Our Immune System Explained- A fascinating story of the war machine we are!

Our immune system is a sophisticated war machine. This post is a fascinating story of how efficiently we are protected against all threats! Through this post I will try to explain in simple language how our defense system is organized and why this organization set-up is so efficient.

Our Defense Set- Up

In terms of biology, life is an ugly battlefield. It is always in a state of war. A constant battle is going on between us and the millions of life forms around us. It’s a battle for survival. We survive on energy derived by killing plants/animals around us. Similarly, other life forms such as viruses, bacteria, fungi also must find source of energy to survive. We are good source of energy for many of these microbes. Hence, they attack us. And this attack is a constant one. So long as we keep winning, we live. The day we lose, we die. Many a times, there is truce with few of these microbes- where we allow these microbes to suck our body’s resources so long as they keep a low profile and don’t really endanger our survival. Many such microbes residing peacefully within our bodies are actually useful and contribute to our survival.

Our defenses are divided into two parts- Innate Immune System and Adaptive Immune System. Let’s understand them through an example of a city called Tribunis.

The Mighty City of Tribunis and Its Enemies

Imagine a huge fortified city called Tribunis. Inside this city live more than 1000 Tribunisians. Tribunis is a rare oasis located at the middle of the vast Sahara Desert. Tribunis is a blessed city with adequately high level of underground water. The land is extremely fertile with lots of crops and orchards. This makes Tribunis a very rich city where food and water are abundant for all.

But, outside this city, life is not that easy. Its all desert. Water and food are generally rare commodities in this arid desert landscape. Hence people living there have had a very difficult life. They have no option but keep fighting with each other constantly to keep their stomachs full. Out these bloody fights and hardships has emerged a leader. His name is Jabara. Jabara is a very powerful leader. He was able to group all these desert people into a single community called Jabaran.

Jabarans are essentially organized plunderers and murderers. Having lived a violent life, Jabarans are very powerful fighters and efficient killers. They have been attacking and looting villages around frequently, massing food and weapons. They have been extremely successful in almost all their conquests. And their empire was expanding rapidly.

However, since past few years, their ambitions have been marred by repeated setbacks. And this is because they have twice failed in successfully attacking the city of Tribunis.

Let’s explore how Tribunis has organized its defenses and have thwarted all attempts of Jabarans to plunder Tribunis.

The First Level Defense of Tribunis

From 10 km outside the main city of Tribunis there are series of multiple walls encircling the entire city. These walls are laced with cameras. These walls also have electric pressure- sensing system. These systems start sending alerts to the defense forces inside the city who then start monitoring and assessing the level of threat. These walls are electrically charged with extremely high voltage, which can incinerate anyone who tries climbing these walls from outside. Then, the land between each of these multiple walls is laced with pressure sensing bombs which will explode if anyone succeeds in crossing any of the walls.

This first level defense system has been extremely efficient. 90% of the foreign attacks have failed to cross even the first wall.

The Second Level Defense of Tribunis

Tribunisian sharpshooters and their special bullets

Once any invader tries crossing the walls of the first level Defense, it triggers an alarm that alerts the defense personnel located inside Tribunis. Once this happens, Tribunisian army closely monitors the situation. Based on the limited information the Tribunisian army has, they try making bullets that can pierce the protection gears of the invaders. Once the invaders are close to the innermost wall, the Tribunisian army deploys its sharp- shooters. These sharp- shooters start firing guns loaded with the “initial bullets” on the invaders. Since these initial bullets are build based on limited information, Tribunisians ensure that these are heavy- duty large- caliber bullets which can ensure smash even the best of the shields/ protection gears.

However, these heavy-duty bullets are very costly, difficult to make, and making them consumes lot of resources.  But these are the best possible bullets that can be made based on initial limited information available. Later, as the fight progresses, more information becomes available which is then utilized by Tribunisian army to study and understand the enemy better. The Tribunisian philosophy is that each rebel group has its own weakness in the shields each use. These specific weaknesses can be studied to make bullets that can accurately pierce those specific shields. Such bullets are not heavy duty and are cheaper to make, while they are extremely effective in killing the specific rebels the bullets are made against.

