Anaemia in a phase 2 study of a blood stage falciparum malaria vaccine.
BACKGROUND
A Phase 1-2b study of the blood stage malaria vaccine AMA1-C1/Alhydrogel was conducted in 336 children in Donéguébougou and Bancoumana, Mali. In the Phase 2 portion of the study (n = 300), no impact on parasite density or clinical malaria was seen; however, children who received the study vaccine had a higher frequency of anaemia (defined as haemoglobin < 8.5 g/dL) compared to those who received the comparator vaccine (Hiberix). This effect was one of many tested and was not significant after adjusting for multiple comparisons.


METHODS
To further investigate the possible impact of vaccination on anaemia, additional analyses were conducted including patients from the Phase 1 portion of the study and controlling for baseline haemoglobin, haemoglobin types S or C, alpha-thalassaemia, G6PD deficiency, and age. A multiplicative intensity model was used, which generalizes Cox regression to allow for multiple events. Frailty effects for each subject were used to account for correlation of multiple anaemia events within the same subject. Intensity rates were calculated with reference to calendar time instead of time after randomization in order to account for staggered enrollment and seasonal effects of malaria incidence. Associations of anaemia with anti-AMA1 antibody were further explored using a similar analysis.


RESULTS
A strong effect of vaccine on the incidence of anaemia (risk ratio [AMA1-C1 to comparator (Hiberix)]= 2.01, 95% confidence interval [1.26,3.20]) was demonstrated even after adjusting for baseline haemoglobin, haemoglobinopathies, and age, and using more sophisticated statistical models. Anti-AMA1 antibody levels were not associated with this effect.


CONCLUSIONS
While these additional analyses show a robust effect of vaccination on anaemia, this is an intensive exploration of secondary results and should, therefore, be interpreted with caution. Possible mechanisms of the apparent adverse effect on haemoglobin of vaccination with AMA1-C1/Alhydrogel and implications for blood stage vaccine development are discussed. The potential impact on malaria-associated anaemia should be closely evaluated in clinical trials of AMA1 and other blood stage vaccines in malaria-exposed populations.
Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIAID/NIH), Rockville, Maryland, USA. ellisru@niaid.nih.gov
Ruth D
RD
Ellis
Michael P
MP
Fay
Issaka
I
Sagara
Alassane
A
Dicko
Kazutoyo
K
Miura
Merepen A
MA
Guindo
Aldiouma
A
Guindo
Mahamadou S
MS
Sissoko
Ogobara K
OK
Doumbo
Dapa
D
Diallo
D000740:Anemia / Q000139:chemically induced*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D015994:Incidence; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000276:immunology; D016778:Malaria, Falciparum / Q000150:complications* / Q000517:prevention & control*; D008297:Male; D008302:Mali
D017780:Malaria Vaccines
Blood. 2004 Aug 15;104(4):1198-200
15113756
PLoS One. 2009;4(3):e4708
19262754
Parasite Immunol. 2009 Sep;31(9):492-500
19691554
Curr Hematol Rep. 2004 Mar;3(2):97-106
14965485
Am J Trop Med Hyg. 1991 Sep;45(3):297-308
1928564
Clin Immunol. 2008 Feb;126(2):211-21
17945537
Hum Vaccin. 2010 Aug;6(8):627-34
20519960
PLoS One. 2008 Feb 13;3(2):e1563
18270560
Nature. 1961 Nov 25;192:733-7
13880318
PLoS Med. 2007 Mar;4(3):e66
17355169
Blood. 2010 Jun 3;115(22):4551-8
20231425
Am J Trop Med Hyg. 2002 Jun;66(6):672-9
12224573
Acta Trop. 2010 Feb;113(2):155-61
19874795
Blood. 2004 Oct 1;104(7):2003-6
15198952
Parasitol Today. 2000 Nov;16(11):469-76
11063857
Vaccine. 2009 May 18;27(23):3090-8
19428923
Vaccine. 2008 Jan 10;26(2):193-200
18054414
JAMA. 2007 May 23;297(20):2220-6
17519411
Expert Rev Vaccines. 2009 Jan;8(1):91-102
19093776
Curr Opin Hematol. 2003 Mar;10(2):108-14
12579035
J Infect Dis. 2008 Nov 1;198(9):1265-75
18752444
Malar J. 2010 Jun 21;9:175
20565971