Another possible weapon against HIV.

<p>An illustration of the principles of using a monoclonal antibody as passive immunization to prevent HIV infection, as compared with the more traditional vaccine approach of active immunization. <i>Created by Nolo Moima</i>, Sunday Times, <i>and Carina Kriel</i>, <i>NICD</i>.</p

bNAb individuals have higher HIV-specific IgG subclass diversity.

<p>(<b>A</b>) A multiplex assay was used to measure levels of HIV-specific IgG subclasses present in 6 month samples from bNAb and no-bNAb individuals to 12 different HIV antigens. Median abundance of antigen-specific IgG2, IgG3 and IgG4 (orange, yellow and purple respectively) are represented as a ratio to IgG1 calculated using median fluorescence intensities. Data are representative of 2 independent experiments. Spearman´s correlations between subclass diversity score and (<b>B</b>) neutralization breadth and (<b>C</b>) Fc polyfunctionality are shown. The score was calculated as the ratio of gp120 ConC IgG2 and IgG4 relative to IgG1 levels. bNAb individuals are shown in red and no-bNAb in blue with dotted trend lines.</p

IgG isolated from individuals that develop bNAbs shows increased gp120-specific binding to Fc receptors and complement proteins.

<p>(<b>A</b>) Binding gp120 ConC-specific IgG isolated from bNAb (red) and no-bNAb (blue) individuals to Fc receptors and C1q measured by an antigen-specific Fc receptor multiplex array. Significant differences (calculated by Mann-Whitney U test) in binding are shown as *p<0.05; **p<0.001; ***p<0.0001. Data are representative of 2 independent experiments. (<b>B</b>) The ratio of activating FcγRIIa (either H131 or R131) to inhibitory FcγRIIb receptor binding at 6 months post infection for bNAb and no-bNAb individuals. Medians are shown and significance was calculated by the Mann-Whitney U test. (<b>C</b>) Correlations between ADCT or ADCD and binding to Fc receptors and C1q shown as MFI. Significant Spearman´s correlation coefficients are indicated. Lines indicate the trend of the correlations.</p

Fc effector function early in HIV infection is higher in individuals that develop bNAbs.

<p>(<b>A</b>) Purified IgG from 13 bNAb, 10 no-bNAb and 5 HIV-negative individuals (in red, blue and grey respectively) at 6 months post-infection was tested for antibody dependent cellular phagocytosis (ADCP), complement deposition (ADCD), cellular trogocytosis (ADCT) and cellular cytoxicity (ADCC) using three HIV-specific antigens gp120 ConC, gp140 C.ZA.1197MB and gp120 CAP45.G3. Significant differences between groups determined by the Mann-Whitney U test are indicated by *p<0.05; **p<0.001. (<b>B</b>) Medians and IQR of different Fc effector functions for bNAb and no-bNAb individuals against all tested antigens over 36 months of infection are indicated as cumulative Fc effector function. Data are representative of 3 independent experiments. (<b>C</b>) Each Fc function was standardized by calculating a Z-score and polyfunctionality determined by addition of the Z-scores for all functions for each individual. Bars above the x-axis indicate Fc polyfunctional individuals, while those below indicate poor Fc polyfunctionality. bNAb and no-bNAb individuals are indicated in red and blue respectively. (<b>D</b>) Spearman´s correlation coefficient for the relationship between the Fc polyfunctionality Z-score and % neutralization breadth calculated by a 44 multi-clade virus panel is shown. The dashed diagonal line indicates the trend of the relationship.</p

Multivariate classifications reveal that individuals who develop bNAbs can be reliably identified by their Fc features at 6 months of infection.

<p>(<b>A</b>) Principal components analysis of 13 bNAb (red) and 10 no-bNAb (blue) using 17 variables. Individual CAPRISA identifiers are shown, with component 1 and 2 explaining 52.3% of the variance in the data set. (<b>B</b>) Confusion matrix showing the classification of bNAb and no-bNAb individuals achieved by random forest classification. Shown are the numbers of individuals for each predicted or observed group with correct classifications indicated in color and misclassifications indicated in white. The 2 bNAb (CAP257 and CAP292) and 2 no-bNAb (CAP88 and CAP228) individuals that were incorrectly classified can be seen in 5A. (<b>C</b>) Importance of the features employed in the random forest classification is indicated by the mean decrease in Gini importance weighting. (<b>D</b>) The model was verified by permutation testing following random shuffling of the classification data 100,000 times. The dashed line indicates the accuracy of the proposed model (82.6%), with shuffles resulting in accuracy greater than this shown as a proportion of the total shuffles (0.38%).</p

