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06 August 2020

Vaccination Special: from Smallpox to COVID-19

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Vaccines are one of the scientific breakthroughs that can boast having saved the most lives throughout history. Some 530 million lives have been saved from smallpox since 1796, when English physician, Edward Jenner, began experimenting with a smallpox vaccine. According to data from the World Health Organization (WHO), today there are vaccinations available for a total of 26 diseases while its Product Development for Vaccines Advisory Committee (PDVAC) is overseeing another 24 that are still under development. Concurrently, there are 219 virus species known to be able to infect humans. The science of vaccine development — vaccinology — thus has considerable scope for ongoing developments and a lot of challenges ahead, beginning with the COVID-19 pandemic, which was unleashed by the SARS-CoV-2 virus.

Smallpox, the first disease to be globally conquered, was declared officially eradicated in 1980. Forty years after this scientific accomplishment, the world is facing a global pandemic of COVID-19, an illness unleashed by the  SARS-CoV-2 virus, a novel coronavirus that is revolutionizing the scientific process of vaccine creation: with a greater commitment than ever before and moving forward in record time. Against the backdrop of a global race for a COVID-19 cure, we take a look at the history of vaccines and the most promising mechanisms for developing new vaccination technologies.

The first vaccine: an experiment with the gardener’s son

When Edward Jenner was a young man, it was already known that smallpox strikes a person only once in a lifetime and variolation, a method of inoculation originating in China and the Middle East, was already practiced. When introduced in Europe, it was rather hit-or-miss, but its use was advocated for children to prevent the disease later in life when it could be much more serious. Jenner would be sent to jail for his experiment today, but the process he devised to finetune variolation certainly worked. Jenner had observed that ranchers and dairy farmers contracted a more benign version of the disease, cowpox, which also made them immune to the human version of the illness. 

The first patient in his extensive study was a child: James Phipps, the gardener’s son. Given the landscape of research and trials at the time, it is not surprising that that the smallpox vaccine met with some reluctance. In fact, 44 years passed after Jenner’s experiments before the U.K. government formalized the vaccination.  Paradoxically, the smallpox vaccine was discovered and and was effective before viruses (the agents that caused the smallpox infection) were scientifically understood. Virology was only established as a field of study in the late nineteenth century.

COVID-19 and a race against time

While the SARS-CoV-2 virus continues to spread around the world, scientists and medical researchers are trying to take advantage of a powerful strategy: sharing knowledge, innovation, and tools on a global scale. COVID-19 has changed science, facilitating more than 1,700 clinical trials in record time. These trials are competing to discover the definitive treatment for this disease, while hundreds of others are seeking the definitive vaccination for the first pandemic of the 21st century. 

The context of vaccine research, testing, development, and validation (and any medical treatment), has changed for the better since Jenner’s time. It is precisely the strict rigor behind the clinical trial process that seems to contribute to the prolonged vaccine production time frames. Nonetheless, in February, the WHO announced that a vaccination could be ready within 18 months, a veritable scientific accomplishment given that the average time to develop and make a vaccine publicly available until now has been 16 years.

Edward Jenner vaccinating his young son. A cow can be seen in the background. It is estimated that smallpox caused 500 million deaths in the 20th century alone. Source: Wikimedia

The operating approach to traditional vaccines is based on Jenner’s reasoning: inoculate an inactive pathogen, tempering or neutralizing the toxins in order to “wake the immune system up” thereby creating antibodies without having to contract the disease in its much more dangerous state. This process is fairly standardized, and many vaccinations that we receive today follow this logic, although it is very laborious: each pathogen requires customized research and development. Vaccinations for some infections, like HIV, have still not been discovered. 

Using recombinant microorganisms to “hack into” viruses

Thanks to the power of new technology, today vaccines seek to prevent the risks associated with directly inoculating a pathogen in the human body and at the same time optimizing the production and development processes that create more versatile tools that require less tweaking when a new pathogen emerges. Recombinant vectors are the key to this change. 

A vector is a microorganism that is used as a vehicle: it transports a part of the genetic material of the virus against which we want to defend ourselves. Vectors can come from viruses, bacteria, or even bacterial DNA molecules that are individually developed in a lab and are filled with pathogen-specific antigens. Compared to traditional vaccination approaches, recombinant technology produces inoculation using only the part of the virus that protects us, thereby avoiding the risk of developing the full-blown disease.

The use of an experimental recombinant vaccine was critical in ending an outbreak of ebola in the Democratic Republic of Congo, and the only vaccine that has proven at all effective against HIV is also a recombinant virus. / Image: Unsplash

The first human vaccine developed according to this method was for hepatitis B, made publicly available in 1986. It proved to be as effective as the traditional version: more than 95 percent of the healthy people vaccinated are properly immunized. The vaccines against human papillomavirus (HPV) and shingles also use this approach. This is also the approach being taken for one of the SARS-CoV-2 vaccines — the vaccination under development by China’s CanSino Biologics and the Beijing Institute of Biotechnology —, which is already being tested on humans. The potential of these methods lies in the fact that the vector itself can contain antigens for different pathogens, meaning: they could provide protection against various diseases at the same time. 

RNA: The promise of future vaccinology

Another technology with enormous vaccination potential involves the use of messenger RNA (mRNA) to instruct cells to produce “their own vaccine.” Messenger RNA could be the key to universal vaccinology because it is the molecule that cells use to translate genes into proteins. These vaccines combine the advantages of live-attenuated (traditional) vaccines with the security of recombinant vaccines: they cannot produce the inoculated infection. In general, these RNA vaccinations are in a pre-clinical state for the treatment of diseases like cancer or infections like HIV or rabies.  They are of particular interest due to their potential to be tailored: in those diseases where molecular characteristics vary greatly from patient to patient or over time.

This is precisely the approach being taken by Moderna Therapeutics and the U.S. National Institute of Allergy and Infectious Diseases (NIAID), whose  mRNA-1273 candidate vaccination is based on the mRNA S protein. On March 16, they began inoculating the first group of 45 volunteers, making this the first western vaccine to move onto clinical trials. If it works, various factors would make it historic: not least of which, its record development time and the huge scientific leap that it would represent by paving the way towards the use of RNA-powered ‘intelligent’ vaccines.


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