Brugia Malayi: Vaccination of Jirds with 60Cobalt-Attenuated Infective Stage Larvae Protects against Homologous Challenge

Yates, John L.; Higashi, Gene I.

doi:10.4269/ajtmh.1985.34.1132

Cited by 90 publications

(38 citation statements)

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“…This difference was significant (P Ͻ 0.05) by Whitney-Mann nonparametric statistics. The data reported here indicate greater than 70% protection in jirds against a challenge infection; this is substantially better than any previous filarial recombinant antigen reported and is in the range achieved by vaccination with radiation-attenuated larvae, 44 to 91% (35). Of the previously tested antigens, paramyosin has yielded disappointing results (20,21), while heat shock protein 70, myosin, and ␣1-type IV collagen have recently been shown not to stimulate protective immunity (30).…”

Section: Resultsmentioning

confidence: 63%

The Abundant Larval Transcript-1 and -2 Genes ofBrugia malayiEncode Stage-Specific Candidate Vaccine Antigens for Filariasis

et al. 2000

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Lymphatic filariasis is a major tropical disease caused by the mosquito-borne nematodes Brugia and Wuchereria. About 120 million people are infected and at risk of lymphatic pathology such as acute lymphangitis and elephantiasis. Vaccines against filariasis must generate immunity to the infective mosquito-derived third-stage larva (L3) without accentuating immunopathogenic responses to lymphatic-dwelling adult parasites. We have identified two highly expressed genes, designated abundant larval transcript-1 and -2 (alt-1 and alt-2), from each of which mRNAs account for >1% of L3 cDNAs. ALT-1 and ALT-2 share 79% amino acid identity across 125 residues, including a putative signal sequence and a prominent acidic tract. Expression of alt-1 and alt-2 is initiated midway through development in the mosquito, peaking in the infective larva and declining sharply following entry into the host. Humans exposed to Brugia malayi show a high frequency of immunoglobulin G1 (IgG1) and IgG3 antibodies to ALT-1 and -2, distinguishing them from adult-stage antigens, which are targeted by the IgG4 isotype. Immunization of susceptible rodents (jirds) with ALT-1 elicited a 76% reduction in parasite survival, the highest reported for a single antigen from any filarial parasite. ALT-1 and the closely related ALT-2 are therefore strong candidates for a future vaccine against human filariasis.Filarial nematodes are helminth parasites which are responsible for lymphatic filariasis, a tropical disease afflicting some 119 million people (26,28,34). The parasites have a complex life cycle in which mosquito-borne infective third-stage larvae (L3) invade the human body, mature to adult worms, and produce large numbers of newborn larvae (microfilariae) which must transit the mosquito vector in order to develop to L3 (16). Overt disease has a major immunopathologic component, and a prominent risk of vaccination with filarial antigens is exacerbation of pathology (22,27,32). The target of immunopathological reactions, however, is thought to be the longlived adult worm and not the infective larva (23,29).To date, strategies to identify vaccine antigens in filariasis have relied on serum antibodies to define antigens, whether by comparing apparently uninfected subjects with infected patients (11) or by using sera from animals vaccinated with radiation-attenuated parasites (19,20). Among the antigens so discovered have been several with high levels of similarity to host antigens (such as muscle proteins), raising an additional specter of autoimmune induction by vaccination. No recombinant filarial antigen yet tested induces significant degrees of immunity to challenge infection (21, 30), indicating that an alternative criterion needs to be adopted.We describe here a molecular biological approach, the analysis of mRNAs which are highly and selectively expressed by the mosquito-derived larva at the time that it is competent to infect the mammalian host. We sought to identify new antigens which are restricted to this stage and absent from the mature for...

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Section: Resultsmentioning

confidence: 63%

The Abundant Larval Transcript-1 and -2 Genes ofBrugia malayiEncode Stage-Specific Candidate Vaccine Antigens for Filariasis

et al. 2000

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“…Numerous studies have demonstrated that immunization with irradiated filarial larvae can lead to significant levels of protection from challenge infection (1,5,21,32,34,36,38). Le Goff et al (19) demonstrated that in the L. sigmodontis model this killing is very rapid, with larval destruction occurring within the first 2 days following challenge.…”

