Author: Sudha Neelam
The invisible tool – Our Immune system
As we courageously social distance, embrace the elegance of facial masks, respect the discipline of personal hygiene, the human immune system is enacting its own version of courage, elegance and discipline. Our immune mechanisms are the invisible pillars of strength in this battle against the invisible enemy.
The immune responses are comprised of a series of players; each one orchestrating their unique role to protect our body. They can be broadly classified in to two types: innate immune responses and adaptive immune responses.
The innate immune responses are the body’s first line of defense against infections. Our skin acts as a physical barrier preventing the entry of the infectious agents(pathogens), fluids like mucous help in clearing the disease-causing agents and a cellular response in the form of phagocytic cells that have the ability to engulf and destroy the pathogens help in clearing the infection and alleviating disease symptoms.
Once the pathogens overcome the innate immune response and gain entry into our system, the adaptive immune response takes charge. The adaptive immune response consists of cells called lymphocytes which secrete antibodies in response to the infection. These antibodies specifically bind to the foreign substances generated by the infectious agent known as the antigens. Pathogens whose antigens are bound to the antibodies are marked for destruction.
Initially the immune system takes several days to identify the pathogen, develop antibodies, bind specifically to its antigens and eventually destroy it. Once the process is complete the immune system remembers the protocol for future battles. It generates what are known as memory cells which hold on to the necessary information for antibody synthesis and once the body encounters the same infection for a second time, the memory cells jump the battle ground fully loaded with the ammunition of antibodies and clear the infectious agents in a much faster and effective manner.
While the innate immune responses cannot get better with repeated exposures to the infectious agent, the adaptive immune responses develop the finesse (in the form of immunological memory and antibody synthesis) to combat the infectious agents. The process of vaccine development takes advantage of this finesse.
The invisible enemy – SARS-CoV- 2 virus
Coronaviruses are a family of viruses that mainly cause upper respiratory infections including the common cold. In the year 2002 severe acute respiratory syndrome (SARS) caused by the coronavirus emerged as one of the first pandemics of the 21st century. Social distancing and quarantine measures helped in the eradication of SARS. The SARS -CoV-2 (severe acute respiratory syndrome corona virus version 2) is a novel coronavirus that causes COVID-19 (coronavirus disease 2019). A virus that is not only invisible/uninvited but also an unknown guest. The SARS-CoV-2 spreads at a much rapid rate than the SARS virus causing severe upper respiratory symptoms and a high mortality rate.
Our immune system has to navigate through the unique novel characteristic of this virus to eliminate it from our bodies. The virus invades, establishes, and conquers its territory inside the host body. This leads to the yin and yang battle between our immune system and the virus. While our immune system works hard to restrain, contain, and destroy the virus, the virus on the other hand tries to dodge the immune responses to thrive and destroy the host.
The severity of the symptoms caused by the virus and the recovery period from the viral infection depends on the number of virus particles the person is initially exposed to and how strong and effective their immune responses are in fighting the virus. While the therapeutics and anti-viral drugs aid in alleviating the symptoms and enhance the survival rates, a stronger, regulated immune response is always beneficial.
A vaccine to the SARS CoV-2 will help in giving the necessary boost to our immune system. It will equip our bodies with significant levels of tolerance to fight the virus without succumbing to its deleterious disease symptoms. A vaccine will remind the uninvited, invisible guests that they overstayed their welcome and it is time to leave.
Developing a vaccine for the novel corona virus is akin to creating characters that would enact an unwritten script. The script in this case revolves around the viral antigens. Antigens can be proteins, lipids or nucleic acids like DNA or RNA. They are responsible for the disease symptoms like sore throat, loss of sense of smell, chest congestion or cough. They activate the body’s immune response resulting in the generation of antibodies. They determine the plot line of the script (the incidence of disease, type of symptoms and severity/transmissibility of the disease) and when and how the story will end (the length of recovery times and the survival/mortality rates). In this case, we must carefully navigate the novelty of the SARS-CoV-2 antigens in designing and testing the vaccine.
Generally, vaccines are made up of viral antigen fragments, or the viral nucleic acids like DNA or RNA that are either inactivated or weakened such that when they are injected in to humans, they elicit a robust immune response without causing any serious disease symptoms. The viral fragments or the DNA/RNA are packaged into lipid coated liposomes. The liposomes are spherical vesicles made up of lipids. The viral antigen fragments or nucleic acids are enclosed within the liposomes and administered into our body. These liposomes will prevent the viral fragments from degradation once they enter the body and deliver them to the appropriate immune cells to induce the immune response and antibody production.
