Vaccine Technologies: Immunization and Malaria Vaccine

Routes of Vaccine Administration

  • Various routes exist, influencing the strength and robustness of the immune response.

    • Subcutaneous or intramuscular: Common for most vaccines (e.g., injected into the shoulder, arm, or buttocks).

    • Oral route: Examples include the BCG vaccine.

    • Intradermal route: Similar to intramuscular but doesn't go as deep into muscle tissue.

    • Scarification: Historical method (smallpox vaccine) involving scraping the skin to introduce the pathogen; not used anymore.

    • Intranasal route: Few vaccines use this route; convenient (avoids injection pain and needle risks) but requires further development.

  • Intramuscular:

    • Traditional route.

    • Leads to local vaccine depot formation.

    • Can cause local side effects, especially with adjuvants.

      • Adjuvants: Molecules and excipients added to vaccines to induce a non-specific immune response, enhancing the specific immune response against the antigen.

  • Subcutaneous and Transdermal:

    • Utilize lymphatic system drainage for transport and contact with cells important for generating a good immune response.

  • Oral Route:

    • Suitable for immunizations where the gastrointestinal tract is the site of infection (e.g., polio virus).

    • Challenging due to the need for vaccines to be stable through varying pH levels and digestive enzymes.

Immunization Schemes

  • Single Shot:

    • Ideal, requiring only one dose.

    • Examples: BCG, mumps, measles, rubella, yellow fever.

  • Multiple Doses:

    • Necessary for vaccines that don't generate a robust immune response with a single dose.

    • Examples: Some polio and hepatitis B vaccines.

  • Booster Vaccinations:

    • Maintain immunity levels that wane over time.

    • Example: COVID-19 vaccine boosters.

Active Vaccination: Malaria Vaccine Example

  • Malaria: A life-threatening disease caused by the eukaryotic parasite Plasmodium, transmitted by Anopheles mosquitoes.

  • Most cases and deaths occur in African regions, particularly sub-Saharan Africa, and also in areas of Asia and Papua New Guinea.

  • Plasmodium falciparum: Responsible for most cases and deaths in the African region.

  • Malaria cases decreased in the 2000s but have recently increased, potentially due to COVID-19 lockdowns affecting healthcare access.

  • Global Malaria Eradication Campaign:

    • Ongoing since the 1950s.

    • Successful strategies had spraying the inside of houses with insecticide DDT.

    • Attack phase: Included health education, bed nets, and drugs.

    • Led to malaria elimination in many developed countries and reduction in sub-Saharan Africa.

    • Epidemics occurred when campaigns failed due to political or other situations disrupting efforts.

    • The ultimate failure of the campaign had a negative impact on malaria control and research programs.

  • Malaria has been eliminated from many countries; in the 1900s, it was present in almost every country except Greenland and Mongolia.

  • Malaria funding has increased tenfold in 100 years.

    • Roll Back Malaria campaign.

    • Millennium Development Goals.

    • Global Fund for HIV, TB.

    • President's Malaria Initiatives (started by George W. Bush).

    • Gates Foundation (founded by Bill and Melinda Gates of Microsoft).

  • Malaria in Papua New Guinea has decreased due to health education, insecticide-impregnated bed nets, and surveillance.

  • Malaria admissions and deaths have decreased since 2005, with a slight uptick in 2015 due to local factors.

  • Malaria prevalence is now mainly located in the highland regions of Papua New Guinea.

The Malaria Life Cycle

  • Mosquito bites a human, introducing sporozoites (malaria parasites) into the liver.

  • Sporozoites develop in the liver for several weeks.

  • Parasites are released from liver cells as merozoites.

  • Merozoites invade red blood cells and multiply.

  • Infected red blood cells burst, releasing more merozoites that infect other red blood cells (blood stage).

  • The blood stage is responsible for chills, fevers, and other symptoms.

  • Merozoites develop into gametocytes, which are taken up by mosquitoes to continue the life cycle.

Malaria Treatment and Prevention

  • Requires a combination of strategies: bed nets, health education, and drugs.

  • Drugs are needed for rapid response, and vaccines for longer-term disease reduction.

