Population differences in vaccine response: the role, reversibility and mediators of immunomodulation by chronic parasitic infections in the tropics

Infectious diseases continue to have major detrimental impacts on health and development in in low-income countries (LICs). They are also pose a global threat, as shown by recent Ebola and Zika epidemics. Vaccines are potent weapons against them, and a potential solution to emerging antibiotic resistance. However, some important vaccines have lower efficacy, or induce weaker immune responses, in tropical LICs and in rural, compared to urban, settings. An important example is BCG (used to protect against tuberculosis [TB]) which provides 80% protection in some temperate countries, but 0% in some tropical settings. New vaccines (including for TB, malaria and Ebola) seem also to be affected. Our goal is to understand why this is so. Greater exposure to parasites, such as worms and malaria, is one possible explanation, and addressed in this proposal. Parasites have evolved over millennia to control host immune responses so that they can survive and reproduce, sometimes for decades, if left untreated. It has long been suggested that these mechanisms might spill-over to impair responses to vaccines and to unrelated infections, but it is not yet clear to what extent this is so. We plan to address this among adolescents in Uganda. Parasites are very common in this age group, which is also the target for school-based immunisation programmes. First, we will compare vaccine responses between three groups: (1) urban-dwellers participating in our Entebbe Mother and Baby Study birth cohort [we have followed up these children from birth and know that they have low parasite exposure]; (2) island communities where over 80% have schistosomiasis [a worm infection transmitted through snails in the lake]; (3) rural communities with high malaria exposure, where over 50% of school-children have malaria infection, without knowing it. Of course, differences between urban and rural people, other than parasite infections, probably influence vaccine response. So, to obtain stronger evidence that parasites have an effect, we will randomly select half the participants in each rural group to receive intensive treatment for the main parasite in their setting. If this alters the vaccine responses (we predict it will improve them), we can be sure that parasites are involved. Some parasite effects may be indirect. As well as parasites (from the biological kingdom "Animalia"), humans host many bacteria and viruses. Interactions between these major life-forms, within the host, have been termed "transkingdom" effects. For example, immune suppression by parasites can activate dormant viruses which, in turn, may add immunological effects. Also, worms damage the intestinal lining. This causes leakage of bacterial products into the blood, stimulating the immune system. So, we will test whether parasite infections and their treatment change levels of viral replication and of bacterial products in the blood, and relate this, also, to vaccine responses. Vaccines are given to deliver lasting protective immune responses against specific infections. Thus, parasite effects on vaccine responses must act via the host immune system. We will use immunological tools, including the cutting-edge method "mass cytometry" which can examine immune cell types in unprecedented detail, to investigate which cells and mediators are altered by parasites. To bring all our work together, we will undertake a statistical approach called "causal mediation analysis" to explore how urban-rural environment, parasites, "transkingdom" effects and immune responses interrelate to determine vaccine responses. This fundamental information will contribute to the development of suitable vaccines for populations living in low-income, tropical settings, where they are greatly needed; and help public health experts to know whether controlling parasites will also improve effectiveness of vaccine programmes: ultimately leading to better health (and greater wealth) for all.