Animal models are used to validate the vaccines before introducing them to humans. Animal models are useful in designing the vaccine, determining the route (oral or intravenous injections)/dose of vaccine administration, the safety and efficacy of the vaccine in inducing an immune response and identifying the duration of the immune response.
Once the vaccine is validated in animal models, the next phase is human testing or what is referred to as clinical trials. This usually happens in several phases. Each phase is designed to test different aspects of the vaccine including the safety, dose, and the extent of immune response. The number of people being tested will gradually increase with each phase of the clinical trials.
The primary goal of phase I is to identify the smallest dose of vaccine that can induce a strong immune response without any major side effects.
During this phase, the vaccine is tested in a small cohort of healthy volunteers without any underlying health conditions. The numbers usually are in the range of 10s or 20s. The effective route of administration of the vaccine such as oral or intravenous and the highest dose of the vaccine that can be tolerated without side effects are evaluated. While the preclinical studies in animal models give an idea of the dosage and safety of the vaccine, it is imperative to re-test those parameters in human volunteers. Phase I is not designed to determine if the vaccine is effective against the disease.
Once the safety and dose of the vaccine is determined in phase I, scientists move on to testing the efficacy of the vaccine in phase II. The phase II will give an indication of how the vaccine helps in mitigating the disease symptoms, the progression of the disease and the time of recovery.
Phase II consists of patients with the disease symptoms and a cohort of subjects without the underlying disease. The numbers in this phase are usually in hundreds and this study is conducted in a blind manner where the volunteers randomly receive either the vaccine or the placebo. With this large group of people scientists gather information about dose, safety, efficacy, and the longevity of the vaccine over a period of several months.
Phase III will provide information on how effective the vaccine is in mitigating the disease spread, the severity of the symptoms and the recovery/survival rate.
In phase III thousands of volunteers are tested in a double blinded manner. Both the scientists and the volunteers are not aware of who is receiving the vaccine or the placebo. This will eliminate any bias in assessing the efficacy and side effects of the vaccine. Phase III is conducted in a larger group of people who are susceptible for the disease. At the end Phase III if scientists can demonstrate the efficacy and safety of the vaccine, it will be sent to FDA (Food and Drug Administration) for approval.
FDA approval and Phase IV
The FDA and will review the results from the clinical trials and determine if there is enough evidence to establish the safety and efficacy of the vaccine. Once FDA approves the vaccine, phase IV is launched. This involves testing the vaccine in hundreds and thousands of patients over a prolonged period of time. This will help in determining the long-term safety and efficacy of the vaccine. Around this time, the manufacturing facility where the vaccine will be produced will also undergo inspection to ensure safe mass production of the vaccine. The FDA will also screen safety, efficacy and purity of each vaccine lot manufactured by the unit.
Normally the entire process will take several years, however given the current pandemic circumstances scientists and FDA are expediating the entire process to come up with a safe and efficacious vaccine in the next 9-18 months. Even with expediated approval and manufacturing process the timeline for administering the vaccine to the general population in order to limit the virus spread will take several months to years.
Battling the invisible enemy
While we are gifted with an abundance of competence to win the battle against this invisible enemy, we seldom understand how to handle the good unless the bad and ugly re-teach us the laws of survival. Our immune system is our number one tool for survival. We need to guard it, nourish it, and cherish it.
Despite the rapid spread of this disease, the severity of symptoms and the disturbing mortality rates, if we can start the battle with a well-equipped army of immune responses, we have a very good chance of winning the battle. However, the ultimate goal for humanity should not be to just survive this battle, but to learn from the battle, win the battle successfully and avoid any uninvited future invasions.
In Greek mythology there is a king called Sisyphus, who was punished for his pompous, conceited, self-aggrandizing behavior by being forced to roll a huge boulder up a steep hill only to have it roll back down every single time it reached the top. Sisyphus ended up repeating this action of moving the boulder up and down the hill for eternity. None of us want to be like Sisyphus yet if we are not cautious, humble and prudent in our actions we all will become one.
Fighting the invisible enemy albeit challenging is not entirely impossible. Scientists are working hard to erase the invisibility and restore normalcy. Meanwhile, each and every one of us can pitch in by accepting the short-term inconveniences and learn to embrace the intangible warmth engulfing our world.