• Urooza Sarma

Vaccines: from smallpox to COVID-19

by Urooza Sarma, Varun Rao, Rahul Rao and Yasir Aheer


Summary:

  • Vaccines may well be our greatest achievement as a species, but their tremendous success means they rarely register in our collective consciousness.

  • Vaccines comprise attenuated or inactivated forms of the disease causing pathogens that activate the body's natural immune response to produce antibodies.

  • If the person contracts the pathogen in the future, the antibodies are rapidly produced causing neutralisation of the invading pathogen.

  • Vaccine development is a rigorous and lengthy process, but there is a tremendous global effort to hasten the delivery of a COVID-19 vaccine.

Nothing better encapsulates the necessity of vaccines than the old adage of “prevention is better than cure.” As humans live for longer, our exposure to a myriad of disease and health conditions increases. While some illnesses are unavoidable, controlling infectious diseases is essential to not only ensure better quality of life, but also to reduce the burden on our health systems. Vaccine development is a lengthy, meticulous and uncompromising process. From basic laboratory scientists, to clinicians and volunteers, the road to a successful vaccine is paved with hurdles that must be overcome, strict monitoring from several scientific and governmental agencies. And of course, public scrutiny.


Ironically, the tremendous success of vaccines has led to their low profile in our collective minds today. For most people, words like smallpox and diphtheria remain confined to historical studies, and successive generations have been spared the horrors of these debilitating illnesses.


Humans now live closer together, and more integrated, than at any other time in our history - more than half of humanity now lives in an urban area. Tremendous strides in the speed and ease of international travel mean that diseases can travel halfway across the world in the blink of an eye. Now more than ever, vaccine development has become imperative to improving human health outcomes. As we’ve seen with the COVID-19 pandemic, infectious disease can be detrimental to human health, but the spill-on effects on the economy are tremendous.


A brief history of vaccines

Vaccines may well be our greatest achievement as a species. Just over a century ago, the infant mortality rate in the US was an astounding 20%. Diseases such as measles, polio and smallpox ran rampant, taking a devastating toll on children worldwide. Recent COVID-19 infections notwithstanding, a large part of our modern way of life is owed to the medical miracles of vaccines.


The first vaccine is credited to Edward Jenner, a doctor from Gloucestershire, England, whose Eureka moment came when he allegedly overheard a milkmaid boast, “I shall never have smallpox for I have had cowpox. I shall never have an ugly pockmarked face.”. In 1796, he inoculated an eight year old boy with pus from a cowpox lesion on a milkmaid’s hand. The boy developed a slight fever, but quickly recovered; he remained unaffected by subsequent exposures to the virus. In a tale sadly familiar to many aspiring researchers, Jenner submitted a paper to the Royal Society describing his groundbreaking discovery, but it was rejected.


Undeterred, Jenner wrote a private publication instead, a seminal work that is widely regarded to be the foundation of modern vaccinology. Jenner went on to become a celebrity, and his vaccine was actively promoted by such luminaries as the President of the USA, the Tsar of Russia, Napoleon and the Pasha of Egypt.


It is easy to forget the debilitating effects of smallpox. It had a mortality rate of 30%, has no cure, and can even cause blindness. The effects are best shown in a famous 1901 picture (here), showing two boys aged 13, only one of whom received the vaccination against this deadly disease. A picture truly does tell a thousand words.


And so the field of vaccination remained focussed solely on cowpox inoculation for smallpox, until a French scientist named Louis Pasteur came along. In 1861, Pasteur first proposed the germ theory of disease, which stated that tiny organisms (‘germs’) that were too small to see with the naked eye caused many of the diseases of the day. In 1885, he developed the life-saving vaccine for the rabies disease, caused by the microorganism of the same name. And finally, Pasteur left one more gift for mankind - he also invented the technique of pasteurisation, which is an important step in the production of beer.




In 1953, Jonas Salk presented a vaccine for polio, a debilitating disease that caused 15,000 cases of paralysis and 1,900 deaths a year in the United States alone. Over the following year, over 600,000 schoolkids were subjected to among the largest clinical trials ever conducted. It was concluded that the Salk vaccine was 80-90% effective at preventing polio.


The first global approach to mass vaccinations was initiated by the World Health Organisation (WHO) and United Nations Children’s Fund (UNICEF). The WHO’s massive Expanded Programme on Immunization ran for over 30 years, and targeted diseases such as diphtheria, whooping cough, tetanus, measles and tuberculosis. The achievements of the programme are impressive - the eradication of smallpox, a 99% reduction in polio infections, and a 78% reduction in measles deaths. Most recently, philanthropic organisations like the Rockefeller Foundation and the Bill and Melinda Gates Foundation have funded significant vaccination initiatives.

