2015 Royal Society Pfizer Award Seminar

Humans and some other primates have an innate immunity to infection by most trypanosomes dependent on endocytosis by the trypanosome of circulating complexes containing haptoglobin related protein (Hpr) and apolipoprotein L1 (apoL1). The presence of Hpr results in efficient receptor mediated uptake of the particle and ApoL1 is the toxin that kills the trypanosome. The molecular mechanism of killing remains controversial. Innate immunity is restricted to primates as the ApoL1 gene is only present in some great apes and baboons.  Trypanosomes able to infect humans have evolved at least twice, each with a different mechanism to counteract TLFs and there is some insight at the molecular and cellular level as to how resistance works. In East Africa, expression of SRA protein by human infective trypanosomes is necessary and sufficient for infectivity. SRA is a classic anti-toxin, it binds apoL1 in the lysosome and blocks killing. In West Africa, expression of TgsGP by human infective trypanosomes is necessary but not sufficient to confer resistance to TLFs, and is combined with a point polymorphism in the haptoglobin-haemoglobin receptor (HpHbR) that reduces TLF uptake. The action of TgsGP is less well characterised.

Plasmodium falciparum invades human erythrocytes using an array of ligands which interact with several receptors including sialic acid (SA), complement receptor 1 (CR1), and basigin. Ligands seem to be deployed strategically, such that alternative pathways are only activated if the preferred pathway is blocked. Therefore, in endemic areas, immune pressure is likely to influence the choice of ligands that the parasites deploy and hence their erythrocyte receptor preferences. We have been investigating the repertoire of invasion pathways used by P. falciparum clinical isolates in Ghana, and examining the relationship between receptor preferences and transmission intensities. Parasite isolates were collected from children aged 2-14 years residing in three zones of Ghana with different levels of endemicity (Accra < Navrongo < Kintampo) and erythrocyte invasion phenotypes were determined by selective removal of receptors using enzyme treatment or antibody inhibition. In addition, relative gene expression of parasite proteins known to be ligands for erythrocyte invasion was examined. The parasites generally expressed SA-independent invasion phenotypes across the endemic areas, with invasion of neuraminidase-treated erythrocytes correlating with transmission intensity. CR1 was a major mediator of SA-independent invasion while basigin was essential for both SA-dependent and –independent invasion mechanisms. Furthermore, expression of the basigin ligand PfRh5 was the best predictor of donor parasitemia, consistent with previous data showing that the PfRh5-basigin pathway is a potential vaccine target.

Background: Many parts of Africa have transitioned from being hyperendemic for malaria to mesoendemic to having unstable/low transmission. It has been debated that whilst highly desirable, a decline could adversely affect naturally acquired immunity, paradoxically leaving individuals more susceptible to malaria.

Methods: Children at the Kenyan coast were prospectively monitored in longitudinal cohort studies between 2000 and 2014. Blood was sampled annually (N=300-400) in cross-sectional surveys for parasite and malaria-specific antibody quantification. Uncomplicated malaria episodes were detected through active and passive case detection. Trends in parasitaemia, age at- and frequency of- clinical presentation were correlated with measures of acquired immunity.

Findings: Parasite prevalence and median densities declined from a PfPR2-10 of 46.3% in the year 2000 to a nadir of 6.3% in 2013 before rising to 13.3% in 2014 and from 2280 to 340 before rising to 1220 parasites/µl respectively, P<0.0001. In contrast, the proportion of children aged 2–10 years and developing uncomplicated malaria in the six months following sampling rose from 20% to 60.5%. The median age at presentation rose from 4 to 7 years, P <0.0001. Antibodies against merozoite surface proteins (MSP-2, -3, AMA1) that were previously strongly associated with a reduced risk of clinical malaria, declined to below protective thresholds. Antibody-dependent opsonic phagocytosis activity against whole merozoites and IgG-mediated complement fixation declined and no longer predicted protection from malaria.

Interpretation: The change in the epidemiology of malaria and loss of acquired immunity indicate that heightened surveillance and control measures to protect older children are necessary as Africa advances towards malaria elimination.

Human African Trypanosomiasis (HAT), also known as sleeping sickness, remains an important public health problem in rural sub-Saharan Africa where the tsetse fly vectors are abundant. The chronic form of HAT caused by Trypanosoma brucei gambiense occurs in Central and West Africa, while the acute T. b. rhodesiense form is present in East and Southern Africa albeit at much lower prevalence. Uncontrolled movement of cattle comprise the major reservoir outside nature conservation areas, where several other ungulates are involved, has of late fueled the spread of T. b. rhodesiense in Uganda. Following the Royal Society Pfizer Award for work on drug resistance mechanisms, we continued to monitor for spread of resistant mutants in the field and to provide guidance for timely interventions that have contributed to the declining incidence. Other work involved following the spread of HAT in new areas by application of molecular identification techniques on parasites circulating in animal reservoirs. In the process, the Uganda HAT distribution map was updated and acts as a reference for relevant control activities. Bioinformatics approaches have also been used to identify a T. b. rhodesiense diagnostic antigen that can be used for development of a serological test, which is hitherto non-existent for this HAT form. In parallel the adaptation and inclusion of tests recently developed elsewhere have been added to the T. b gambiense diagnostic algorithm that should speed up efforts towards elimination. Currently, a genomics approach to determine the genetic determinants of susceptibility to HAT is on-going in 8 countries across Africa, to provide new insights for novel drugs and diagnostic development.

