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Biocompatible anionic polymeric microspheres as priming delivery system for effetive HIV/AIDS Tat-based vaccines.

Titti F, Maggiorella MT, Ferrantelli F, Sernicola L, Bellino S, Collacchi B, Fanales Belasio E, Moretti S, Pavone Cossut MR, Belli R, Olivieri E, Farcomeni S, Compagnoni D, Michelini Z, Sabbatucci M, Sparnacci K, Tondelli L, Laus M, Cafaro A, Caputo A, Ensoli B - PLoS ONE (2014)

Bottom Line: Controllers, as opposed to vaccinated and viremic cynos, exhibited significantly higher pre-challenge antibody responses to peptides spanning the glutamine-rich and the RGD-integrin-binding regions of Tat.Altogether these findings indicate that the Tat/H1D/Alum regimen of immunization holds promise for next generation vaccines with Tat protein or other proteins for which maintenance of the native conformation and activity are critical for optimal immunogenicity.Our results also provide novel information on the role of anti-Tat responses in the prevention of HIV pathogenesis and for the design of new vaccine candidates.

View Article: PubMed Central - PubMed

Affiliation: National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.

ABSTRACT
Here we describe a prime-boost regimen of vaccination in Macaca fascicularis that combines priming with novel anionic microspheres designed to deliver the biologically active HIV-1 Tat protein and boosting with Tat in Alum. This regimen of immunization modulated the IgG subclass profile and elicited a balanced Th1-Th2 type of humoral and cellular responses. Remarkably, following intravenous challenge with SHIV89.6Pcy243, vaccinees significantly blunted acute viremia, as compared to control monkeys, and this control was associated with significantly lower CD4+ T cell depletion rate during the acute phase of infection and higher ability to resume the CD4+ T cell counts in the post-acute and chronic phases of infection. The long lasting control of viremia was associated with the persistence of high titers anti-Tat antibodies whose profile clearly distinguished vaccinees in controllers and viremics. Controllers, as opposed to vaccinated and viremic cynos, exhibited significantly higher pre-challenge antibody responses to peptides spanning the glutamine-rich and the RGD-integrin-binding regions of Tat. Finally, among vaccinees, titers of anti-Tat IgG1, IgG3 and IgG4 subclasses had a significant association with control of viremia in the acute and post-acute phases of infection. Altogether these findings indicate that the Tat/H1D/Alum regimen of immunization holds promise for next generation vaccines with Tat protein or other proteins for which maintenance of the native conformation and activity are critical for optimal immunogenicity. Our results also provide novel information on the role of anti-Tat responses in the prevention of HIV pathogenesis and for the design of new vaccine candidates.

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Schedule of immunization and anti-Tat antibody responses in cynomolgus monkeys vaccinated with Tat/H1D and Tat/Alum.(A) Nine monkeys were injected intramuscularly with Tat/H1D microspheres at weeks 0, 4, 12 and 18, and boosted subcutaneously with the Tat in Alum at weeks 21 and 36, respectively. Nine control monkeys were primed with H1D alone boosted with Alum alone. (B) IgM and (C) IgG antibody titers in vaccinated monkeys. The arrows on the top of the each panel indicate the time at which the Tat/H1D, the Tat/Alum or H1D and Alum alone were given. The dashed lines indicate the cut-off values (samples showing titers <1∶25 for IgM and <1∶100 for IgG were scored as negative).
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pone-0111360-g001: Schedule of immunization and anti-Tat antibody responses in cynomolgus monkeys vaccinated with Tat/H1D and Tat/Alum.(A) Nine monkeys were injected intramuscularly with Tat/H1D microspheres at weeks 0, 4, 12 and 18, and boosted subcutaneously with the Tat in Alum at weeks 21 and 36, respectively. Nine control monkeys were primed with H1D alone boosted with Alum alone. (B) IgM and (C) IgG antibody titers in vaccinated monkeys. The arrows on the top of the each panel indicate the time at which the Tat/H1D, the Tat/Alum or H1D and Alum alone were given. The dashed lines indicate the cut-off values (samples showing titers <1∶25 for IgM and <1∶100 for IgG were scored as negative).

Mentions: Nine monkeys (AF134, AF924, AG269, AG291, AH484, AH776, M770F, O854G, BD765B) were immunized i.m. at weeks 0, 4, 12 and 18 with the Tat (10 µg)/H1D (60 µg) formulation and boosted subcutaneously (s.c.) at weeks 21 and 36 with Tat (10 µg) in the presence of Alum (Fig. 1A). The dose of Tat (10 µg) was chosen based on previous immunization studies in monkeys (22) while the Tat/H1D ratio used was chosen because it gives an adsorption efficiency of 100% as determined previously (23, 25). Nine control monkeys (AC601, AI075, AF942, AG249, AG347, AG934, AC032, AC739, AC921) received the H1D microspheres and Alum alone according to the same schedule and routes of administration. At week 50 all monkeys were challenged intravenously (i.v.) with 15 MID50 of the highly pathogenic SHIV89.6Pcy243, grown and titrated in cynomolgus monkeys [34].


