Oral Vaccines:Posibilities and challenges

By Abir AhmadMaiken Dragnet

Francisco Muñoz MaestreThomas A. Enger Morey

Branislava StancovićArild Sveen

Conor Cahill/The News Market

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)

• Inoculated cowpox as a means to immunize against smallpox

• Published his findings in 1798.

History of vaccine developmentEdward Jenner (1749-1823)

• 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 developmentLouis Pasteur (1822-1895)

• 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 developmentRobert Koch (1843-1910)

• Global, simultaneous research

• Maurice Hilleman

• Sanitation and hygiene

History of vaccine developmentFrom 1900 to the present

Case studyOral polio vaccine

• 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 studyBenefits of Oral polio vaccine

Case studyOral rabies vaccine

• 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 studyBenefits of oral rabies vaccine

Case studyOral rotavirus vaccine

• 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 studyBenefits of oral rotavirus vaccine

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

• 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 possibilitiesTraining of vaccinators

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

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

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)

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)

Challenges in developing oral vaccines

• Protecting the antigens against degradation in the digestive system

• Issues with delivery site and antigen uptake

• Other challenges

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

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

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

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)

Delivery sites and antigen uptake

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

Local systemic immunity

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

Conclusion

• More effective vaccines are still needed!

• Oral vaccines have both advantages and drawbacks

• More knowledge is necessary for future oral vaccines

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