Research in the Democratic Republic of Congo, and in particular by Professor Muyembe, has contributed greatly to our knowledge about the two defining epidemics of our time – Ebola and HIV/ AIDS. Both infectious diseases exploit fault lines in society, health systems and beliefs, thrive on stigma, and disproportionally affect vulnerable populations. At the same time slow responses promoted the spread of both viruses. The rapid adoption of science and innovation played a major role throughout the global response to AIDS, in the first place the discovery of effective antiretroviral therapy. Whereas epidemiology, virology and clinical trials were the main initial scientific disciplines involved, HIV research in Africa now includes multiple biological and social science disciplines.

There have been major spin offs of HIV research, such as the development of anti-viral therapies for HBV and HCV infections, and research capacity strengthening in many low and middle income countries. In comparison Ebola research was quite on the margins until the current Ebola epidemic in West Africa. For the first time during a major outbreak, clinical trials with candidate Ebola drugs and vaccines have been conducted, resulting in the demonstration that ring vaccination with a VSV based vaccine is effective. New mechanisms to support the development of vaccines for neglected and emerging infections are needed.

When Ebola Virus Disease (EVD) emerged in Yambuku, DRC in 1976, it was first mistaken for a severe and unusual presentation of typhoid or yellow fever. We initially investigated the etiology of this mysterious, deadly, and unresponsive disease to common drug therapies, collecting blood and liver necropsy with our bare hands. As blood culture and Widal tests began to rule out typhoid, and liver pathology from deceased patients turned up negative for yellow fever, we began to understand the clinical manifestations of this novel disease while taking care to provide compassionate care to patients, including successful convalescent blood transfusions. Ebola virus was further identified by the Institute of tropical medicine in a blood sample of a sick Belgian nun we transferred to Kinshasa. We pieced together an epidemiologic picture of the transmission and amplification of EVD in hospital settings and in communities during traditional funerals. Over the course of this and other isolated outbreaks, we developed a national strategy comprised of simple public health interventions to effectively quell the spread of disease with the help of international partners. This strategy includes strong community engagement, passive and active case detection, contact tracing, multisectorial case management, hygiene and sanitation, social mobilisation, and psycho-social support for survivors and their families. With strong national leadership coordinating all control and research activities, we have successfully guided DRC through several subsequent EVD epidemics and have also helped other nations manage outbreaks in the Congo basin and beyond. Our longstanding and exceptional experiences with Ebola make DRC a leader in disease comprehension, management, and control strategy implementation.

Invasive pneumococcal diseases, caused by over 90 serotypes of Streptococcus pneumonia, are responsible for about 1 million deaths among children under 5. Although pneumococcal polysaccharide conjugate vaccines are effective, they protect only against a limited number of serotypes, and the prospect of increasing the serotype coverage is restricted by both technical complexities and high cost. There has been increasing interest in the development of pneumococcal protein vaccines with antigens that could overcome these limitations. However, there is neither a functional assay nor a known concentration of antibodies against these proteins that is associated with protection. Therefore this study evaluated the relationship between maternally acquired antibodies to some major pneumococcal protein antigens at birth and nasopharyngeal colonisation of infants during the first two months of life. 

Concentrations of antibodies against three of the major pneumococcal protein antigens, pneumococcal surface protein A [PspA], pneumolysin (rPly), and choline binding protein A [CbpA] were determined at birth, one and two months of age and related to nasopharyngeal carriage of the pneumococcus. There was significant maternal transfer of antibodies to these pneumococcal protein antigens measured from the cord blood, and the concentrations waned in the first two months of life except for PspA. Nasopharyngeal carriage of the pneumococcus was also variable and increased with time after delivery. The relationship of nasopharyngeal carriage of the pneumococcus and antibody concentrations to the major pneumococcal protein antigens will be discussed. 

Low uptake of research evidence in policy formulation has been associated with inadequate approaches in supply of evidence to policy makers, including inabilities of researchers to effectively communicate their research and knowledge for policy influence. Critical areas of focus entail carrying out research in which knowledge is produced, packaged and communicated by researchers and intermediaries who know the local context, needs and capacities of policy makers; communication and planning of research and information involving strategic thinking and appropriate timing; and involving policy makers in the initial planning stages of research projects for effective implementation of the research evidence.  Advocates of evidence-informed policy making processes maintain that the depth and quality of knowledge used by policy makers influences the effectiveness of policies. The uptake of research evidence in the policy making process is on the front burner of global discourses on approaches and strategies for development.  Low- and middle-income countries, face challenges in using research evidence when compared with high-income nations. Given that many institutions and training providers use self-assessment as a major tool for assessing capacity, it seems likely that capacity gaps are frequently underestimated.  In addition, networks and linkages, even when well developed, do not address the lack of demand of research evidence from policy makers despite the fact that these channels can help raise awareness of research amongst policy makers and serve as a conduit for knowledge flow where the demand exists. We have undertaken a unique approach to improve the translation of research evidence and learning into policy and practice for effective maternal, newborn and child health (MNCH) interventions in 5 African countries. The focus is to identify and maximise opportunities for policy influence for MNCH issues in the countries, build consensus for MNCH issues to drive policy outreach at national and regional levels and to strengthen the capacity of Implementation Research Teams for long-term and systematic engagement with decision makers in their respective countries for more effective uptake of the evidence they generate. Key evidence generated will impact on the quality of healthcare, health, general health systems, community health workers on maternal and child health within the various African countries.