Malaria is still responsible for up to 1 million deaths per year worldwide, highlighting the need for protective malaria vaccines. Helminth infections that are prevalent in malaria endemic areas can modulate immune responses of the host. Here we show that Strongyloides ratti, a gut-dwelling nematode that causes transient infections, did not change the efficacy of vaccination against Plasmodium berghei. An ongoing infection with Litomosoides sigmodontis, a tissue-dwelling filaria that induces chronic infections in BALB/c mice, significantly interfered with vaccination efficacy. The induction of P. berghei circumsporozoite protein (CSP)-specific CD8 1 T cells, achieved by a single immunization with a CSP fusion protein, was diminished in L. sigmodontis-infected mice. This modulation was reflected by reduced frequencies of CSP-specific CD8 1 T cells, reduced CSP-specific IFN-c and TNF-a production, reduced CSP-specific cytotoxicity, and reduced protection against P. berghei challenge infection. Implementation of a more potent vaccine regime, by first priming with CSP-expressing recombinant live Salmonella prior to CSP fusion protein immunization, restored induction of CSP-specific CD8 1 T cells and conferred almost sterile immunity to P. berghei challenge infection also in L. sigmodontis-infected mice. In summary, we show that appropriate vaccination regimes can overcome helminth-induced interference with vaccination efficacy.Key words: Immune modulation . Litomosoides sigmodontis . Plasmodium .
Strongyloides ratti . Vaccination Supporting Information available online
IntroductionIt is estimated that more than 1 billion people are infected with helminths worldwide, predominantly in the tropics and subtropics. To prevent both helminth expulsion and the induction of immune pathology, helminths have developed elaborated strategies to dampen the immune response of their host [1, 2]. This helminth-mediated modulation of host's à These authors contributed equally to this work.Ãà Shared last authorship. immune system also affects the immune response to third party antigens and thus may impair vaccination efficacy [3][4][5]. Pre-existing helminth infections have already been shown to interfere with the cellular and humoral responses elicited by vaccinations against tetanus [6][7][8][9], tuberculosis [10][11][12][13] and cholera [14,15]. Approximately, 225 million people are infected with Plasmodium worldwide and malaria causes almost 1 million deaths per year [16] (http://www.who.int/malaria/en/2010). Therefore, major efforts have been undertaken to develop vaccinations against malaria. Since the blood-stage of Plasmodium infection is responsible for the clinical symptoms, a vaccine that targets the preceding liver-stage and thus prevents the establishment of the blood-stage infection is desirable. Recently, we described the induction of Plasmodium berghei-specific CD8 1 T cells in BALB/c mice by vaccination with a recombinant fusion protein consisting of the detoxified Bordetella pertussis adenylate cyclase toxin (ACT) fu...