Effects of sex but not race and geographic origin on vaccine-induced HIV-specific antibody responses

Abstract

Background: Sex, race and geographic location may affect vaccine-induced immune responses, yet few preventive HIV vaccine trials have systematically evaluated such effects. The main objective of this study was therefore to examine the role of these factors on vaccine-induced HIV-specific immune responses within the HVTN 204 trial. This randomized, double-blinded, placebo-controlled phase 2 trial enrolled 480 Black and Caucasian adults from Africa and the Americas, who received a trivalent DNA-HIV-1 vaccine prime followed by a rAd5 vector HIV-1 vaccine boost.

Methods: Available serum samples from baseline and four weeks after the final vaccination boost from Black (n=85, 59% female) and Caucasian (n=49, 51% female) HVTN 204 vaccine recipients from South Africa and the United States of America were studied using an Enzyme-Linked Immunosorbent Assay to determine titers of Envelope-specific IgG1, IgG3 and IgA antibodies. Recognition of linear Envelope peptide-specific IgG responses was mapped in a randomly selected subgroup analysis using a custom-designed peptide microarray (n = 41, 49% female). Associations between vaccine-induced Envelope-specific antibody responses and sex assigned at birth (female or male), race and geographic location were then analyzed by the Mann-Whitney U test, Fisher's exact test and multivariate logistic regression.

Results: Four weeks post-final vaccination boost, we observed that Envelope-specific antibody titers were significantly increased for IgG1 but reduced for IgA in females (female vs. male median titer: 900 vs. 300, p=0.030 and <100 vs. 100, p=0.007, respectively). Multivariate logistic regression confirmed that female sex increased the odds for higher Envelope-specific IgG1 and low IgA titers compared to males. In terms of antibody epitopes, the V2 region was more frequently recognized in females than males (p=0.008). Race and geographic location had no apparent influence on antibody isotype titers investigated.

Conclusion: Female sex was associated with higher vaccine-induced IgG Envelope-specific binding antibody titers and recognition of V2 region of HIV Envelope in HVTN 204 volunteers. No such associations were detected for race or geographic location. Understanding biological factors driving these sex-based differences may improve the design of a new generation of HIV vaccine candidates.

Keywords: HIV-1; HVTN 204; antibody; race; sex; vaccines.

Figure 1

Females and South Africans have increased anti-CN54rgp140-specific IgG1 background signal. Optical densities (OD) in participants with background signal pre-vaccination are stratified by sex (left panels), race and geographic location (right panels) of participants. (A) IgG1 (n=37), (B) IgG3 (n=73), and (C) IgA (n=90). Each dot represents one individual. Median lines are indicated in graphs. Statistical analysis was performed using the Mann-Whitney U-test.

Figure 2

Increased IgG1 titers but decreased IgA titers in females. Titers in vaccinated participants are stratified by sex (left panels), race and geographic location (right panels) of participants. (A) IgG1 (n=115), (B) IgG3 (n=134), and (C) IgA (n=105). Each dot represents one individual. Median lines are indicated in graphs. Statistical analysis was performed using the Mann-Whitney U-test.

Figure 3

Variations in B cell epitope recognition based on both sex and geographic location. Comparison of IgG responses targeting single peptide immuno-dominant regions as measured by peptide microarray. Each graph (A–D) depicts mean FI values post-vaccination without baseline-correction for one representative peptide of the 4 immuno-dominant regions. Corresponding HXB2 amino acid positions are stated. Each symbol indicates the maximum FI value of one single study participant. The cut-off for positive signals is indicated by a dotted line. P-values were calculated using a Mann-Whitey-U test. Only p-values <0.05 are shown. n US F=10; n US M=10; n SA F=10M; n SA M=11. IDR, immuno-dominant region; F, female; M, male; US, United States of America; SA, Republic of South Africa.

Figure 4

Forest plot displaying odds ratios for a positive antibody response influenced by sex, age and race. (A) IgG1 (n=115), (B) IgG3 (n=134), and (C) IgA (n=105). Forest plot displaying odds ratios for the interaction of positive IgG1, IgG3 and IgA antibody responses with sex, age (19–24 vs. 25–50 years) and race (Black vs. Caucasian) for HVTN 204 vaccinees. The individual risk factors are indicated on the y-axis; adjusted odds ratios and 95% confidence intervals (CI) are shown on the x-axis. The actual odds ratios and 95% CI are shown on the right side of each graph. Age stratification is adopted from the WHO classification of youth vs adult. Statistical analysis was performed by multivariate logistic regression.