Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 May 8;8(9):e167664.
doi: 10.1172/jci.insight.167664.

ALVAC-HIV and AIDSVAX B/E vaccination induce improved immune responses compared with AIDSVAX B/E vaccination alone

Margaret C Costanzo  1   2 , Dominic Paquin-Proulx  1   2 , Alexandra Schuetz  2   3 , Siriwat Akapirat  3 , Zhanna Shubin  1   2 , Dohoon Kim  1   2 , Lindsay Wieczorek  1   2 , Victoria R Polonis  1 , Hung V Trinh  1   2 , Mangala Rao  1 , Hanna Anenia  1   2 , Michael D Barrera  1   2 , Jacob Boeckelman  1   2 , Barbara Nails  1   2 , Pallavi Thapa  1   2 , Michelle Zemil  1   2 , Carlo Sacdalan  4 , Eugene Kroon  4 , Boot Kaewboon  3 , Somporn Tipsuk  3 , Surat Jongrakthaitae  3 , Sanjay Gurunathan  5 , Faruk Sinangil  6 , Jerome H Kim  7 , Merlin L Robb  1   2 , Julie A Ake  1 , Robert J O'Connell  1   3 , Punnee Pitisutthithum  8 , Sorachai Nitayaphan  3 , Suwat Chariyalertsak  9 , Michael A Eller  1   2 , Nittaya Phanuphak  4 , Sandhya Vasan  1   2 ; RV306; RV328 study groups
Affiliations

ALVAC-HIV and AIDSVAX B/E vaccination induce improved immune responses compared with AIDSVAX B/E vaccination alone

Margaret C Costanzo et al. JCI Insight. .

Abstract

The RV144 phase III vaccine trial demonstrated that ALVAC-HIV and AIDSVAX B/E administration over 6 months resulted in 31% efficacy in preventing HIV acquisition, while administration of AIDSVAX B/E alone in both VAX003 and VAX004 studies failed to show efficacy. In this study, we aimed to understand the impact of ALVAC-HIV on the development of cellular, humoral, and functional immune responses compared to the administration of AIDSVAX B/E alone. ALVAC-HIV in combination with 3 doses of AIDSVAX B/E significantly increased CD4+ HIV-specific T cell responses, polyfunctionality, and proliferation compared with 3 doses of AIDSVAX B/E alone. Additionally, Env-specific plasmablasts and A244-specific memory B cells were identified with a significantly higher magnitude in the group that received ALVAC-HIV. Subsequently, data revealed increased magnitude of plasma IgG binding to and avidity for HIV Env in participants who received ALVAC-HIV compared with 3 doses of AIDSVAX B/E alone. Lastly, levels of the Fc-mediated effector functions antibody-dependent cellular cytotoxicity, NK cell activation, and trogocytosis were significantly increased in participants who received ALVAC-HIV compared with those receiving AIDSVAX B/E alone. Taken together, these results suggest that ALVAC-HIV plays an essential role in developing cellular and humoral immune responses to protein-boosted regimens relative to protein alone.

Keywords: AIDS vaccine; AIDS/HIV.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: SG is an employee and shareholder of Sanofi Pasteur. FS is an employee of Global Solutions for Infectious Diseases.

