterizes the biopharma industry. Each drug costs over 2 billion dollars and only 14% of drug candidates that enter human clinical trials get FDA approved. Since vaccines are given to healthy, not infected, individuals, the standards for safety and efficacy are high. This is especially the case since, besides dexamethasone, an anti-inflammatory, symptom-reducing drug, there are no present, proven drugs that can alleviate the pathology triggered by the SARS-CoV2 virus. 

In addition to testing for safety and efficacy, pharmaceutical companies face the herculean challenge of scaling up manufacturing in order to provide affordable doses for everyone on the planet. In essence, the manufacturing process is analogous to me ordering a pizza from Pizza Hut right now, and expecting 100,000 to be available for delivery by tomorrow when I call, hungry again in the morning. This whole process does not happen in isolation. Money talks and capital funding is essential to propel the development forward. Money and manufacturing, compiled with ethics, drug fine-tuning and optimization for intracellular delivery, pharmacokinetic evaluation (‘ADME’= absorption, distribution, metabolism and excretion of drugs once they enter the human body) and efficient large-scale delivery and distribution of a delicate, biological product makes for a very challenging job for the biopharma industry. It helps to think of one of these pharmaceutical companies, such as Astrozeneca, as an octopus. Each arm of the octopus is simultaneously doing a different task while thinking three steps ahead in order to shorten the pace of the drug development in a ‘Time-Lapse Effect’ to save lives and bring society back to normal.

All in all, the goal of the race to the COVID-19 vaccine, with such a press for time and solutions, is not necessarily to cure the viral infection altogether, but to quell the severity and/or spread of the infection enough so that mortality decreases and the healthcare industry is less overwhelmed/more available to treat other conditions that regularly require medical attention. By priming the immune system, vaccines will permit the recovery of patients to be faster and more mild when exposed to the actual pathogenic virus.

"How are safety and efficacy of vaccines evaluated in patients?"

Safety is well defined when evaluating vaccines, however efficacy largely depends on the nature of the disease, COVID-19, and the virus, SARS-CoV2. Scientists do not accurately understand this disease, virus or the pathology-inducing link between the two. This uncertainty makes it difficult to assess whether any ‘safe’ vaccines or drugs developed for COVID-19 are actually having a beneficial effect. 

Up to now, the main focus in trials has been to evaluate the presence and levels of neutralizing antibodies, since antibodies are associated with long-term immunity and the assays used to quantify antibodies, such as ELISAs (Enzyme-Linked Immunosorbent Assay), are easy and cheap. Nevertheless, too much focus on only antibodies to interpret safety and efficacy may be misplaced. The cellular response of T cells is also important, if not even more so. In fact, a recent Nature publication suggested that the antibodies from recovered COVID-19 patients only last approximately 2 months. For the original SARS-CoV1 epidemic, a short term longevity of antibodies was also observed, which should come to no surprise since both SARS-inducing coronaviruses are very genetically similar. 

The need for both antibody and T cell response evaluation when interpreting safety and efficacy is crucial in order to better anticipate the long-term outcome of the vaccines. Will there be a need for more than one dosage? If yes, how often? All these are important questions. Moreover, the relative importance of antibodies or memory T cell response remains unknown. Whether one has a compensatory effect on the other may be possible. After all, this highlights how the adaptive immune system is divided in both the humoral (antibodies) and cellular (lymphocyte) immunity components, and how both of these immune components are intricately linked together, such as through the T-B cell Cooperation necessary for antibody clonal expansion (fine tuning of antibody receptor and exponentially producing copies of antibody).

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