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Genetic immunisation by liver stage antigen 3 protects chimpanzees against malaria despite low immune responses.

ABSTRACT: BACKGROUND: The true interest of genetic immunisation might have been hastily underestimated based on overall immunogenicity data in humans and lack of parallelism with other, more classical immunisation methods. PRINCIPAL FINDINGS: Using malaria Liver Stage Antigen-3 (LSA-3), we report that genetic immunization induces in chimpanzees, the closest relative of humans, immune responses which are as scarce as those reported using other DNA vaccines in humans, but which nonetheless confer strong, sterile and reproducible protection. The pattern was consistent in 3/4 immunized apes against two high dose sporozoite challenges performed as late as 98 and 238 days post-immunization and by a heterologous strain. CONCLUSIONS: These results should, in our opinion, lead to a revisiting of the value of this unusual means of immunisation, using as a model a disease, malaria, in which virulent challenges of volunteers are ethically acceptable.

SUBMITTER: Daubersies P

PROVIDER: S-EPMC2441826 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Genetic immunisation by liver stage antigen 3 protects chimpanzees against malaria despite low immune responses.

Daubersies Pierre P Ollomo Benjamin B Sauzet Jean-Pierre JP Brahimi Karima K Perlaza Blanca-Liliana BL Eling Wijnand W Moukana Hubert H Rouquet Pierre P de Taisne Charles C Druilhe Pierre P

PloS one 20080716 7

<h4>Background</h4>The true interest of genetic immunisation might have been hastily underestimated based on overall immunogenicity data in humans and lack of parallelism with other, more classical immunisation methods.<h4>Principal findings</h4>Using malaria Liver Stage Antigen-3 (LSA-3), we report that genetic immunization induces in chimpanzees, the closest relative of humans, immune responses which are as scarce as those reported using other DNA vaccines in humans, but which nonetheless conf ...[more]

PMID: 18628827

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Project description:The generation of effective levels of antigen-specific immunity at the mucosal sites of pathogen entry is a key goal for vaccinologists. We explored topical vaginal application as an approach to initiate local antigen-specific immunity, enhance previously existing systemic immunity or re-target responses to the mucosae. To deliver a protein vaccine formulation to the vaginal mucosal surface, we used a novel vaginal ring device comprising a silicone elastomer body into which three freeze-dried, rod-shaped, hydroxypropylmethylcellulose inserts were incorporated. Each rod contained recombinant HIV-1 CN54gp140 protein (167μg)±R848 (167μg) adjuvant. The inserts were loaded into cavities within each ring such that only the ends of the inserts were initially exposed. Sheep received a prime-boost vaccination regime comprising intramuscular injection of 100μg CN54gp140+200μg R848 followed by three successive ring applications of one week duration and separated by one month intervals. Other sheep received only the ring devices without intramuscular priming. Serum and vaginal mucosal fluids were sampled every two weeks and analysed by CN54gp140 ELISA and antigen-specific B cells were measured by flow cytometry at necropsy. Vaccine antigen-specific serum antibody responses were detected in both the intramuscularly-primed and vaginal mucosally-primed groups. Those animals that received only vaginal vaccinations had identical IgG but superior IgA responses. Analysis revealed that all animals exhibited mucosal antigen-specific IgG and IgA with the IgA responses 30-fold greater than systemic levels. Importantly, very high numbers of antigen-specific B cells were detected in local genital draining lymph nodes. We have elicited local genital antigen-specific immune responses after topical application of an adjuvanted antigen formulation within a novel vaginal ring vaccine release device. This regimen and delivery method elicited high levels of antigen-specific mucosal IgA and large numbers of local antigen-reactive B cells, both likely essential for effective mucosal protection.

Dataset Information

Genetic immunisation by liver stage antigen 3 protects chimpanzees against malaria despite low immune responses.

Publications

Genetic immunisation by liver stage antigen 3 protects chimpanzees against malaria despite low immune responses.

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