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
. 2022 Jan 25;10(2):187.
doi: 10.3390/vaccines10020187.

Ex Vivo Evaluation of Mucosal Responses to Vaccination with ALVAC and AIDSVAX of Non-Human Primates

Carolina Herrera  1 , Ronald Veazey  2 , Melissa M Lemke  3 , Kelly Arnold  3 , Jerome H Kim  4 , Robin J Shattock  1
Affiliations

Ex Vivo Evaluation of Mucosal Responses to Vaccination with ALVAC and AIDSVAX of Non-Human Primates

Carolina Herrera et al. Vaccines (Basel). .

Abstract

Non-human primates (NHPs) remain the most relevant challenge model for the evaluation of HIV vaccine candidates; however, discrepancies with clinical trial results have emphasized the need to further refine the NHP model. Furthermore, classical evaluation of vaccine candidates is based on endpoints measured systemically. We assessed the mucosal responses elicited upon vaccination with ALVAC and AIDSVAX using ex vivo Rhesus macaque mucosal tissue explant models. Following booster immunization with ALVAC/AIDSVAX, anti-gp120 HIV-1CM244-specific IgG and IgA were detected in culture supernatant cervicovaginal and colorectal tissue explants, as well as systemically. Despite protection from ex vivo viral challenge, no neutralization was observed with tissue explant culture supernatants. Priming with ALVAC induced distinct cytokine profiles in cervical and rectal tissue. However, ALVAC/AIDSVAX boosts resulted in similar modulations in both mucosal tissues with a statistically significant decrease in cytokines linked to inflammatory responses and lymphocyte differentiation. With ALVAC/AIDSVAX boosts, significant correlations were observed between cytokine levels and specific IgA in cervical explants and specific IgG and IgA in rectal tissue. The cytokine secretome revealed differences between vaccination with ALVAC and ALVAC/AIDSVAX not previously observed in mucosal tissues and distinct from the systemic response, which could represent a biosignature of the vaccine combination.

Keywords: HIV-1; mucosal immunology; vaccine.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Specific anti-gp120 HIV-1CM244 IgG and IgA levels elicited during vaccination with ALVAC/AIDSVAX. (a) Immunization and sampling schedule. (b–e) Explant culture supernatants were harvested during the 15 days of culture of tissues obtained 2 weeks after each vaccination ((b,c) cervical (open symbols) and vaginal (closed symbols); (d,e) rectal (open symbols) and sigmoidal (closed symbols)). The data shown are the sum of the Ab concentrations measured in triplicate at harvest days 3, 7, 11, and 15 during the culture period for tissue explants from each macaque. (f,g) Vaginal and (h,i) rectal secretions were extracted from Weck-Cel sponges collected from each animal 2 weeks after each vaccination, and Ab concentrations were measured in triplicate. (j,k) Serum was obtained for each animal from blood collected 1 and 2 weeks after each vaccination and Ab concentrations were quantified in triplicate. Means are shown with lines. Statistical significance: * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, **** p ≤ 0.0001.
Figure 2
Figure 2
Ex vivo challenge of mucosal explants with SHIVBaL. (a) Cervical and (b) rectal explants cut from biopsies and tissue resected at necropsy were obtained at weeks -4 and 26, respectively. Explants were incubated with SHIVBaL for 2 h, washed four times in PBS, and cultured on gel foam for 15 days. The levels of p27 in the culture supernatants were measured by ELISA at day 15. The data are the means of at least duplicates for each macaque. Lines connect the data from the two time points for each animal. Statistical significance: ** p ≤ 0.01, *** p ≤ 0.001.
Figure 3
Figure 3
Effect of vaccination on the mucosal and systemic cytokine profile. Heatmap representing cytokines in (a) cervical or (c) rectal tissues, and in (e) serum that are upregulated (red) or downregulated (green) 1 or 2 weeks after each vaccination in comparison to the baseline profiles at week -4. Differences are shown in Log2 from two independent experiments performed in quadruplicate. Interaction maps of the functional pathways associated with the cytokine/chemokine nodes modulated at week 26 in (b) cervical explants, (d) rectal tissue or (f) serum. Colors: blue: downregulated; orange: upregulated. Symbols: oval: transmembrane receptor; square: cytokine/chemokine; diamond: enzyme; inverted triangle: kinase; hourglass: canonical pathway; octagon: function. Lines: solid: direct interaction; dashed: indirect interaction; doted: inferred correlation from Ingenuity Pathway Analysis machine-based learning.
Figure 4
Figure 4
Correlogram of the vaccine responses elicited in the mucosal and systemic compartments. The correlations between the levels of secreted cytokines and the concentrations of total, gp120-specific and the specific activity of IgG and IgA in cervical tissue (a,d), rectal explants (b,e), and serum (c,f) at week 26 (a–c) or week 6 (d–f) were analyzed by a correlation matrix. Positive Pearson correlation coefficients are displayed in blue and negative correlations are displayed in red. The color intensity indicated in the side bar is proportional to the correlation coefficient. The size of the circle is proportional to the statistical significance of the correlation. Statistical significance from p ≤ 0.05.
Figure 5
Figure 5
Correlogram of the vaccine responses elicited in mucosal explants. The correlations between the levels of secreted cytokines and susceptibility to ex vivo challenge with SHIVBaL ([p27] (pg/mL) at day 15 and % of inhibition) in cervical (a,c) and rectal explants (b,d) at week 26 (a,b) or week 6 (c,d) were analyzed by a correlation matrix. Positive Pearson correlation coefficients are displayed in blue and negative correlations are displayed in red. The color intensity indicated in the side bar is proportional to the correlation coefficient. The size of the circle is proportional to the statistical significance of the correlation. Statistical significance from p ≤ 0.05.
See this image and copyright information in PMC

