Impact of exposure to malaria and nutritional status on responses to the experimental malaria vaccine ChAd63 MVA ME-TRAP in 5-17 month-old children in Burkina Faso

Abstract

The experimental malaria vaccine ChAd63 MVA ME-TRAP previously showed protective efficacy against Plasmodium falciparum infection in Phase IIa sporozoite challenge studies in adults in the United Kingdom and in a Phase IIb field efficacy trial in Kenyan adults. However, it failed to demonstrate efficacy in a phase IIb trial in 5-17 month-old children in an area of high malaria transmission in Burkina Faso. This secondary analysis investigated whether exposure to malaria or nutritional status might be associated with reduced responses to vaccination in this cohort. Parasite blood smears and anti-AMA-1 IgG titres were used to assess history of exposure to malaria and weight-for-length Z scores were calculated to assess nutritional status. Differences in vaccine-specific anti-TRAP IgG titre and ex vivo IFNγ ELISpot response were measured between groups. In total, n = 336 volunteers randomised to receive the experimental vaccine regimen were included in this analysis. A positive smear microscopy result was associated with reduced anti-TRAP IgG titre (geometric mean titre: 2775 (uninfected) vs 1968 (infected), p = 0.025), whilst anti-AMA-1 IgG titres were weakly negatively correlated with reduced ex vivo IFNγ ELISpot response (r = -0.18, p = 0.008). Nutritional status was not associated with either humoral or cellular immunogenicity. Vaccine efficacy was also measured separately for vaccinees with positive and negative blood smears. Although not significant in either group compared to controls, vaccine efficacy measured by Cox hazard ratio was higher in uninfected compared to infected individuals (19.8% [p = 0.50] vs 3.3% [p = 0.69]). Overall, this data suggests exposure to malaria may be associated with impaired vaccine immunogenicity. This may have consequences for the testing and eventual deployment of various vaccines, in areas with high endemicity for malaria.

Trial registration: Pactr.org, identifier PACTR201208000404131; ClinicalTrials.gov, identifier NCT01635647.

Keywords: Burkina Faso; ME-TRAP; immunosuppression; malaria; nutrition; vaccine; viral vector.

Figure 1

T cell and antibody responses to the vaccine antigen ME-TRAP, stratified by parasite smear microscopy status. (A) IgG titres against TRAP, measured at day 0 and day 63 (one week post-boost vaccination). Data are shown in standardised ELISA units. (B) ex vivo IFNγ ELISpot response to ME-TRAP, measured at day 0 and day 63. Data are shown in spot forming cells per 10⁶ peripheral blood mononeucleocytes. (C) Fold change in IgG titre against TRAP between day 0 and day 63. (D) Fold change in ex vivo IFNγ ELISpot response to ME-TRAP between day 0 and day 63. For all plots, - and + indicate individuals split by negative and positive P. falciparum smear microscopy results respectively. p values shown are Mann-Whitney tests. Lines and error bars denote geomeans and 95% confidence intervals.

Figure 2

T cell and antibody responses to the vaccine antigen ME-TRAP, correlated with anti-AMA-1 IgG titres. (A) Anti-TRAP IgG titres measured at day 63 (one week post-boost vaccination) correlated with anti-AMA-1 IgG titres also measured at day 63. Data are shown in standardised ELISA units. (B) ex vivo IFNγ ELISpot response to ME-TRAP, measured at day 63 correlated with anti-AMA-1 IgG titres also measured at day 63. ELISpot data are shown in spot forming cells per 10⁶ peripheral blood mononeucleocytes and standardised ELISA units for anti-AMA-1 titres. Correlation was measured by Spearman r. Solid lines are simple linear regression with dotted lines showing 95% confidence intervals.

Figure 3

T cell and antibody responses to the vaccine antigen ME-TRAP, stratified by nutritional status. (A) Anti-TRAP IgG titres measured at day 63 (one week post-boost vaccination) stratified by weight-for-length Z scores <-2.0 and >-2.0. Data are shown in standardised ELISA units. (B) ex vivo IFNγ ELISpot response to ME-TRAP, measured at day 63 stratified by weight-for-length Z scores <-2.0 and >-2.0. Data are shown in spot forming cells per 10⁶ peripheral blood mononeucleocytes. WLZ <-2.0 suggests moderate or severe malnutrition. p values shown are Mann-Whitney tests. Lines and error bars denote geomeans and 95% confidence intervals.

Figure 4

Protective efficacy against clinical malaria, stratified by parasite smear microscopy status. (A) Kaplan-Meier survival analysis for patients meeting the primary case definition for malaria (defined as fever (axillary temperature ≥37.5°C) with P. falciparum count > 5,000 trophozoites/µl of blood). (B) Kaplan-Meier survival analysis for patients meeting the secondary case definition for malaria (defined as fever (axillary temperature ≥37.5°C) with P. falciparum count > 0 trophozoites/µl of blood). Participants receiving the experimental vaccine regimen were stratified by P. falciparum smear microscopy status (ME-TRAP & uninfected/ME-TRAP & infected) and compared to participants receiving the rabies control vaccine regimen.