Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya

Bernhards R Ogutu, Odika J Apollo, Denise McKinney, Willis Okoth, Joram Siangla, Filip Dubovsky, Kathryn Tucker, John N Waitumbi, Carter Diggs, Janet Wittes, Elissa Malkin, Amanda Leach, Lorraine A Soisson, Jessica B Milman, Lucas Otieno, Carolyn A Holland, Mark Polhemus, Shon A Remich, Christian F Ockenhouse, Joe Cohen, W Ripley Ballou, Samuel K Martin, Evelina Angov, V Ann Stewart, Jeffrey A Lyon, D Gray Heppner, Mark R Withers, MSP-1 Malaria Vaccine Working Group, K Monique Wasunna, Nadia Tornieporth, Marie Claude Dubois, Els de Kock, Alfred Tiono, Kenneth Eckels, R Scott Miller, Sally Robinson, Farhat Khan, Rich Potter, Sathit Pichyangkul, Montip Gettyacamin, Mark Fukuda, Bernhards R Ogutu, Odika J Apollo, Denise McKinney, Willis Okoth, Joram Siangla, Filip Dubovsky, Kathryn Tucker, John N Waitumbi, Carter Diggs, Janet Wittes, Elissa Malkin, Amanda Leach, Lorraine A Soisson, Jessica B Milman, Lucas Otieno, Carolyn A Holland, Mark Polhemus, Shon A Remich, Christian F Ockenhouse, Joe Cohen, W Ripley Ballou, Samuel K Martin, Evelina Angov, V Ann Stewart, Jeffrey A Lyon, D Gray Heppner, Mark R Withers, MSP-1 Malaria Vaccine Working Group, K Monique Wasunna, Nadia Tornieporth, Marie Claude Dubois, Els de Kock, Alfred Tiono, Kenneth Eckels, R Scott Miller, Sally Robinson, Farhat Khan, Rich Potter, Sathit Pichyangkul, Montip Gettyacamin, Mark Fukuda

Abstract

Objective: The antigen, falciparum malaria protein 1 (FMP1), represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1) of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System), it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccine's safety, immunogenicity, and efficacy in African children.

Methods: A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12-47 months in general good health.Children were randomised in a 1ratio1 fashion to receive either FMP1/AS02 (50 microg) or Rabipur(R) rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature >/=37.5 degrees C with asexual parasitaemia of >/=50,000 parasites/microL of blood) occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE) was measured over a six-month period following third vaccinations.

Results: 374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-1(42) antibody concentrations increased from1.3 microg/mL to 27.3 microg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: -26% to +28%; p-value = 0.7).

Conclusions: FMP1/AS02 is not a promising candidate for further development as a monovalent malaria vaccine. Future MSP-1(42) vaccine development should focus on other formulations and antigen constructs.

Trial registration: Clinicaltrials.gov NCT00223990.

Conflict of interest statement

Competing Interests: Drs. Jeffrey Lyon and Evelina Angov hold a patent for production of the FMP1 antigen. Drs. Amanda Leach, W. Ripley Ballou, and Joe Cohen are employees of GlaxoSmithKline Biologicals, the manufacturer of AS02. Drs. Elissa Malkin and Filip Dubovsky and Ms. Jessica Milman were employed by The PATH Malaria Vaccine Initiative, which provided funding for this trial.

Figures

Figure 1. Schematic of trial profile.
Figure 1. Schematic of trial profile.
Figure 2. Trial profile.
Figure 2. Trial profile.
Figure 3. Kaplan-Meier curves for cumulative proportion…
Figure 3. Kaplan-Meier curves for cumulative proportion with at least one episode of clinical malaria; both intention-to-treat and according-to-protocol cohorts are presented.
Figure 4. Geometric mean anti-MSP-1 42 antibody…
Figure 4. Geometric mean anti-MSP-142 antibody concentrations estimated from the model, log10-transformed.

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