Similar articles

  • Characterization of HIV-1 gp120 antibody specificities induced in anogenital secretions of RV144 vaccine recipients after late boost immunizations.
    Akapirat S, Karnasuta C, Vasan S, Rerks-Ngarm S, Pitisuttithum P, Madnote S, Savadsuk H, Rittiroongrad S, Puangkaew J, Phogat S, Tartaglia J, Sinangil F, de Souza MS, Excler JL, Kim JH, Robb ML, Michael NL, Ngauy V, O'Connell RJ, Karasavvas N; RV305 Study Group. Akapirat S, et al. PLoS One. 2018 Apr 27;13(4):e0196397. doi: 10.1371/journal.pone.0196397. eCollection 2018. PLoS One. 2018. PMID: 29702672 Free PMC article. Clinical Trial.
  • ALVAC-HIV and AIDSVAX B/E vaccination induce improved immune responses compared with AIDSVAX B/E vaccination alone.
    Costanzo MC, Paquin-Proulx D, Schuetz A, Akapirat S, Shubin Z, Kim D, Wieczorek L, Polonis VR, Trinh HV, Rao M, Anenia H, Barrera MD, Boeckelman J, Nails B, Thapa P, Zemil M, Sacdalan C, Kroon E, Kaewboon B, Tipsuk S, Jongrakthaitae S, Gurunathan S, Sinangil F, Kim JH, Robb ML, Ake JA, O'Connell RJ, Pitisutthithum P, Nitayaphan S, Chariyalertsak S, Eller MA, Phanuphak N, Vasan S; RV306; RV328 study groups. Costanzo MC, et al. JCI Insight. 2023 May 8;8(9):e167664. doi: 10.1172/jci.insight.167664. JCI Insight. 2023. PMID: 37154156 Free PMC article.
  • Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaques.
    Luo K, Liao HX, Zhang R, Easterhoff D, Wiehe K, Gurley TC, Armand LC, Allen AA, Von Holle TA, Marshall DJ, Whitesides JF, Pritchett J, Foulger A, Hernandez G, Parks R, Lloyd KE, Stolarchuk C, Sawant S, Peel J, Yates NL, Dunford E, Arora S, Wang A, Bowman CM, Sutherland LL, Scearce RM, Xia SM, Bonsignori M, Pollara J, Edwards RW, Santra S, Letvin NL, Tartaglia J, Francis D, Sinangil F, Lee C, Kaewkungwal J, Nitayaphan S, Pitisuttithum P, Rerks-Ngarm S, Michael NL, Kim JH, Alam SM, Vandergrift NA, Ferrari G, Montefiori DC, Tomaras GD, Haynes BF, Moody MA. Luo K, et al. JCI Insight. 2016 Dec 8;1(20):e88522. doi: 10.1172/jci.insight.88522. JCI Insight. 2016. PMID: 27942585 Free PMC article.
  • ALVAC-HIV vaccines: clinical trial experience focusing on progress in vaccine development.
    Marovich MA. Marovich MA. Expert Rev Vaccines. 2004 Aug;3(4 Suppl):S99-104. doi: 10.1586/14760584.3.4.s99. Expert Rev Vaccines. 2004. PMID: 15285709 Review.
  • New concepts in HIV-1 vaccine development.
    Stephenson KE, D'Couto HT, Barouch DH. Stephenson KE, et al. Curr Opin Immunol. 2016 Aug;41:39-46. doi: 10.1016/j.coi.2016.05.011. Epub 2016 Jun 3. Curr Opin Immunol. 2016. PMID: 27268856 Free PMC article. Review.
See all similar articles

Cited by

References

    1. Buchbinder S.P., Mehrotra D.V., Duerr A., Fitzgerald D.W., Mogg R., Li D., Gilbert P.B., Lama J.R., Marmor M., Del Rio C., et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): A double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet. 2008;372:1881–1893. doi: 10.1016/S0140-6736(08)61591-3. - DOI - PMC - PubMed
    1. Rerks-Ngarm S., Pitisuttithum P., Nitayaphan S., Kaewkungwal J., Chiu J., Paris R., Premsri N., Namwat C., de Souza M., Adams E., et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med. 2009;361:2209–2220. doi: 10.1056/NEJMoa0908492. - DOI - PubMed
    1. Gray G.E., Bekker L.G., Laher F., Malahleha M., Allen M., Moodie Z., Grunenberg N., Huang Y., Grove D., Prigmore B., et al. Vaccine Efficacy of ALVAC-HIV and Bivalent Subtype C gp120-MF59 in Adults. N. Engl. J. Med. 2021;384:1089–1100. doi: 10.1056/NEJMoa2031499. - DOI - PMC - PubMed
    1. Burton D.R. Advancing an HIV vaccine; advancing vaccinology. Nat. Rev. Immunol. 2019;19:77–78. doi: 10.1038/s41577-018-0103-6. - DOI - PMC - PubMed
    1. Chen X., Zhou T., Schmidt S., Duan H., Cheng C., Chuang G.-Y., Gu Y., Louder M., Lin B., Shen C.-H., et al. Vaccination induces maturation of diverse unmutated VRC01-class precursors to HIV-1 broadly neutralizing antibodies in an Ig-humanized mouse model. In Proceedings of the 4th HIV Research for Prevention conference (HIVR4P//Virtual), 27–28 January–3–4 February 2021. J. Int. AIDS Soc. 2021;24:e25659. doi: 10.1002/jia2.25659. - DOI - PMC - PubMed

LinkOut - more resources