Peripheral blood monocyte-to-lymphocyte ratio at study enrollment predicts efficacy of the RTS,S malaria vaccine: analysis of pooled phase II clinical trial data

BMC Medicine

Philip Bejon⁴  Kevin Marsh⁴  Adrian VS Hill²  Selidji T Agnandji¹  Ally Olotu³  Helen A Fletcher²  George M Warimwe² 

[1] Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany;The Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom;Kenya Medical Research Institute-Wellcome Trust Research Programme, P.O. Box 230–80108, Kilifi, Kenya;Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford OX3 7LJ, United Kingdom

关键词: Monocyte-to-lymphocyte ratio;    Vaccine;    Malaria;   

Others  :  856938
DOI  :  10.1186/1741-7015-11-184

 received in 2013-05-22, accepted in 2013-07-26,  发布年份 2013

【 摘 要 】

Background

RTS,S is the most advanced candidate malaria vaccine but it is only partially protective and the causes of inter-individual variation in efficacy are poorly understood. Here, we investigated whether peripheral blood monocyte-to-lymphocyte ratios (ML ratio), previously shown to correlate with clinical malaria risk, could account for differences in RTS,S efficacy among phase II trial participants in Africa.

Methods

Of 11 geographical sites where RTS,S has been evaluated, pre-vaccination ML ratios were only available for trial participants in Kilifi, Kenya (N = 421) and Lambarene, Gabon (N = 189). Using time to first clinical malaria episode as the primary endpoint we evaluated the effect of accounting for ML ratio on RTS,S vaccine efficacy against clinical malaria by Cox regression modeling.

Results

The unadjusted efficacy of RTS,S in this combined dataset was 47% (95% confidence interval (CI) 26% to 62%, P <0.001). However, RTS,S efficacy decreased with increasing ML ratio, ranging from 67% (95% CI 64% to 70%) at an ML ratio of 0.1 to 5% (95% CI -3% to 13%) at an ML ratio of 0.6. The statistical interaction between RTS,S vaccination and ML ratio was still evident after adjustment for covariates associated with clinical malaria risk in this dataset.

Conclusion

The results suggest that stratification of study participants by ML ratio, easily measured from full differential blood counts before vaccination, might help identify children who are highly protected and those that are refractory to protection with the RTS,S vaccine. Identifying causes of low vaccine efficacy among individuals with high ML ratio could inform strategies to improve overall RTS,S vaccine efficacy.

