Advancing a multivalent ‘Pan-anthelmintic’ vaccine against soil-transmitted nematode infections

Zhan, Bin; Beaumier, Coreen M; Briggs, Neima; Jones, Kathryn M; Keegan, Brian P; Bottazzi, Maria Elena; Hotez, Peter J

A recurring concern with combining multiple antigens in a vaccine is the potential for immune interference. For example, the immune response to one antigen may dominate or interfere with the others in the vaccine. In endemic areas, many people suffering from helminth infections are polyparasitized [75] , making a coinfection animal model critical to vaccine development. Currently, multiple animal models are used as surrogates for human Ascaris and Trichuris infections, including rodents, pigs and nonhuman primates, with rodents and pigs used most frequently [23, 41, 42, [45] [46] [47] [48] [49] [76] [77] [78] . Rodent models, in other words, mice and rats, are more attractive than pigs or nonhuman primates for initial immunogenicity and efficacy studies as their small size and ease of handling allow larger numbers of animals to be evaluated concurrently. Additionally, genetically defined inbred strains allow identification of genetic backgrounds responsible for susceptibility and resistance to parasites. Several strains, including AKR, SCID and Nude, have been shown to be susceptible to T. muris, developing patent infections [49] . In contrast, while A. suum larvae migrate through the liver and lungs of C57BL/6-infected mice, to date, mice cannot support the development of adult worms, nor patent A. suum infections [79] . Nonetheless, several A. suum antigens identified by screening with immune serum from pigs have been shown to reduce lung larval burdens in susceptible mice, suggesting that protective immune responses in susceptible mice correlate with protective response in pigs [41, 42, [44] [45] [46] [47] [48] . Since C57BL/6 mice infected with a low dose of T. muris develop a T H 1-skewed immune response and a susceptible phenotype [80] , this mouse strain could potentially serve as an initial coinfection model for evaluating a pan-helminthic vaccine against Ascaris and Trichuris infections. Furthermore, mice would be invaluable in evaluating regulatory mandated immunogenicity testing of antigen/adjuvant combinations and future potency testing of a clinical vaccine [81] . Ultimately, to thoroughly evaluate a coformulated vaccine, both mice and pigs may be necessary to establish sufficient protection data to advance a potential vaccine candidate into product development. Pigs offer some promise as a laboratory vaccine model [82] although they have not yet been used extensively for evaluating T. suis. Further studies will be undertaken to assess whether studies confirming host protection in pigs will be on the critical path for vaccine development.