FROM VARIOLATION TO VACCINATION

The world anxiously awaits the discovery of a vaccine against the novel corona virus which is the only foreseeable hope of restoring the old order and thereby our dreams of a future which has been so brutally and abruptly interrupted by this pandemic.

Vaccines are an integral part of medicine today. Each vaccine contains a small amount of the disease germ or germ particle along with ingredients that provide stability, prevent contamination of multi- dose vials by bacteria or fungi and sometimes substances to boost the immune response. Vaccines are essentially prophylactic in that they prevent or ameliorate the effects of a future infection but can be therapeutic as well, to fight a disease that has already occurred, such as cancer. Upon receiving a vaccine the immune system in the body recognizes that specific disease causing germ in the vaccine as being foreign, responds by making antibodies to that germ for the future for a finite length of time, and remembers the germ so that the immune system is able to rapidly destroy it before sickness sets in.

Naturally acquired immunity that comes from the disease itself can be at the cost of serious and at times lethal complications. Vaccines imitate that infection in a less severe form and cause the immune system to produce T- lymphocytes and antibodies. As the minor side effects such as fever, malaise, aches go away the body is left with “memory” T- lymphocytes and B- lymphocytes that will remember how to fight the disease in the future. This process takes a few weeks and one may develop the disease before protection has occurred.

There are five main types of vaccine:

1. Live attenuated such as measles mumps rubella and chickenpox /TB vaccine.
2. Inactivated vaccines such as polio vaccine.
3. Toxoid vaccine to prevent diseases caused by bacteria producing toxins such as diphtheria and tetanus.
4. Subunit vaccine that includes only the essential antigenic part of the germ such as the pertussis component.
5. Conjugate vaccines to fight bacteria that have an outer coating of polysaccharides such as those against meningitis.

Vaccines may need multiple doses or a booster dose after so many years. Some viruses like the flu virus change every season so an annual dose is required. Severe allergy to any component of vaccine is a contraindication. Pregnancy and immunosuppression are contraindications to live vaccines. There are certain precautions for each individual vaccine as well, which must be taken into consideration prior to administration. The bogey of autism secondary to childhood vaccines or their preservatives has been raised in the past, but multiple studies have shown no link and original work that raised this concern was found to be flawed.

The evolution of vaccination is fascinating. There was a concept of immunity as early as 430 B.C when the Greek historian Thucydides noted in his account of the plague that killed a third of the population of Athens, that those who recovered were resistant to future attacks of the same disease. The history of vaccination is intricately connected to smallpox epidemics. The first efforts to vaccinate were in fact variolation which was the practice of using secretions from the pustules of someone with smallpox or variola to infect a healthy individual and create a mild form of the disease. The origin of inoculation is possibly from India where itinerant Brahmins inoculated by dipping a sharp iron needle into a smallpox pustule then puncturing the skin repeatedly in a small circle or perhaps in China where variolation was practiced by nasal insufflation of powdered smallpox scabs. In Africa mothers would tie a cloth around a child’s smallpox covered arm and then transfer the cloth to a healthy child.

In the 18^th and 19^th centuries the practice made its way to England thanks to Lady Montagu the wife of the British ambassador to Turkey who had observed variolation. New England and other American colonies saw smallpox arrive with cargo ships to Boston with devastating effects. Cotton Mather, an influential minister in Boston was told of the practice of variolation by his slave Onesimus who had experienced variolation in Africa and he took the bold step of introducing this concept despite much resistance.

Variolation did not prevent the disease, it just made it milder, and in some cases, people still developed severe symptoms and died. In late 1700, Edward Jenner noted that milkmaids got cow pox on their hands, but not smallpox. He took fluid from the cowpox and scratched it into his gardener’s son’s arm, a practice now called vaccination from vacca or cow. Two months later he inoculated the boy again, now with smallpox matter and no disease developed and the vaccine was a success. Louis Pasteur’s 1885 rabies vaccine came next followed by development of antitoxins and vaccines against diphtheria, tetanus, anthrax, cholera, plague typhoid, tuberculosis, yellow fever, herpes simplex. Middle of 20^th century was an active time for the development of vaccines.  Noteworthy is the development of the injectable killed virus Salk polio vaccine and the live attenuated oral Sabin polio vaccine amidst the intense rivalry between the two teams. Recombinant DNA technology and new delivery techniques addressed noninfectious conditions such as addiction and allergies. Among the fastest vaccines ever produced was the current mumps vaccine isolated by a scientist Dr. Hilleman who was working for Merck, obtained from the throat washings of his daughter JerylLynn in 1963 with the eponymous vaccine being licensed in 1967. In recent years, the Ebola vaccine though long in development was granted Breakthrough Therapy designation and FDA worked closely with the company and completed its evaluation for safety and effectiveness in six months.

Researchers around the world are developing more than 165 vaccines, and 28 vaccines are in human trial for the novel corona virus. Work began in January 2020 with deciphering the Sars-Co V-2 genome. Phase 1- about 18 vaccines testing safety and dosage, Phase II -12 vaccines in expanded safety trials, Phase III – 6 vaccines in large scale efficacy tests and 1 vaccine has been approved for limited use. Vaccines typically take years of research and testing before reaching the clinics, but scientists all over the world are racing to provide a safe and effective vaccine by next year. Many governments including the US have bank rolled these efforts. Moderna along with NIH have launched a Phase III trial on July 27^th, 2020 on a Messenger RNA based vaccine. The final trial will enroll 30,000 healthy people at about 89 sites around US- Moderna has $1 billion in support from the US government. Operation Warp Speed is supporting a portfolio of similar vaccines so that they can meet FDA’s gold standards and reach the public without delay. University of Oxford and Jenner institute is also a front runner with U.K investing $6.5 million along with layers of private and international investors; India’s Bharat Biotech and Zydus Cadila have started Phase 1 and 2 clinical trials.  Germany, Russia and China are heavily funding their own trials. Serum Institute of India, Pune, under the chairmanship of Dr. Cyrus S. Poonawala is poised to be a big player in the manufacturing and distribution of the vaccine. It will also be a part of Phase 3 Novavax trials in India. One out of every two children in the world is vaccinated by a vaccine from the Serum Institute.

The successful companies will be runaway winners from both humanitarian and financial standpoints. Many ethical challenges regarding cost, prioritization of delivery, transparency of risk- benefit data remain. One thing is clear, there will be no resolution of the Covid-19 Crisis without the utmost harmonious and strategic cooperation of all global participants.

Udita Jahagirdar M.D., F.A. C. O. G.