Strain-specific Plasmodium falciparum growth inhibition among Malian children immunized with a blood-stage malaria vaccine

The blood-stage malaria vaccine FMP2.1/AS02A, comprised of recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1) and the adjuvant system AS02A, had strain-specific efficacy against clinical malaria caused by P. falciparum with the vaccine strain 3D7 AMA1 sequence. To evaluate a potential correlate of protection, we measured the ability of participant sera to inhibit growth of 3D7 and FVO strains in vitro using high-throughput growth inhibition assay (GIA) testing. Sera from 400 children randomized to receive either malaria vaccine or a control rabies vaccine were assessed at baseline and over two annual malaria transmission seasons after immunization. Baseline GIA against vaccine strain 3D7 and FVO strain was similar in both groups, but more children in the malaria vaccine group than in the control group had 3D7 and FVO GIA activity ≥15% 30 days after the last vaccination (day 90) (49% vs. 16%, p<0.0001; and 71.8% vs. 60.4%, p = 0.02). From baseline to day 90, 3D7 GIA in the vaccine group was 7.4 times the mean increase in the control group (p<0.0001). In AMA1 vaccinees, 3D7 GIA activity subsequently returned to baseline one year after vaccination (day 364) and did not correlate with efficacy in the extended efficacy time period to day 730. In Cox proportional hazards regression models with time-varying covariates, there was a slight suggestion of an association between 3D7 GIA activity and increased risk of clinical malaria between day 90 and day 240. We conclude that vaccination with this AMA1-based malaria vaccine increased inhibition of parasite growth, but this increase was not associated with allele-specific efficacy in the first malaria season. These results provide a framework for testing functional immune correlates of protection against clinical malaria in field trials, and will help to guide similar analyses for next-generation malaria vaccines. Clinical trials registry: This clinical trial was registered on clinicaltrials.gov, registry number NCT00460525.

[1]  F. Lunel,et al.  Mechanisms underlying the monocyte-mediated antibody-dependent killing of Plasmodium falciparum asexual blood stages , 2015, The Journal of Experimental Medicine.

[2]  E. Bergmann-Leitner,et al.  Miniaturized Growth Inhibition Assay to Assess the Anti-blood Stage Activity of Antibodies. , 2015, Methods in molecular biology.

[3]  Bjoern Peters,et al.  Ex vivo tetramer staining and cell surface phenotyping for early activation markers CD38 and HLA-DR to enumerate and characterize malaria antigen-specific CD8+ T-cells induced in human volunteers immunized with a Plasmodium falciparum adenovirus-vectored malaria vaccine expressing AMA1 , 2013, Malaria Journal.

[4]  D. Carucci,et al.  DNA Prime/Adenovirus Boost Malaria Vaccine Encoding P. falciparum CSP and AMA1 Induces Sterile Protection Associated with Cell-Mediated Immunity , 2013, PloS one.

[5]  O. Doumbo,et al.  Molecular basis of allele-specific efficacy of a blood-stage malaria vaccine: vaccine development implications. , 2013, The Journal of infectious diseases.

[6]  J. Stockman.  A Field Trial to Assess a Blood-Stage Malaria Vaccine , 2013 .

[7]  A. Hubbard,et al.  Antibodies to Plasmodium falciparum antigens predict a higher risk of malaria but protection from symptoms once parasitemic. , 2011, The Journal of infectious diseases.

[8]  K. Marsh,et al.  Effect of the Pre-erythrocytic Candidate Malaria Vaccine RTS,S/AS01E on Blood Stage Immunity in Young Children , 2011, The Journal of infectious diseases.

[9]  Peter D. Crompton,et al.  In Vitro Growth-Inhibitory Activity and Malaria Risk in a Cohort Study in Mali , 2009, Infection and Immunity.

[10]  M. P. Cummings,et al.  Extreme Polymorphism in a Vaccine Antigen and Risk of Clinical Malaria: Implications for Vaccine Development , 2009, Science Translational Medicine.

[11]  M. Fay,et al.  Anti-Apical-Membrane-Antigen-1 Antibody Is More Effective than Anti-42-Kilodalton-Merozoite-Surface-Protein-1 Antibody in Inhibiting Plasmodium falciparum Growth, as Determined by the In Vitro Growth Inhibition Assay , 2009, Clinical and Vaccine Immunology.

