Abdulla, Salim

Greenwood, Brian

Hamel, Mary J

LSHTM Research Online

Hamel, MJ; Abdulla, S; Greenwood, B; Comm, SSW (2012) RTS,S/AS01Malaria Vaccine in African Children REPLY. The New England jour-nal of medicine, 366 (8). pp. 765-766. ISSN 0028-4793Downloaded from: http://researchonline.lshtm.ac.uk/57353/DOI:Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.Available under license: Copyright the publishersn engl j med 366;8 nejm.org february 23, 2012764T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n ec o r r e s p o n d e n c eRTS,S/AS01 Malaria Vaccine in African ChildrenTo the Editor: In the article by the RTS,S Clini-cal Trials Partnership (Nov. 17 issue)1 on the phase 3 trial of RTS,S (ClinicalTrials.gov num-ber, NCT00866619), an analysis of the efficacy of RTS,S/AS01 against severe malaria was not re-ported for the vaccine’s target age group of in-fants who were 6 to 12 weeks of age and who received RTS,S with routine childhood vaccines. However, this efficacy can be calculated as 17% (P = 0.23) (see Table 1 in the Supplementary Ap-pendix, available with the full text of this letter at NEJM.org). Therefore, in the age group for whom RTS,S is intended, the efficacy against severe malaria was minimal. This finding was unex-pected,2 and the goal of 50% efficacy against se-vere malaria of the Malaria Vaccine Technology Roadmap (www.malariavaccine.org/files/Malaria_ Vaccine_TRM_Final.pdf) was not met.Moreover, in the reported 12-month data, there was already significant waning of vaccine efficacy against clinical malaria, and the 17% efficacy against severe malaria in young infants was measured over an average of 7 months. Thus, over longer periods, there will probably be less efficacy. Lower vaccine immunogenicity3,4 and the rapid waning of induced antibodies and vaccine efficacy5 shown in phase 2a and field trials1,4,5 probably contribute to the lower efficacy of RTS,S in young infants. By the time severe malaria develops in infants vaccinated at 2 to 4 months of age (for instance, 7 months after vaccination), vaccine efficacy may be minimal.Adrian V.S. Hill, D.M., D.Phil.Jenner Institute Oxford, United Kingdom adrian.hill@ndm.ox.ac.ukDr. Hill reports collaborating with GlaxoSmithKline Biologi-cals and the Program for Appropriate Technology in Health Malaria Initiative to assess RTS,S/AS02 and being a coinventor and codeveloper of other malaria vaccine candidates. No other potential conflict of interest relevant to this letter was reported.1. RTS,S Clinical Trials Partnership. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N Engl J Med 2011;365:1863-75.2. Asante KP, Abdulla S, Agnandji S, 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; 11:741-9.3. Abdulla S, Oberholzer R, Juma O, et al. Safety and immuno-genicity of RTS,S/AS02D malaria vaccine in infants. N Engl J Med 2008;359:2533-44.4. Aide P, Aponte JJ, Renom M, et al. Safety, immunogenicity and duration of protection of the RTS,S/AS02(D) malaria vaccine: one year follow-up of a randomized controlled phase I/IIb trial. PLoS One 2010;5(11):e13838.5. Guinovart C, Aponte JJ, Sacarlal J, et al. Insights into long-lasting protection induced by RTS,S/AS02A malaria vaccine: fur-ther results from a phase IIb trial in Mozambican children. PLoS One 2009;4(4):e5165.To the Editor: In the fight against malaria, people must be careful not to overestimate the impact of any single new intervention. I have concerns that the vaccine’s researchers “did not observe a reduction in the rate of death from ma-laria or from any cause” in the vaccine group. I also am concerned that the article may be mis-leading when the authors state that the “vaccine reduced malaria by half.” As a Peace Corps volun-teer in Senegal, I saw how news could be mis-interpreted in rural villages. In my current pro-this week’s letters764 RTS,S/AS01 Malaria Vaccine in African Children766 Escherichia coli O104:H4 Outbreak in Germany767 Apixaban versus Enoxaparin in Medically Ill  Patients768 A Man with Memory Loss and Partial Seizures770 Machine Perfusion or Cold Storage in Deceased-Donor Kidney TransplantationThe New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on January 21, 2014. For personal use only. No other uses without permission.  