A human immunodeficiency virus prime-boost immunization regimen in humans induces antibodies that show interclade cross-reactivity and neutralize several X4-, R5-, and dualtropic clade B and C primary isolates

Abstract

A human immunodeficiency virus (HIV) vaccine that will be useful in diverse geographic regions will need to induce a broad immune response characterized by cross-clade immunity. To test whether a clade B-based HIV candidate vaccine could induce interclade humoral responses, including neutralizing activity against primary HIV-1 isolates, sera were tested from recipients of a vaccine consisting of recombinant canarypox virus vCP205 and recombinant gp120(SF2). Serum antibodies exhibited strong immunochemical cross-reactivity with V3 peptides from clades B, C, and F, with weaker activity for several V3 peptides from clades A, D, G, and H; essentially no reactivity could be demonstrated with V3 peptides from clades E and O. Extensive cross-clade reactivity was also documented by enzyme-linked immunosorbent assay with all nine recombinant HIV envelope glycoproteins tested from clades B, D, and E. In addition, vaccinees' sera displayed significant neutralizing activity against 5 of 14 primary isolates tested, including one X4 virus and two dualtropic viruses (from clade B) and two R5 viruses (from clades B and C). This is the first demonstration of the induction by a candidate HIV vaccine constructed from clade B laboratory strains of HIV of neutralizing activity against R5 and clade C primary isolates. The data suggest that, by virtue of their ability to induce cross-clade immune responses, appropriately formulated HIV vaccines based on a finite number of HIV isolates may ultimately be able to protect against the wide range of HIV isolates affecting the populations of many geographic regions.

Figures

FIG. 1

Reactivity of HIV-positive, HIV-negative, and vaccinees' sera with 53 V3 peptides from groups M (clades A through H) and O. The OD values are color coded as shown by the spectrum at the top of the figure. Each row represents data generated with serum from a single individual in the study. The columns show reactions of the sera with each different peptide; the peptides are grouped according to clade in decreasing order of reactivity within that clade. Also shown are results with HIV-positive sera SX3, SX5, SX7, SX14, and SX16 and an HIV-positive serum included with the panel of sera received from DAIDS and HIV-negative sera (one from a vaccine volunteer who received placebo only, and two from HIV-negative participants in the vaccine trials bled prior to their immunization).

FIG. 2

Average reactivity of vaccinees' sera with recombinant envelope proteins. The average OD values detected in vaccinees' sera (solid bars) with the designated recombinant proteins are shown on the y axis. Only the results with vaccinees' sera giving reactions above the cut-off were used to calculate the average values. The number of vaccinees' sera (out of 20) giving a positive reaction with a designated protein is shown at the top of each bar. The average OD detected in the three HIV-1-negative control sera (one from a vaccine volunteer who received placebo only, two from HIV-negative participants in the vaccine trials bled prior to their immunization, and two from HIV-negative uninfected unimmunized individuals) with each recombinant protein is also shown (open bars). The average OD detected with all three HIV-positive sera (SX5, SX7, and SX16) (gray bars) is shown. The reactivity with a recombinant protein, NS1, from human parvovirus B19 was used as a negative control. The vertical bars show standard deviations.

FIG. 3

Neutralization of HIV primary isolates from several clades by sera from vaccinees and by HIV-positive and HIV-negative control sera. The percent neutralization shown on the y axis was determined for five primary isolates from clade B (top panel), five from clade C (middle panel), and four from clade F (bottom panel) with vaccinees' sera (open symbols), HIV-positive sera (SX5 and SX16) (red symbols), and HIV-negative sera (▸). The mean percent neutralization for each virus strain is indicated by a black line (vaccinees' sera) or by a red line (HIV-positive sera). The GHOST cell neutralization assay was used (9), with sera used at a final dilution of 1:20.

FIG. 4

Levels of neutralization of each serum (tested at a 1:20 dilution) against each of the 14 primary isolates. The percent neutralization by each serum-virus combination is shown. For ease of interpretation, the levels of neutralization are color coded: yellow represents nonsignificant neutralization (