  • Many drugs have been used, including chloroquine, sulfoxidine, and artemisinin, but drug resistance has developed in parasites.

  • Chloroquine was effective but compromised due to drug resistance first developed near the Myanmar, Laos, and Thailand border.

  • Artemisinin resistance is also developing in this region.

  • New drugs are being developed to minimize drug resistance.

Vaccine Targets within the Malaria Life Cycle

  • Complex life cycle provides multiple targets.

  • Primary targets: parasites in the mosquito, sporozoites (liver stage), and merozoites (blood stage).

  • Goal: Inject an antigen to generate an immune response, so that the next time the person is bitten by a mosquito, they have built up immunity to it and shouldn't suffer the consequences of the disease.

  • Focus on two molecules:

    • CS protein (circumsporozoite protein) on sporozoites.

    • AMA1 (apical membrane antigen 1) on merozoites, responsible for binding to red blood cells.

CS Protein (Circumsporozoite Protein)

  • Located on the sporozoite, which invades the liver stages.

  • Key Researchers: Joe Cohen (GlaxoSmithKline) and Lip Bru (Walter Reed Army Institute).

  • Large protein with N, A, and P (asparagine, alanine, and proline) repeats.

  • Research has identified a particularly immunogenic area of the protein.

    • RTSS: Is a subunit of the CS protein attached to a virus-like particle, used for injection.

RTSS Vaccine Development Timeline

  • 1984: Walter Reed Army Institute and GlaxoSmithKline collaboration began.

  • 1995: First clinical trials started.

  • 1998: First trials in Africa.

  • 2004: Key proof of concept studies in children in Mozambique.

  • Phase 3 study started (large trial to test vaccine efficacy).

  • Phase 3 results with booster dose obtained.

  • Vaccine approved (timeline from 1984 to 2015/2016).

  • This long timeline is typical for vaccines against diseases not common in developed countries.

  • Significant funding from the Bill and Melinda Gates malaria vaccine initiative.

  • Compared to COVID-19 vaccine development (remarkably short timeline).

RTSS Vaccine Efficacy

  • Successful but with room for improvement.

  • Infants: 27% vaccine effectiveness.

  • 30% vaccine effectiveness against clinical malaria at 20 months, declining over time.

  • No efficacy against severe malaria (cerebral malaria).

  • Children: 45% vaccine effectiveness.

  • Booster dose increased vaccine effectiveness to 36% at 20 months.

  • No efficacy against severe malaria.

  • Better than no vaccine, particularly in endemic areas, but needs improvement.

Malaria Vaccine Implementation Programme (MVIP)

  • Established by the WHO to deliver the Muscuics vaccine to those in need.

  • Monitoring and evaluation of mortality and continuing safety issues.

AME1 (Apical Membrane Antigen 1)

  • Protein on merozoite stages, secreted onto the surface.

  • Helps merozoites enter red blood cells.

  • Malaria parasite hides from the immune response (antibodies and T cells cannot see the parasite inside red blood cells).

  • Clinical trials in Mali showed disappointing vaccine efficacy (17% against all strains, 64% against 3D7 strains).

  • AMA1 used in the vaccine was 3D7 AMA1 which is a drawback due to polymorphism.

  • Polymorphism: Different strains of malaria parasites have different sequences of AME1, allowing them to evade the immune response.

Addressing AMA1 Polymorphism

  • Funded by the Bill and Melinda Gates Foundation.

  • Collaboration between La Trobe University, the Burnet Institute, and the Walter Reed Army Institute.

  • Used crystal structure data.

  • Identified a conserved hydrophobic pocket crucial for binding and entering red blood cells.

  • Amino acids surrounding this loop are highly variable.

  • Injected molecule into animals, the antibodies seem to be around this area.

  • Mutated these amino acids to alanine to de-immunize the region and focus the immune response on more important regions.

  • Patent taken out, papers published.

  • Licensed to the Walter Reed Army Institute.

Antibody Binding

  • Crystal structure shows antibody binding to AME1 protein.

  • Single domains (chunks of antibodies) derived from sharks.

  • Shark antibody binds to AMA1 green pocket.

  • May be useful for passive immunity.

  • Further discussion in the next lecture.