IDEA (project completed)

Dissecting the Immunological Interplay between Poverty Related Diseases and Helminth Infections: An African- European Research Initiative

Background

Only recently it has become widely appreciated that the so called Neglected Infectious Diseases (NIDs) represent a major public health burden with a particularly heavy impact related to their widespread distribution across most developing countries.  NIDs are caused by a large variety of infectious agents and predominantly by various types of worms.  Worms are highly prevalent in tropical regions.  Although most infections are asymptomatic, heavy infections result in significant morbidity.  Despite limited evidence, recent years have seen significant scale-up of population-based national programmes for integrated control of worms, following concerted advocacy and major philanthropic donations.  These programmes raise important research questions about the public health implications of co-infection and treatment for other diseases such as malaria, HIV and TB1.  Indeed there is growing epidemiological evidence of interaction between worms and these diseases.  The most recent estimates indicate that about two billion people are infected with worms, corresponding to a large proportion of the world’s population.  Three hundred million are severely affected, and about 50% of cases are children.  The worm infections include schistosomiasis and several species of intestinal worms also known as soil-transmitted helminths.  WHO estimates that approximately 200,000 deaths every year are caused by schistosomiasis alone (http://www.who.int/en/).

Soil-transmitted helminths are present in all the developing countries, while schistosoma needs fresh, still water for survival, and is therefore predominately found in lake regions.  The various types of schistosoma affect children and also adults with particular occupations such as fishermen and irrigation workers.  Generally schistosoma infections are associated with helminth infections.  The soil-transmitted helminths affect both children and adults.

Given the wide geographic overlap in occurrence, co-infections between worms and HIV, TB and malaria occur in tens of millions of people, both children and adults.  In this regard, preliminary epidemiological data generated from a small number of studies indicates that around 25% of individuals affected by HIV, malaria or helminth infections are co-infected.  Although worm infections and HIV, TB and malaria have been extensively investigated, only recently has there been heightened attention to the potential impact of co-infections between worms and HIV, TB and malaria.  Firstly, the interaction between these diseases has potential major public health implications as it increases the disease burden, and because effective vaccines are not yet available for these infections.  Secondly, although the worm-, HIV-, TB- and malaria-specific immune responses have been the target of extensive investigation, the precise immune correlates of protection remain unknown for all these diseases.  Thirdly, there is no information on whether worms-induced immunity modulates HIV-, TB- and malaria-specific immune responses.  Fourthly, there is limited knowledge of the influence of underlying worm infections on the clinical course of HIV, TB and malaria.  Finally, the impact of worm infections on vaccination requires further investigation, as very limited data suggests reduced effectiveness of vaccines in subjects with worm infections.

Objectives

The four major objectives of IDEA are to determine:

-   The worm-induced modulation of the functional and molecular profile of HIV-, TB- and malaria-specific immune responses.  In particular to determine how worm innate and adaptive immune responses instruct the subsequent development of HIV-, TB-, and malaria-specific immune responses;

-   The impact by worm co-infections on measures of disease activity for HIV, TB and malaria.  This investigation will promote the understanding of interactions between various pathogens and their influence on disease activity;

-   The immunologic markers of worm-, HIV-, TB-, and the control of pathogen replication and associated disease;

-   The modulation by worm co-infections of vaccine-induced immune responses.

EVI is primarily involved in the work package concerning the interaction of worm infections with vaccination and vaccine induced the immune responses against malaria, TB and HIV.

South-North collaboration

Major Milestones for WP4

-   Ethics approval obtained for the malaria vaccine worms study: Q3 2011

-   Ethics and regulatory approval obtained for the HIV vaccine worms study: Q3 2014

-   Ethics approval obtained for the TB vaccine worms study: Q1 2014

-   Initial results of worm infections on malaria vaccination obtained: Q4 2013

-   Initial results of worm infections on HIV vaccination obtained: Q3 2015

-   Initial results of worm infections on TB vaccination obtained: Q1 2015

Achievements for the work-package co-led by EVI

-   Malaria vaccine/helminth clinical trial is incorporated into the phase IIb, randomised, controlled, double-blind, multi-centre study to evaluate the efficacy, safety, and immunogenicity of GMZ2 candidate malaria vaccine in children aged 12 – 60 months.  The clinical trial was conducted at Albert Schweitzer Hospital in Lambaréné (Gabon) and was completed at the beginning of 2013.  Samples were collected in order to analyse the influence of helminth infection on vaccine-induced immunity.  The immunological results will be available mid-2015.

