Saviours of our life from deadly pathogens

Vaccines are powerful weapons in our arsenal against many fatal viral diseases. Eventually they became vital for our survival against several deadly pathogens. Vaccines saved millions of lives from deadly diseases like polio, measles, mumps, rubella, rabies and we globally eradicated disease like smallpox (almost eradicated polio by last year).

Once a virus enters our system (a cell), the resident guard cells recognizes the signs of the infection (viral proteins or chemical signal calls from an infected cell). Within weeks after a viral infection our body will create tailored antibodies and immune cells which will inactivate the intruder and eventually these immune responses subside. But the memory to create those weapons retains and even after several years our body will initiate a quick immune response on a second attack by the same pathogen. Antibodies are specific proteins produced by our defense system (triggered by the presence of a pathogen or its proteins) to selectively destroy the invading pathogens. Our immune system is very efficient in directing specific immune cells (like activated T-cells) also to scavenge the pathogens or even kill the infected body cell (altruism). We have a strong immune response, a reason why we are protected from several pathogens that we encounter daily. Note that the viruses are masters in evading several antiviral mechanisms of the host. There exists a constantly evolving battle between these intracellular parasites and host defense system. Both the invader and the host emerge with newer strategies to conquer each other, the fight continues.

Vaccines activate and teach our defense system by creating antibodies that neutralize the attacking pathogens and activate the cell mediated immune responses and keep the memory of the attack so that our body mobilizes the arsenal quickly upon a real attack by that pathogen. Nowadays, making a vaccine is much faster due to technological advances but the clinical trials to approve them for efficient & safe use takes times in months. We are hearing about frustrating delay in COVID-19 vaccine development and hopefully you may learn the reasons for that scenario, after reading this blog.

History of vaccines

Variolation (image source Wikipedia)

During 11th century A.D., China practiced primitive form of vaccination called ´variolation´ for smallpox. They took the pustules from smallpox patients, dried them up and blow the pustule contents into the nose of healthy individuals to protect them from deadly smallpox infection. Later in 17th century, Lady Montagu the wife of the British ambassador in Constantinople, brought this practice of variolation to Europe.

  • Smallpox vaccine
Edward Jenner (image source Wikipedia)

Smallpox, a dreadful viral disease that killed millions all over world since medieval times. During 1796, Edward Jenner in England, noted that milkmaids don’t get smallpox since they get a milder version called cowpox (Variolae vaccinae). He took pustules from a cowpox virus-infected milkmaid and inoculated a boy named James Phipps with the pustule contents. Later he challenged that inoculated boy with smallpox pustule and noticed that the boy was protected from smallpox (such a challenge experiment is difficult to imagine these days!). This became a practice which saved many lives from this deadly disease. Very interestingly, Jenner did not know anything about viruses at that time. You can watch very distressing images of smallpox infections to realize from ‘what‘ the vaccine saved us (see references, painful to watch those images!). Thanks to vaccines, in 1980, WHO announced the eradication of smallpox one of the greatest achievements in history of mankind.

  • Rabies vaccine
Louis Pasteur (image source Wikipedia)

Almost a century later, Louis Pasteur in France developed the Rabies vaccine and coined the word ´vaccine´ for all protective inoculations (vacca means cow in Latin) in honor of Edward Jenner´s work on cowpox. Rabies is a very deadly zoonotic disease which kills several thousand even these days. Louis Pasteur developed the rabies vaccine by weakening rabies virus in rabbits and subsequently harvesting it from infected rabbits´ spinal cords (not knowing the disease-causing agent is a virus). By serially growing the virus in a different species (here rabbit), the virus gets adapted to that species with mutations. This may result in less adaptation to its original host, along with decrease in virulence of the virus (attenuated). Such live but attenuated virus still retain the features that provide the immune system enough information to develop immunity to the original virus. Pasteur is also known for his works on chicken cholera vaccine and anthrax vaccine for cattle.

A bit more on vaccines; Passive and active forms of immunization

In ´active form´ of immunization, inactive forms of the pathogen or pieces of pathogen are applied as vaccines to trigger the immune system to produce the antibodies or the cells to fight against the pathogen. This provides long-term protection against that pathogen.

The ´passive form´ of immunization provides short-term protection where antibodies or immune cells from recovered person is applied to another person who is at the risk of infection. Recently, you might have read about the convalescent serum therapy given to many COVID-19 patients at risk, where antibodies from blood donated by COVID-19 survivors were applied to risk group patients (which provides a temporary protection).

Rules for an effective vaccine

  • It should trigger the immune response in vaccinated person
  • It should create the appropriate protective response (either antibodies, activated immune cells or both).
  • It should protect the vaccinated person from that specific pathogen
  • It should provide long-term protection
  • It should be safe (no side effects), easy to use, long-term storage

Making different types of active vaccines

  • Live-attenuated vaccine

Live-attenuated vaccine are weakened (attenuated) form of the pathogen. E.g. Salk´s polio vaccine (read below).

  • Inactivated vaccine

Chemically inactivated form of the pathogen. E.g. Sabin´s polio vaccine (read below).

