NOVEL VACCINE TECHNOLOGIES AND APPLICATIONS
1. A (SHORT) HISTORY OF VACCINATION
Vaccines are a ‘recent invention’ compared the thousands of years that humans have suffered from major epidemics.
- Well known “starting” vaccines
o Yellow fever vaccine => military or economics posed huge problems => needed a solution
Vaccination only started to be effectively used in the 20th century in a structured manner. Right now there are:
1. Several vaccines developed (and rules were implemented)
2. Routine vaccinations introduced
3. Large populations vaccinated
With the exception of safe water, no other intervention, not even antibiotics, has had such a major effect on mortality
reduction and population growth.
Before: not very structured, quite “artisanal”
1.1 EPIDEMICS & PANDEMICS
The Plague / black death with huge outbreaks around 1700 caused half the population of Europe to die. Also the Roman
Empire crumbled probably because of a plague outbreak. They already knew a lot about infectious diseases and took note of
mortality numbers etc., but there were very limited interventions possible.
Usually goes down → however this is mainly due to deaths not because of cured.
Around 1889 there was a big Russian Flu epidemic. Now it seems this pandemic was not the flu but
probably a coronavirus epidemic. (called it a Flu because back ten only flus were known to spread such
a disease) Should have diverged at the same time → same symptoms produced at that time: loss of
taste and smell, coughing, mucus, etc. (might have been a prequel to coronavirus epidemic)
Major plagues only started occurring since around 1350, because people started trading and traveling
a lot. Links between people and continents are ideal for pathogens to spread. When before 1350
zoonotic pathogens jumped to people, it usually remained in one city. Here all people possibly died
but it did not spread further.
Highest death toll = black death, bulbonic plague (50% of the population died) → major setback at that time
Vaccines are a ‘recent invention’: before vaccines...
Before vaccines, the practice of quarantine already started during the 14th century to protect coastal cities from plague
epidemics.
- Port authorities required ships arriving in Venice from infected ports to sit at anchor for 40 days before landing.
- The origin of the word quarantine is from the Italian “quaranta giorni”; or 40 days.
One of the first instances of relying on geography and statistical analysis was in mid-19th century London, during a cholera
outbreak.
- In 1854, Dr. John Snow came to the conclusion that cholera was spreading via tainted water and decided to display
neighbourhood mortality data directly on a map.
- This method revealed a cluster of cases around a specific water pump.
- Knew something was up with the water but weren’t aware that it was a bacterium.
1
,The origin of variolation Smallpox and variolation
Many people died of smallpox, but some recovered. These recovered individuals then remained healthy in subsequent
outbreaks: they had developed immunity. In the 12th century this was observed by the Chinese: recovered people are
resistant to infection in new outbreaks. (one of the only viruses that has been eradicated)
• Infants who survived the resulting disease were protected from smallpox in later life (lifelong immunity)
o Probably observed prior but not written down
• Using scabs from mild smallpox cases minimized mortality
o = inoculation/variolation: deliberate infection with smallpox by inserting scabs from infected individuals
into small cuts in their skin
o The way of inoculation had an effect => most promising method was found (inoculum loop)
▪ Localized infection → induced a strong local inflammation preventing the virus from spreading
rapidly
▪ Knowledge started spreading from China to western world
o Still a chance of death -> 1% compared with ± 20%
➔ The knowledge of variolation spread westward to Europe by the early 18th century
The precise origin of variolation remains unknown. It seems to have developed somewhere in Central Asia around the 12th
century. In the 16th century, Brahmin Hindus in India practiced a form of variolation by introducing dried pus from smallpox
pustules into the skin of a patient. The Golden Mirror of Medicine, a medical text dated 1742, listed four forms of inoculation
against smallpox practiced in China since 1695:
1. The nose plugged with powdered scabs laid on cotton wool
2. Powdered scabs blown into the nose
3. The undergarments of an infected child put on a healthy child for several days
4. A piece of cotton smeared with the contents of a vesicle and stuffed into the nose
Variolation was introduced into England by Lady Mary Wortley Montagu in 1721, after her return from Constantinople. While
living in Turkey, she frequently observed variolation and had her own son variolated. Dr. Charles Maitland, who performed
the procedure on her son, later performed the first variolation in England on Lady Montagu’s daughter. The treatment was
effective, but results were erratic and 2-3% of persons treated died of smallpox contracted from the variolation itself.
