The document discusses the need for a malaria vaccine and challenges in developing one. It provides details on various vaccine candidates and approaches, including pre-erythrocytic (preventing infection of liver), asexual blood stage (preventing growth in red blood cells), and sexual stage (blocking transmission) vaccines. Top candidates mentioned are RTS,S/AS02, which has undergone phase 3 trials, and SPf66, the first to undergo field testing. Developing an effective and durable malaria vaccine faces difficulties due to the parasite's complex life cycle and ability to evade the immune system.

1. Malaria Vaccines
Dr.Md.Mustafeed Uddin

2. THE NEED FOR A MALARIA VACCINE
• "Malaria is a stubborn disease, slow to kill, quick to
incapacitate and hard to cure. All through human history,
in times of peace as in times of war, it has taken its
steady toll of human life. Against this persistent affliction,
many of the best minds in public health and in medicine
have, during the past few decades, been forging
increasingly effective weapons. Not a year passes
without some improvement in techniques or tactics
against what has been termed the greatest single threat
to human health"
• ~ R.B. Fosdick, President of the Rockefeller Foundation,
1946

3. Global malaria map
•

6. Problems in vaccine
development
• Difficulty of evaluation
• Parasites’ ingenious ways of avoiding hosts’ immune response
• Complexity of conducting clinical and field trials
• Mutation of the parasites
• Antigenic variations e.g. MSA-I has 8 variants, MSA-2 has 10
and CSP has 6 variants
• Multiple antigens, specific to species and stage

7. Challenges for Malaria Vaccine
• Four antigenetically distinct malaria species
– Each has ~6,000 genes
– First gene only identified in 1983
• Immunity in malaria is complex and immunological responses
and correlates of protection are incompletely understood.
• Identifying and assessing vaccine candidates takes time and is
expensive
• There is no clear ‘best approach’ for designing a malaria vaccine

8. Malaria vaccine initiative (MVI)
MVI is working with the International Centre for Genetic Engineering
and Biotechnology (ICGEB) in New Delhi, India, to develop a vaccine
against Plasmodium vivax. This development effort includes Bharat
Biotech International Ltd. (Hyderabad), which will manufacture the
vaccine for preclinical testing followed by initial safety trials in adults.

9. 9
MVI mission, vision, and goal
• Mission: To accelerate the
development of malaria
vaccines and ensure their
availability and accessibility in
the developing world
• Vision: A world free from
malaria
• Goal: To develop by 2025 a
malaria vaccine with 80% or
greater efficacy that lasts for
at least four years
MVI was established in 1999 as a program of PATH,
an international nonprofit organization that creates sustainable,
culturally relevant solutions, enabling communities worldwide to
break longstanding cycles of poor health.

10. $600 M costs for development
• At least nine malaria vaccine candidates are in development, but
Mosquirix is the furthest along. Glaxo has been refining it for 20
years and expects to have spent up to $600 million on it by the time
it comes to market. About $100 million has been paid by the Bill and
Melinda Gates Foundation through the PATH Malaria Vaccine
Initiative.
• No decision has been made about the price to be offered to poor
countries and international health agencies. But “if a child will
benefit, price will not stand in the way,” said Dr. Christian Loucq,
director of the vaccine initiative.
• The vaccine is given in three injected doses. That is an obstacle in
poor countries, which have difficulties immunizing even against polio
— done with oral drops requiring no medical skill.
• But even one dose has some protective effect, the Lancet study
found.
• It is unknown how long protection lasts. But because the youngest
children are the most vulnerable, Dr. Alonso said, vaccination buys
them time to build up natural immunity, which is acquired by
surviving multiple mosquito bites.

11. Researchers in Kenya working on MVI under
CDC

12. Nurse Dinah Mauti Maragwa gives malaria
candidate vaccine to an infant at the Siaya
KEMRI/CDC Malaria Vaccine Trial Site in Kenya

13. KEMRI Clinical Officer Paul Ogai reviews a prospective
participant's vaccination card during trial enrollment at the
KEMRI/CDC site

14. Ideal malarial vaccine
• prevent the infection at the first instance and if this is not
possible, should decrease the intensity of infection and
should be successful in preventing malaria transmission.
• Reduce the clinical disease severity.
• Reduce the transmission.