Tribunisian Commandos

When you are facing your enemy at arm’s length, fists and daggers are more useful than guns! This is exactly what the Tribunisian Commandos are prepared for. Their specialization is close range hand- to- hand combat scenarios. Once the invaders have crossed all barriers and entered the city, the Tribunisian commandos rush with all might and start attacking the enemies with their swords and daggers. This is happening simultaneously while the Tribunisian sharpshooters are gunning the enemies from a distance.

Of course, every enemy is different. And these commandos know that using single fighting technique for all enemies is not efficient. So, initially, due to limited availability of information and experience, the Tribunisian commandos use all their might and skills against the invaders. But this is tiring and can potentially burn out the Tribunisian commandos if they keep working so hard. Fortunately, they are smart. As they face the enemies, the commandos learn their weaknesses and eventually develop a combat mechanism specific to this enemy. This way, they work only against enemies’ weaknesses efficiently and kill them with little effort.

The Traitors

Some enemies are more sly and hence sometime more vicious. These clever invaders are good at bribing, influencing, and brainwashing the citizens, converting them into traitors. These traitors then allow the invaders to use the city’s resources to attack the city itself. Unfortunately, these traitors can’t be identified from a long distance by the sharpshooters of Tribunis. Hence, the task of identifying and eliminating these traitors fall on the able hands of Tribunisian commandos.  Being “on the ground” fighting at arm’s length, these commandos are trained to recognize the traitors and kill these traitors.

Post War Analysis and Preparedness

Once the battle is over, Tribunisian defenses do a detailed analysis of their actions. They start preparing for a situation if the same enemy attacks in future. One of the most important part of this preparedness is to create an enemy specific database that can be referred to again later if the same enemy attacks. The sharpshooters punch in data about the customized bullets that work specifically against this enemy. Similarly, the commandos also record the customized fighting technique that woks specifically against this enemy.

Next, time if the same enemy attacks, the Tribunisian defenses directly start making the enemy specific bullets and supplying the same to the sharpshooters. Its much cheaper and easier to make these customized bullets rather than making the non- specific resource intensive large caliber bullets that are meant to be used initially in all enemies. Similarly, the Tribunisian Commandos don’t waste time and energy going all out with full strength- they use the specific fighting technique they had recorded in the database, that works against this enemy.

The 3^rd Jabaran Conquest of Tribunis

The Jabarans had earlier tried attacking the city of Tribunis on two occasions. In both the occasion they had failed. In the first attempt, they couldn’t cross the initial barrier walls of the city. Most of the assailants died stepping on the explosives between the walls.

In the next attack the Jabarans were smarter- with special shield they could cross the walls without getting killed by the explosives. But the second level defenses on Tribunis proved too overwhelming for the Jabarans. The Jabaran invading army was completely wiped off.

The Jabaran battle strategists determined that in the last attack they were outnumbered, and hence they lost. This time, the Jabarans have determined to attack only once they have collected soldiers in large numbers. They also aim to brainwash and gather support from few vulnerable citizens of Tribunis. They know already how to cross the walls.

It been more than a year now. The Jabarans have regrouped with a large army of killers. They started their siege silently few days back. They crossed one wall after the other. There were a lot of explosions. Few did get killed. But most were able to cross all the walls, thanks to their specially prepared shields.

But the pressure sensors and explosions have already alerted the Tribunisian army. The moment the Jabarans cross the innermost wall, the Tribunisian sharpshooters start shooting at them. A special type of bullets is already under production. The initial bullets fired are the high caliber heavy duty ones. But quickly they get replaced by Jabaran specific smart bullets which easily pierce the Jabaran shields. Many Jabarans get killed.

The Jabarans are surprised. This was unexpected. They did not expect the Tribunisians to have such smart bullets. The large caliber bullets would have got exhausted soon. But these smart bullets are easy to make and are very effective.

Luckily for the Jabarans, they have a very large army attacking Tribunis this time. The sharpshooters are successful in killing who they fire at. But the enemy numbers tilt the battle towards Jabarans for some time. They are now very much inside the city.