(brought the knowledge back to England → and also Europe)
Benjamin Jesty (1774)
Cattle breeder Benjamin Jesty was immune to smallpox after contracting cowpox from his herd. Like many country farmers
in the area, he knew dairymaids seemed to be protected from smallpox after having contracted cowpox. He deliberately
inoculated his wife and children with cowpox to avoid a smallpox epidemic. He took his wife and children to a nearby field
where he knew he could find cattle with cowpox and inoculated them. His experiment succeeded; they were unaffected by
the outbreak. → also other farmers succeeded in this.
- Similar symptoms as small pox
- Induces immunity that protects against the real human virus
- Edward jenner was made aware of this and used this as a physician
o Scratched the skin to make a barrier → put liquid on the skin
- Problem: cowpox was not widely spread, sometimes could be difficult to find a vaccine → needed to transport live
cattle → in living room (accessible for rich people)
- Poor people → arm-arm transmission – transmission of virus
- Used in the royal philanthropic vaccine mission
2
,Jesty’s actions constituted the first known real vaccine—the use of cowpox to protect against smallpox.
→ first know of attenuated deliberated inoculation
Take the vaccine around the world: Take orphans to south America; promised a better life. Upon arrival, children were
infected, went back to their home cities to further spread.
Rinderpest – cattle plague (1754)
- No cure, but inoculation tried: placing bits of material previously dipped in morbid discharge into
an incision in dewlap
o Worked, but not always and not without risk
o Disastrous results in NL -> interest in inoculation declined sharply across the country
- General principles of inoculation were accepted BUT nobody had an idea how it worked
- All the cattle died → causing huge problems for humans
- Didn’t work as well as smallpox
1.2 WHAT IS A VACCINE
A biological suspension of a live or inactivated pathogen or fractions/subunits thereof (i.e. purified protein subunits,
conjugated and non-conjugated polysaccharides, or split virions) which can be administered by various routes (IM, SC, ID, Oral,
Intranasal) to induce specific long-term immunity (immune memory) and prevent disease caused by a specific pathogen
against which it has been developed.
Goal: induce memory and protect against a disease
Edward Jenner: first large scale vaccinations with cowpox
While Jenner did use the term “vaccine,” he is not the originator of the term vaccination; that honor belongs to his friend
Richard Dunning, who used it in 1800
- Cowpox was not widespread, so sometimes difficult to find for use as a vaccine
o “vacca” = cow
- Jenner expanded his studies: proved cowpox could be passed from person to person
o -> “large-scale” inoculation against smallpox w/o outbreaks of natural cowpox
For the first several decades of the 19th century, arm-to-arm transfer was the primary method of human vaccination. BUT
other diseases, e.g. TB were occasionally transmitted along with the cowpox virus → a need for an alternative way to
vaccinate and to ensure a steady supply of cowpox vaccine.
Standardizing calf-derived vaccines (~1855)
Animal vaccination from one cow to another was done to keep a steady supply of cowpox lymph to vaccinate humans. In
1866, Lanoix and Chambon collected cowpox of 2 outbreaks of cowpox in France, mixed them, and used this to produce their
vaccine.
Following Robert Koch’s recommendation, German scientists began to use glycerin to kill bacteria and to preserve the lymph.
This generated a ready supply of a stable calf lymph of consistent potency. By the end of the 1890s, the use of glycerinated
calves’ lymph was standard everywhere.
Louis Pasteur: vaccine against bacteria – serendipity
- Louis Pasteur in France investigated fowl cholera (Pasteurella multocida)
- Grew Pasteurella and used different dilutions to infect chickens
- One of his students: accidental aged P. multocida was used, and this did not kill
chickens, but protected against infection with fresh P. multocida (Serendipity)
o Used older plates → none of the chickens died = use the same chickens →
didn’t die when previously inoculated but the new ones did die
o Repeated => found attentional inactivation
3
, Henry Toussaint (1880): anthrax vaccine
Toussaint noticed blood of bovines that died of anthrax was full of bacteria. He tried to “filter” it to use it as vaccine but
realized the bacteria could pass through the filter. He decided to heat the blood for 10 min at 55°C or subject it to diluted
phenol. This produced an attenuated vaccine that he injected in animals. These were protected by all 3 methods, but
Toussaint thought that the heat-treated was best.