Trial registration

ClinicalTrials.Gov numbers NCT00380393 and NCT00436007

【 授权许可】

   
2013 Warimwe et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Snow RW, Amratia P, Kabaria CW, Noor AM, Marsh K: The changing limits and incidence of malaria in Africa: 1939–2009. Adv Parasitol 2012, 78:169-262.
• [2]World Health Organization: World Malaria Report. Geneva, Switzerland: World Health Organization; 2011.
• [3]Agnandji ST, Lell B, Soulanoudjingar SS, Fernandes JF, Abossolo BP, Conzelmann C, Methogo BG, Doucka Y, Flamen A, Mordmüller B, Issifou S, Kremsner PG, Sacarlal J, Aide P, Lanaspa M, Aponte JJ, Nhamuave A, Quelhas D, Bassat Q, Mandjate S, Macete E, Alonso P, Abdulla S, Salim N, Juma O, Shomari M, Shubis K, Machera F, Hamad AS, Minja R, et al.: First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N Engl J Med 2011, 365:1863-1875.
• [4]Abdulla S, Oberholzer R, Juma O, Kubhoja S, Machera F, Membi C, Omari S, Urassa A, Mshinda H, Jumanne A, Salim N, Shomari M, Aebi T, Schellenberg DM, Carter T, Villafana T, Demoitié MA, Dubois MC, Leach A, Lievens M, Vekemans J, Cohen J, Ballou WR, Tanner M: Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N Engl J Med 2008, 359:2533-2544.
• [5]Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Milman J, Mandomando I, Spiessens B, Guinovart C, Espasa M, Bassat Q, Aide P, Ofori-Anyinam O, Navia MM, Corachan S, Ceuppens M, Dubois MC, Demoitié MA, Dubovsky F, Menéndez C, Tornieporth N, Ballou WR, Thompson R, Cohen J: Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet 2004, 364:1411-1420.
• [6]Aponte JJ, Aide P, Renom M, Mandomando I, Bassat Q, Sacarlal J, Manaca MN, Lafuente S, Barbosa A, Leach A, Lievens M, Vekemans J, Sigauque B, Dubois MC, Demoitié MA, Sillman M, Savarese B, McNeil JG, Macete E, Ballou WR, Cohen J, Alonso PL: Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial. Lancet 2007, 370:1543-1551.
• [7]Bojang KA, Milligan PJ, Pinder M, Vigneron L, Alloueche A, Kester KE, Ballou WR, Conway DJ, Reece WH, Gothard P, Yamuah L, Delchambre M, Voss G, Greenwood BM, Hill A, McAdam KP, Tornieporth N, Cohen JD, Doherty T, RTS, S Malaria Vaccine Trial Team: Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. Lancet 2001, 358:1927-1934.
• [8]Polhemus ME, Remich SA, Ogutu BR, Waitumbi JN, Otieno L, Apollo S, Cummings JF, Kester KE, Ockenhouse CF, Stewart A, Ofori-Anyinam O, Ramboer I, Cahill CP, Lievens M, Dubois MC, Demoitie MA, Leach A, Cohen J, Ballou WR, Heppner DG Jr: Evaluation of RTS,S/AS02A and RTS,S/AS01B in adults in a high malaria transmission area. PLoS One 2009, 4:e6465.
• [9]Sacarlal J, Aide P, Aponte JJ, Renom M, Leach A, Mandomando I, Lievens M, Bassat Q, Lafuente S, Macete E, Vekemans J, Guinovart C, Sigaúque B, Sillman M, Milman J, Dubois MC, Demoitié MA, Thonnard J, Menéndez C, Ballou WR, Cohen J, Alonso PL: Long-term safety and efficacy of the RTS, S/AS02A malaria vaccine in Mozambican children. J Infect Dis 2009, 200:329-336.
• [10]Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Aide P, Sigauque B, Milman J, Mandomando I, Bassat Q, Guinovart C, Espasa M, Corachan S, Lievens M, Navia MM, Dubois MC, Menendez C, Dubovsky F, Cohen J, Thompson R, Ballou WR: Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet 2005, 366:2012-2018.
• [11]Bejon P, Lusingu J, Olotu A, Leach A, Lievens M, Vekemans J, Mshamu S, Lang T, Gould J, Dubois MC, Demoitié MA, Stallaert JF, Vansadia P, Carter T, Njuguna P, Awuondo KO, Malabeja A, Abdul O, Gesase S, Mturi N, Drakeley CJ, Savarese B, Villafana T, Ballou WR, Cohen J, Riley EM, Lemnge MM, Marsh K, von Seidlein L: Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N Engl J Med 2008, 359:2521-2532.