Jabarans have also been successful in converting a lot of Tribunisian citizens into traitors. These traitors are helping Jabarans with resources such as food and weapons.

It’s now upon the Tribunisian commandos to save the city. Trained in hand to hand combat, they quickly take charge of the battle.  Jabarans are known merciless slayers. They are cunning, strong and fearfully ruthless. It was natural for Jabarans to assume that it’s just a matter of time before they capture and plunder the entire city.

And, hence, it was really a devastating surprise for the Jabarans when they realized that the Tribunisian commandos are easily killing the Jabaran soldiers. The Tribunisian commandos have smartly accessed the database developed from earlier battle to learn and employ the battle technique that works more effectively against Jabarans. The commandos are proving to be too powerful for the Jabarans. These commandos are also effectively identifying and killing the internal traitors within Tribunis.

The Jabarans are now stuck from three ways. The sharpshooters are shooting with bullets against which the Jabaran shields are helpless. A large number of Jabaran killers have died due to this and many continue dying. Similary lethal have been the Tribunisian commandos who have been efficiently slaying Jabaran invaders in large numbers. And these commandos have effective blocked the supply of resources as well by identifying and killing all the traitors.

Within next few days, one by one, all the Jabaran plunderers get slaughtered. Once again, the great city of Tribunis came ahead as invincible.

History books will record that The 3rd Jabaran Conquest of Tribunis was won by Tribunis.

The Innate Immune System

Like the series of walls guarding the city of Tribunis, our body also has such protective mechanisms as the initial defense against any microbial invasion. These initial protective mechanisms together constitute what we call as the Innate Immune System. Innate immune system is our primary line of defense and is immediate in its response to any threat.[1]

The Innate Immune System is always on guard- surveilling for any threats. This is done by reading “signatures”. Anything that is present in our body or enters our body carries a set of molecular structures known as antigens. Each antigen has its own unique set of signatures. Based on prior experience and certain rules, any antigen can be classified as “dangerous” or “harmless” or “suspect”. A suspect antigen is one which is new to our body and the defense doesn’t know if it’s dangerous or harmless.[2]

How does body really recognize if an antigen is “dangerous” or “harmless” or “suspect”? What are the rules used to guide such discrimination? To know answers to these questions, click here.

Let’s imagine a COVID-19 virus entering our body for the first time. The entry point is nose. Since it’s the first time and the body has no prior experience dealing with it, it is classified as “suspect”. However, as per the rules, seeing the huge number of “suspect” antigens, our innate immune system gets into action. Local cells release defense chemicals known as “chemokines” which is akin to “call for help“. These chemokines attract soldier cells such as neutrophils and lymphocytes to the site of infection. The capillary and lymphatic channels dilate so that the defense cells can flow in faster and in great numbers. This leads to “stuffiness” and “loss of sense of smell”. The water in blood starts getting utilized to make mucous. This leads to “runny nose”. Mucous is sticky and serves to imprison viral particles within its inherent mesh. Sensory nerves around bronchi and nose get activated- making the patient cough and sneeze. The mucous that has trapped thousands of viral particles get thrown out via coughing and sneezing. It’s an innovative way of “washing out” the virus particles! The defense chemicals reach brain instructing it to go on “war” mode. In this mode, brain resets its thermostat to a higher level- body temperature rises leading to fever. Thousands of years of evolution have programmed our immune to system to the fact that invaders efficiently invade only when temperature is conducive. Fever is a defense as a part of that evolutionary programming- higher temperature tends to inactivate the invaders. The “war” mode consumes a lot of energy. This contributes to headache, muscle ache, generalized weakness. [3]

The Adaptive Immune System

In a large number of patients, the innate immune system will destroy the COVID-19 virus. However, if the infection is overwhelming and Innate Immune System finds itself inadequate, Adaptive Immune System gets activated. This is our second level defense. Just like the Tribunisian second level defense, our Adaptive Immune System also has “sharpshooters” and “commandos”.

