Vaccines: an immunological revolution

Vaccines: an immunological revolution

by Juliana Ariffin

Did you know that if you went back in time, most of you would be immune to some of the most devastating diseases that have ravaged humankind in the past? We owe this invisible armour that we possess to the hard work and sacrifice of our predecessors who discovered… you guessed it. Vaccines!

The world’s first vaccine vanquishes smallpox, the killer of kings

Approximately 3,000 years ago in ancient Egypt, there lived a young pharaoh by the name of Ramses V. Not much is known about his reign, except that  almost 4 years after he was anointed as the ‘living god’ of Egypt, Ramses V probably felt unusually lethargic and feverish.

He might also have thrown up a few times, had a sore throat or a bad headache. Initially, these symptoms might have been attributed to a minor malady, such as the flu or stress. However, these symptoms were just a prelude. Within the next few days, a bumpy rash appeared all over his face and body, and sores developed in his mouth, throat and nose. These rashes then swelled further and leaked infectious pus.

Finally in 1157 B.C., approximately two weeks after he fell sick, Ramses V died, leaving only his scarred and mummified remains as his legacy. These would be discovered in 1910 A.D., and would become the earliest physical evidence of smallpox [2], one of the deadliest, and now extinct, diseases to have plagued humankind.

Of variolation and vaccines

Unfortunately for Ramses V, no reliable way to guard against smallpox existed during his time. In fact, since 10,000 B.C., humans have been vulnerable to smallpox epidemics that trailed the pattern of human migration, resulting in a marked impact on human history—smallpox is known to have been more influential in bringing down the Aztec and Incan empires than the invading Spanish Conquistadors [3]. By the end of the 18th century, smallpox had killed five European kings, and by the 20th century 300-500 million people worldwide had died from smallpox, a number far exceeding the combined fatalities from the two world wars [3].

The fight against smallpox, and thus the discovery of vaccines, began in 430 B.C. when the Athenian, Thucydides, observed that survivors of smallpox became immune to it. In 910 A.D., the Persian alchemist-physician-philosopher, Abu Bakr Muhammad Bin Zakariya Ar-Razi (Rhazes), also noted the immunity of survivors and person-to-person transmission of smallpox, leading him to propose the first theory of acquired immunity [3, 4].

Thucydides and Rhazes were not alone in their observations. By 600 A.D., physicians in China were grinding up dried smallpox scabs with musk to inoculate the noses of healthy people, while people in India wore shirts from infected patients and slept alongside smallpox victims [3, 5]. In Africa and the Middle East, scrapings from smallpox pustules from a mildly infected individual were applied onto a scratch or a vein of a healthy person. These methods of transmitting smallpox are called variolation, and were conducted with the hope that a minor infection with smallpox would occur, stimulating the immune response and conferring immunity against the disease [3, 5].

Variolation was practised for hundreds of years although it was not a foolproof method, due to variations in the amount of virus transmitted, and the fact that inoculated individuals could still transmit the disease. Still, it saved the lives of many, including Catherine the Great and her son [5], and was used by George Washington to safeguard the American army during the War of Independence against Great Britain [6].

In 1795, Edward Jenner observed that milkmaids who had contracted cowpox were immune to smallpox. He experimented using the pus from a cowpox pustule on a milkmaid, Sarah Nelmes, to inoculate scratches on the arm of an 8-year-old boy, James Phipps. Luckily for James, he developed cowpox, but like the milkmaids, was immune to smallpox. Jenner then developed the world’s first vaccine using cow serum containing the cowpox virus [7]. This method of preventing smallpox was strongly supported by the then U.S President, Thomas Jefferson, and Napoleon Bonaparte, who had his entire army vaccinated in 1805 and ordered all French civilians to be vaccinated a year later [8]. Over the next few centuries, immunity against smallpox became widespread, resulting in global eradication of the disease in 1980 [9].

How vaccines work

Since Edward Jenner’s discovery, vaccines have been developed for many other diseases including polio, chicken pox, hepatitis B, human papillomavirus (HPV) and influenza.

