Upload
lehanh
View
215
Download
0
Embed Size (px)
Citation preview
5/4/2018
1
Lars Hviid ([email protected])Centre for Medical ParasitologyDepartment of Immunology and Microbiology
NECTM7 04/05/18
Malaria vaccines – where are we now?
Slide 1
Background: A very interested – but disinterested – “real” doctor
<
Robert Killick-Kendrick
5/4/2018
2
Naturally acquired immunity to malaria
• It takes a long time to develop• Protection from severe disease develops first• Pregnant women get malaria regardless• Babies don’t get malaria (even when born to
infected mothers)
• “Curb your enthusiasm”!
NECTM7 04/05/18
5 10 15 20 25 50
Deaths
DiseaseParasitaemia
Inci
den
ce
Age (years)
0
Slide 3
The P. falciparum life cycle and potential vaccine targets
• Sporozoites• Inf. hepatocytes• Merozoites• Inf. erythrocytes• Gametocytes• Mosquito stages
NECTM7 04/05/18
Dias 4
Slide 4
5/4/2018
3
Types of vaccines
NECTM7 04/05/18Slide 5
• Empiric vaccines (“Trial-and-error”)
• “Darwinian” vaccines (“Emulation”)
• “Intelligent design” vaccines
Vaccination against sporozoites
NECTM7 04/05/18Slide 6
5/4/2018
4
Vaccination against sporozoites
NECTM7 04/05/18Slide 7
NECTM7 04/05/18Slide 8
“Already, I feel premonitory twinges of lonesomeness…”Paul F Russel: Man’s mastery of malaria (1955)
Ruth and Victor Nussenzweig
5/4/2018
5
The RTS,S vaccine (Mosquirix ®)
NECTM7 04/05/18Slide 9
• Based on the major sporozoite surface protein CSP, linked to hepatitis B surface antigen
• Assembled into non-infectious virus-like particles
• Delivered i.m. with adjuvant AS01• EMA Positive Opinion July 2015
• Indication: Immunization of children 6 weeks-17 months of age against P. falciparum malaria and Hepatitis B
• Schedule: 3 doses @ 5-9 mo. + booster 15-18 mo. later
• Condition: Phase IV study to assess feasibility, impact, and safety concerns
RTS,S vaccine efficacy (Olotu et al. New Engl J Med 374, 2519, 2016)
5/4/2018
6
Immune escape?
Neafsey et al. N Engl J Med 2015 NECTM7 04/05/18Slide 11
Other sporozoite-based vaccines: Sanaria PfSPZ
• Irradiation-attenuated, aseptic, purified, vialed, cryopreserved, sporozoites
• Efficaceous against homologous challenge
• Less so against heterologous challenge
• Requires multiple i.v. injections• Long-term durability of protection
unknown
NECTM7 04/05/18Slide 12
Dan Carruci (L) and Stephen Hoffman (R)
Sissoko et al. Lancet Infect Dis 17: 498, 2017
5/4/2018
7
Other sporozoite-based vaccines: genetic attenuation
NECTM7 04/05/18Slide 13
Stefan Kappe trusting his vaccine
Illustration: Kreutzfeld, Müller, Matuschewski. Front Cell Infect Microbiol (2017)
Other sporozoite-based vaccines: CHMI under Chloroquine cover
NECTM7 04/05/18Slide 14
Robert Sauerwein
• Bites by quite few (<50) mosquitoes infected with virulent parasites
• CQ prophylaxis
• Remarkably efficient (sterile!) and durable (several years!) protection against homologous challenge
• Less so against heterologous challenge
• Protective mechanism unclear
Illustration: Roestenberg et al.N Engl J Med (2009)
5/4/2018
8
Vaccination against the liver stages
NECTM7 04/05/18Slide 15
• Subunit vaccines to induce mainly cellular immunity
• Many different antigens and combinations tested
• Numerous immunization protocols and regimens tested
Adrian Hill
Slide 16Cowman and Crabb. Cell 124: 755, 2006
Vaccination against merozoites
NECTM7 04/05/18
• Complex, multi-step process involving many host-parasite molecular interactions
• Invasion is fast (max. few minutes)• Major target of naturally acquired
immunity• Multiple pathways (redundancy)• Antigenic polymorphism
• Few targets thoroughly investigated
5/4/2018
9
The merozoite antigen PfRH5: the exception to the rule
NECTM7 04/05/18Slide 17
Simon Draper
Vaccination against the infected erythrocytes• Intracellular parasites expressing adhesive
antigens on the surface of the infected erythrocyte• These antigens function to avoid splenic
destruction of the infected erythrocytes (the reason that only ring-stages are seen in smears)
• The adhesins (mainly PfEMP1) are a major virulence factor
• … and (therefore) a major target of naturally acquired immunity
• Multiple evasion mechanisms• Substantial polymorphism• Clonal antigenic variation• …
Slide 18NECTM7 04/05/18
5/4/2018
10
Clinical presentation is related to site of IE sequestration
Centre for Medical Parasitology
06 March 2018Slide 19
Cerebral malaria
Severe malarial anaemia
Placental malaria
The infected erythrocytes: PfEMP1 and sequestration
NECTM7 04/05/18Slide 20
5/4/2018
11
PfEMP1-based vaccination
• Vaccination against disease rather than vaccination against infection• “Darwinian” vaccines, emulating/enhancing naturally acquired immunity• Impact on morbidity/mortality, probably little direct impact on transmission• Regular boosting: improved durability?• Protection appears to rely mainly on MBCs rather than on sustained high
IgG levels• Antigen polymorphism and clonal antigenic variation a major concern
• PfEMP1 proteins associated with severe malaria appear to be functionally and antigenically constrained
• Clinical Phase 1a/b trials of VAR2CSA-based vaccines against placental malaria in progress
NECTM7 04/05/18Slide 21
Vaccination against gametocytes (and beyond)
NECTM7 04/05/18Slide 22
• Transmission-blocking vaccines• Altruistic• Antigenic targets conserved• Require high coverage• Little or no boosting• Sustained high antibody levels
required.
5/4/2018
12
Malaria vaccine challenges
• The protective mechanisms are not always clear• Multiple, stage-restricted antigens• Antibody-dependent responses are often low and/or transient• Antigens are often polymorphic – some are also clonally variant• Immune escape
• Multi-antigen, multi-stage vaccines
• The main “customers” are low priority • Political incentives
NECTM7 04/05/18Slide 23
Malaria vaccines for whom?
• Residents of areas with transmission of malaria parasites• Vulnerable groups (e.g., young children, pregnant women)
• Travellers• Tourists• Soldiers
• What efficacy will be required?• What durability of protection (e.g. sustained antibody levels)?• Deployability?• Logistic challenges (accessibility, timing, doses required, financing).
NECTM7 04/05/18Slide 24
5/4/2018
13
• Careful prioritization of resources• Increased involvement by affected countries
• Continued research at all levels• Collaboration with affected country scientists
• Vaccines would likely be very cost-effective tools in malaria control and eradication
• … and a tool to reduce inequality
• We are not there yet!
NECTM7 04/05/18Slide 25
1900
1925
1950
1975
2000
2015
Vaccines and shrinking the map
Based on: Snow et al.Nature 550: 515, 2017
Acknowledgements
• Friends and colleagues at Centre for Medical Parasitology• Friends and colleagues everywhere else, not least in Africa!• Multiple sponsors for financial support over the years• You for listening
• Thank you!
NECTM7 04/05/18Slide 26
5/4/2018
14
NECTM7 04/05/18Slide 27