The basics of a vaccine and what is the most recent development with COVID-19 vaccine.
Author: Hao W.
The biggest challenge right now with the COVID-19 pandemic is when are we going to get a vaccine, is it able to protect us, and when are we going to get a cure? To answer these questions, we need to first understand the basics of a vaccine and what is the most recent development with COVID-19 vaccine.
What is COVID-19, or SARS-CoV-2?
A SARS-CoV-2 virus particle is about 90 nanometers, which is around one millionth the volume of a human cell. It contains four different proteins and a strand of RNA, which has the genetic information make all the other four proteins to make another viral particle. Virus itself cannot replicate. It needs to enter a host cell, such as cells in the human lung, and use enzymes in the host cell to make proteins that the virus needs.
The outer proteins sit on a membrane provided by the cell in which the virion was created. This membrane, made of lipids, breaks up when it encounters soap and water, which is why hand-washing is such a valuable barrier to infection.
The most prominent protein is called spike. This protein stands out of the membrane and gives the virus the crown shape. Two other proteins, envelope protein and membrane protein, sit in the membrane between these spikes. Inside the lipid membrane,there is a fourth protein, nucleocapsid. Nucleocapsid wraps around the RNA and provide stability.
How do SARS-CoV-2 gets in a cell and infect more cells?
First contact between a virion and a cell is made by the spike protein coming in contact with Ace2, which is a protein found on the surface of some human cells, particularly those in the respiratory tract. After the virus enters the human cell, it starts to utilize the human cell machinery to replicate RNA and produceviral proteins to make more viral particles. Eventually, the newly packaged viral particles are released outside of the cell and start infecting other cells.
What is a vaccine and how does it protect us?
A vaccine contains the infectious agent that cause the disease. However, the infectious agents in a vaccine have been either killed or weakened to the point that they don’t make you sick. Instead, a vaccine stimulates your immune system to fightagainst the infectious agent. The immune system is our body’s army to fight diseases. The immunity can be broadly divided into two categories: innate immunity and adaptive immunity. Innate immunity is the host’s first line of defense and is intended to prevent infection and attack the invading pathogens. Innate immunity is fast, within minutes to a few hours, and it is nonspecific, which means it cannot differentiate one germ or virus from another.
Adaptive immunity, on the other hand, takes days or weeks. Adaptive immunity is also more specific. It can differentiate one infectious agent from another. However, the most important characteristic of adaptive immunity is the fact that this mechanism has memories. Vaccines utilize the memory of the adaptive immune response to protect us from an infectious agent that our body had been exposed before.
At the heart of every vaccine is an antigen, which is the very component that provokes the body to generate antibodies as well as other immune responses. When a cell has been infected by a virus, it is forced to make more viral proteins. These viral proteins will activate B cells to produce antibodies. These antibodies circulate through the bloodstream and bind specifically to the viral proteins. Once antibodies bind to viral proteins, these proteins can no longer bind to cell surface receptors and therefore cannot enter human cells. These antibodies also flag the virus for disruption by the immune system. If the immune system works effectively, the virus will be destroyed without infecting human cells and we will not get sick from it.
Viral proteins also activate another group of immune cells, call T cells. After the human cells make viral proteins, these viral proteins will display on the surface of the human cell and again serve as flags for activated T cells and macrophages to destroythese infected cells before virus have the time to produce more virus.
In addition to the killer effect of T cells, these cells also have memories, call memory T cells. Once it has been exposed and stimulated by an infectious agent, it will start attacking the same or similar infectious agent once it enters your body next time. Before the virus makes you sick, it is already killed by your own immune system. This is how vaccines prevent diseases, such as measles or polio vaccines.
What are the current efforts and designs to make SARS-CoV-2
There are four designs to make the SARS-CoV-2 vaccine, including virus vaccines, viral vector vaccines, Nucleic acid vaccines, and protein-based vaccines. These four designs can be put into two categories: viral protein- based or Nucleic acid based.
