Vaccination and Edward Jenner

                      Vaccination and Edward Jenner.

                        P.K.Ghatak, MD.

In 1980, the World Health Organization (WHO) declared Smallpox was eliminated from this earth forever. The world stop to thank Edward Jenner for his gift, the Vaccine, to humanity.

It may seem strange but true that Dr, Edward Jenner was not the first person to notice having cowpox provided lifelong immunity to smallpox; nor he was the first to produce a vaccine against smallpox. That honor goes to ancient India, China and Africa.

People, from the beginning of human civilization, learned from experience that surviving a smallpox ordeal, protected them from the future smallpox.

In India:

They searched and found a way to introduce smallpox under a control condition. They called the process Tika and the court appointed people who administered Tika were called Tikadars. Furthermore, they collected pus from smallpox pustules of a patient and applied a drop of the material on the skin of the arm of an uninfected individual and made superficial cuts with a sharp scalpel of the skin going through the pus. The process was not fully safe, some developed full-blown smallpox and died, however, the vast majority of vaccinated people were protected. The vaccination was only available for the royal family and high officials. Vaccination reached China through Tibet.

In China:

Chinese collected scabs from smallpox patients, dried and pulverized the scabs to a power. They introduce this power in the right nostril of males by a sliver blowpipe and in the left nostril of the females. The westerns called this a Variolation. China claimed variolation was an original Chinese invention.

In Istanbul, Turkey:

In 1718, Lady Mary W. Montague, the wife of British ambassador in the court of Ottoman sultan in Istanbul, observed and was impressed with Variolation. She asked the Dr. Charles Maitland, the embassy surgeon, to variolate her 5 year old son. This was effective. She wrote to her friends in England about variolation in order to protect people from smallpox.

In England:

Lady Montague returned to England and in 1721 she asked Dr. Maitland to variolation her 4 year daughter in presence of royal physicians. This was also successful. Maitland was granted a license to practice variolation in England. In 1722, he successfully inoculated two daughters of Price of Wales. The process gradually spread all over the Europe.

In a village in England:

In 1774, a farmer named Jesty, in Yetminster, knew from his own experience the protective property of cowpox. He deliberately infected his family with cowpox. Using the material from lesions on cow's udder and making scratches on the skin with a stocking needle and rubbing the material on the skin lesion. All of them survived the epidemic that was raging through the country.

An epithet is erected to memorialize the event, as shown below. [taken from BBC publication].

In another village:

In the 1760s, a country doctor, Dr. John Fewster practiced vaccination in the village named Thronbury, Gloucestershire, England. His method of vaccination was almost similar to the one described earlier.

The virus:

The smallpox virus is known as Vaccinia. It belongs to Orthopoxvirus. Orthopox viruses are zoonotic (virus can infect human from animal). There are 12 important orthopox viruses. Some of these viruses are specie specific for one kind of animal but most are infectious to wide varieties of mammals and birds.

Chickenpox virus, appears close to smallpox virus but in fact it is a completely different virus called Herpes varicella zoster virus.

Cowpox virus is known by CPXV.

Monkeypox virus is called Mpox virus.

Camel pox virus is called CMLV

Mice pox virus is called Ectomelia virus (ECTV).

Vaccinia virus is large, shaped like a brick, contains 170 to 230 genes. It is a double-stranded DNA virus. The centrally located gens are involves in replication within the cytoplasm of the cells, in contrast with most viruses which duplicate inside the nucleus. The peripherally located genes manipulate victim's immune system and promote cell deaths.

Smallpox is called Variola in medical science. This term came from Switzerland in 570 AD, from a Latin word Varius or Varus meaning mark on the skin.

Chicken pox is called Varicella.

Dr. Edward Jenner:

Edward was born in 1749. Edward Jenner was Stephen Jenner's son, a priest in Berkeley, Gloucestershire, England. After completing his studies, at the age of 13 he went to work to a country surgeon. In there, he heard the story of dairymaids who had cowpox did not contact smallpox and they had unblemished face as a proof. At age 21, he was an apprentice under the famous surgeon John Hunter and learned systemic study of diseases. Thereafter, he returned to his own village and began a general practice. He studied the mystery of cowpox in preventing smallpox. He understood the basic concept of immunity and collected cowpox material and began inoculating people. Variolation and inoculation were often used interchangeably. [inoculare a Latin word meaning graft, inoculation term was derived from it]

He experimented on a 8 year old boy with pus obtained from lesions on had of a dairymaid. Two months later, in July 1796, he inoculated the boy again with pus obtained from a smallpox patient. The boy did not develop any illness. He wrote this case report and added his concept of immunity, and sent the paper to the Royal Society for publication. But the paper refused to publish it. He resubmitted the paper with additional cases. In 1797, the paper was published. He named his procedure as Vaccination.[vacca = cow, vaccinia = cowpox.]