B- Cells: The Sharpshooters

As the virus particles defeat the initial barriers of the immune system, the B cells get deployed. The B- cells have powerful guns. They are highly resourceful and make customized bullets that are can work specifically against the enemy they are facing. However, the effectiveness of these customizations depends on the amount of information available. These bullets are known as Immunoglobulins (Ig) or Antibodies. They are our Adaptive Immune System’s sharpshooters. Since this is the first time the COVID-19 virus has attacked the body, the information is limited. Hence, initially, the B- Cells make caliber heavy duty antibodies specific against this virus. These “heavy” antibodies are known as IgMs. However, as in case of Tribunisian sharpshooters, making large caliber antibodies consumes a lot of energy and is not an efficient way of fighting. “M” in IgM comes from “Million” and signifies the fact that IgMs are very large and heavy.

As battle keeps progressing, B cells gather complete information about the virus. Based on this, they start making lighter antibodies/ immunoglobulins which can specifically and effectively neutralize the virus. These antibodies are known as IgGs.[4]

T- Cells

The T cells represent the other component of our Adaptive Immune System. There are many types of T cells inside our body. Each type has a specific biological signature and well-defined functions. And I won’t dare to bore you with details of each type.

What’s important for us to know is that of these many types, there are two predominant ones. One is marked by signature called CD4 and the other one is marked by CD8. [5]If the signature is present you mark it as + or else, you will mark it as -. So, CD4+ T cells would mean T cells bearing signature of CD4. Similarly, CD8- T cells would mean T cells NOT bearing signature of CD8. Hope the nomenclature is clear.

CD4+ T cells are also known as helper T cells. CD8+ T cells are also known as cytotoxic T cells.

While understanding the details will require a great deal of training in immunobiology, what you can generalize is that CD8+ T cells are designed to attack and destroy cells that pose as threats. These CD8+ T cells are like the Tribunisian commandos, they are efficient in hand- to- hand close range combats. Initially they attack the virus with full force. But eventually, as additional information about the virus becomes available, these CD8+ T cells develop a technique that is specific and very effective against COVID-19. [5]

It is important to note that COVID-19 is a virus. And like any other virus, its quite stealthy. The COVID-19 viral particles invade several patient cells and hide inside them. They then use the resources of the cells they are hiding inside, for making more viruses. Once the virus is inside the body, it cannot multiply without the help of host the cells. Unlike bacteria of fungi which can multiply on their own after consuming food from the hosts, viruses do not have any such capability of self-multiplication without help. Our own cells are responsible for expanding small clan of virus into a huge army!

These “self” cells, which give shelter to the virus particles and allow them to multiply, are really like the traitor citizens of Tribunis who have been brainwashed by Jabarans.

CD8+ T cells are extremely capable in identifying these stealthy “traitors”. Once identified, CD+ T cells attack and efficiently obliterate these cells. Once the traitor cell is killed, it ends up killing the virus hiding inside it.[5]

CD4+ T cells are equally important. They are termed as “Helper” T cells and this terminology, although quite accurate in indicating role, is quite misleading. The immediate assumption is that they are just “helpers”. But, in reality, they are amongst the most crucial components of T cells. Without their help, its literally impossible for B cells or CD8+ T cells to functions. The antibodies are so specific and effective because of the information processing driven by CD4+ T cells. The CD8+ T cells are very powerful and dangerous- they soon can become ruthless mercenaries from being a responsible protector. If this happens, these mercenaries will “kill just for the love of it”. The candle that is meant to provide light to the house can soon set the whole house of fire. One of the most important roles of CD4+ T cells is to avoid this terrible eventuality- which we call as cytokine storm. Once cytokine storm starts it generally ends up killing the patient. CD4+ T cells are vital in taming the extent to which our immune system reacts and provides a strong supervision on whether the soldiers of our immune system are working as loyal protectors or merciless mercenaries. [5]

This is a simplified explanation behind why I keep saying that CD4/CD8 ratio can be used to predict outcome of COVID-19 infection in any patient. This test, costing INR 600, can be a simple measure to tell you if you should be worried if you get any infection including COVID-19. A person with CD4/CD8 ratio <1 should be definitely careful. If you want to explore this in detail, click here.