These vaccines work by introducing an agent (Infobox 1) from a disease-causing microorganism that is recognised by the immune system as a threat. This agent stimulates an immune reaction that persists for years in the form of ‘immunological memory’, enabling a quicker and more effective immune response upon future encounters with the microorganism. This system of speedy recognition and the launching of a specific defence is termed adaptive immunity, and is what enables the body to destroy invading microorganisms before they enter cells, or to destroy infected cells before the microorganism can multiply to huge numbers within the body. When developing a vaccine, the biggest concern is how best to induce an immune reaction while keeping the risk of developing the disease low.

Infobox 1: Types of vaccines and the diseases they protect against [18, 19]. Infographic by Kong Yink Heay.

Infobox 1: Types of vaccines and the diseases they protect against [18, 19]. Infographic by Kong Yink Heay.

While vaccination protects against a disease, it doesn’t always confer lasting protection. Just as normal memories fade, immunological memory can also decline, resulting in lost immunity years after the initial vaccination. This can be detected by measuring antibody levels against the vaccinated agent. In cases where immunity has declined, administration of a ‘booster’ shot, or an extra administration of a vaccine following the earlier dose, helps to regain immunity. Example of vaccines that normally require follow-up booster shots include the oral polio vaccine (OPV) which persists for only 6 months and tetanus, which requires a booster shot every 10 years.

Herd immunity and pox parties

Children are usually vaccinated as soon as their immune system is sufficiently developed, and many countries have a schedule of recommended vaccinations. However, the large number of injections for vaccinations and booster shots, as well as the fear of side effects often leads to problems in compliance with the schedule.

One of the biggest hindrances for vaccination was the fraudulent claim by Andrew Wakefield, a former British surgeon and medical researcher who published a paper that described a link between the measles, mumps and rubella (MMR) vaccine, and the occurrence of autism and bowel disease [10]. Although his research was not reproducible, was shown to be financially motivated and was also revealed to be conducted without ethical approval [10], mass media disseminated his findings reporting a link between vaccination and autism. As a result, many parents have chosen to ‘protect’ their children from autism by not allowing them to be vaccinated.

Instead, some parents have resorted to holding pox parties where healthy children are exposed to a child infected with a disease such as chickenpox, measles, or rubella. Similarly to variolation, this hopefully allows for an infection and acquisition of natural immunity. If the majority of the public were vaccinated, and if vaccinations conferred lasting protection, this would not be such a major concern for everyone. Indeed, the biggest threat would be unvaccinated children succumbing to severe disease and being at risk of fatality or deformity.

However, as mentioned above, vaccinations do not confer lasting protection. I Also, individuals who are too young, too old, pregnant, or immunocompromised are unable to receive vaccinations. These individuals are at high risk of contracting disease if they come in contact with an infected individual.

Normally, the number of vaccinated individuals is high enough that it confers what is termed ‘herd immunity’ (Fig. 1) to a population, where the incidence of contracting the disease is so low that even unvaccinated individuals will be protected. However, if the number of unvaccinated individuals increases, such as an increase in immunocompromised individuals or when children are intentionally not vaccinated (even if they do not attend pox parties), herd immunity is no longer effective and the population becomes at risk of a disease epidemic [11].

Figure 1: Herd Immunity (image credit to Bioninja [20]).

Figure 1: Herd Immunity (image credit to Bioninja [20]).

What’s next for vaccines, and is vaccination all we need?

The importance and impact of vaccines is clear if one looks through our history and compares the widespread epidemics of the past with the current number of cases for diseases where an effective vaccine is available and in use.

However, this does not mean that we can rest on our laurels and stop vaccinating, even for diseases that are seemingly rare. For example in 1974, 80% of Japanese children were vaccinated with pertussis (whooping cough) vaccine, and no deaths were recorded among the 393 cases of whooping cough that occurred that year. In contrast, when the vaccination rate dropped to 10% in 1979, 13,000 cases of whooping cough were recorded and 41 people died [12].

In fact, the only disease that has been globally eradicated is smallpox, although it still exists within a few carefully protected laboratories. As such, smallpox would still be devastating if it is ever released, as few people are vaccinated against smallpox now [12, 13].