How Vaccines Work

Our immune system has a specialised army of cells that form the immune system, which acts as a defense against invading microorganisms, called pathogens. The immune system can be divided into two modes: innate and adaptive. In the battle against an invading pathogen, the innate immune system comprises the fast-acting, front line soldiers that fight the pathogen head on by engulfing it whole and releasing fragments of it. Fragmentation does two things:

  1. It deactivates the immediate threat of the pathogen.

  2. Provides pieces of the pathogen that can act as danger signals to the adaptive immune system.

The adaptive immune system is slower to respond, but takes the information provided by the innate immune system to form the best plan of action specific to the pathogen in question. It forms antibodies that neutralise or inactivate the pathogen, thus fighting the ongoing infection. These antibodies also get archived and are easily activated in case of a recurrent infection by that pathogen. The next time the pathogen infects the body, the immune system recognises it and activates the pathogen-specific plan faster, thus preventing the detrimental effects of the ongoing infection.


In a nutshell, vaccines harness this natural ability of our immune system to fight specific disease. Vaccines are biological suspensions consisting of attenuated, inactivated or fragmented forms of the disease causing pathogens or fractions of it. When injected into humans, this can activate the immune response to induce antibody development. If the person contracts the pathogen in the future, the antibodies are rapidly produced causing neutralisation of the invading pathogen and presenting infectious disease or its sequelae.

Stages of vaccine development:

Simplistically, vaccine development capitalises on an elegant system already in place in human bodies. Yet its success relies on proving high efficacy and safety before inoculation of the greater population. The key to a successful vaccine is developing a biological suspension that is strong enough to elicit an immune response to a pathogen, yet not strong enough to cause any of the undesired effects of the infection.

Stages of vaccine development (source: Milken Institute School of Public Health, George Washington University).

Therefore, long before human trials can begin, vaccine development starts with understanding the composition of the microorganism and developing the best version of the pathogen to achieve this balance. Known as the exploratory stage, this involves basic laboratory research to answer investigatory questions such as “what makes up the structure and function of the microbe? and “which parts of it can we inactivate to attenuate its infectious capability and how do we go about doing this?” Typically, this takes a minimum of around 2 years, but as we have seen with the COVID-19 pandemic, can be tremendously sped up with a worldwide collaborative effort and open access to findings by different laboratories.


The exploratory stage is followed by the pre-clinical stage, wherein different formulations of the vaccine are tested in animal models, such as mice and monkeys. As mammals with similar immune systems, this allows for understanding the extent of the immune response and monitoring any adverse effects. With appropriate ethics, using animal models allows scientists to investigate safe dosage and methods of administration (intranasal, intramuscular etc.) but importantly, also allows for ‘challenge studies’. Challenge studies involve administering the vaccine to the animal model, and then administering the animals with the infection causing pathogen. This is essential in verifying whether the vaccine and its associated immune response are efficient at clearing the actual infection.


Next, cue three phases of randomised and placebo-controlled clinical trials. Phase one is initially performed on a small group of healthy volunteers to assess the extent of immune response the top contending vaccines elicit. Phase two involves testing the candidate vaccine on a larger group of people representing different demographics of the population, including age and sex.


After determining the best dosing schedule and mode of delivery, the vaccine is administered to a much larger group of the population. Unlike with animal models, human studies cannot include the challenge element, and thus test subjects are studied over a long period of time to record infection rates, compared with the placebo groups, along with any other random test-subjects. Successful clinical trials lead to the process of licensing and are subjected to rigorous safety standards before being approved from governing drug agencies, such as the FDA. Typically, an ongoing phase four exists throughout its life where the manufacturer continues to monitor the efficacy and long-term safety of the vaccine.


Parting thoughts


Along with the advances made in science, our ability to create, rigorously test and scale up the production of vaccines has grown tremendously since that first inoculation by Jenner in 1796. The current COVID-19 pandemic has shone the spotlight on the importance of vaccines in making our modern lives possible and the sense of urgency is palpable. In light of these factors, it would behoove mankind to continue our relentless development of vaccines through research funding and public education. If the ongoing pandemic is any indication, the survival of our species may depend on them.

Co-Authors:



















Disclaimer: This article is based on our personal opinion and does not reflect or represent the views of any organisation that we might be associated with.