Transience of vaccine-induced HIV-1-specific CTL and definition of vaccine "response"

Harvard University, Cambridge, Massachusetts, United States
Vaccine (Impact Factor: 3.62). 05/2006; 24(17):3426-31. DOI: 10.1016/j.vaccine.2006.02.023
Source: PubMed


Many vaccine approaches emphasize producing HIV-1-specific CD8+ T-lymphocyte (CTL) responses. Towards this goal, many studies simply classify vaccinees as "responders" or "nonresponders," based on arbitrary cutoff criteria. HIV-1-uninfected participants receiving the TBC-3B vaccine were assessed for HIV-1-specific CTL by interferon-gamma ELISpot, and compared to HIV-1-infected control subjects not on antiretroviral therapy. Vaccinees also were tested for HIV-1-specific antibody responses and generalized CD8+ T-lymphocyte activation. Different criteria for vaccine "responder" status were applied to the measured CTL values. The vaccinees showed evidence of vaccine exposure by CD8+ T-lymphocyte activation and HIV-1-specific antibodies. Considering any single positive HIV-1-specific CTL measurement a vaccine "response," all vaccinees could be classified as "responders," but even slight increases in the stringency of response criteria resulted in a steep decline of the "response" rate. In contrast, HIV-1-infected persons were clearly "responders" against the same proteins by the same criteria. Quantitative assessment of CTL demonstrated low and transient HIV-1-specific CTL compared to natural infection. These analyses emphasize the pitfalls of summarizing vaccine study results using simple cutoff criteria to define response rates, and suggest the utility of more comprehensive descriptions to describe vaccine immunogenicity and persistence of responses.

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    • "Serially diluted standard curves utilized purified human immunoglobulin (IgG or IgA) ranging from 7.8–500 ng/ml (Jackson Immunoresearch Laboratories, West Grove, PA). Samples were run in duplicate, along with a positive control sample, for which performance characteristics and acceptable ranges had been previously established [21], [22]. Plates were incubated for 60 min at 37°C, and washed five times in wash buffer prior to the addition of 100 µl of peroxidase conjugated rabbit anti-human IgG or IgA (Dako Corp, Carpenteria, CA). "
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    ABSTRACT: Mucosal immunity is central to sexual transmission and overall pathogenesis of HIV-1 infection, but the ability of vaccines to induce immune responses in mucosal tissue compartments is poorly defined. Because macaque vaccine studies suggest that inguinal (versus limb) vaccination may better target sexually-exposed mucosa, we performed a randomized, double-blinded, placebo-controlled Phase I trial in HIV-1-uninfected volunteers, using the recombinant Canarypox (CP) vaccine vCP205 delivered by different routes. 12 persons received vaccine and 6 received placebo, divided evenly between deltoid-intramuscular (deltoid-IM) or inguinal-subcutaneous (inguinal-SC) injection routes. The most significant safety events were injection site reactions (Grade 3) in one inguinal vaccinee. CP-specific antibodies were detected in the blood of all 12 vaccinees by Day 24, while HIV-1-specific antibodies were observed in the blood and gut mucosa of 1/9 and 4/9 evaluated vaccinees respectively, with gut antibodies appearing earlier in inguinal vaccinees (24-180 versus 180-365 days). HIV-1-specific CD8(+) T lymphocytes (CTLs) were observed in 7/12 vaccinees, and blood and gut targeting were distinct. Within blood, both deltoid and inguinal responders had detectable CTL responses by 17-24 days; inguinal responders had early responses (within 10 days) while deltoid responders had later responses (24-180 days) in gut mucosa. Our results demonstrate relative safety of inguinal vaccination and qualitative or quantitative compartmentalization of immune responses between blood and gut mucosa, and highlight the importance of not only evaluating early blood responses to HIV-1 vaccines but also mucosal responses over time. NCT00076817.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "The requirement for immunological assays used in vaccine trials to be rigorously validated has resulted in much work to maximize the sensitivity and specificity of ELISpot assays, ensure their reproducibility, minimize inter-laboratory and inter-operator variability and to automate and standardize the counting of the spot forming units (SFU) (Vaquerano et al., 1998; Schmittel et al., 2000; Mwau et al., 2002; Janetzki et al., 2004; Cox et al., 2005; Janetzki et al., 2005; Lehmann, 2005; Samri et al., 2006; Janetzki et al., 2008; Maecker et al., 2008). However, criteria for defining a positive response have been subject to considerable debate and controversy (Mwau et al., 2002; Hudgens et al., 2004; Jamieson et al., 2006; Jeffries et al., 2006; Moodie et al., 2010; Slota et al., 2011). "
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    ABSTRACT: In the absence of replication of wells, empirical criteria for enzyme-linked immunospot (ELISpot) positivity use fixed differences or ratios between spot forming units (SFU) counts between test and control. We propose an alternative approach which first identifies the optimally variance-stabilizing transformation of the SFU counts, based on the Bland-Altman plot of the test and control wells. The second step is to derive a positivity threshold from the difference in between-plate distribution functions of the transformed test and control SFU counts. This method is illustrated using 1309 assay results from a cohort study of influenza in Vietnam in which some, but not all, of the peptide pools have clear tendencies for SFU counts to be higher in test than control wells.
    Full-text · Article · Mar 2013 · Journal of immunological methods
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    • "This level was lower than that observed in chronically HIV-1-infected individuals on antiretroviral drug treatment, who demonstrated mean blood levels of 17,256 ± 8838 units/␮g IgG + IgA [20]. Thus, humoral responses against the HIV-1 component of the vaccine appeared to be less vigorous than natural responses against HIV-1 infection or the vaccinia component of the vaccine [20] [32] [35]. "
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    ABSTRACT: Mucosal immune responses induced by HIV-1 vaccines are likely critical for prevention. We report a Phase 1 safety and immunogenicity trial in eight participants using the vaccinia-based TBC-3B vaccine given subcutaneously to determine the relationship between HIV-1 specific systemic and gastrointestinal mucosal responses. Across all subjects, detectable levels of blood vaccinia- and HIV-1-specific antibodies were elicited but none were seen mucosally. While the vaccinia component was immunogenic for CD8(+) T lymphocyte (CTL) responses in both blood and mucosa, it was greater in blood. The HIV-1 component of the vaccine was poorly immunogenic in both blood and mucosa. Although only eight volunteers were studied intensively, the discordance between mucosal and blood responses may highlight mechanisms contributing to recent vaccine failures.
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