Even with the reduced death toll from transmissible diseases, the benefit and potential of vaccines is yet to be fully unearthed. For instance, vaccination may help to combat the increased incidence of antibiotic resistant bacteria. An example of this is Streptococcus pneumoniae, which is estimated to kill more than 800,000 children under five years of age annually, even though a vaccine against it already exists. If children were vaccinated, the number of infections and therefore the use of antibiotics would drop, reducing the likelihood of antibiotic resistant strains evolving [14].

Vaccines have also been implicated to be effective against a larger range of diseases through non-specific effects. For instance, the measles vaccine has been shown to also protect against pneumonia, sepsis and diarrhoea, and children vaccinated against tuberculosis (TB) have a lower death rate from diseases other than TB. Ongoing research suggests that these vaccines may be altering our immune responses in ways that affect not only our immunity to infectious diseases, but also the occurrence of allergies and immune reactions to cancer, pointing to a great need for further study of these vaccines [15].

Recent research on new vaccines have begun to use innovative techniques, such as the splicing of HIV surface proteins with a modified cold virus to enable safe delivery and an immune response against HIV [16]. Vaccines are also being combined with host dendritic cells to activate an immune response to target a patient’s tumour cells [17]. Other vaccines that are on the horizon are vaccines against malaria, Zika virus and Ebola.

Only time will tell if these new vaccines against cancer and infectious diseases are effective. But as our success with smallpox has shown, we can only keep researching until we find a safe and effective vaccine for each of these diseases. Then, all that would be left to do would be to apply a stringent global vaccination regime, and to hope and guard against mutated microorganisms.

About the Author

JULIANA ARIFFIN is a postdoctoral fellow researching liver inflammation at Beth Israel Deaconess, Medical Center, Harvard Medical School. Prior to this, she studied human immune responses at The Institute for Molecular Biosciences, The University of Queensland. In her spare time she reads and writes fiction, dabbles in photography and considers genetically engineering a zombie propagating virus to repopulate the earth. Check out Juliana’s Scientific Malaysian profile at http://www.scientificmalaysian.com/members/julianna/

This article first appeared in the Scientific Malaysian Magazine Issue 12. Check out other articles in Issue 12 by downloading the PDF version for free here: Scientific Malaysian Magazine Issue 12 (PDF version)

References

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2) Erik Hornung. (1997). The Pharaoh, p.292 in The Egyptians (ed.) Sergio Donadoni and Robert Bianchi, University of Chicago Press.

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12) Centers for Disease Control and Prevention, Vaccines and Immunisations (http://www.cdc.gov/vaccines/vac-gen/whatifstop.htm).

13) Centers for Disease Control and Prevention, Emergency Preparedness and Response, Smallpox. (http://www.bt.cdc.gov/agent/smallpox/vaccination/faq.asp).

14) Penny Sarchet. (2016). Use vaccines as a weapon against antibiotic-resistant bacteria, Newscientist. (https://www.newscientist.com/article/2077157-use-vaccines-as-a-weapon-against-antibiotic-resistant-bacteria/)

15) Michael Brooks. (2016). Booster shots: the accidental advantages of vaccines, Newscientist. (https://www.newscientist.com/article/dn24027-booster-shots-the-accidental-advantages-of-vaccines/)

16) Lindsey et al., (2016). Assessment of the Safety and Immunogenicity of 2 Novel Vaccine Platforms for HIV-1 Prevention: A Randomised Trial, Annals of Internal Medicine. (http://annals.org/article.aspx?articleid=2484873)

17) Abhishek et al., (2016). Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma, Science Translational Medicine. (http://stm.sciencemag.org/content/8/328/328ra27)

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19) World Health Organisation, Vaccine Safety Basics, Types of Vaccine.  (http://vaccine-safety-training.org/types-of-vaccine.html)

20) Bioninja, Vaccination (http://ib.bioninja.com.au/higher-level/topic-11-animal-physiology/111-antibody-production-and/vaccination.html)