[12]  V. A. Stewart,et al.  Phase 1/2a Study of the Malaria Vaccine Candidate Apical Membrane Antigen-1 (AMA-1) Administered in Adjuvant System AS01B or AS02A , 2009, PloS one.

[13]  K. Marsh,et al.  Acquisition of Growth-Inhibitory Antibodies against Blood-Stage Plasmodium falciparum , 2008, PloS one.

[14]  Danny W. Wilson,et al.  Antibody-Mediated Growth Inhibition of Plasmodium falciparum: Relationship to Age and Protection from Parasitemia in Kenyan Children and Adults , 2008, PloS one.

[15]  M. Fay,et al.  Phase 1 Trial of AMA1-C1/Alhydrogel plus CPG 7909: An Asexual Blood-Stage Vaccine for Plasmodium falciparum Malaria , 2008, PloS one.

[16]  E. Bergmann-Leitner,et al.  Evaluation of immunoglobulin purification methods and their impact on quality and yield of antigen-specific antibodies , 2008, Malaria Journal.

[17]  V. A. Stewart,et al.  Safety and Immunogenicity of an AMA-1 Malaria Vaccine in Malian Adults: Results of a Phase 1 Randomized Controlled Trial , 2008, PloS one.

[18]  A. Batchelor,et al.  Structural basis of antigenic escape of a malaria vaccine candidate , 2007, Proceedings of the National Academy of Sciences.

[19]  E. Bergmann-Leitner,et al.  Critical evaluation of different methods for measuring the functional activity of antibodies against malaria blood stage antigens. , 2006, The American journal of tropical medicine and hygiene.

[20]  Hong Zhou,et al.  Phase 1 Clinical Trial of Apical Membrane Antigen 1: an Asexual Blood-Stage Vaccine for Plasmodium falciparum Malaria , 2005, Infection and Immunity.

[21]  青木 彩佳.  Serine Repeat Antigen（SERA5）Is Predominantly Expressed among the SERA Multigene Family of Plasmodium falciparum, and the Acquired Antibody Titers Correlate with Serum Inhibition of the Parasite Growth , 2005 .

[22]  L. Marrama,et al.  Antibodies to the conserved C-terminal domain of the Plasmodium falciparum merozoite surface protein 1 and to the merozoite extract and their relationship with in vitro inhibitory antibodies and protection against clinical malaria in a Senegalese village. , 2005, The Journal of infectious diseases.

[23]  C. Rogier,et al.  Cytophilic Immunoglobulin Responses to Plasmodium falciparum Glutamate-Rich Protein Are Correlated with Protection against Clinical Malaria in Dielmo, Senegal , 2000, Infection and Immunity.

[24]  B. Nahlen,et al.  Differential effect and interaction of monocytes, hyperimmune sera, and immunoglobulin G on the growth of asexual stage Plasmodium falciparum parasites. , 1999, The American journal of tropical medicine and hygiene.

[25]  A. Thomas,et al.  The Glutamate-Rich Protein (GLURP) of Plasmodium falciparum Is a Target for Antibody-Dependent Monocyte-Mediated Inhibition of Parasite Growth In Vitro , 1998, Infection and Immunity.

[26]  F. Lunel,et al.  Mechanisms underlying the monocyte-mediated antibody-dependent killing of Plasmodium falciparum asexual blood stages , 1995, The Journal of Experimental Medicine.

[27]  A. Tartar,et al.  Merozoite surface protein-3: a malaria protein inducing antibodies that promote Plasmodium falciparum killing by cooperation with blood monocytes. , 1994, Blood.

[28]  A. Sabchareon,et al.  Antibodies that protect humans against Plasmodium falciparum blood stages do not on their own inhibit parasite growth and invasion in vitro, but act in cooperation with monocytes , 1990, The Journal of experimental medicine.

[29]  R. Hayes,et al.  Antibodies to blood stage antigens of Plasmodium falciparum in rural Gambians and their relation to protection against infection. , 1989, Transactions of the Royal Society of Tropical Medicine and Hygiene.