Memory

Once any battle starts, our immune system voraciously starts collecting information about the invaders. And all this information is stored.  Each time a new information is collected, the same is analyzed for evaluating best course of action. These analyses and evaluations are also “memorized”.

There is a constant ongoing surveillance by the innate immune system, and it keeps checking there is any molecular signature (also can be called as antigen) within our body which looks “dangerous”. This evaluation is possible because our defense system maintains a memory of two databases for such signatures- one can be called “green database” and other can be called “red database”.  Any antigen that has signatures matching the “green database” is recognized as harmless and is not attacked. Any antigen whose signatures match the any of the ones in the “red database” is identified as dangerous- such antigens will be attacked and destroyed. Any other antigen, whose signatures do not match the “green database” and nor is part of the “red database” can be called as a “suspect”.  A “suspect” is actively watched. If the “suspect” does not harm, gradually its signatures are stored in “green database”. And if the “suspect” does prove harmful, its signatures get stored in “red database”. [6]

Now, if the “suspect” is deemed harmful, the B cells and the T cells start developing weapons based on information available- the information keeps getting richer as exposure time with the invader keeps increasing. Initially, B cells make IgMs to tackle the threat on an immediate basis. But, soon they learn how to make the efficient and specific IgGs. And this information of IgG structure that works against this specific invader is stored in memory cells. Similarly, the T cells also develop a memory of how to tackle this invader in a specific way that works best against this unique invader.[7]

Once this memory is established, it becomes the reference point if the same invader attacks our body again. So, if a harmful virus attacks us second time, the innate immune system recognizes from its memory of existing signatures that the virus is harmful and had attacked earlier. This information is relayed to the Adaptive Immune System. The T cells and B cells start working instantly. B cells again do initially make IgM as an immediate response. But now it doesn’t have to learn how to make IgGs against this virus. It retrieves data from memory and knows exactly how to prepare the specific IgGs that work. Hence, very quickly, B cells start making those IgGs in huge amounts. These IgGs go on and destroy the circulating viruses. Similarly, T cells also refer back to the existing memory for this virus and start actions that are specifically successful against this virus. The T cells also know from the memory how the traitors who help this virus look like, and hence the actions are swift and specific.[7]

The action of the immune system against any invader it is facing for the first time is known as primary immune response. The action of the immune system against an invader based on the memory developed from a previous experience with the same invader is known as secondary immune response. [8]

Implications of Immune Memory

Swift and Effective Action

So, the memory is very important, especially against dangerous invaders. The established memory against any such invader allows our immune system to quickly recognize and classify the invader as dangerous. And the immune system knows exactly how to kill this invader. So, the response time becomes super swift.

Prevents Cytokine Storm

Similarly, the T cells and the B cells no longer have to spend time in figuring out what action would be most efficient. Rather than using highly devastating weapons and bombs that can end up killing innocent citizens, the army of our immune system can specifically target and kill only the invaders and traitors. The immune cells don’t become anxious and start dropping big devastating bombs. They are well prepared because they can predict the outcomes. Thus, memory of previous invasion by an enemy allows immune system to be less reactive and more proactive.

This prevents the immune system to react vigorously and drift into cytokine storm where it’s the immune system which ends up killing the patient.

Vaccines- Developing Immune Memory without actual infection

Vaccination is an artificial way of developing immune memory. Instead of exposing to actual dangerous invader, the signatures of the invader is introduced with the hope that body’s immune system will learn how to neutralize any pathogen that bears those signatures. If successful, body develops a memory of how to fight against that pathogen, without really entering into a live battle. After vaccination, once memory is developed, if the actual pathogen attacks the body, body’s immune system swiftly tackles the pathogen as if it has encountered the pathogen earlier. [9]

So, vaccines have the capability of preventing infection from causing any devastation, and also reduces the risk of fatal complications such cytokine storm dramatically.[10]