Figures

Figure 1
Figure 1. RV306 and RV328 study design.
(A) Each RV306 participant received ALVAC-HIV and AIDSVAX B/E either alone or in combination at the indicated time points. RV328 participants received AIDSVAX B/E alone at the indicated time points. Comparative analysis was performed on week 50 for RV306 and week 26 for RV328, coinciding with 3 AIDSVAX B/E protein administrations within each study. Univariate analysis of TH023-specific CD4+ T cells expressing IFN-γ (B), IL-2 (C), and TNF-α (D). COMPASS revealed significantly higher functionality (E) and polyfunctionality (F) scores as well as increased proliferation (G) in CD4+ TH023 T cell responses in participants who received ALVAC-HIV. The dotted red line in G indicates the cutoff for positivity. For functionality and polyfunctionality scores, n = 33 for participants receiving ALVAC-HIV and AIDSVAX B/E and n = 30 for those who received AIDSVAX B/E alone. For CD4+ T cell proliferation, n = 34 for participants receiving ALVAC-HIV and AIDSVAX B/E and n = 26 for those who received AIDSVAX B/E alone. Data are presented as the median and IQR. Statistical significance was assessed using the Mann-Whitney U test.
Figure 2
Figure 2. Prevalence of HIV Env–specific antibody-secreting plasmablasts and memory B cells.
Env-specific IgG-secreting plasmablasts (A and B) and memory B cells (C and D) in PBMCs were enumerated by a direct ELISpot assay for gp120 A244 (A and C) and MN (B and D). n = 36 for participants receiving ALVAC-HIV and AIDSVAX B/E and n = 30 for those who received AIDSVAX B/E alone. Dotted red lines indicate the cutoff for positivity. SFC, spot-forming cells. Data are presented as the mean ± SEM. Statistical significance was assessed using Mann-Whitney U test.
Figure 3
Figure 3. Plasma IgG HIV-1 Env and V1V2 antibody binding titers and avidity of antibody-antigen interaction are significantly higher with ALVAC-HIV.
(A and B) IgG antibody binding titers for HIV-1 gp120 and scaffolded gp70 V1V2 antigens were measured by ELISA. Each symbol represents the average of triplicate measurements for a participant. Geometric mean antibody titers against gp120 A244gD– D11 (A, left), gp120 MNgD– D11 (A, right), gp70 V1V2 (92TH023) (B, left), and gp70 V1V2 (case A2) (B, right) are shown. Each panel graphically displays geometric mean titers, color-coded by group. Error bars depict 95% CIs. Statistical significance was assessed using the Mann-Whitney U test with step-down Bonferroni adjustment. n = 190 for participants receiving ALVAC-HIV and AIDSVAX B/E and n = 30 for those who received AIDSVAX B/E alone. (C) Kd off-rate (1/s). A lower Kd off-rate corresponds to higher avidity. Statistical analysis was performed using the rank-based nonparametric 1-way ANOVA (Kruskal-Wallis H test). The FDR was determined using the 2-stage step-up method of Benjamini, Krieger, and Yekutieli, with confidence level at 0.05. For Kd off-rate with A244, n = 62 for participants receiving ALVAC-HIV and AIDSVAX B/E and n = 23 for those who received AIDSVAX B/E alone. For Kd off-rate with MN, n = 58 for participants receiving ALVAC-HIV and AIDSVAX B/E and n = 25 for those who received AIDSVAX B/E alone. Data are shown as the mean and 95% CI.
Figure 4
Figure 4. TZM-bl neutralizing antibody levels and antibody effector function levels after 3 AIDSVAX B/E vaccinations in participants who received ALVAC-HIV versus participants who received AIDSVAX B/E alone.
ID50 against MW965 (A), TH023 (B), MN (C), and SF162 (D) PSVs, with and without ALVAC-HIV. Each panel graphically depicts ID50, color coded by group (blue, with ALVAC; black, without ALVAC). Error bars depict 95% CIs. Statistical significance was assessed using the Mann-Whitney U test. n = 190 for participants receiving ALVAC-HIV and AIDSVAX B/E and n = 30 for those who received AIDSVAX B/E alone. Plasma antibody effector activity is shown for ADCP (E), ADNP (F), ADCD (G), trogocytosis (H), ADCC (I), and NK cell activation, as measured by production of IFN-γ, TNF-α, or MIP-1β (J) for participants receiving ALVAC-HIV and AIDSVAX B/E (n = 50) and those who received AIDSVAX B/E alone (n = 30). Dotted red lines indicate the cutoff for positivity. Data are presented as the median and IQR. Statistical significance determined by unpaired, nonparametric Mann-Whitney U test.
Figure 5
Figure 5. Network analysis.
(A) Associations between antibody features were determined using nonparametric Spearman’s correlation coefficient. *P < 0.05, **P < 0.01, ***P < 0.001. (B) Antibody binding (squares, IgG; triangles, IgA) and functions (circles) as well as T cell polyfunctionality (hexagons) were included in network analysis. Statistically significant associations (P < 0.05) were used to generate networks in Cytoscape (version 3.7.2). Positive associations are shown in red and negative associations are shown in blue. The thickness of the lines represents the strength of the association (r values). In participants who received ALVAC-HIV, Fc functions vs. binding and neutralization used n = 50, CD4+ cell functions vs. binding neutralization used n = 35, CD4+ T cell responses vs. Fc function used n = 16. In participants who received AIDSVAX B/E alone, all network and association comparisons used n = 30. ADNKA, antibody-dependent NK cell activation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Punnee Pitisuttithum PG, et al. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinantv glycoproteinv 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J Infect Dis. 2006;194(12):1661–1671. doi: 10.1086/508748. - DOI - PubMed
    1. Vanichseni ST, et al. Recruitment, screening and characteristics of injection drug users participating in the AIDSVAX B/E HIV vaccine trial, Bangkok, Thailand. AIDS. 2004;18(2):311–316. doi: 10.1097/00002030-200401230-00022. - DOI - PubMed
    1. Harro CD, et al. Recruitment and baseline epidemiologic profile of participants in the first phase 3 HIV vaccine efficacy trial. J Acquir ImmuneDefic Syndr. 2004;37(3):1385–1392. doi: 10.1097/01.qai.0000122983.87519.b5. - DOI - PubMed
    1. Flynn NM, et al. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J Infect Dis. 2005;191(5):654–665. doi: 10.1086/428404. - DOI - PubMed
    1. Gilbert PB, et al. Correlation between immunologic responses to a recombinant glycoprotein 120 vaccine and incidence of HIV-1 infection in a phase 3 HIV-1 preventive vaccine trial. J Infect Dis. 2005;191(5):666–677. doi: 10.1086/428405. - DOI - PubMed

Publication types