Viral protein-based vaccines: The idea is to develop a vaccine using the virus itself or introducing the viral structure to the cell to stimulate immune response. The virus or viral vector is weakened or inactivated to a point that is not going to make you sick. This is a rather mature technology. It is how measlesvaccine; polio vaccine, the seasonal flu vaccine and many other licensed vaccines are made.
Although there are at least 100 companies or academic institutions using this approach to develop the SARS-CoV-2 vaccine, two vaccines had made significant progress in the past few weeks and had entered phase 1 clinical trials.
Sinovac Biotech in Beijing is using the inactivated approach. In this approach, the virus will be inactivated with heat or formaldehyde. During the SARS-CoV-1 outbreak of 2003, Sinovac created a vaccine using inactivated virus particles. This vaccine only went through phase I clinical trials and didn’t continue with phase 2 because the outbreak had ended. Now Sinovac is taking the same approach to sars-cov-2. The advantage of this approach is that the vaccine has already started development during the SARS outbreak 17 years ago, which can make it faster than other approaches. By the end of April, Sinovac already started the phase 1 clinical trial to look at safety of the sars-cov-2 vaccine.
University of Oxford have also begun testing a COVID-19 vaccine in human volunteers at the end of April. This vaccine is made from a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees. This vaccine has been genetically engineered to make the spike protein on the surface of SARS-CoV-2. The research team is hoping to makethe body recognize and develop an immune response to the Spike protein that will help stop the SARS-CoV-2 virus from entering human cells and therefore prevent infection. Oxford researchers convinced British regulators to push forward with a large Phase II study involving 6,000 people while the outbreak in the UK is still trending upward.
Although the method to use inactivated or weakened virus to stimulate human immune response has been a mature approach to produce virus, the disadvantages can be concerning too. The development might have been too quick that the animals used in the preclinical studies are not enough to claim safety. Additionally, for this method to work, the live virus used to challenge the animals might have already mutated from the strain that infect human. This will lead to partial protection which is dangerous once the vaccine goes on for human trials.
Nucleic-acid vaccines
In the recent years, there has been a novel technology to produce DNA or RNA vaccine. Instead of injecting virus or viral structure into the human cell, a RNA fragment that codes for the viral protein will be injected in the cell. The cell then utilizes its own machinery to produce viral protein and stimulate immune response. Once the viral protein is produced, the remaining immune response process is mostly the same with the protein-based vaccines.
The leading company in this category is Moderna, a pharmaceutical company based in Boston. Moderna’s RNA vaccine has received greenlight from FDA to start the phase 2 trial during the first week of May.
There are several advantages with the RNA based vaccine. RNA vaccine is much easier to produce than protein-based vaccine. With the current pandemic, it is critical to have massive product to meet the need of the world. RNA vaccine is also easier to modify to adapt to mutations. SARS-CoV-2 has been reported to mutate frequently. Having a RNA based vaccine can be more effective to change the course of an ongoing pandemic.
The disadvantage of the RNA based vaccine mostly lies on the instability of RNA fragment. RNA is prone to degradation, which make storage and transportation challenging and critical. So far, there has been no RNA vaccine to any known disease. There might be other side effects and toxicities that are currently unknown and has no cure.
What is the most recent development in COVID-19 vaccine?
As of May 2020, three different vaccines had entered human clinical trials and showed promising results. The vaccine developed by the Oxford group had been reported to be successful in protecting small monkeys. After given a single shot of the vaccine, some of the monkeys developed antibodies again the virus within 14 days of exposure. The antibody production peaked after 28 days. These results are very similar to that of the Sinovac Biotech group, which has also been shown to be safe and tolerable. The mRNA vaccine had also reported promising result that boosted confidence to enter phase 2 clinical trials.
One thing we should all keep in mind is that protective results in monkeys doesn’t necessarily mean they will protect humans. Good safety profile doesn’t mean the vaccine is effective. However, there is hope. We should all be hopeful and do our part to contain the virus.
Author bio: Hao Wu, PHD in cell biology. Currently working as a global clinical trial manager in pharmaceutical industry