Section: Resultsmentioning

confidence: 99%

Interleukin-5 Is Essential for Vaccine-Mediated Immunity but Not Innate Resistance to a Filarial Parasite

et al. 2000

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The study of protective immune mechanisms effective against filarial nematodes has been hampered by the inability of these important human pathogens to infect laboratory mice. Recently, Litomosoides sigmodontis, a natural parasite of rats, has been developed as a valuable model for the study of filarial infection. BALB/c mice are fully susceptible to infection with L. sigmodontis third-stage larvae and develop patent infection. In contrast, mice on the C57BL background are resistant, and parasites undergo only a single molt and do not mature to adulthood. We used interleukin-5 (IL-5)-deficient mice on the C57BL/6 background to address the role of IL-5 and eosinophils in the innate resistance of C57BL/6 mice. We found no differences in parasite survival between IL-5-deficient and C57BL/6 mice. However, when these mice were used for the analysis of vaccine-mediated immunity, a critical role for IL-5 was elucidated. Mice genetically deficient in IL-5 were unable to generate a protective immune response when vaccinated with irradiated larvae, whereas C57BL/6 mice were fully protected from challenge infection. These studies help to clarify the highly controversial role of eosinophils in filarial infection.Filarial nematodes are the causative agents of lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness). Together, these parasites (Wuchereria bancrofti, Brugia malayi, and Onchocerca volvulus) afflict more than 140 million people worldwide (37). A major stumbling block in the study of filarial disease is the inability of these human pathogens to establish infection in well-characterized laboratory animals. A recent advance in filariasis research has been the development of a murine model of infection, using the rodent filarial parasite Litomosoides sigmodontis (24). L. sigmodontis is the only filarial species able to complete its full development cycle in inbred laboratory mice.One of the benefits of this new model is that susceptibility to infection is murine strain dependent, allowing genetic dissection of the mechanisms that determine innate resistance as has been done for other parasitic systems such as Trichuris muris and Leishmania major (11,30). BALB/c mice are fully susceptible to L. sigmodontis infection, and parasites develop through to patency. In contrast, mice on the C57BL background are resistant and patent infections are never seen (27). Interestingly, this pattern of resistance and susceptibility is similar to that seen for the protozoan parasite L. major and opposite to that of the intestinal nematode T. muris.How cells of the innate immune system (e.g., granulocytes and macrophages) might mediate protective immunity to nematode parasites is an unresolved and controversial issue. In particular, despite their distinctive association with nematode infection, the exact role of eosinophils is not established for either intestinal or tissue locales and remains an area of considerable scientific debate (3,16,35). Numerous studies have shown that the characteristic eosinophilia observed i...

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“…Evidence from several animal models in which the life cycles of Brugia species are reliably maintained indicates that a moderate degree of resistance to infection can be achieved by immunization with live, radiation-attenuated infective L3's (35,36). However, the immunologic or biochemical nature of any protective antigens effecting immunity in these models has yet to be elucidated, a fact emphasizing the need for multiple alternative approaches.…”

Section: Antigen Recognition By Igg Antibody In Ens and Mfsmentioning

confidence: 99%

Protective immunity in bancroftian filariasis. Selective recognition of a 43-kD larval stage antigen by infection-free individuals in an endemic area.

Freedman¹,

Nutman²,

Ottesen³

1989

J. Clin. Invest.

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There is little information about naturally occurring protective immunity in individuals living in areas endemic for lymphatic filariasis, though an immunologically hyperresponsive, uninfected group of "endemic normal" individuals that may be immune has been previously recognized. To analyze the nature of the hyperresponsiveness and its potential relation to a state of protective immunity in such individuals, strict clinical, parasitological, and serological criteria were applied to select seven "infection-free" endemic normal individuals (ENs) from a population of 459 persons resident in an area heavily endemic for bancroftian filariasis. Immunoblot analysis was used to compare the qualitative antigen recognition patterns of these endemic normal individuals to those of a group of 12 clearly infected microfilaremic individuals (MFs) from the same endemic area. Though immunoblot analysis using microfilarial and adult stage filarial antigens revealed no distinct differences in antigen recognition patterns between the two groups, when responses to infective larval stage antigens were assessed, 7/7 (100%) of the ENs were found to recognize a 43-kD antigen that was recognized by only 1/12 (8%) of the MFs. These findings are consistent with the concept that recognition of unique larval antigens may induce protective immunity to human filarial parasites and they identify a candidate immunogen for further functional assessment.

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Brugia Malayi: Vaccination of Jirds with 60Cobalt-Attenuated Infective Stage Larvae Protects against Homologous Challenge

Cited by 90 publications

References 0 publications

The Abundant Larval Transcript-1 and -2 Genes ofBrugia malayiEncode Stage-Specific Candidate Vaccine Antigens for Filariasis

The Abundant Larval Transcript-1 and -2 Genes ofBrugia malayiEncode Stage-Specific Candidate Vaccine Antigens for Filariasis

Interleukin-5 Is Essential for Vaccine-Mediated Immunity but Not Innate Resistance to a Filarial Parasite

Protective immunity in bancroftian filariasis. Selective recognition of a 43-kD larval stage antigen by infection-free individuals in an endemic area.

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