1. The history of vaccine development began with early attempts at variolation and inoculation against smallpox in the 1000s/1600s. Edward Jenner published findings on using cowpox to immunize against smallpox in 1798. Louis Pasteur discovered ways to attenuate microorganisms and created the first rabies vaccine in 1885. 2. Oral vaccines have advantages over traditional needle vaccines like easier administration, lower costs, and increased compliance. However, challenges include protecting antigens from degradation and ensuring delivery and uptake in the intestinal mucosa. 3. Successful oral vaccines currently in use include polio, rotavirus, and cholera vaccines, while further research is still needed to develop

1. By Abir Ahmad
Maiken Dragnet
Francisco Muñoz Maestre
Thomas A. Enger Morey
Branislava Stancović
Arild Sveen
Conor Cahill/The News Market

2. History of vaccine development
• First attempt to fight against disease
• 1-2% vs. 30% mortality rate
• Came to europe with the
crusades. Variolation
following after.
Variolation (1000/1600)

3. • Inoculated cowpox as a means to
immunize against smallpox
• Published his findings in 1798.
History of vaccine development
Edward Jenner (1749-1823)

4. • Disproved the hypothesis of
spontaneous generation in 1862.
• Discovered ways to attenuate
(weaken) microorgansims.
– Aging in the precense of oxygen
– Cultivation on elevated temperatures
– Passage through species
– Drying of samples
• Created rabies ”vaccine” in 1885
History of vaccine development
Louis Pasteur (1822-1895)

5. • The bacteria that causes tuberculosis was
discovered in 1882.
• Created Koch’s postulates which was used to
identify the relationship between a microorganism
and its disease:
1. The suspected pathogen must be found in all
diseased organisms.
2. The suspected pathogen must be isolated from
the diseased organism and grown into a pure
culture.
3. The culture should exhibit the same sympthoms
when inoculated into a healthy organism of the
same species.
4. The suspected pathogen must be retrieveable
from the inoculated organism and be identified
as the same particular pathogen originally being
studied.
History of vaccine development
Robert Koch (1843-1910)

6. • Global, simultaneous research
• Maurice Hilleman
• Sanitation and hygiene
History of vaccine development
From 1900 to the present

7. Case study
Oral polio vaccine

8. • Consists of a mixture of live
attenuated poliovirus strains
• Produces antibodies in the blood
protects against polio paralysis
• Local immune response in the
intestines  inhibits subsequent
infections
Case study
Benefits of Oral polio vaccine

9. Case study
Oral rabies vaccine

10. • A potential solution to rabies in
wildlife populations
– Example: The spread of rabies in foxes in
Switzerland was halted when 60% of the
fox population was vaccinated orally
Case study
Benefits of oral rabies vaccine

11. Case study
Oral rotavirus vaccine

12. • In Australia: Approx. 10,000 children under
5 years of age hospitalized each year
before introduction of the vaccine
• More than 70% decline in annual rotavirus
hospitalizations since 2007
Case study
Benefits of oral rotavirus vaccine

13. Safety:
Main concerns with traditional needle
vaccination:
• Transmission of contagious diseases:
patient to patient/health staff.
•Skin integrity is broken
•Needle injuries as an occupational risk
for health workers
In developing countries vaccination is often followed by improper practices:
•Using the same needle and/or syringe for many injections
•Not sterilizing needles and syringes between patients
•Improper disposal of needles and syringes
Advantages and possibilities

14. • Does not require trained health personnel
• A good example of simplicity of oral vaccine delivery; volunteer
vaccinators in India vaccinating over 150 million children
Speed of vaccine delivery
Oral vaccines decrease time of
delivery without compromising
safety compared to traditional
needle vaccines
Advantages and possibilities
Training of vaccinators

15. Cold chain
A term that refers to procedures, equipment and materials necessary to keep vaccines
in certain temperatures.
• All the equipment and materials used to keep the cold chain cost different programs
around the world approximately 200 to 300 million dollars per year.
• And in addition to the cost in many parts of the world it is not possible to maintain
cold chain.
•Studies in Chad and Mali have showed that some oral
vaccines can be potent even if the cold chain is broken for few
days.
•Oral polio vaccines where kept outside of cold chain for 87.9
hours and at the ambient temperatures over 45°C keep their
potency.
Advantages and possibilities

16. Discomfort and Compliance
• Decreased pain and suffering in
administration process and pain of
injection site after vaccination.
• Patience are more willing to comply
with recommended vaccine schedules.
• Needle phobia is avoided.
Costs
•Costs of devices used to deliver vaccines
•Costs of medical care due to iatrogenic (human error) blood-
borne pathogen trasmision
Advantages and possibilities