-   The HIV study is a phase I double blind placebo-controlled clinical trial aiming to evaluate the safety and immunogenicity of the combination of two vaccine candidates in prime-boost regime DNA-HIV-PT123 and AIDSVAX® B/E in HIV uninfected adult participants with or without underlying Schistosoma mansoni infection.  Following approval by ethical and regulatory authorities, the clinical trial has started in November 2014 and is progressing according to plan.

-   The TB clinical study aims at testing the effect of Schistosoma mansoni infection on the immunogenicity induced by TB vaccine candidate MVA85A in BCG-vaccinated African adolescents.  The study protocol has been reviewed and approved by national and local ethics committees and regulatory authorities and the clinical trial began in June 2014.  The last follow-up was in January 2015 and first data are expected in mid-2015.

References:

  1. Eziefula AC, Brown M.  Intestinal nematodes: disease burden, deworming and the potential importance of co-infection.  Curr Opin Infect Dis. 2008 Oct; 21(5):516-22.

Publications

J Infect. 2015 Nov;71(5):526-33. doi: 10.1016/j.jinf.2015.07.009. Epub 2015 Aug 5
Trop Med Int Health. 2015 Sep;20(9):1190-1195. doi: 10.1111/tmi.12531. Epub 2015 May 27
FASEB J. 2015 Jul;29(7):3027-39. doi: 10.1096/fj.14-266239. Epub 2015 Apr 7
Clin Vaccine Immunol. 2015 Jul;22(7):778-88. doi: 10.1128/CVI.00162-15. Epub 2015 May 6
J Infect Dis. 2015, vol. 212, issue 2 Jul. pii: jiv382
Philos Trans R Soc Lond B Biol Sci. 2015 Jun 19;370(1671). pii: 20140137. doi: 10.1098/rstb.2014.0137
Parasit Vectors. 2015 Jun 11;8:314. doi: 10.1186/s13071-015-0891-5
Front Immunol. 2015 May 11;6:217. doi: 10.3389/fimmu.2015.00217. eCollection 2015
PLoS Negl Trop Dis. 2015 Apr 2;9(4):e0003660. doi: 10.1371/journal.pntd.0003660
J Infect. 2015 Mar;70(3):299-306. doi: 10.1016/j.jinf.2014.10.009. Epub 2014 Oct 22
PLoS One. 2015 Mar 20;10(3):e0122020. doi: 10.1371/journal.pone.0122020. eCollection 2015
Malar J. 2015 Feb 25;14:94. doi: 10.1186/s12936-015-0608-4
E Bio Medicine2015(2):107-108; doi:10.1016/j.ebiom.2015.01.009
EBioMedicine (2014) doi: 10.1016/j.ebiom.2014.12.001
BMC Infectious Diseases. 2014 Dec 9;14(1):644
PLoS One. 2014 Nov 5;9(11):e111517. doi: 10.1371/journal.pone.0111517. eCollection 2014
J Infect Dis. 2014 Oct 15;210(8):1207-16. doi: 10.1093/infdis/jiu257
PLOS Neglected Tropical Diseases 2014 Mar 27;8(3):e2755. doi: 10.1371
American Society of Tropical Medicine and Hygiene. 2014 Mar; 90(3):535-45. doi: 10.4269/ajtmh.13-0268. Epub 2014 Jan 20 
PLoS Neglected Tropical Diseases, 7(3) doi: 10.1371/journal.pntd.0002094
The Journal of Infection.  doi: 10.1016/j.jinf.2013.02.004
Cytokine & Growth Factor Reviews, 24(4): 335-43.  doi: 10.1016/j.cytogfr.2013.01.002
PLoS One 2012 7:e50325
PLoS One 2012;7(2):e30883
Current Opinion in HIV and AIDS 2012 7:245-53
Curr Opin HIV AIDS 2012, VMay;7(3):211-3
J Infect Dis  2012 May; 205(9):1425-35
Journal of Infectious Diseases 2012 205(5), 841-852
PLoS One. 2011; 6(11):e27539