He began publishing and teaching doctors about vaccination, even to a point of ruining his own practice. In 1802, the British parliament granted him 10,000 pound and again 20,000 pounds to compensate his time and materials. Jenner supplied anyone who requested vaccine and often sent his assistants to teach the procedure. Jenner sent his vaccine to Benjamin Waterhouse of Harvard University. Dr. Waterhouse gave some of it to Thomas Jefferson. Due to Jefferson's efforts, The Institute of National Vaccine Program was set up in the USA.

In 1840 by the act of the British parliament, the following law was adapted:

     I. Vaccination was official policy, and variolation was banned for smallpox inoculation.

2. Government provided vaccine, made from cowpox, free of charge to all.

In the subsequent years, the vaccination against smallpox reached in most European countries and in the new world. And the WHO took the vaccine to every corner of the earth.

Jenner was the first person to use a scientific method to control an infectious disease by the use of a live agent. In the late 19^th century it became evident, immunity decline over the years and revaccination was necessary. Jenner suffered a stroke and died several months later in 1823 and was berried in a Berkeley church.

The WHO and Vaccinia Vaccine:

In 1959, the World Health Organization took up the challenge of eliminating smallpox. Soviet Union supplied the heat stable, freeze-dried Vaccinia vaccine. On 8 May 1980, almost 100 years after Jenner began vaccination in England, the WHO announced that the world was free of smallpox and recommended all counties cease vaccination.

No one knows:

Smallpox virus genome structure is deciphered and is utilized to trace interspecies migration of orthopoxvirus and mutations of virus. It is a valuable tool for studying the source of an outbreak and how to start manufacturing vaccines. In 1939 scientists looked for the origin of virus used for vaccination. To their surprised, they discovered that none of the 6 varieties of vaccine used in the worldwide vaccination program contained cowpox or horse-pox virus. In fact, they have not to come up with an answer when and how the switch of virus took place. However, the present vaccine found to be effective against Mpox. However, new vaccine are on the way.

Plague

 

                                        Plague.

                                     P.K.Ghatak, M.D.

Plague is an infectious disease of the rodents and small wild mammals. It is caused by a bacterium, Yersinia pestis. Rats are the natural victims and also hosts of Yersinia pestis. Y. pestis spreads among the animals from the bites of the infected fleas known as Xenopsylla cheopis. Humans are accidental victims. Beside from the bites of infected rat fleas, humans can also get infection while handling dead infected animal having open skin lesions, eating dead animal and occasionally from a patient by inhaling aerosolized bacteria.

The bacteria:

Yersinia pestis belongs to the family of Enterobacteria.

Yersinia pestis evolved from Y. pseudotuberculosis. Over the thousands of years Y. pestis has acquired three important Plasmids, which made Y. pestis more aggressive, invasive, successfully counteract host immune defense and weaken the endothelial adhesion between the cells and produce extensive subcutaneous hemorrhage.

Y. pestis is a coccobacillus, measuring 0.5 to 1.0 micro meter by 3 micro meter. It has a rigid cell wall composed of peptoglycan which protects them and it has another outer wall made with liposaccharide which secrets a biofilm enhancing Y. pestis to adhere to the cells of the victims. When stained with Giemsa stain it resembles a safety pin due to presence of metachromatic granules at both ends. Y. pestis is non motile. It grows in most culture media and prefers 28 degree C but can also remains active in 40 degree C. It thrives equally well in high and low oxygen environments.

The Flea.

Out of two thousands of fleas, only about 100 species of fleas are known to carry Yarsinia and then, only three species are related to plague outbreaks. The most universal is Xenopsylla cheopis; the second one is X.brasilences, common in Africa, South Americas and India; and the last one is X.astia seen in South East Asia. In endemics Pulex irritants, a human flea and Ctenocephalides canis and felis, cat and dog fleas also act as vectors.

The fleas are ectoparsites. The insect is small in size, grows to a maximal size of 6 mm. It is flat from side to side, has 3 body parts but only the larger abdomen is visible without magnification. There are two appendages in the mouth with saw like serrated edges, used in cutting the skin of victims for blood. It can jumps up to 2 feet with its long hind legs. Flea also finds house cats and dogs as good hosts and from the pets the fleas also can also infest humans.