But I personally feel, infection is best way of vaccination if you are able to protect yourself from complications of the infection and don’t end up gravely. No vaccine can fully mimic a live pathogen attacking. Vaccination is like learning to ride a bicycle with two additional support wheels at the back. You do learn, but it’s really not actual cycling. So, whether the vaccination will be a success depends really on the biology of pathogen we are referring to. In many, vaccination is a great strategy. In many, it can be a failure.[9][11]

In case of viral infections like COVID-19, where the virus is changing structure rapidly, the antigens and their signatures might not constantly be the same. And if signatures change dramatically the immune system will have to learn against the virus bearing new signatures all over again, even though the person might be vaccinated. This is the main reason why we still don’t have any vaccine against HIV- the virus changes its signatures rapidly. Similarly flu virus keeps changing signatures. Hence, vaccines also keep changing against flu and you have to get vaccinated again and again.[9]

How to make immune memory effective?

Immune memory is similar to our brain memory. We rarely forget the most painful experiences. We rarely forget what’s revised again and again. We remember longer by associations. We remember better when we are younger.

Same rules apply to immune memory.

If you had a mild infection, the immune memory won’t be long lasting. More painful the vaccine, longer is the memory. This is so clearly exemplified with our experience with pertussis vaccine in kids. The initial “whole- cell” pertussis vaccine was extremely painful. It would give high fever, and with pain the kids would cry for days. So, scientists came up with “acellular” pertussis vaccine which was marketed as “painless”. Data now clearly shows that the earlier “painful” whole- cell pertussis vaccine is more efficacious than the “painless” acellular pertussis vaccine.[12][13][14]

Like or brain memory, immune memory also needs revision. Else, slowly it diminishes. So, if a virus keeps attacking again and again, our immune system doesn’t forget how to fight against that virus easily. That’s the whole logic behind booster doses of vaccines. They are revisions to refresh immune memory.

Immune system memory also can keep refreshing itself via association. So, if we have immune memory against a virus and another virus attacks which has “similar” signatures, it allows immune memory of previous virus to sustain. Let’s imagine a scenario where you have taken vaccine against COVID-19 virus. And in coming months the virus changes its structure and now bears few different signatures. If this new strain of COIVD-19 attacks you, the earlier immune memory will still be effective to a large extent since lot of signatures are similar. Of course, it can’t be 100% effective because the structure is a bit different. But, this infection will refresh the earlier memory as it is the same memory being referred to now to fight the new strain. This is similar to revision.

Lastly, younger we are better is the immune memory retention. Vaccines don’t work efficiently in older individuals, as compared to the younger ones. And you must remember that age cannot define how old you are. Some 80 years old individuals can biologically much younger than many of their 50 years old counterparts. I personally believe that the real age can be judged by CD4/CD8 ratio. If the ratio is <1, you are old! Please click here to know more on this.

Final Thoughts

Our immune system is a very intelligent and comprehensive defense mechanism. The innate immune system represents the fist level of defense. It is complimented by a powerful second level defense system called the adaptive immune system. Together they have the ability to swiftly act against any threat, gather information, analyze and improvise based on analysis. Thus, our immune system keeps learning each time any pathogen attacks.

The immune system also has memory which allows it to store all the strategies and tactics it learnt to neutralize any pathogen. Because of this memory, the secondary immune response to a repeat attack by any pathogen is much swifter and specific. Immune memory also helps prevent cytokine storm.

Vaccines might not be the best way for our body to learn how to fight against a pathogen and develop memory for the same. But, nevertheless, it’s the safest way to develop such memory and give body nearly all the advantages of this immune memory.

Immune memory, whether via natural infection or via vaccine, is stronger if the depth of experience is richer (eg. pain, fever etc) and is getting frequent revisions.

Lastly, how the efficient the immune system is, depends on biological age which cannot be measured simply by your date of birth. CD4/CD8 ratio might be an easy, cheap and efficient way of measuring this age. If the ratio is <1, it’s a matter of concern.

Hope you like this post and gathered some new insights. Do share your thoughts in the comments section.

References

[1]        T. Hato and P. C. Dagher, “How the innate immune system senses trouble and causes trouble,” Clin. J. Am. Soc. Nephrol., vol. 10, no. 8, pp. 1459–1469, Aug. 2015, doi: 10.2215/CJN.04680514.

