Malaria vaccines where are we now?

Size: px

Start display at page:

Download "Malaria vaccines where are we now?"

Erica Pierce
5 years ago
Views:

1 Malaria vaccines where are we now? Lars Hviid Centre for Medical Parasitology Department of Immunology and Microbiology Slide 1 Background: A very interested but disinterested real doctor < Robert Killick-Kendrick 1

Naturally acquired immunity to malaria Incidence It takes a

develops first Pregnant women get malaria regardless Babies

2 Naturally acquired immunity to malaria Incidence 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! Disease Parasitaemia Deaths Age (years) Slide 3 The P. falciparum life cycle and potential vaccine targets Sporozoites Inf. hepatocytes Merozoites Inf. erythrocytes Gametocytes Mosquito stages Dias 4 Slide 4 2

3 Types of vaccines Empiric vaccines ( Trial-and-error ) Darwinian vaccines ( Emulation ) Intelligent design vaccines Slide 5 Vaccination against sporozoites Slide 6 3

4 Vaccination against sporozoites Slide 7 Already, I feel premonitory twinges of lonesomeness Paul F Russel: Man s mastery of malaria (1955) Ruth and Victor Nussenzweig Slide 8 4

5 The RTS,S vaccine (Mosquirix ) Based on the major sporozoite surface protein CSP, linked to hepatitis B surface antigen Assembled into non-infectious viruslike 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: mo. + booster mo. later Condition: Phase IV study to assess feasibility, impact, and safety concerns Slide 9 RTS,S vaccine efficacy (Olotu et al. New Engl J Med 374, 2519, 2016) 5

purified, vialed, cryopreserved, sporozoites Efficaceous against

6 Immune escape? Neafsey et al. N Engl J Med 2015 Slide 11 Other sporozoite-based vaccines: Sanaria PfSPZ Sissoko et al. Lancet Infect Dis 17: 498, 2017 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 Dan Carruci (L) and Stephen Hoffman (R) Slide 12 6

Other sporozoite-based vaccines: genetic attenuation Illustration:

Front Cell Infect Microbiol (2017) Stefan Kappe trusting his vaccine

Bites by quite few (<50) mosquitoes infected with virulent parasites CQ

) protection against homologous challenge Less so against heterologous

7 Other sporozoite-based vaccines: genetic attenuation Illustration: Kreutzfeld, Müller, Matuschewski. Front Cell Infect Microbiol (2017) Stefan Kappe trusting his vaccine Slide 13 Other sporozoite-based vaccines: CHMI under Chloroquine cover 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) Robert Sauerwein Slide 14 7

Vaccination against the liver stages Adrian Hill Subunit vaccines to induce mainly

protocols and regimens tested Slide 15 Vaccination against merozoites Complex, multi-step

few minutes) Major target of naturally acquired immunity Multiple pathways (redundancy)

8 Vaccination against the liver stages Adrian Hill Subunit vaccines to induce mainly cellular immunity Many different antigens and combinations tested Numerous immunization protocols and regimens tested Slide 15 Vaccination against merozoites 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 Slide 16 Cowman and Crabb. Cell 124: 755,

The merozoite antigen PfRH5: the exception to the rule Simon Draper Slide 17 Vaccination against the infected erythrocytes Intracellular parasites expressing adhesive antigens on the surface of the

9 The merozoite antigen PfRH5: the exception to the rule Simon Draper Slide 17 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 18 9

10 Centre for Medical Parasitology Clinical presentation is related to site of IE sequestration Cerebral malaria Placental malaria Severe malarial anaemia 06 March 2018 Slide 19 The infected erythrocytes: PfEMP1 and sequestration Slide 20 10

PfEMP1-based vaccination Vaccination against disease rather than vaccination against infection Darwinian vaccines, emulating/enhancing naturally acquired immunity Impact on morbidity/mortality,

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 Slide 21 Vaccination against gametocytes (and beyond) Transmission-blocking vaccines Altruistic Antigenic targets conserved Require high coverage Little or no boosting Sustained high antibody levels required. Slide 22 11

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 Slide 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). Slide 24 12

1900 Vaccines and shrinking the map 1925 1950 1975 Careful prioritization of resources Increased

scientists Vaccines would likely be very cost-effective tools in malaria control and eradication and a tool

nature 550: 515, 2017 Slide 25 Acknowledgements Friends and colleagues at Centre for Medical Parasitology

13 1900 Vaccines and shrinking the map 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! Based on: Snow et al.nature 550: 515, 2017 Slide 25 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! Slide 26 13

14 Slide 27 14

Malaria and vaccination: an update. Robert Sauerwein Dept. of Medical Microbiology Radboud University Medical Center, Nijmegen, the Netherlands

Malaria and vaccination: an update ) Robert Sauerwein Dept. of Medical Microbiology Radboud University Medical Center, Nijmegen, the Netherlands Malaria Control Drugs for treatment and/or prophylaxis Artemisinin-based