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HIV-1 conserved elements p24CE DNA vaccine induces humoral immune responses with broad epitope recognition in macaques.

Kulkarni V, Valentin A, Rosati M, Rolland M, Mullins JI, Pavlakis GN, Felber BK - PLoS ONE (2014)

Bottom Line: In contrast, antibodies elicited by p55gag DNA vaccine failed to recognize p24CE protein and did not recognize linear epitopes spanning the CE.Interestingly, boosting of p24CE DNA primed animals with p55gag DNA resulted in augmentation of antibodies able to recognize p24gag as well as the p24CE proteins, thereby inducing broadest immunity.This novel and effective strategy to broaden responses could be applied against other antigens of highly diverse pathogens.

View Article: PubMed Central - PubMed

Affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.

ABSTRACT
To target immune responses towards invariable regions of the virus, we engineered DNA-based immunogens encoding conserved elements (CE) of HIV-1 p24gag. This conserved element vaccine is designed to avoid decoy epitopes by focusing responses to critical viral elements. We previously reported that vaccination of macaques with p24CE DNA induced robust cellular immune responses to CE that were not elicited upon wild type p55gag DNA vaccination. p24CE DNA priming followed by p55gag DNA boost provided a novel strategy to increase the magnitude and breadth of the cellular immune responses to HIV-1 Gag, including the induction of strong, multifunctional T-cell responses targeting epitopes within CE. Here, we examined the humoral responses induced upon p24CE DNA or p55gag DNA vaccination in macaques and found that although both vaccines induced robust p24gag binding antibody responses, the responses induced by p24CE DNA showed a unique broad range of linear epitope recognition. In contrast, antibodies elicited by p55gag DNA vaccine failed to recognize p24CE protein and did not recognize linear epitopes spanning the CE. Interestingly, boosting of p24CE DNA primed animals with p55gag DNA resulted in augmentation of antibodies able to recognize p24gag as well as the p24CE proteins, thereby inducing broadest immunity. Our results indicate that an effectively directed vaccine strategy that includes priming with the conserved element vaccine followed by boost with the complete immunogen induces broad cellular and humoral immunity focused on the conserved regions of the virus. This novel and effective strategy to broaden responses could be applied against other antigens of highly diverse pathogens.

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Pepscan analysis of humoral responses induced upon heterologous prime-boost regimens of macaques primed with p55gag DNA and boosted with p24CE DNA.Plasma collected after the prime (left panels) and after the boost vaccinations (right panels) were subjected to Pepscan analysis as described in Figures 3 and 5.
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pone-0111085-g006: Pepscan analysis of humoral responses induced upon heterologous prime-boost regimens of macaques primed with p55gag DNA and boosted with p24CE DNA.Plasma collected after the prime (left panels) and after the boost vaccinations (right panels) were subjected to Pepscan analysis as described in Figures 3 and 5.

Mentions: We also compared the antibody responses by Pepscan analysis of plasma samples collected after the prime (from Figure 3) and after the boost (Figures 5 and 6). In macaques primed with p24CE and boosted with p55gag DNA (Figure 5), we observed no significant changes in the reactivity to linear epitopes except for M695, M437, P314 and R315, which showed increased recognition of 1 or 2 CE (M695:CE4; M437: CE1 and CE2; P314: CE1 and CE3) or new responses (R315: CE5 and CE7). Although p55gag DNA vaccination did not induce antibodies against many linear peptides (see Figure 3B), it is noteworthy that it was able to alter responses in 4 of 10 animals, suggesting that it increased pre-existing low peptide recognition rather than inducing de novo responses.


HIV-1 conserved elements p24CE DNA vaccine induces humoral immune responses with broad epitope recognition in macaques.

Kulkarni V, Valentin A, Rosati M, Rolland M, Mullins JI, Pavlakis GN, Felber BK - PLoS ONE (2014)

Pepscan analysis of humoral responses induced upon heterologous prime-boost regimens of macaques primed with p55gag DNA and boosted with p24CE DNA.Plasma collected after the prime (left panels) and after the boost vaccinations (right panels) were subjected to Pepscan analysis as described in Figures 3 and 5.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4206485&req=5

pone-0111085-g006: Pepscan analysis of humoral responses induced upon heterologous prime-boost regimens of macaques primed with p55gag DNA and boosted with p24CE DNA.Plasma collected after the prime (left panels) and after the boost vaccinations (right panels) were subjected to Pepscan analysis as described in Figures 3 and 5.
Mentions: We also compared the antibody responses by Pepscan analysis of plasma samples collected after the prime (from Figure 3) and after the boost (Figures 5 and 6). In macaques primed with p24CE and boosted with p55gag DNA (Figure 5), we observed no significant changes in the reactivity to linear epitopes except for M695, M437, P314 and R315, which showed increased recognition of 1 or 2 CE (M695:CE4; M437: CE1 and CE2; P314: CE1 and CE3) or new responses (R315: CE5 and CE7). Although p55gag DNA vaccination did not induce antibodies against many linear peptides (see Figure 3B), it is noteworthy that it was able to alter responses in 4 of 10 animals, suggesting that it increased pre-existing low peptide recognition rather than inducing de novo responses.

Bottom Line: In contrast, antibodies elicited by p55gag DNA vaccine failed to recognize p24CE protein and did not recognize linear epitopes spanning the CE.Interestingly, boosting of p24CE DNA primed animals with p55gag DNA resulted in augmentation of antibodies able to recognize p24gag as well as the p24CE proteins, thereby inducing broadest immunity.This novel and effective strategy to broaden responses could be applied against other antigens of highly diverse pathogens.

View Article: PubMed Central - PubMed

Affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.

ABSTRACT
To target immune responses towards invariable regions of the virus, we engineered DNA-based immunogens encoding conserved elements (CE) of HIV-1 p24gag. This conserved element vaccine is designed to avoid decoy epitopes by focusing responses to critical viral elements. We previously reported that vaccination of macaques with p24CE DNA induced robust cellular immune responses to CE that were not elicited upon wild type p55gag DNA vaccination. p24CE DNA priming followed by p55gag DNA boost provided a novel strategy to increase the magnitude and breadth of the cellular immune responses to HIV-1 Gag, including the induction of strong, multifunctional T-cell responses targeting epitopes within CE. Here, we examined the humoral responses induced upon p24CE DNA or p55gag DNA vaccination in macaques and found that although both vaccines induced robust p24gag binding antibody responses, the responses induced by p24CE DNA showed a unique broad range of linear epitope recognition. In contrast, antibodies elicited by p55gag DNA vaccine failed to recognize p24CE protein and did not recognize linear epitopes spanning the CE. Interestingly, boosting of p24CE DNA primed animals with p55gag DNA resulted in augmentation of antibodies able to recognize p24gag as well as the p24CE proteins, thereby inducing broadest immunity. Our results indicate that an effectively directed vaccine strategy that includes priming with the conserved element vaccine followed by boost with the complete immunogen induces broad cellular and humoral immunity focused on the conserved regions of the virus. This novel and effective strategy to broaden responses could be applied against other antigens of highly diverse pathogens.

Show MeSH
Related in: MedlinePlus