Extended safety, immunogenicity and efficacy of a blood-stage malaria vaccine in malian children: 24-month follow-up of a randomized, double-blinded phase 2 trial

Matthew B Laurens, Mahamadou A Thera, Drissa Coulibaly, Amed Ouattara, Abdoulaye K Kone, Ando B Guindo, Karim Traore, Idrissa Traore, Bourema Kouriba, Dapa A Diallo, Issa Diarra, Modibo Daou, Amagana Dolo, Youssouf Tolo, Mahamadou S Sissoko, Amadou Niangaly, Mady Sissoko, Shannon Takala-Harrison, Kirsten E Lyke, Yukun Wu, William C Blackwelder, Olivier Godeaux, Johan Vekemans, Marie-Claude Dubois, W Ripley Ballou, Joe Cohen, Tina Dube, Lorraine Soisson, Carter L Diggs, Brent House, Jason W Bennett, David E Lanar, Sheetij Dutta, D Gray Heppner, Christopher V Plowe, Ogobara K Doumbo, Matthew B Laurens, Mahamadou A Thera, Drissa Coulibaly, Amed Ouattara, Abdoulaye K Kone, Ando B Guindo, Karim Traore, Idrissa Traore, Bourema Kouriba, Dapa A Diallo, Issa Diarra, Modibo Daou, Amagana Dolo, Youssouf Tolo, Mahamadou S Sissoko, Amadou Niangaly, Mady Sissoko, Shannon Takala-Harrison, Kirsten E Lyke, Yukun Wu, William C Blackwelder, Olivier Godeaux, Johan Vekemans, Marie-Claude Dubois, W Ripley Ballou, Joe Cohen, Tina Dube, Lorraine Soisson, Carter L Diggs, Brent House, Jason W Bennett, David E Lanar, Sheetij Dutta, D Gray Heppner, Christopher V Plowe, Ogobara K Doumbo

Abstract

Background: The FMP2.1/AS02A candidate malaria vaccine was tested in a Phase 2 study in Mali. Based on results from the first eight months of follow-up, the vaccine appeared well-tolerated and immunogenic. It had no significant efficacy based on the primary endpoint, clinical malaria, but marginal efficacy against clinical malaria in secondary analyses, and high allele-specific efficacy. Extended follow-up was conducted to evaluate extended safety, immunogenicity and efficacy.

Methods: A randomized, double-blinded trial of safety, immunogenicity and efficacy of the candidate Plasmodium falciparum apical membrane antigen 1 (AMA1) vaccine FMP2.1/AS02A was conducted in Bandiagara, Mali. Children aged 1-6 years were randomized in a 1∶1 ratio to receive FMP2.1/AS02A or control rabies vaccine on days 0, 30 and 60. Using active and passive surveillance, clinical malaria and adverse events as well as antibodies against P. falciparum AMA1 were monitored for 24 months after the first vaccination, spanning two malaria seasons.

Findings: 400 children were enrolled. Serious adverse events occurred in nine participants in the FMP2.1/AS02A group and three in the control group; none was considered related to study vaccination. After two years, anti-AMA1 immune responses remained significantly higher in the FMP2.1/AS02A group than in the control group. For the entire 24-month follow-up period, vaccine efficacy was 7.6% (p = 0.51) against first clinical malaria episodes and 9.9% (p = 0.19) against all malaria episodes. For the final 16-month follow-up period, vaccine efficacy was 0.9% (p = 0.98) against all malaria episodes. Allele-specific efficacy seen in the first malaria season did not extend into the second season of follow-up.

Interpretation: Allele-specific vaccine efficacy was not sustained in the second malaria season, despite continued high levels of anti-AMA1 antibodies. This study presents an opportunity to evaluate correlates of partial protection against clinical malaria that waned during the second malaria season.

Trial registration: Clinicaltrials.gov NCT00460525 NCT00460525.

Conflict of interest statement

Competing Interests: SD and DEL hold patents for the FMP2.1 vaccine antigen. OG, JV, MCD, WRB, and JC are employees of GlaxoSmithKline Vaccines, the manufacturer of the proprietary Adjuvant System AS02A, and hold shares in GlaxoSmithKline. None of the other authors have declared conflict of interest. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Disposition of study participants.
Figure 1. Disposition of study participants.
Figure 2. Levels of anti-apical membrane antigen…
Figure 2. Levels of anti-apical membrane antigen 1 (AMA1) antibody to homologous recombinant AMA1 for FMP2.1/AS02A vaccine and rabies vaccine recipients during the entire follow-up period (study days 0–730).
Error bars indicate 95% confidence intervals.
Figure 3. Cumulative incidence of first clinical…
Figure 3. Cumulative incidence of first clinical malaria episode by treatment group during the entire follow-up period (study days 0–730), intention-to-treat.
Figure 4. Vaccine efficacy against first episode…
Figure 4. Vaccine efficacy against first episode of clinical malaria with apical membrane antigen 1 (AMA1) cluster 1 loop (c1L) identical to the vaccine strain 3D7 during the entire follow-up period (study days 0–730), intention-to-treat.

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