Predictors of Health Outcomes among Children in the RTS,S/AS01E Malaria Vaccine Trial in Siaya, Kenya Open Access

Abstract

Malaria causes significant morbidity and mortality around the world, especially in Sub-Saharan Africa. In Kenya, approximately 7.7 million cases of presumed and confirmed malaria occurred in 2015. Researchers are developing a malaria vaccine as a means of prevention. GlaxoSmithKline sponsored a trial that examined the efficacy of the RTS,S/AS01 vaccine candidate among infants (6-12 weeks) and children (5-17 months) in Siaya, Kenya. Using data from this trial, this research assessed the relationship between parasitemia levels (zero, low (1/μL-49,999/μL), medium (50,000/μL-199,999/μL), high (200,000/μL-499,999/μL), and super-high (>500,000/μL)), vaccination status (RTS,S/AS01 with booster, RTS,S/AS01 without booster, and comparator), and health outcomes (death, severe anemia, severe malaria, stunting, underweight, and wasting). Descriptive statistics and Poisson regression models were used to determine association between the variables. The distribution of parasitemia significantly differed by study arm (p<0.025), with median maximal parasite density of 277,919, 95% CI [241,065, 320,409] for RTS,S/AS01 with booster, 314,386, 95% CI [278,354, 355,083] for RTS,S/AS01 without booster, and 377,047, 95% CI [342,283, 415,341] for comparator, respectively; the two RTS,S arms were different from the comparator but not significantly different from each other. Multivariate models with a referent of zero parasitemia indicated that parasitemia significantly predicted severe malaria (super-high parasitemia IRR 7.39, 95% CI [2.35, 23.23]; high parasitemia IRR 4.62, 95% CI [1.45, 14.66]) but not severe anemia, stunting, underweight, or wasting. Unexpectedly, individuals with zero parasitemia had higher rate of death than participants with super-high, high, and medium parasitemia (IRR 0.12, 95% CI [0.05, 0.30]; IRR 0.11, 95% CI [0.04, 0.28]; IRR 0.10, 95% CI [0.01, 0.80], respectively). Study arm did not significantly predict any of the examined outcomes, although parasitemia did. Reassuringly, the highest episodes of parasitemia occurred in the control, and not the vaccine arm, and were not associated with an increased risk of death. This suggests that in this site, the RTS,S/AS01 vaccine candidate was safe. Future large scale pilots will further assess the safety of rare events.

Table of Contents

TABLE OF CONTENTS CHAPTER 1: INTRODUCTION 1 Context of the Problem 1

Problem Statement 3

Research Purpose 3

CHAPTER 2: LITERATURE REVIEW 4

Global Burden of Malaria 4

Malaria in Kenya 5

Malaria Biology 6

Malaria Health Outcomes 8

Risk Factors for Malaria 13

Malaria Prevention 14

CHAPTER 3: METHODOLOGY 16

Dataset Compilation 16

Statistical Analysis 17

Ethical Considerations 18

Limitations 18

CHAPTER 4: RESULTS 20

Study Population 20

Unadjusted, Univariate, and Multivariate Modelling Results 20

CHAPTER 5: DISCUSSION 24

Conclusions 24

Public Health Implications 26

Future Research 26

REFERENCES 28 TABLES AND FIGURES 37

Figure 2. Distribution of parasitemia differs significantly by study arm 37

Table 1. Exclusion criteria for enrollment into RTS,S/AS01 vaccine trial 38

Table 2. Case definitions for clinical endpoints in the RTS,S/AS01 vaccine trial 39

Table 3. Frequency of variable observations 40

Table 4. Participant characteristics 41

Table 5. Frequency of health outcomes among participants 42

Table 6. Poisson regression results for death 43

Table 7. Poisson regression results for severe anemia 44

Table 8. Poisson regression results for severe malaria 45

Table 9. Poisson regression results for stunting 46

Table 10. Poisson regression results for underweight 47

Table 11. Poisson regression results for wasting 48

APPENDICES 49

Figure 1. Life cycle of malaria in both the mosquito and human stages 49

About this Master's Thesis

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School	Rollins School of Public Health
Department	Hubert Department of Global Health
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, General Health Sciences, Epidemiology
Keyword	global health RTS,S vaccine Kenya malaria
Committee Chair / Thesis Advisor	Gutman, Julie R, Emory University
Partnering Agencies	CDC

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