17. Oral vaccines in use today
• Attenuated live microorganisms
– Can replicate in the gut  survive degradation
– Advantages
• easy to use
• inexpensive
– Challenges
• tendency to revert back to a virulent form
• become excessively pathogenic when used in the wrong target
population
– Examples
• Polio, rabies, rotavirus, adenovirus, typhus, malaria, smallpox, Cholera
(live)

18. Oral vaccines in use today
• Inactivated/killed pathogens
– Digestion-resistant bacterial walls  “survival”
– Advantages
• Little risk in comparison to attenuated live microorganisms
– Challenges
• Are less immunogenic
• Multiple doses (expensive)
• Need inclusion of adjuvants
• Adjuvants are often toxic to humans (example: mercury)
– Examples
• Only one commercially available killed o.v.; AIDS (therapeutic)
• other unlicensed killed vaccines (marketed as food supplements)
– whole cell cholera toxin recombinant B subunit (Sweden)
– E.coli 0111 for diarrhea (Slovakia)

19. Challenges in developing oral
vaccines
• Protecting the antigens against degradation in
the digestive system
• Issues with delivery site and antigen uptake
• Other challenges

20. Protection and delivery methods of
the antigen
• Encapsulation materials:
– PLG-microparticles (good protection, size dependant delivery)
– Liposomes (moderate protection, good delivery)
– Cochleates (moderate protection, good delivery)
– pH- dependent microspheres (good protection, size dependant delivery)
• Liquid formulations with and without buffers
• Enteric- coated tablets

21. Protection and delivery methods of
the antigen
• Edible oral vaccines, expressed in transgenic plants/yeast
– plant-made measles vaccine
– Tomato plants: Hepatitis B
– Yeast: human papilloma virus antigen
• Disadvantages:
– Ethical concerns (GMO)
– May lead to tolerance instead of immunity

22. Mucosal immune system
• Antigens enter the mucous membranes
• 90% of immunocompetent cells, 400 m2 surface
• Mucosa in the gut:
– Single celled epithelium layer – enterocytes
– Connective tissue – lamina propria
– Mucosa associated lymphoid tissue (MALT, GALT)
• Macrophages, dendritic cells, naïve and
immunocompetent B-/T-lymphocytes ++
• Most of the body’s IgA

23. Delivery sites and antigen uptake
• Microfold cells (M-cells)
– Most significant uptake of antigens
– Found in Peyer’s patches
– “Anonymous” in humans
• Dendritic cells
– Extend dendrites through tight junctions in epithelium
– Only about 1% of immune cell population
• Enterocytes
– Limited capacity (some HLA class II receptors)

24. Delivery sites and antigen uptake

25. Local  systemic immunity
• Inductive site: M-cell, DC, enterocytes
• Antigen uptake
– APC or lymphocytes at inductive site
– Transport to lymph nodes
– Proliferation, maturation
– Drainage of active lymphocytes into blood
– Return to effector sites (local, distant)
• Example: Large intestine targeted vaccine  vaginal
immunity

26. Local  systemic immunity

27. Other challenges
• Tolerance vs. immunity
– Friendly gut flora  system prone to tolerance
– Many and/or large doses, adjuvants may be necessary
• Delivery site, age, particle size, dose ++
– Example: Macrophage phagocytosis up to 1-5 µm
• Environmental enteropathy: changes in small intestine
due to fecal exposure
– Blunted villi, large amount of intraepithelial lymphocytes…
• Age
– Reduced immunogenic response with increased age

28. Conclusion
• More effective vaccines are still needed!
• Oral vaccines have both advantages and
drawbacks
• More knowledge is necessary for future oral
vaccines

29. Source list
• Azizi A et al: Enhancing Oral Vaccine Potency by Targeting Intestinal
M Cells. PLoS 2010
• Brandtzaeg P et al: Terminology: nomenclature of mucosa-
associated lymphoid tissue. Mucosal Immunity 2008
• Levine MM: Immunogenicity and efficacy of oral vaccines in
developing countries: lessons from a live cholera vaccine. BMC
Biology 2010
• Kernéis S et al: Conversion by Peyer's Patch Lymphocytes of Human
Enterocytes into M Cells that Transport Bacteria. Science 1997
• Chadwick S et al: Delivery strategies to enhance mucosal
vaccination. Expert Opin. Biol. Ther. 2009
• Pavot V et al: New insights in mucosal vaccine development.
Vaccine 2011