First ‘licensed’ vaccines up to the 19th century
At the beginning of the 20th century, five human vaccines were in use:
- Jenner’s original smallpox vaccine
- Pasteur’s rabies vaccine (both containing live virus)
- Three bacterial vaccines: typhoid, cholera, and plague (all killed)
In addition, immunization with diphtheria or tetanus antitoxin was an accepted, unofficial, practice.
- The 19th century’s end also saw the end of arm-to-arm lymph inoculation as a vehicle for smallpox vaccination →
use of glycerinated calf lymph in 1898
- Most fundamental concepts of vaccinology had been introduced by the end of the 19th century; the early 20th
century would bring refinements to these theoretical underpinnings
- Not until the advent of cell culture 50 years later would the field again become so fertile
1.3 VACCINE TIMELINE
A. Vaccines in first half of 20th century:
Live attenuated Killed whole Native protein or
organism polysacharide
Tuberculosis Pertussis (1926) Diphteria toxoid
(1927) (1923)
Yellow fever Influenza (1936 Tetanus toxoid
(1935) (1926
Typhus (1938)
TBE (1937)
Typhoid vaccines
Typhoid fever is a bacterial disease caused by Salmonella typhi. Symptoms are similar to other GI illnesses: fever, headache,
nausea, constipation/diarrhoea, loss of appetite, and rose-coloured rash on the body. It may also lead to intestinal bleeding
and perforation, which can lead to severe intestinal damage. It only occurs in humans; there is no animal reservoir for the
bacteria (orofecal route). The problems was that there were asymptomatic carriers that still spread the disease: Typhoid
Mary.
Richard Pfeiffer and Wilhelm Kolle in Germany and Almroth Wright in England worked independently on killed typhoid
vaccines. Wright proposed mass immunization of British troops with killed typhoid vaccine during the Boer War (1899), but
there was opposition because of adverse reactions. The result was catastrophic: more than 58,000 cases of typhoid and 9000
deaths in the British Army. Ultimately, at Wright’s insistence, the War Board initiated a broad-based trial that showed the
overwhelming effectiveness of the vaccine.
By the beginning of World War I in 1914 there was a general typhoid vaccination in the British Army (not mandatory) and also
typhoid vaccination of the general public in the US.
4
1. A (SHORT) HISTORY OF VACCINATION
Vaccines are a ‘recent invention’ compared the thousands of years that humans have suffered from major epidemics.
- Well known “starting” vaccines
o Yellow fever vaccine => military or economics posed huge problems => needed a solution
Vaccination only started to be effectively used in the 20th century in a structured manner. Right now there are:
1. Several vaccines developed (and rules were implemented)
2. Routine vaccinations introduced
3. Large populations vaccinated
With the exception of safe water, no other intervention, not even antibiotics, has had such a major effect on mortality
reduction and population growth.
Before: not very structured, quite “artisanal”
1.1 EPIDEMICS & PANDEMICS
The Plague / black death with huge outbreaks around 1700 caused half the population of Europe to die. Also the Roman
Empire crumbled probably because of a plague outbreak. They already knew a lot about infectious diseases and took note of
mortality numbers etc., but there were very limited interventions possible.
Usually goes down → however this is mainly due to deaths not because of cured.
Around 1889 there was a big Russian Flu epidemic. Now it seems this pandemic was not the flu but
probably a coronavirus epidemic. (called it a Flu because back ten only flus were known to spread such
a disease) Should have diverged at the same time → same symptoms produced at that time: loss of
taste and smell, coughing, mucus, etc. (might have been a prequel to coronavirus epidemic)
Major plagues only started occurring since around 1350, because people started trading and traveling
a lot. Links between people and continents are ideal for pathogens to spread. When before 1350
zoonotic pathogens jumped to people, it usually remained in one city. Here all people possibly died
but it did not spread further.
Highest death toll = black death, bulbonic plague (50% of the population died) → major setback at that time
Vaccines are a ‘recent invention’: before vaccines...
Before vaccines, the practice of quarantine already started during the 14th century to protect coastal cities from plague
epidemics.
- Port authorities required ships arriving in Venice from infected ports to sit at anchor for 40 days before landing.
- The origin of the word quarantine is from the Italian “quaranta giorni”; or 40 days.
One of the first instances of relying on geography and statistical analysis was in mid-19th century London, during a cholera
outbreak.
