Safety and immune responses after a 12-month booster in healthy HIV-uninfected adults in HVTN 100 in South Africa: A randomized double-blind placebo-controlled trial of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccines

English version

Autoři: Fatima Laher ^aff001; Zoe Moodie ^aff002; Kristen W. Cohen ^aff002; Nicole Grunenberg ^aff002; Linda-Gail Bekker ^aff003; Mary Allen ^aff004; Nicole Frahm ^aff002; Nicole L. Yates ^aff005; Lynn Morris ^aff006; Mookho Malahleha ^aff008; Kathryn Mngadi ^aff009; Brodie Daniels ^aff010; Craig Innes ^aff011; Kevin Saunders ^aff005; Shannon Grant ^aff002; Chenchen Yu ^aff002; Peter B. Gilbert ^aff002; Sanjay Phogat ^aff012; Carlos A. DiazGranados ^aff012; Marguerite Koutsoukos ^aff013; Olivier Van Der Meeren ^aff013; Carter Bentley ^aff002; Nonhlanhla N. Mkhize ^aff006; Michael N. Pensiero ^aff004; Vijay L. Mehra ^aff004; James G. Kublin ^aff002; Lawrence Corey ^aff002; David C. Montefiori ^aff005; Glenda E. Gray ^aff001; M. Juliana McElrath ^aff002; Georgia D. Tomaras ^aff005
Působiště autorů: Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa ^aff001; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America ^aff002; Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa ^aff003; Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America ^aff004; Departments of Surgery and Immunology, Duke Human Vaccine Institute, Durham, North Carolina, United States of America ^aff005; National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa ^aff006; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa ^aff007; Setshaba Research Centre, Soshanguve, South Africa ^aff008; Centre for the AIDS Programme of Research in South Africa, Durban, South Africa ^aff009; South African Medical Research Council, Durban, South Africa ^aff010; Aurum Institute, Klerksdorp Research Centre, Klerksdorp, South Africa ^aff011; Sanofi Pasteur, Swiftwater, Pennsylvania, United States of America ^aff012; GSK Vaccines, Rixensart, Belgium ^aff013
Vyšlo v časopise: Safety and immune responses after a 12-month booster in healthy HIV-uninfected adults in HVTN 100 in South Africa: A randomized double-blind placebo-controlled trial of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccines. PLoS Med 17(2): e32767. doi:10.1371/journal.pmed.1003038
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pmed.1003038

Souhrn

Background

HVTN 100 evaluated the safety and immunogenicity of an HIV subtype C pox-protein vaccine regimen, investigating a 12-month booster to extend vaccine-induced immune responses.