Both male and female flea must have twice a day blood meal for survival and female must have blood meal before laying eggs in the rat holes. At each bite it takes 0.1 to 0.2 2microM of blood of the victim. The fleas do not search for their prays, they wait till a victim arrives which they detected by sensing temperature and humidity variations. Then it jumps and land on the victim. From this point on the lives fleas take differnt paths:

If the rat is not infected with Yersinia, then the fleas keep on living on that rat for 100 days. Only the female flea drops to ground to lay eggs and then waits for her next victim. If the rat has plague bacillus, the bacillus starts to grow in rats gut and the growing colony produce a biofilm in the gut. At the esophagus and midgut junction, the lumen is narrow due to a sphincter; the biofilm produces a complete block and intestinal obstruction. The fleas feel starved and change hosts and bites repeatedly but fail to swallow, instead regurgitate its gut content and the thereby spread the infection among the rats, small mammals and humans.

Life cycle of the flea.

The flea undergoes 4 stages to complete a life cycle : egg, larva, pupa and imago or adult. Each gravid flea lays 30 eggs in the dart of the rat hole, every day for 50 to 100 days. In a week the eggs hatch. The larva eats rat feces and yet- to - hatch other eggs and organic compounds; and molts twice in 10 days. After that it develops into a cocoon in which a pupa grows and 14 days later an imago or adult flea is born. The young flea must have a blood meal before it can sexually mature.

The rat.

The common household black rat the Rattus ratus, and the brown swear rat the Rattus novegious act both as the reservoir and victims of plague bacillus.

When an infected flea bites the rat , if the innoculum is small, the rat becomes sick but recovers and then develops a king of immune -understanding with Yarsinia pestis. The bacterium multiplies in rat and rat survives. This create a permanent  rat reservoir of the plague bacillus. If on the other hand, the rat gets a heavy dose of Yarsinia it dies.

The humans.

The incubation period of plague is 2 to 8 days. At the site of flea bite an eschar develops. But it may not be noticed. A papule, nodule, vesicle pustule may be visible in some patients. The initial symptoms are chills, high fever, headaches and prostration. The course of illness may take one of the three forms – Bubonic plague, Septicemic plague or Pneumonic plague.

Bubonic plague:

In 24 hours after a flea bite and beginning of fever, many marble sized axillary or inguinal lymphnodes develop. These enlarged nodes are painful and warm to touch. After the initial regional lymphnodes enlargement, usually in the groin, the nodes in axilla and cervical areas also enlarge. The nodes become matted together. The enlargement of liver and spleen are common. Blochy subcutaneous hemorrhage develop at various places and the fingers and toes turn black due to development of gangrene. This gives the patients a black appearance and so the bubonic plague was also called Black Death. Without the use of antibiotics, the death rate in bubonic plague is 30 %.

In some unfortunate patients the initial immune reaction fails to limit the infection at the local site and the bacteria enters the blood vessels. The bacteria now become widespread and the septicemia develops. The usual symptoms and signs of septicemia develop, among them -  hypotension, circulatory collapse, hypoxemia and cerebral symptoms dominate and also determine the course of the illness. In the days with no antibiotics the death rate was 100%.

Septicemic plague:

Septicemia may develop as indicated above, following a bubonic plague onset, but septicemic plague may also develop without the bubonic stage.

Pneumonic plague:

The Yersinia pestis can be air borne with the droplets when a patient coughs. The bacteria inter the victim's body through the nose and throat. The symptoms are high fever, sore throat and cervical adenopathy. This is followed by cough, chest pain, shortness of breath, hypoxemia and hemoptysis. Within a day or two septicemia develops. Mortality is parallel with septicemic plague.

Diagnosis of plague:

The CBC and other tests reveals an aggressive acute infection. A sample of fluid obtained from the base of a bubo, detects pestis on stained smears. In septicemia blood cultures are performed and in pneumonic plague tracheal aspirates are cultured. In endemic areas of the world , the immunoflurosence assay of the capsular F1 antigen of Y. pestis is available and utilized. In more affluence countries Y. pestis antigen by PSA is performed. In the USA Plague must be reported to the local health authorities and CDC and cultures are send to CDC for confirmation.

Treatment:

Gentamycin is generally prescribed, in some countries Streptomycin is still in use. In addition Qunolines and tetracyclines are also effective. In meningoencephalitis chloramphenicol is recommended.

The Scientists:

In 1894 two bacteriologists, Alexander Yersin, a Frenchman and an associate of Koch, a Japanese national, Ketasoto Shibasaburo, working independently, during an outbreak of bubonic plague in Honk Kong, identified a bacteria in the fluid taken from a bubo. Yersin confirmed the organism as plague bacillus by injection the fluid in an animal and subsequently recovering the same organism from its tissues after sacrificing it. He named the bacillus Pasteurella pestis. In 1970 the bacterium was renamed Yersinia pestis.