- In 1854, Dr. John Snow came to the conclusion that cholera was spreading via tainted water and decided to display
neighbourhood mortality data directly on a map.
- This method revealed a cluster of cases around a specific water pump.
- Knew something was up with the water but weren’t aware that it was a bacterium.
1
,The origin of variolation Smallpox and variolation
Many people died of smallpox, but some recovered. These recovered individuals then remained healthy in subsequent
outbreaks: they had developed immunity. In the 12th century this was observed by the Chinese: recovered people are
resistant to infection in new outbreaks. (one of the only viruses that has been eradicated)
• Infants who survived the resulting disease were protected from smallpox in later life (lifelong immunity)
o Probably observed prior but not written down
• Using scabs from mild smallpox cases minimized mortality
o = inoculation/variolation: deliberate infection with smallpox by inserting scabs from infected individuals
into small cuts in their skin
o The way of inoculation had an effect => most promising method was found (inoculum loop)
▪ Localized infection → induced a strong local inflammation preventing the virus from spreading
rapidly
▪ Knowledge started spreading from China to western world
o Still a chance of death -> 1% compared with ± 20%
➔ The knowledge of variolation spread westward to Europe by the early 18th century
The precise origin of variolation remains unknown. It seems to have developed somewhere in Central Asia around the 12th
century. In the 16th century, Brahmin Hindus in India practiced a form of variolation by introducing dried pus from smallpox
pustules into the skin of a patient. The Golden Mirror of Medicine, a medical text dated 1742, listed four forms of inoculation
against smallpox practiced in China since 1695:
1. The nose plugged with powdered scabs laid on cotton wool
2. Powdered scabs blown into the nose
3. The undergarments of an infected child put on a healthy child for several days
4. A piece of cotton smeared with the contents of a vesicle and stuffed into the nose
Variolation was introduced into England by Lady Mary Wortley Montagu in 1721, after her return from Constantinople. While
living in Turkey, she frequently observed variolation and had her own son variolated. Dr. Charles Maitland, who performed
the procedure on her son, later performed the first variolation in England on Lady Montagu’s daughter. The treatment was
effective, but results were erratic and 2-3% of persons treated died of smallpox contracted from the variolation itself.
(brought the knowledge back to England → and also Europe)
Benjamin Jesty (1774)
Cattle breeder Benjamin Jesty was immune to smallpox after contracting cowpox from his herd. Like many country farmers
in the area, he knew dairymaids seemed to be protected from smallpox after having contracted cowpox. He deliberately
inoculated his wife and children with cowpox to avoid a smallpox epidemic. He took his wife and children to a nearby field
where he knew he could find cattle with cowpox and inoculated them. His experiment succeeded; they were unaffected by
the outbreak. → also other farmers succeeded in this.
- Similar symptoms as small pox
- Induces immunity that protects against the real human virus
- Edward jenner was made aware of this and used this as a physician
o Scratched the skin to make a barrier → put liquid on the skin
- Problem: cowpox was not widely spread, sometimes could be difficult to find a vaccine → needed to transport live
cattle → in living room (accessible for rich people)
- Poor people → arm-arm transmission – transmission of virus
- Used in the royal philanthropic vaccine mission
2
,Jesty’s actions constituted the first known real vaccine—the use of cowpox to protect against smallpox.
→ first know of attenuated deliberated inoculation
Take the vaccine around the world: Take orphans to south America; promised a better life. Upon arrival, children were
infected, went back to their home cities to further spread.
Rinderpest – cattle plague (1754)
- No cure, but inoculation tried: placing bits of material previously dipped in morbid discharge into
an incision in dewlap
o Worked, but not always and not without risk
o Disastrous results in NL -> interest in inoculation declined sharply across the country
- General principles of inoculation were accepted BUT nobody had an idea how it worked
- All the cattle died → causing huge problems for humans
- Didn’t work as well as smallpox
1.2 WHAT IS A VACCINE
A biological suspension of a live or inactivated pathogen or fractions/subunits thereof (i.e. purified protein subunits,
conjugated and non-conjugated polysaccharides, or split virions) which can be administered by various routes (IM, SC, ID, Oral,
Intranasal) to induce specific long-term immunity (immune memory) and prevent disease caused by a specific pathogen
against which it has been developed.