15. Classification of malaria vaccine
Stage of
plasmodium
Antigens Salient features
Pre-erythrocytic Irradiated sporozoites , Circum Sporozoite
Protein (CSP) or peptides, Liver stage Antigens
-1 (LSA-1)
Stage/species specific; antibody
blocks infection of liver; large
immunising dose required; can abort
an infection
Merozoite and
Erythrocytes
Erythrocyte Binding Antigen (EBA-175),
Merozoite Surface Antigen 1&2 (MSA-1&2) ;
Ring Infected Erythrocyte Surface Antigen
(RESA); Serine Repeat Antigen (SERA);
Rhoptry Associated Protein (RAP); Histidine
Rich Protein (HRP); Apical Membrane
Antigen-1 (AMA-1)
Specific for species and stage;
Cannot abort an infection; Prevents
invasion of erythrocytes, thus
reducing severity of infection
Gametocytes &
gametes
Pfs 25, 48/45k, Pfs 230 Prevents infection of mosquitoes;
antibody to this antigen prevents
either fertilization or maturation of
gametocytes, zygotes or ookinetes; is
of use in endemic areas but not
suited for travelers; antibody blocks
transmission cycle
Combined vaccine
(cocktail)
SPf 66 (based on pre-erythrocytic and asexual
blood stage proteins of Pf)
Based on incorporation of antigens
from different stages into one vaccine
to produce an immune response,
blocking all stages of the parasite
development

17. Pre- Erythrocytic Stage
Vaccines
• How they work:
– Generates Ab response against sporozoites and prevents
them from invading the liver
– Prevents intra-hepatic multiplication by killing parasite-
infected hepatocytes
• Intended Use:
– Ideal for travelers - protects against malaria infection

18. Asexual Erythrocytic Stage
Vaccines
• How they work:
– Elicit antibodies that will inactivate merozoites and/or
target malarial Ag expressed on RBC surface
– Inhibit development of parasite in RBCs
• Intended Use:
– Morbidity reduction in endemic countries

19. Sexual Stage Vaccines
• How they work:
– Induces Ab against sexual stage Ag
– Prevents development of infectious sporozoites in
salivary glands of mosquitoes
– Prevent or decrease transmission of parasite to new
hosts
• Intended Use:
– Decreased malaria transmission

20.  SPf66
 AdCh63/MVA MSP1
 PfSPZ
 MSP3
 GMZ2
 AMA1-C1/Alhydrogel +CPG 7909
 FMP1AS02A

21. spf66
 The first vaccine developed that has undergone field trials
 Developed by Manuel Elkin Patarroyo in 1987.
 It presents a combination of antigens from the sporozoite (using CS
repeats) and merozoite parasites.
 During phase I trials a 75% efficacy rate was demonstrated and the
vaccine appeared to be well tolerated by subjects and
immunogenic.
 The phase IIb and III trials were less promising, with the efficacy
falling to between 38.8% and 60.2%.
 Despite the relatively long trial periods and the number of studies
carried out, it is still not known how the SPf66 vaccine confers
immunity; it therefore remains an unlikely solution to malaria

22. Csp
• Based on the circumsporoziote protein, but additionally has
the recombinant protein covalently bound to a purified
Pseudomonas aeruginosa toxin (A9).
• A complete lack of protective immunity was demonstrated in
those inoculated at early stage.
• The study group used in Kenya had an 82% incidence of
parasitaemia whilst the control group only had an 89%
incidence.
• Elicits a cellular response enabling the destruction of infected
hepatocytes

23. NYVAC - Pf. 7
 Blocks transmission of the parasite from vertebrate host to mosquitoes.
 The highly attenuated NYVAC vaccinia virus strain has been utilized to
develop a multiantigen , multistage vaccine candidate for malaria.
 Genes encoding seven Pf antigens derived from the
1. sporozoite (CSP and sporozoite surface protein 2),
2. Liver (liver stage antigen 1),
3. blood (merozoite surface protein 1, serine repeat antigen, and apical
membrane antigen 1),
4. sexual (25-kDa sexual-stage antigen)
 inserted into a single NYVAC genome to generate NYVAC-Pf7.
 safe and well tolerated.
 Specific antibody responses against four of the P. falciparum antigens
were characterized during 1a clinical trial.

24. Rts,s /as02
 Most recently developed recombinant vaccine
 The RTS,S attempted by fusing the protein CPS with a surface
antigen from Hepatitis B, hence creating a more potent and
immunogenic vaccine. When tested in trials an emulsion of oil
in water and the added adjuvants of monophosphoryl A the
vaccine gave 7 out of 8 volunteers challenged with P.
falciparum protective immunity

25. VACCINATING MOSQUITOES
• In mosquitoes, there are proteins on the surface of
gametes and ookinets that may prove useful in
formulating a vaccine that protects mosquitoes from
infection.
• Antibodies to these proteins prevent the parasite from
taking up residence in the mid-gut of mosquitoes and
forming oocysts. However, in order for such vaccines to
reach mosquitoes they must be combined with efforts
to vaccinate people living in endemic areas.

26. Latest update
• LONDON (24 APRIL 2015)— Final results from a large-
scale Phase III trial of the RTS,S malaria vaccine
candidate, including the impact of a booster dose,
published today in The Lancet, show that the vaccine
candidate helped protect children and infants from
clinical malaria for at least three years after first
vaccination.

27. References
• CDC website
• Malariavaccine.org
• PATH malaria vaccine initiative
• Stanford university – Parasite website.