  • Subunit vaccine

Here pieces of pathogen (antigens-proteins or genetic material) are used to evoke the immune response. E.g. SARS CoV2´s mRNA based Moderna vaccine against COVID-19 under testing (read below).

  • Vector-based recombinant vaccine

With the modern genetic engineering methods, we can use another crippled virus (viral vector) as the delivery vehicle. This ´cargo van´ virus will introduce the genetic message of another pathogenic protein into our cells. The pathogenic protein produced will elicit the appropriate immune response in host. E.g. Ervebo against ebola virus (read below).

  • Toxoid vaccine

Immune response can be targeted to the toxin created by the pathogen.

Vaccination mediated herd immunity

To stop a viral transmission, enough number of people in the population should be immunized (note: we don’t have to immunize 100% of the population to break the chain of viral transmission). The percentage of the population to be immunized to attain the herd immunity vary for different viruses. A highly transmissible diseases like measles need around 95%, while for COVID-19 somewhere between 50-70% of the population should be immunized either by natural infection or vaccination to attain the herd immunity.

Delay in approval; several phases in clinical trials

With any new medical intervention, Scientists should conduct careful experiments for attaining necessary evidences to obtain its approval as a medical treatment. It involves several phases; experiments start with animal testing after the discovery. After successful animal experiments with the novel treatment protocol, the next stages are the clinical phases in human subjects. Early phase involves dose determination and safety tests in a few healthy human volunteers. Later phases test many human participants to determine the efficacy of the treatment.

Vaccine trials takes months to years to complete and involve 2 experimental groups. One is control group treated with ´placebo´ (mostly an established vaccine against a different pathogen) and other group is treated with ´vaccine candidate´. These studies are ´double-blinded´ which means both the parties, the administrator and the recipient do not know if the recipient is receiving the vaccine, to avoid any bias. In some studies, on deadly diseases, in place of placebo control group, there will be ´immediate´ and ´delay´ vaccination groups due to ethical considerations (to provide all the volunteers a promising treatment for a deadly disease as quickly as possible).

Phase 1 trial; involve safety and immunogenicity studies in a small number of closely monitored human subjects.

Phase 2 trial; involve dose studies and hundreds of human subjects are needed.

Phase 3 trial; studies effectiveness and additional safety data required for approval as medical treatment, thousands of human subjects are needed.

Phase 4 trialstudies on many vaccines on side effects and long-term immunity, once they are on the market.

Some modern-day vaccines

There are several life-saving vaccines in the list. WHO ensures that the vaccines used in immunization programmes are safe and effective (list of the prequalified vaccines are in the references). Below, I will be discussing some of the cherry-picked ones.

  • Polio vaccine
Jonas Salk (image source Wikipedia)

Poliomyelitis (polio) is a highly infectious viral disease, mostly children under 5 years of age are main victims. Polio virus spread through fecal-oral route (contaminated water/food) and multiplies in the intestine. The virus can subsequently invade the nervous system and cause paralysis.

Jonas Salk developed injectable polio vaccine and became the saviour of several kids from paralysis and iron lungs (many ended up in tank ventilator called iron lungs to assist breathing). Jonas Salk was quite unconventional and used inactivated polio virus (chemically inactivated using formalin) to mobilize the immune system to fight against the virus. More than one million school kids participated in the polio trial in 1954. In 1955, the vaccine was announced safe and he became a hero after the vaccine development. Interestingly, in an interview he was asked about who owns the patent of the polio vaccine, his said ´there is no patent, could you patent the sun? ´ Prevention of polio is one of the greatest achievements of medical science. Later in 1962, Albert Sabin introduced the oral poliovirus vaccine which is a live-attenuated vaccine. This vaccine was simple to use but with a rare risk of reversion of attenuated virus to virulence.

  • Influenza vaccine

Influenza virus, that causes flu is a segmented RNA virus (not a single string), notorious for frequent mutations, escapes our immune surveillance system and that is the reason why every year we need different flu vaccine.A commonly used influenza vaccine is developed by chemically inactivating the influenza virus grown (after finding the current seasonal strain and guided by WHO) in chicken egg embryo (watch the video at the end).

  • Ebola vaccine

Another deadly zoonotic disease caused by ebola virus, that result in hemorrhagic fever which leads to internal bleeding and death. Several types of vaccines are being developed for this disease, making use of the modern technology. Some of the vaccines are ready to use and some are in clinical trials. Two interesting ones are discussed here. One is viral vector-based active vaccine with brand name ´Ervebo´, it uses another genetically modified another virus to produce an important protein of ebola virus as antigen. Another one, is a passive therapy, i.e. making antibodies against ebola virus a genetically modified in tobacco plants (a cousin of tobacco, the one that people uses for smoking), which is then harvested for making antibody cocktail against ebola named ´Zmapp´ (see video below).

All eyes are on SARS CoV2 vaccine now

According to WHO´s list, there are more than 100 vaccine candidates under different stages of testings. Some are undergoing clinical trials, and some are on preclinical trails. Here I am discussing 2 main vaccine candidates which got wide attention which may become the saviour/s of millions of lives in future.