Copyright © 2012 Massachusetts Medical Society. All rights reserved. correspondencen engl j med 366;8 nejm.org february 23, 2012 765grams for malaria prevention, I have also seen the positive impact of our work. The hope sur-rounding this vaccine may tempt populations in malaria-endemic countries to abandon proven methods such as insecticide-treated bed nets. This would be a tragedy, because such public health interventions are working and have been associated with a 20% decrease in deaths from malaria over the past 10 years and with complete eradication of the disease in several countries.1Andrew C.L. Sherman, M.D.University of Rochester Rochester, NY andrew_sherman@urmc.rochester.eduNo potential conflict of interest relevant to this letter was re-ported.1. World malaria report 2010. Geneva: World Health Organiza-tion, 2010.To the Editor: The RTS,S Clinical Trials Part-nership describes the favorable interim results of the first large-scale vaccine field trial ever con-ducted for a human parasitic disease, in this case Plasmodium falciparum malaria, which is  respon-sible for most of approximately 655,000 yearly deaths from malaria.1 We believe that the release of these initial 14-month data showing an approx-imate 56% reduction in the incidence of first clinical malaria episodes in the older cohort of children (5 to 17 months of age) will enable early consideration of the potential impact of the vac-cine in sub-Saharan Africa by public health plan-ners. This consideration will facilitate efficient review by the European Medicines Agency once the trial is complete, accelerating licensure. Should the final results of the study, expected in late 2014,2  confirm the net benefits seen in this in-terim analysis, every day saved on the pathway to implementing the RTS,S immunization program will reduce suffering and potentially save lives.Thomas L. Richie, M.D., Ph.D.U.S. Military Malaria Vaccine Program Silver Spring, MD thomas.richie@med.navy.milRichard L. Haberberger, Ph.D.Naval Medical Research Center Silver Spring, MDNo potential conflict of interest relevant to this letter was re-ported.1. World Malaria Report 2011. Geneva: World Health Organi-zation, 2011:72-4.2. World Health Organization. Malaria: initiatives for vaccine research (IVR) (http://www.who.int/vaccine_research/diseases/malaria/vaccine_candidate_policy/en/).The Authors Reply: Hill’s reanalysis of our data is flawed, and the calculated estimate of vaccine efficacy in the younger age category is incorrect. Hill erroneously assumed that all cases of severe malaria that did not occur during the 12-month postvaccination period in the first 6000 children enrolled in the older age category occurred in the younger age category. He overlooked the fact that an additional 2923 children were enrolled in the older age category and that follow-up extended up to 22 months after vaccination, providing more participants and a longer follow-up period dur-ing which cases of severe malaria in these older children contributed to the pooled analysis (see Table 7 in the Supplementary Appendix of our ar-ticle, available at NEJM.org). Hill incorrectly as-signed 187 cases of severe malaria to the younger age category, whereas there were only 66 cases (Table 10a in the Supplementary Appendix).The lower estimate of vaccine efficacy against severe malaria in the pooled age categories as compared with the first 6000 children in the older age category who were followed for 12 months might be explained by lower vaccine ef-ficacy against severe malaria in the younger age category. A second explanation could be waning protection. Vaccine efficacy in the younger age category will be analyzed later this year, after participants in the younger age category have completed 12 months of follow-up in accordance with our predefined analysis plan. Data on the duration of protection will be available in 2014. The analysis plan was designed to allow dissemi-nation of key findings as soon as they become available, even though this results in our sharing data without being able to fully explain all find-ings. We think that this approach is worthwhile, since the information we have shared has been useful in stimulating debate in the scientific com-munity and among health authorities on the po-tential role of this vaccine and in refining fore-casts to ensure manufacturing capacity for timely availability of vaccine.Sherman recognizes the need for continued support for proven methods for malaria preven-tion, including insecticide-treated bed nets. As emphasized in our article, the RTS,S/AS01 ma-laria vaccine is not intended as an alternative to established malaria-control measures but rather as an additional tool for integrated control. Dur-ing the phase 3 RTS,S/AS01 trial, every effort has been made to ensure that all enrolled children sleep under an insecticide-treated bed net. Our The New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on January 21, 2014. For personal use only. No other uses without permission.  