Methods and findings

A phase 1–2 randomized double-blind placebo-controlled trial enrolled 252 participants (210 vaccine/42 placebo; median age 23 years; 43% female) between 9 February 2015 and 26 May 2015. Vaccine recipients received ALVAC-HIV (vCP2438) alone at months 0 and 1 and with bivalent subtype C gp120/MF59 at months 3, 6, and 12. Antibody (IgG, IgG3 binding, and neutralizing) and CD4+ T-cell (expressing interferon-gamma, interleukin-2, and CD40 ligand) responses were evaluated at month 6.5 for all participants and at months 12, 12.5, and 18 for a randomly selected subset. The primary analysis compared IgG binding antibody (bAb) responses and CD4+ T-cell responses to 3 vaccine-matched antigens at peak (month 6.5 versus 12.5) and durability (month 12 versus 18) timepoints; IgG responses to CaseA2_gp70_V1V2.B, a primary correlate of risk in RV144, were also compared at these same timepoints. Secondary and exploratory analyses compared IgG3 bAb responses, IgG bAb breadth scores, neutralizing antibody (nAb) responses, antibody-dependent cellular phagocytosis, CD4+ polyfunctionality responses, and CD4+ memory sub-population responses at the same timepoints. Vaccines were generally safe and well tolerated. During the study, there were 2 deaths (both in the vaccine group and both unrelated to study products). Ten participants became HIV-infected during the trial, 7% (3/42) of placebo recipients and 3% (7/210) of vaccine recipients. All 8 serious adverse events were unrelated to study products. Less waning of immune responses was seen after the fifth vaccination than after the fourth, with higher antibody and cellular response rates at month 18 than at month 12: IgG bAb response rates to 1086.C V1V2, 21.0% versus 9.7% (difference = 11.3%, 95% CI = 0.6%–22.0%, P = 0.039), and ZM96.C V1V2, 21.0% versus 6.5% (difference = 14.5%, 95% CI = 4.1%–24.9%, P = 0.004). IgG bAb response rates to all 4 primary V1V2 antigens were higher 2 weeks after the fifth vaccination than 2 weeks after the fourth vaccination: 87.7% versus 75.4% (difference = 12.3%, 95% CI = 1.7%–22.9%, P = 0.022) for 1086.C V1V2, 86.0% versus 63.2% (difference = 22.8%, 95% CI = 9.1%–36.5%, P = 0.001) for TV1c8.2.C V1V2, 67.7% versus 44.6% (difference = 23.1%, 95% CI = 10.4%–35.7%, P < 0.001) for ZM96.C V1V2, and 81.5% versus 60.0% (difference = 21.5%, 95% CI = 7.6%–35.5%, P = 0.002) for CaseA2_gp70_V1V2.B. IgG bAb response rates to the 3 primary vaccine-matched gp120 antigens were all above 90% at both peak timepoints, with no significant differences seen, except a higher response rate to ZM96.C gp120 at month 18 versus month 12: 64.5% versus 1.6% (difference = 62.9%, 95% CI = 49.3%–76.5%, P < 0.001). CD4+ T-cell response rates were higher at month 18 than month 12 for all 3 primary vaccine-matched antigens: 47.3% versus 29.1% (difference = 18.2%, 95% CI = 2.9%–33.4%, P = 0.021) for 1086.C, 61.8% versus 38.2% (difference = 23.6%, 95% CI = 9.5%–37.8%, P = 0.001) for TV1.C, and 63.6% versus 41.8% (difference = 21.8%, 95% CI = 5.1%–38.5%, P = 0.007) for ZM96.C, with no significant differences seen at the peak timepoints. Limitations were that higher doses of gp120 were not evaluated, this study was not designed to investigate HIV prevention efficacy, and the clinical significance of the observed immunological effects is uncertain.

Conclusions

In this study, a 12-month booster of subtype C pox-protein vaccines restored immune responses, and slowed response decay compared to the 6-month vaccination.

Trial registration

ClinicalTrials.gov NCT02404311.

South African National Clinical Trials Registry (SANCTR number: DOH--27-0215-4796).

Klíčová slova:

Antibodies – Antibody response – Booster doses – Immune response – Memory T cells – T cells – Vaccination and immunization – Vaccines

Zdroje

1. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361(23):2209–20. doi: 10.1056/NEJMoa0908492 19843557

2. Corey L, Gilbert PB, Tomaras GD, Haynes BF, Pantaleo G, Fauci AS. Immune correlates of vaccine protection against HIV-1 acquisition. Sci Transl Med. 2015;7(310):310rv7. doi: 10.1126/scitranslmed.aac7732 26491081

3. Lewis GK, DeVico AL, Gallo RC. Antibody persistence and T-cell balance: two key factors confronting HIV vaccine development. Proc Natl Acad Sci U S A. 2014;111(44):15614–21. doi: 10.1073/pnas.1413550111 25349379

4. Robb ML, Rerks-Ngarm S, Nitayaphan S, Pitisuttithum P, Kaewkungwal J, Kunasol P, et al. Risk behaviour and time as covariates for efficacy of the HIV vaccine regimen ALVAC-HIV (vcp1521) and AIDSVAX B/E: a post-hoc analysis of the Thai phase 3 efficacy trial RV 144. Lancet Infect Dis. 2012;12(7):531–7. doi: 10.1016/S1473-3099(12)70088-9 22652344

5. Yates NL, Liao HX, Fong Y, deCamp A, Vandergrift NA, Williams WT, et al. Vaccine-induced Env V1-V2 IgG3 correlates with lower HIV-1 infection risk and declines soon after vaccination. Sci Transl Med. 2014;6(228):228ra39. doi: 10.1126/scitranslmed.3007730 24648342

6. Pollara J, Easterhoff D, Fouda GG. Lessons learned from human HIV vaccine trials. Curr Opin HIV AIDS. 2017;12(3):216–21. doi: 10.1097/COH.0000000000000362 28230655