RNA vaccine

Moderna´s (an US based biotech company) COVID-19 vaccine consists of a piece of genetic information of spike protein of SARS CoV2 (information in the form of RNA molecule). It is designed to produce a part of viral spike and trigger the immune system to make antibodies that recognize and neutralize the spike protein that SARS CoV2 uses to enter host cells. It is under clinical trials now (into Phase 2 trials, very promising).

Vector-based vaccine

Beijing Institute of Biotechnology (China) and Oxford University (UK) are ahead with clinical trials for vector based COVID-19 vaccine. The Jenner Institute’s (University of Oxford) Vector based COVID-19 vaccine a promising vaccine candidate for multiple reasons. They named it ´ChAdOx1 nCoV19´ which is the abbreviation of Chimpanzee Adenovirus Oxford1 novel CoronaVirus 2019). Here they use another mild virus (a crippled Adenovirus), that cannot replicate in host cells, but to deliver the code for spike protein of SARS CoV2 and subsequently to elicit the immune response. The genetically modified Adenovirus will infect the host cells but cannot replicate itself. Upon infection, it faithfully expresses the cargo it carries (here the spike protein of SARS CoV2). This foreign protein will evoke the defense system and produce the appropriate immune mechanisms in vaccinated host.

They had an advantage compared to other vaccine candidates, the platform had undergone and proven safety clinical trials with regard to MERS, another closely related Coronavirus from the same family. Further, recently they reported in BioRxiv that a single dose of this vaccine prevented SARS CoV2 pneumonia in monkeys. Giant vaccine manufacturers like Serum Institute of India (world’s largest supplier of vaccines) is involved in the massive production to provide huge world-wide demands of the vaccine if this promising vaccine candidate turns into ´the COVID-19 vaccine´. Fingers crossed!

Several other promising and interesting vaccine candidates undergoing trials these days. British American Tobacco company is going forward with clinical trials of a recombinant COVID-19 vaccine, where they produce SARS CoV2 protein in tobacco plants (similar engineering approach to ebola vaccine Zmapp, mentioned above). 

Anti-vaxxers

Opposition to this life-saving approach (vaccination) is not new. Soon after Jenner´s smallpox vaccination, there was anti-vaccination movement (below, see the interesting cartoon from 1802, inspired by the controversy related to Jenner´s vaccine; that parts of cow may grow after the cowpox pustule inoculation). This hesitancy towards vaccination, unfortunately observed even present days, could be due to several reasons like religious, political, sanitary, fear and pseudoscientific. A very recent study shows that though these anti-vaccination protests are small, but worryingly growing amid this COVID-19 pandemic time (to date, more than 300,000 COVID-19 deaths worldwide). Anti-vaxxers spread emotional messages on children’s health, advocate alternative medicines and connect vaccinations to conspiracy theories. On the other hand, pro-groups have a direct message that ´vaccines work and save lives´. By analyzing the social media activities, the study warns that within a matter of 10 years the anti-vaccination campaigns may dominate over the pro-vaccination views, which is alarming. A better way of communicating with concerned parents about the real risks and benefits of vaccination is warranted. Once the intensity of this novel emerging disease subsides, the anti-vaxxers may gain momentum.

Cartoon from 1802, inspired by the controversy related to Jenner´s vaccine.

Conclude

            In the absence of an efficient anti-viral drug against COVID-19, a vaccine is essential to stop the spread of SARS CoV2 virus. Attaining herd immunity through natural infection of this virus takes long time, moreover at the expense of millions of lives. Vaccination, in a way is teaching our body how to fight against a killer virus, when it encounters a real one. Nowadays we have technologies to quickly make vaccines against any novel virus, approval of a safe and efficient vaccine demands rigorous testing and hence takes time. Some of the vaccine candidates are showing promising preliminary results. We may have to continue practising social distancing measures, contact tracing and quarantine measures until there is an effective treatment protocol, to avoid choking the health system. Even though vaccine trials take time, it is important to ascertain that COVID-19 vaccines that eventually appear in market are safe and effective, or else this may cause more damages than the disease itself. Once approved, another challenge in the future may be bulk production and vaccinating billions in a short period of time.

Videos of this blog

Influenza vaccine production using egg embryos

Ebola vaccine development using Tobacco plants

References

Clinical trials

https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-product-approval-process

List of WHO-prequalified vaccines

https://extranet.who.int/gavi/PQ_Web/

Anti-vaccination campaign

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140172/

https://www.bbc.com/news/uk-england-leicestershire-50713991

https://www.nature.com/articles/s41586-020-2281-1

Vector based vaccine for COVID-19; ChAdOX1 nCoV19

https://www.biorxiv.org/content/10.1101/2020.05.13.093195v1

WHO’s COVID-19 vaccine candidates list

Convalescent serum for COVID-19 treatment

https://www.nature.com/articles/d41587-020-00011-1

Moderna’s mRNA vaccine to fast-track clinical trials

https://time.com/5835785/moderna-coronavirus-vaccine-phase-2/

Smallpox infection images (graphic images!)

https://www.bbc.com/news/uk-england-birmingham-45101091

Published by Rajeev

Neuroscientist, living in the North, passionate about brain, new molecular tools, viral vectors.

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