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Lars Hviid (lhviid@sund.ku.dk)Centre for Medical ParasitologyDepartment of Immunology and Microbiology

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Malaria vaccines – where are we now?

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Background: A very interested – but disinterested – “real” doctor

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Robert Killick-Kendrick

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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”!

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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

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Dias 4

Slide 4

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Types of vaccines

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• Empiric vaccines (“Trial-and-error”)

• “Darwinian” vaccines (“Emulation”)

• “Intelligent design” vaccines

Vaccination against sporozoites

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Vaccination against sporozoites

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“Already, I feel premonitory twinges of lonesomeness…”Paul F Russel: Man’s mastery of malaria (1955)

Ruth and Victor Nussenzweig

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The RTS,S vaccine (Mosquirix ®)

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• 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)

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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

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Dan Carruci (L) and Stephen Hoffman (R)

Sissoko et al. Lancet Infect Dis 17: 498, 2017

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Other sporozoite-based vaccines: genetic attenuation

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Stefan Kappe trusting his vaccine

Illustration: Kreutzfeld, Müller, Matuschewski. Front Cell Infect Microbiol (2017)

Other sporozoite-based vaccines: CHMI under Chloroquine cover

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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)

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Vaccination against the liver stages

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• 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

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• 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

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The merozoite antigen PfRH5: the exception to the rule

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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• …

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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

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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

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Vaccination against gametocytes (and beyond)

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• Transmission-blocking vaccines• Altruistic• Antigenic targets conserved• Require high coverage• Little or no boosting• Sustained high antibody levels

required.

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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

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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).

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• 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!

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1900

1925

1950

1975

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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!

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