Goal: induce memory and protect against a disease
Edward Jenner: first large scale vaccinations with cowpox
While Jenner did use the term “vaccine,” he is not the originator of the term vaccination; that honor belongs to his friend
Richard Dunning, who used it in 1800
- Cowpox was not widespread, so sometimes difficult to find for use as a vaccine
o “vacca” = cow
- Jenner expanded his studies: proved cowpox could be passed from person to person
o -> “large-scale” inoculation against smallpox w/o outbreaks of natural cowpox
For the first several decades of the 19th century, arm-to-arm transfer was the primary method of human vaccination. BUT
other diseases, e.g. TB were occasionally transmitted along with the cowpox virus → a need for an alternative way to
vaccinate and to ensure a steady supply of cowpox vaccine.
Standardizing calf-derived vaccines (~1855)
Animal vaccination from one cow to another was done to keep a steady supply of cowpox lymph to vaccinate humans. In
1866, Lanoix and Chambon collected cowpox of 2 outbreaks of cowpox in France, mixed them, and used this to produce their
vaccine.
Following Robert Koch’s recommendation, German scientists began to use glycerin to kill bacteria and to preserve the lymph.
This generated a ready supply of a stable calf lymph of consistent potency. By the end of the 1890s, the use of glycerinated
calves’ lymph was standard everywhere.
Louis Pasteur: vaccine against bacteria – serendipity
- Louis Pasteur in France investigated fowl cholera (Pasteurella multocida)
- Grew Pasteurella and used different dilutions to infect chickens
- One of his students: accidental aged P. multocida was used, and this did not kill
chickens, but protected against infection with fresh P. multocida (Serendipity)
o Used older plates → none of the chickens died = use the same chickens →
didn’t die when previously inoculated but the new ones did die
o Repeated => found attentional inactivation
3
, Henry Toussaint (1880): anthrax vaccine
Toussaint noticed blood of bovines that died of anthrax was full of bacteria. He tried to “filter” it to use it as vaccine but
realized the bacteria could pass through the filter. He decided to heat the blood for 10 min at 55°C or subject it to diluted
phenol. This produced an attenuated vaccine that he injected in animals. These were protected by all 3 methods, but
Toussaint thought that the heat-treated was best.
First ‘licensed’ vaccines up to the 19th century
At the beginning of the 20th century, five human vaccines were in use:
- Jenner’s original smallpox vaccine
- Pasteur’s rabies vaccine (both containing live virus)
- Three bacterial vaccines: typhoid, cholera, and plague (all killed)
In addition, immunization with diphtheria or tetanus antitoxin was an accepted, unofficial, practice.
- The 19th century’s end also saw the end of arm-to-arm lymph inoculation as a vehicle for smallpox vaccination →
use of glycerinated calf lymph in 1898
- Most fundamental concepts of vaccinology had been introduced by the end of the 19th century; the early 20th
century would bring refinements to these theoretical underpinnings
- Not until the advent of cell culture 50 years later would the field again become so fertile
1.3 VACCINE TIMELINE
A. Vaccines in first half of 20th century:
Live attenuated Killed whole Native protein or
organism polysacharide
Tuberculosis Pertussis (1926) Diphteria toxoid
(1927) (1923)
Yellow fever Influenza (1936 Tetanus toxoid
(1935) (1926
Typhus (1938)
TBE (1937)
Typhoid vaccines
Typhoid fever is a bacterial disease caused by Salmonella typhi. Symptoms are similar to other GI illnesses: fever, headache,
nausea, constipation/diarrhoea, loss of appetite, and rose-coloured rash on the body. It may also lead to intestinal bleeding
and perforation, which can lead to severe intestinal damage. It only occurs in humans; there is no animal reservoir for the
bacteria (orofecal route). The problems was that there were asymptomatic carriers that still spread the disease: Typhoid
Mary.
Richard Pfeiffer and Wilhelm Kolle in Germany and Almroth Wright in England worked independently on killed typhoid
vaccines. Wright proposed mass immunization of British troops with killed typhoid vaccine during the Boer War (1899), but
there was opposition because of adverse reactions. The result was catastrophic: more than 58,000 cases of typhoid and 9000
deaths in the British Army. Ultimately, at Wright’s insistence, the War Board initiated a broad-based trial that showed the
overwhelming effectiveness of the vaccine.
By the beginning of World War I in 1914 there was a general typhoid vaccination in the British Army (not mandatory) and also
typhoid vaccination of the general public in the US.
4
