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. 2012 Jul 5;428(2):121-7.
doi: 10.1016/j.virol.2012.03.012. Epub 2012 Apr 21.

Breadth of cellular and humoral immune responses elicited in rhesus monkeys by multi-valent mosaic and consensus immunogens

Sampa Santra  1 , Mark Muldoon, Sydeaka Watson, Adam Buzby, Harikrishnan Balachandran, Kevin R Carlson, Linh Mach, Wing-Pui Kong, Krisha McKee, Zhi-Yong Yang, Srinivas S Rao, John R Mascola, Gary J Nabel, Bette T Korber, Norman L Letvin
Affiliations

Breadth of cellular and humoral immune responses elicited in rhesus monkeys by multi-valent mosaic and consensus immunogens

Sampa Santra et al. Virology. .

Abstract

To create an HIV-1 vaccine that generates sufficient breadth of immune recognition to protect against the genetically diverse forms of the circulating virus, we have been exploring vaccines based on consensus and mosaic protein designs. Increasing the valency of a mosaic immunogen cocktail increases epitope coverage but with diminishing returns, as increasingly rare epitopes are incorporated into the mosaic proteins. In this study we compared the immunogenicity of 2-valent and 3-valent HIV-1 envelope mosaic immunogens in rhesus monkeys. Immunizations with the 3-valent mosaic immunogens resulted in a modest increase in the breadth of vaccine-elicited T lymphocyte responses compared to the 2-valent mosaic immunogens. However, the 3-valent mosaic immunogens elicited significantly higher neutralizing responses to Tier 1 viruses than the 2-valent mosaic immunogens. These findings underscore the potential utility of polyvalent mosaic immunogens for eliciting both cellular and humoral immune responses to HIV-1.

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Figures

Fig. 1
Fig. 1
The coverage of potential T cell epitopes (PTEs) by different vaccine candidates. Shown is the coverage of PTEs by different vaccine candidates as would be detected by the 5 Env proteins used to monitor this study (red), the 10 proteins used in a previous study (green) (Santra et al., 2008) and the 2010 Los Alamos database of HIV-1 sequences (blue). All proteins in each set were broken down into all possible PTEs (9 amino acid fragments) and each of these PTEs was considered. The fraction of perfect matches (dark shades), the fraction that differed by one amino acid (lighter shades) and the fraction that differed by two amino acids (light shades) from the 9-mers found in the immunogen proteins were calculated. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
Breadth of Env-specific T lymphocyte responses in the 12 individual monkeys from each experimental group, showing number of peptide epitopes recognized per protein. (A) The breadth of the vaccine-elicited cellular immune responses was determined by assessing peripheral blood T lymphocyte recognition of 5 different envelope sequences using a peptide/IFN-γ ELISpot assay. PBL from each vaccinated monkey were evaluated for IFN-γ ELISpot responses to pools of 15-mers overlapping by 11 amino acids spanning each of the 5 selected envelope sequences. Epitopes of each of the 5 indicator envelope proteins recognized by PBL of each of the experimentally vaccinated monkeys were enumerated by matrix mapping and confirmation with individual peptides. If two overlapping peptides gave a positive response, it was counted as a single response. The minimum numbers of possible T cell responses that can recognize each strain are shown. (B) A box plot showing the distribution of numbers of vaccine responses per strain elicited by the different vaccines.
Fig. 3
Fig. 3
Depth of cross-reactive T cell responses elicited by various vaccines. The peptides used for the ELISpot assays were designed to maintain their alignment, so they could be directly compared between strains. For each animal, if a vaccine response was found to a peptide, the cross-reactive potential of the response was assessed by counting how many of the 5 test strains were targeted by the response. For each vaccine, the PBL of a monkey that recognized only one strain (blue) were tallied for all animals in the group. Similarly, PBL populations that recognized 2 of the 5 strains (light blue), 3 of the 5 (purple), 4 of 5 (light green), and all 5 strains (pink) are shown. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 4
Fig. 4
Vaccine-elicited binding antibody and neutralizing antibody responses. (A) Five weeks post-rAd5 boost serum samples were collected from monkeys vaccinated with either 2-valent or 3-valent mosaic immunogens. Antibodies from these serum samples were assessed for binding to purified BaL.01 and Du156.12 gp120 and 93TH057 gp120 core envelope proteins by ELISA. (B) The sera were also assessed for the presence of neutralizing antibodies to a limited number of Tier 1 and Tier 2 viruses. There was a significant increase in the level of Tier 1 neutralization for each of the 3 strains tested in the 3-valent mosaic group (MN, p-value=0.003, using a non-parametric Wilcoxon rank sum test; MW965, p-value=0.0007; and DJ263, p-value=0.0004).
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