[2]        P. van Endert and J. A. Villadangos, “Antigen processing and recognition,” Current Opinion in Immunology, vol. 19, no. 1. Curr Opin Immunol, pp. 63–65, Feb. 2007, doi: 10.1016/j.coi.2006.11.015.

[3]        S. Koyama, K. J. Ishii, C. Coban, and S. Akira, “Innate immune response to viral infection,” Cytokine, vol. 43, no. 3. Cytokine, pp. 336–341, Sep. 2008, doi: 10.1016/j.cyto.2008.07.009.

[4]        T. W. Lebien and T. F. Tedder, “B lymphocytes: How they develop and function,” Blood, vol. 112, no. 5, pp. 1570–1580, Sep. 2008, doi: 10.1182/blood-2008-02-078071.

[5]        P. de Candia, F. Prattichizzo, S. Garavelli, and G. Matarese, “T Cells: Warriors of SARS-CoV-2 Infection,” Trends in Immunology, vol. 42, no. 1. Elsevier Ltd, pp. 18–30, Jan. 01, 2021, doi: 10.1016/j.it.2020.11.002.

[6]        S. Akira, “Pathogen recognition by innate immunity and its signaling,” Proc. Japan Acad. Ser. B, vol. 85, no. 4, pp. 143–156, 2009, Accessed: Nov. 07, 2012. [Online]. Available: http://japanlinkcenter.org/JST.JSTAGE/pjab/85.143?from=Google.

[7]        G. Natoli and R. Ostuni, “Adaptation and memory in immune responses,” Nature Immunology, vol. 20, no. 7. Nature Publishing Group, pp. 783–792, Jul. 01, 2019, doi: 10.1038/s41590-019-0399-9.

[8]        S. Sell, “How vaccines work: immune effector mechanisms and designer vaccines,” Expert Review of Vaccines, vol. 18, no. 10. Taylor and Francis Ltd, pp. 993–1015, Oct. 03, 2019, doi: 10.1080/14760584.2019.1674144.

[9]        F. Zepp, “Principles of vaccination,” in Methods in Molecular Biology, vol. 1403, Humana Press Inc., 2016, pp. 57–84.

[10]      A. Ciabattini, P. Garagnani, F. Santoro, R. Rappuoli, C. Franceschi, and D. Medaglini, “Shelter from the cytokine storm: pitfalls and prospects in the development of SARS-CoV-2 vaccines for an elderly population,” Seminars in Immunopathology, vol. 42, no. 5. Springer Science and Business Media Deutschland GmbH, pp. 619–634, Oct. 01, 2020, doi: 10.1007/s00281-020-00821-0.

[11]      N. Phin, “Public Health Scotland – the first year: successes and lessons,” J. R. Coll. Physicians Edinb., vol. 51, no. S1, pp. S34–S39, Jun. 2021, doi: 10.4997/JRCPE.2021.239.

[12]      M. Edmunds et al., “Retrospective cohort study investigating extent of pertussis transmission during a boarding school outbreak, England, December 2017 to June 2018,” Eurosurveillance, vol. 26, no. 26, Jul. 2021, doi: 10.2807/1560-7917.ES.2021.26.26.1900736.

[13]      K. Wilkinson, C. H. Righolt, L. J. Elliott, S. Fanella, and S. M. Mahmud, “Pertussis vaccine effectiveness and duration of protection – A systematic review and meta-analysis,” Vaccine, vol. 39, no. 23. Elsevier Ltd, pp. 3120–3130, May 27, 2021, doi: 10.1016/j.vaccine.2021.04.032.

[14]      T. R. Fulton, V. K. Phadke, W. A. Orenstein, A. R. Hinman, W. D. Johnson, and S. B. Omer, “Protective Effect of Contemporary Pertussis Vaccines: A Systematic Review and Meta-analysis,” Clin. Infect. Dis., vol. 62, no. 9, pp. 1100–1110, May 2016, doi: 10.1093/cid/ciw051.