Copyright © 2012 Massachusetts Medical Society. All rights reserved. T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 366;8 nejm.org february 23, 2012766findings thus far show that in a population in which approximately 75% of the children were using insecticide-treated bed nets, cases of clin-ical malaria were reduced by 55% in the children who received the RTS,S/AS01 vaccine, indicating that the RTS,S/AS01 malaria vaccine could be an important addition to established malaria-con-trol tools.Mary J. Hamel, M.D.Centers for Disease Control and Prevention Atlanta, GASalim Abdulla, M.D., Ph.D.Ifakara Health Institute Dar es Salaam, TanzaniaBrian Greenwood, M.D.London School of Hygiene and Tropical Medicine London, United Kingdomfor the RTS,S Synthesis and Writing CommitteeThe findings and conclusions in this letter have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy.Since publication of their article, the authors report no fur-ther potential conflict of interest.Escherichia coli O104:H4 Outbreak in GermanyTo the Editor: In their article on last year’s out-break of Escherichia coli O104:H4 in Germany, Frank et al. (Nov. 10 issue)1 report some striking features. Nearly 90% of patients were adults (me-dian age, 42 years), with an overrepresentation of women (68%). In pediatric series, girls also pre-dominate over boys but not to such a marked degree.2 Moreover, the attack rate of the hemo-lytic–uremic syndrome associated with diarrhea (845 of 3816 cases, or 22%) in Germany exceeded the rate of 5 to 15% in most previous reports of outbreaks. In children, the administration of an-tibiotics to empirically treat the prodromal en-teritis has been associated with a significantly increased risk of progression to the hemolytic–uremic syndrome.3,4 This finding is supported by preclinical data in the infection model in the gnotobiotic piglet.5 The pattern of antibiotic use to treat bloody diarrhea may differ between chil-dren and adults. This may explain the high pro-portion of patients with the hemolytic–uremic syndrome in the German outbreak, independent of the pathogenicity of the unusual bacterial strain. Clarification of antibiotic use to treat the antecedent enteritis may shed light on this par-ticular outbreak and help guide the prescription of antibiotics in patients with gastroenteritis and bloody diarrhea.Howard Trachtman, M.D.NYU Langone Medical Center New York, NY howard.trachtman@nyumc.orgNo potential conflict of interest relevant to this letter was re-ported.1. Frank C, Werber D, Cramer JP, et al. Epidemic profile of Shiga-toxin–producing Escherichia coli O104:H4 outbreak in Ger-many. N Engl J Med 2011;365:1771-80.2. Trachtman H, Cnaan A, Christen E, et al. Effect of an oral Shiga toxin-binding agent on diarrhea-associated hemolytic ure-mic syndrome in children: a randomized controlled trial. JAMA 2003;290:1337-44.3. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of hemolytic–uremic syndrome after antibiotic treatment of Esch-erichia coli O157:H7 infections. N Engl J Med 2000;342:1930-6.4. Pavia AT, Nichols CR, Green DP, et al. Hemolytic-uremic syndrome during an outbreak of Escherichia coli O157:H7 infec-tions in institutions for mentally retarded persons: clinical and epidemiological observations. J Pediatr 1990;116:544-51.5. Zhang Q, Donohue-Rolfe A, Krautz-Peterson G, et al. Gno-tobiotic piglet infection model for evaluating the safe use of antibiotics against Escherichia coli O157:H7 infection. J Infect Dis 2009;199:486-93.The Authors and a Colleague Reply: Tracht-man hypothesizes that the frequent use of anti-microbial drugs in adults may explain the un-usually high proportion of patients with the hemolytic–uremic syndrome in the German out-break of Shiga-toxin–producing E. coli O104:H4 infection. The outpatient use of antimicrobial drugs in Germany is low as compared with inter-national standards,1 and the administration of such drugs is generally not recommended for the empirical treatment of acute (bloody) diarrhea. In the case of Shiga-toxin–producing  E. coli in-fection, it is recommended that practitioners re-frain from administering antimicrobials.2,3 In hypothesis-generating interviews that we con-ducted early in the outbreak investigation, only 6 of 36 adult patients with the hemolytic–uremic syndrome (17%) for whom data were available reported having taken antimicrobials in the course of their illness or having received a correspond-ing prescription. This finding is consistent with treatment regimens reported to us by many hos-pitals and specific recommendations issued dur-The New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on January 21, 2014. For personal use only. No other uses without permission.  Copyright © 2012 Massachusetts Medical Society. All rights reserved. 

RTS,S/AS01 Malaria Vaccine in African Children REPLY

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RTS,S/AS01 Malaria Vaccine in African Children REPLY

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