• [12]Asante KP, Abdulla S, Agnandji S, Lyimo J, Vekemans J, Soulanoudjingar S, Owusu R, Shomari M, Leach A, Jongert E, Salim N, Fernandes JF, Dosoo D, Chikawe M, Issifou S, Osei-Kwakye K, Lievens M, Paricek M, Möller T, Apanga S, Mwangoka G, Dubois MC, Madi T, Kwara E, Minja R, Hounkpatin AB, Boahen O, Kayan K, Adjei G, Chandramohan D, et al.: Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial. Lancet Infect Dis 2011, 11:741-749.
• [13]Olotu A, Lusingu J, Leach A, Lievens M, Vekemans J, Msham S, Lang T, Gould J, Dubois MC, Jongert E, Vansadia P, Carter T, Njuguna P, Awuondo KO, Malabeja A, Abdul O, Gesase S, Mturi N, Drakeley CJ, Savarese B, Villafana T, Lapierre D, Ballou WR, Cohen J, Lemnge MM, Peshu N, Marsh K, Riley EM, von Seidlein L, Bejon P: Efficacy of RTS, S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5–17 months in Kenya and Tanzania: a randomised controlled trial. Lancet Infect Dis 2011, 11:102-109.
• [14]Agnandji ST, Lell B, Fernandes JF, Abossolo BP, Methogo BG, Kabwende AL, Adegnika AA, Mordmuller B, Issifou S, Kremsner PG, Sacarlal J, Aide P, Lanaspa M, Aponte JJ, Machevo S, Acacio S, Bulo H, Sigauque B, Macete E, Alonso P, Abdulla S, Salim N, Minja R, Mpina M, Ahmed S, Ali AM, Mtoro AT, Hamad AS, Mutani P, Tanner M, RTS,S Clinical Trials Partnership, et al.: A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N Engl J Med 2012, 367:2284-2295.
• [15]Olotu A, Fegan G, Wambua J, Nyangweso G, Awuondo KO, Leach A, Lievens M, Leboulleux D, Njuguna P, Peshu N, Marsh K, Bejon P: Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure. N Engl J Med 2013, 368:1111-1120.
• [16]Bejon P, White MT, Olotu A, Bojang K, Lusingu JP, Salim N, Otsyula NN, Agnandji ST, Asante KP, Owusu-Agyei S, Abdulla S, Ghani AC: Efficacy of RTS,S malaria vaccines: individual-participant pooled analysis of phase 2 data. Lancet Infect Dis 2013, 13:319-327.
• [17]Warimwe GM, Murungi LM, Kamuyu G, Nyangweso GM, Wambua J, Naranbhai V, Fletcher HA, Hill AV, Bejon P, Osier FH, Marsh K: The ratio of monocytes to lymphocytes in peripheral blood correlates with increased susceptibility to clinical malaria in Kenyan children. PLoS One 2013, 8:e57320.
• [18]Agnandji ST, Asante KP, Lyimo J, Vekemans J, Soulanoudjingar SS, Owusu R, Shomari M, Leach A, Fernandes J, Dosoo D, Chikawe M, Issifou S, Osei-Kwakye K, Lievens M, Paricek M, Apanga S, Mwangoka G, Okissi B, Kwara E, Minja R, Lange J, Boahen O, Kayan K, Adjei G, Chandramohan D, Jongert E, Demoitié MA, Dubois MC, Carter T, Vansadia P, et al.: Evaluation of the safety and immunogenicity of the RTS,S/AS01E malaria candidate vaccine when integrated in the expanded program of immunization. J Infect Dis 2010, 202:1076-1087.
• [19]Mwangi TW, Ross A, Snow RW, Marsh K: Case definitions of clinical malaria under different transmission conditions in Kilifi District, Kenya. J Infect Dis 2005, 191:1932-1939.
• [20]Olotu A, Fegan G, Wambua J, Nyangweso G, Ogada E, Drakeley C, Marsh K, Bejon P: Estimating individual exposure to malaria using local prevalence of malaria infection in the field. PLoS One 2012, 7:e32929.
• [21]Olotu A, Moris P, Mwacharo J, Vekemans J, Kimani D, Janssens M, Kai O, Jongert E, Lievens M, Leach A, Villafana T, Savarese B, Marsh K, Cohen J, Bejon P: Circumsporozoite-specific T cell responses in children vaccinated with RTS,S/AS01E and protection against P. falciparum clinical malaria. PLoS One 2011, 6:e25786.
• [22]Mitchell LA, Henderson AJ, Dow SW: Suppression of vaccine immunity by inflammatory monocytes. J Immunol 2012, 189:5612-5621.
• [23]Norris BA, Uebelhoer LS, Nakaya HI, Price AA, Grakoui A, Pulendran B: Chronic but not acute virus infection induces sustained expansion of myeloid suppressor cell numbers that inhibit viral-specific T cell immunity. Immunity 2013, 38:309-321.