Another pair of French and Japanese, working independently identified the rat as the reservoir and fleas as vector. In 1897 Dr. Orgata Masanori found rat fleas carried the plague bacillus in Formosa now called Taiwan. In 1898 a French investigator, Paul-Louis Simond from Pasteur institute , working in India demonstrated rat to rat transmission of plague by the bites for infected fleas.

The Nobel Prize:

None of the above scientists was awarded Nobel prize in medicine, but in 1957, a French novelist Albert Camus was awarded Nobel prize in literature for his novel The Stranger and The Plague( 1947).

The Pandemics of Plague:

The earliest recorded history of black death is present in ancient Buddhist text describing in the time of Buddha. An outbreak of plague in Vasali in India, now in Bihar province, India was documented and also noted its subsequent spread to Sri Lanka.

Scientists believe a mild variety of plague within rat colonies in Central Asia was always present. No one is sure when and how it became virulent and jumped to humans. In early days the disease was called pestilence. The priests blamed people for living a sinful like for pestilence and God panished then with pestilence; and recommended penance, self flagellation, prayers and puja in order to please God. No solution came from above but  a temporary relief was obtained from inhalation of fragrant herbs and flowers.

However even at that time, the spread of plague along the silk route was well known.

The First Pandemic:

The first pandemic occurred in Rome in the time of Roman emperor Justinian during the years 541 to 544. The disease originated in Abyssinia, Africa ( now Ethiopia and Eritrea). It spread westwards to Alexandria and to the east to Jerusalem and to Constantinople (Istanbul). In Constantinople alone 10,000 people died every day. Eventually, the plague reached Denmark, Ireland, Middle East and Asia Minor. In 542 estimated total deaths in Europe, Asia and Africa was 100, 000. Type of plague was bubonic.

Plague continued to smolder with local endemics for another 200 years.

The Second Pandemic of 1342 to 1352. It is better know as The Black Deaths.

The black death originated in Asia minor. The disease was carried to Kaffa (Fedosya in Ukraine) by the Tatar army of Khan Janibeg. It then spread to the port city of Crimea. By ship with rats and sick people the plague reached Genoa and then to all port cities of the Mediterranean. England and Norway were next victims. The Tartars could not win the war and returned home and they carried plague with them to Russia and to India. A quarter of population of India perished from Bubonic plague, 10 to 20 % of people died in Europe.

A second wave of bubonic plague occurred in 1361 in England and took another 10% of population with it.

The Quarantine. The 40 days of isolation.

The officials in Venice prohibited ship from unloading goods and did not allow people to leave the ships, initially for a period of 30 days, in order to control the spread of plague (the Trentna).

 However, not achieving the desired results, they extended the prohibition to 40 days. Soon quarantine became a tool for containment of any infectious disease. Different States in Europe, restricted movements of people from traveling east to west and it became known as Cordon Senilarie.

The Great Plague of London of 1665 to 1666.

A major outbreak of Pneumonic plague occurred in London, England in 1665. 7,000 people died daily. The severity of the illness is aptly expressed in a nursery rhyme :

Ring, a-ring o'rosies

A pocketful of posies

Atishoo, atishoo

We all fell down.

In a simple from:

A red blistery rash

Fragrant herbs and flowers

Sneezing and coughing

All are dead.

The Third Pandemic of 1894.

In 1855 Yunnan, China, a local outbreak of plague took place. It spread near and far along the opium smuggling routes. In 1984 Canton and then Honk Honk saw increasing number of bubonic plague victims. The plague arrived to Bombay, India ( Mumbai) via cargo ships. It produced panic in Bombay and people scattered out of the city, plague went along with them wherever they went. This plague killed a third of Indian population of that time.

In 1900 plague reached Australia and local outbreaks continued till 1925.

The 3^rd pandemic ended in 1959. Total death estimated to be 15 million.

It is not over:

In 1990 island of Madagascar saw multi-drug resistant Plague. The island is a potent source of new plague.

The Final Word:

From the early beginning, the humanity faced uncertain future on the earth. Infection took a major toll on sick children and elderly; the childbirth was a horror story. No one recorded untimely demise of so many young mothers leaving behind theirs families. The progress of the medical science, public health and vaccination were able to eliminate Small Pox and put Cholera out from most countries and cornered Plague with very effective antibiotics and public health measures.

However, like Heisenberg's uncertain principle, the present generation are both here and there in their belief in the public health and particularly in vaccination.

 A multi-drug resistant laboratory engineered airborne plague bacillus delivered and exploded over densely populated cities by a terrorist group, might take us back to the days of Penance, Payer and Puja.

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