Incidence of severe Plasmodium falciparum malaria as a primary endpoint for vaccine efficacy trials in Bandiagara, Mali

Abstract

Potential endpoints for blood stage malaria vaccine efficacy trials include uncomplicated malaria disease, which is hard to differentiate from other febrile illnesses, and mortality, which requires prohibitively large sample sizes. Strictly defined severe malaria predicts malaria-associated mortality where case fatality rates are known. To assess the suitability of severe malaria as a trial endpoint, we conducted a census in 1999 and measured the incidence of severe malaria from 1999 to 2001 in Bandiagara, Mali. The annual incidence of severe malaria in children <6 years of age was 2.3% (n=2,284) yielding an estimated sample size of 4,580 for a vaccine trial designed to detect 50% efficacy with 80% power at P=0.05 with 5% loss to follow-up. A trial using severe malaria as an endpoint in this setting would thus require expanding the study population or the length of the trial. This approach may be useful in assessing the suitability of potential sites for malaria vaccine trials.

Introduction

Plasmodium falciparum malaria is a multistage parasite invoking stage-specific host immune responses. To date, the approach to malaria vaccine development has primarily concentrated on eliciting these stage-specific immune responses. Malaria vaccine candidates can be divided into those that stimulate a pre-erythrocytic (sporozoite or liver) immune response, those that block transmission of malaria by promoting an antibody response against antigens expressed in the sexual stage within the midgut of the mosquito, those that target the asexual blood stages of the parasite, and vaccines reducing the toxic effect of the infection. Natural immunity against malaria appears to be acquired over time, requires multiple infective bites, and is lost in the absence of continued exposure. The goal of blood stage malaria vaccines is to protect against disease and death, which can be achieved through acquisition of such immunity.

Defining clinical endpoints for malaria vaccine efficacy trials has proved challenging. In the case of a pre-erythrocytic vaccine, designed to induce sterile immunity, breakthrough infection is easily determined by first parasitemia or first symptomatic infection. Blood stage vaccines are intended to block disease and not infection. Unfortunately, defining clinical disease can often be difficult. There are no protective antibody thresholds, nor in vitro immunologic assays that can distinguish immune individuals from non-immune individuals [1]. In the absence of an objective immune assay, the endpoint of a blood stage vaccine is often reduction of a carefully defined clinical illness in immunized population specific to the site at which the trial is conducted. Accurate definitions of malaria disease are not only age and site specific, they likely vary over the course of a transmission season as immunity is acquired. Additionally, malarial disease has a variety of clinical symptoms, broad range of parasitemia, and may be confused with other childhood illnesses that occur in the setting of baseline levels of malaria infection. Without accurate interpretations of malaria disease, accurate predictions of malaria-associated mortality may not be achieved.

Investigators have sought to find alternative methods of estimating vaccine efficacy through surrogate endpoints. The use of malaria attributable fraction of fever has been advocated as a marker for clinical malaria. Logistic regression methods modeling fever as a continuous function of parasitemia appear to offer precise estimates of disease, although definitions vary by site and parasite transmission intensity. Additionally, results are unreliable in children under 12 months or greater than 9 years of age [2], [3], [4]. Some advocate using all-cause or malaria-associated mortality as an endpoint, but this would require prohibitively large sample sizes. As an example, insecticide-impregnated bednet studies that showed decreases in all-cause mortality had sample sizes in the tens and hundreds of thousands involving large catchment areas and multiple villages [5], [6], [7].

For the purposes of conducting phase III studies, the World Health Organization (WHO) recommends establishing protection against a single primary efficacy endpoint [8]. Severe disease and malaria mortality represent the greatest public health consequences of infection. Incidence of severe malaria as an endpoint offers the advantages of being a good indicator of malaria-associated mortality where case fatality rates are known with and requiring fewer subjects than a mortality endpoint. Thus, in a setting with a 10% case fatality rate for severe malaria, 10-fold fewer subjects would be required for a study with severe malaria as the primary endpoint than a study assessing mortality due to malaria. While imperfect, the criteria for severe malaria as defined by the WHO are a standardized definition that can be applied uniformly [9]. Although this definition has its limitations, few would disagree that in contrast to children meeting case definitions of uncomplicated malaria, most children who meet criteria for severe malaria are suffering from malaria disease and have a worse prognosis.