Sequential Immunization with gp140 Boosts Immune Responses Primed by Modified Vaccinia Ankara or DNA in HIV-Uninfected South African Participants

<div><p>Background</p><p>The safety and immunogenicity of SAAVI DNA-C2 (4 mg IM), SAAVI MVA-C (2.9 x 10⁹ pfu IM) and Novartis V2-deleted subtype C gp140 (100 mcg) with MF59 adjuvant in various vaccination regimens was evaluated in HIV-uninfected adults in South Africa.</p><p>Methods</p><p>Participants at three South African sites were randomized (1:1:1:1) to one of four vaccine regimens: MVA prime, sequential gp140 protein boost (M/M/P/P); concurrent MVA/gp140 (MP/MP); DNA prime, sequential MVA boost (D/D/M/M); DNA prime, concurrent MVA/gp140 boost (D/D/MP/MP) or placebo. Peak HIV specific humoral and cellular responses were measured.</p><p>Results</p><p>184 participants were enrolled: 52% were female, all were Black/African, median age was 23 years (range, 18–42 years) and 79% completed all vaccinations. 159 participants reported at least one adverse event, 92.5% were mild or moderate. Five, unrelated, serious adverse events were reported. The M/M/P/P and D/D/MP/MP regimens induced the strongest peak neutralizing and binding antibody responses and the greatest CD4+ T-cell responses to Env. All peak neutralizing and binding antibody responses decayed with time. The MVA, but not DNA, prime contributed to the humoral and cellular immune responses. The D/D/M/M regimen was poorly immunogenic overall but did induce modest CD4+ T-cell responses to Gag and Pol. CD8+ T-cell responses to any antigen were low for all regimens.</p><p>Conclusions</p><p>The SAAVI DNA-C2, SAAVI MVA-C and Novartis gp140 with MF59 adjuvant in various combinations were safe and induced neutralizing and binding antibodies and cellular immune responses. Sequential immunization with gp140 boosted immune responses primed by MVA or DNA. The best overall immune responses were seen with the M/M/P/P regimen.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01418235" target="_blank">NCT01418235</a></p></div

Peak IgG binding antibody response.

<p>Binding magnitude of IgG responses to gp120 and gp140 antigens are shown as mean fluorescent intensity (MFI) in top, middle and lower panels, respectively. Positive responders are indicated in red and negative responders in blue. The mid-line of the box denotes the median and the ends of the box denote the 25th and 75th percentiles. The whiskers that extend from the top and bottom of the box extend to the most extreme data points that are no more than 1.5 times the interquartile range (i.e., height of the box) or if no value meets this criterion, to the data extremes. The number and percent positive responders in each group are shown above the graphs. Placebo recipients from all treatment groups are shown together. T1: MVA prime, sequential gp140 boost (M/M/P/P); T2 (MP/MP): concurrent MVA/gp140; T3 (D/D/M/M): DNA prime, sequential MVA boost; T4 (D/D/MP/MP): DNA prime, concurrent MVA/gp140 boost) or placebo.</p

Severe or potentially life threatening adverse adverse events.^*

<p>Severe or potentially life threatening adverse adverse events.^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161753#t003fn001" target="_blank">*</a>}</p

Comparisons of peak CD4+ and CD8+ T cell response by treatment group (Fisher's exact test).^*

<p>Comparisons of peak CD4+ and CD8+ T cell response by treatment group (Fisher's exact test).^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161753#t005fn001" target="_blank">*</a>}</p

CONSORT flow diagram: number of individuals assessed for eligibility, enrolled and randomized to vaccine or placebo, followed-up and analysed.

<p>T1: MVA prime, sequential gp140 boost (M/M/P/P); T2 (MP/MP): concurrent MVA/gp140; T3 (D/D/M/M): DNA prime, sequential MVA boost; T4 (D/D/MP/MP): DNA prime, concurrent MVA/gp140 boost) or placebo. P1-P4 = placebo.</p