Biocompatible anionic polymeric microspheres as priming delivery system for effetive HIV/AIDS Tat-based vaccines.

Titti F, Maggiorella MT, Ferrantelli F, Sernicola L, Bellino S, Collacchi B, Fanales Belasio E, Moretti S, Pavone Cossut MR, Belli R, Olivieri E, Farcomeni S, Compagnoni D, Michelini Z, Sabbatucci M, Sparnacci K, Tondelli L, Laus M, Cafaro A, Caputo A, Ensoli B - PLoS ONE (2014)

Schedule of immunization and anti-Tat antibody responses in cynomolgus monkeys vaccinated with Tat/H1D and Tat/Alum.(A) Nine monkeys were injected intramuscularly with Tat/H1D microspheres at weeks 0, 4, 12 and 18, and boosted subcutaneously with the Tat in Alum at weeks 21 and 36, respectively. Nine control monkeys were primed with H1D alone boosted with Alum alone. (B) IgM and (C) IgG antibody titers in vaccinated monkeys. The arrows on the top of the each panel indicate the time at which the Tat/H1D, the Tat/Alum or H1D and Alum alone were given. The dashed lines indicate the cut-off values (samples showing titers <1∶25 for IgM and <1∶100 for IgG were scored as negative).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214729&req=5

pone-0111360-g001: Schedule of immunization and anti-Tat antibody responses in cynomolgus monkeys vaccinated with Tat/H1D and Tat/Alum.(A) Nine monkeys were injected intramuscularly with Tat/H1D microspheres at weeks 0, 4, 12 and 18, and boosted subcutaneously with the Tat in Alum at weeks 21 and 36, respectively. Nine control monkeys were primed with H1D alone boosted with Alum alone. (B) IgM and (C) IgG antibody titers in vaccinated monkeys. The arrows on the top of the each panel indicate the time at which the Tat/H1D, the Tat/Alum or H1D and Alum alone were given. The dashed lines indicate the cut-off values (samples showing titers <1∶25 for IgM and <1∶100 for IgG were scored as negative).
Mentions: Nine monkeys (AF134, AF924, AG269, AG291, AH484, AH776, M770F, O854G, BD765B) were immunized i.m. at weeks 0, 4, 12 and 18 with the Tat (10 µg)/H1D (60 µg) formulation and boosted subcutaneously (s.c.) at weeks 21 and 36 with Tat (10 µg) in the presence of Alum (Fig. 1A). The dose of Tat (10 µg) was chosen based on previous immunization studies in monkeys (22) while the Tat/H1D ratio used was chosen because it gives an adsorption efficiency of 100% as determined previously (23, 25). Nine control monkeys (AC601, AI075, AF942, AG249, AG347, AG934, AC032, AC739, AC921) received the H1D microspheres and Alum alone according to the same schedule and routes of administration. At week 50 all monkeys were challenged intravenously (i.v.) with 15 MID50 of the highly pathogenic SHIV89.6Pcy243, grown and titrated in cynomolgus monkeys [34].

Bottom Line: Controllers, as opposed to vaccinated and viremic cynos, exhibited significantly higher pre-challenge antibody responses to peptides spanning the glutamine-rich and the RGD-integrin-binding regions of Tat.Altogether these findings indicate that the Tat/H1D/Alum regimen of immunization holds promise for next generation vaccines with Tat protein or other proteins for which maintenance of the native conformation and activity are critical for optimal immunogenicity.Our results also provide novel information on the role of anti-Tat responses in the prevention of HIV pathogenesis and for the design of new vaccine candidates.

View Article: PubMed Central - PubMed

Affiliation: National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.

ABSTRACT
Here we describe a prime-boost regimen of vaccination in Macaca fascicularis that combines priming with novel anionic microspheres designed to deliver the biologically active HIV-1 Tat protein and boosting with Tat in Alum. This regimen of immunization modulated the IgG subclass profile and elicited a balanced Th1-Th2 type of humoral and cellular responses. Remarkably, following intravenous challenge with SHIV89.6Pcy243, vaccinees significantly blunted acute viremia, as compared to control monkeys, and this control was associated with significantly lower CD4+ T cell depletion rate during the acute phase of infection and higher ability to resume the CD4+ T cell counts in the post-acute and chronic phases of infection. The long lasting control of viremia was associated with the persistence of high titers anti-Tat antibodies whose profile clearly distinguished vaccinees in controllers and viremics. Controllers, as opposed to vaccinated and viremic cynos, exhibited significantly higher pre-challenge antibody responses to peptides spanning the glutamine-rich and the RGD-integrin-binding regions of Tat. Finally, among vaccinees, titers of anti-Tat IgG1, IgG3 and IgG4 subclasses had a significant association with control of viremia in the acute and post-acute phases of infection. Altogether these findings indicate that the Tat/H1D/Alum regimen of immunization holds promise for next generation vaccines with Tat protein or other proteins for which maintenance of the native conformation and activity are critical for optimal immunogenicity. Our results also provide novel information on the role of anti-Tat responses in the prevention of HIV pathogenesis and for the design of new vaccine candidates.

Show MeSH
Related in: MedlinePlus