7. Bekker LG, Moodie Z, Grunenberg N, Laher F, Tomaras GD, Cohen KW, et al. Subtype C ALVAC-HIV and bivalent subtype C gp120/MF59 HIV-1 vaccine in low-risk, HIV-uninfected, South African adults: a phase 1/2 trial. Lancet HIV. 2018;5(7):e366–78. doi: 10.1016/S2352-3018(18)30071-7 29898870

8. Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras GD, Alam SM, et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. 2012;366(14):1275–86. doi: 10.1056/NEJMoa1113425 22475592

9. Sarzotti-Kelsoe M, Bailer RT, Turk E, Lin CL, Bilska M, Greene KM, et al. Optimization and validation of the TZM-bl assay for standardized assessments of neutralizing antibodies against HIV-1. J Immunol Methods. 2014;409:131–46. doi: 10.1016/j.jim.2013.11.022 24291345

10. Montefiori DC. Measuring HIV neutralization in a luciferase reporter gene assay. Methods Mol Biol. 2009;485:395–405. doi: 10.1007/978-1-59745-170-3_26 19020839

11. Horton H, Thomas EP, Stucky JA, Frank I, Moodie Z, Huang Y, et al. Optimization and validation of an 8-color intracellular cytokine staining (ICS) assay to quantify antigen-specific T cells induced by vaccination. J Immunol Methods. 2007;323(1):39–54. doi: 10.1016/j.jim.2007.03.002 17451739

12. Tomaras GD, Yates NL, Liu P, Qin L, Fouda GG, Chavez LL, et al. Initial B-cell responses to transmitted human immunodeficiency virus type 1: virion-binding immunoglobulin m (IgM) and IgG antibodies followed by plasma anti-gp41 antibodies with ineffective control of initial viremia. J Virol. 2008;82(24):12449–63. doi: 10.1128/JVI.01708-08 18842730

13. Yates NL, deCamp AC, Korber BT, Liao HX, Irene C, Pinter A, et al. HIV-1 envelope glycoproteins from diverse clades differentiate antibody responses and durability among vaccinees. J Virol. 2018;92(8):e01843–17. doi: 10.1128/JVI.01843-17 29386288

14. Tay MZ, Liu P, Williams LD, McRaven MD, Sawant S, Gurley TC, et al. Antibody-mediated internalization of infectious HIV-1 virions differs among antibody isotypes and subclasses. PLoS Pathog. 2016;12(8):e1005817. doi: 10.1371/journal.ppat.1005817 27579713

15. Moncunill G, Dobano C, McElrath MJ, De Rosa SC. Omip-025: evaluation of human T- and NK-cell responses including memory and follicular helper phenotype by intracellular cytokine staining. Cytometry A. 2015;87(4):289–92. doi: 10.1002/cyto.a.22590 25407958

16. Agresti A, Coull BA. Approximate is better than “exact” for interval estimation of binomial proportions. Am Stat. 1998;52(2):119–26.

17. Huang Y, Gilbert PB, Montefiori DC, Self SG. Simultaneous evaluation of the magnitude and breadth of a left and right censored multivariate response, with application to HIV vaccine development. Stat Biopharm Res. 2009;1(1):81–91. doi: 10.1198/sbr.2009.0008 20072667

18. Lin L, Finak G, Ushey K, Seshadri C, Hawn TR, Frahm N, et al. COMPASS identifies T-cell subsets correlated with clinical outcomes. Nat Biotechnol. 2015;33(6):610–6. doi: 10.1038/nbt.3187 26006008

19. Gottardo R, Bailer RT, Korber BT, Gnanakaran S, Phillips J, Shen X, et al. Plasma IgG to linear epitopes in the V2 and V3 regions of HIV-1 gp120 correlate with a reduced risk of infection in the RV144 vaccine efficacy trial. PLoS ONE. 2013;8(9):e75665. doi: 10.1371/journal.pone.0075665 24086607

20. Shen X, Laher F, Moodie Z, McMillan AS, Spreng RL, Gilbert PB, et al. HIV-1 vaccine sequences impact V1V2 antibody responses: a comparison of two poxvirus prime gp120 boost vaccine regimens. Sci Rep. In press. doi: 10.1038/s41598-020-57491-z

21. Chung AW, Ghebremichael M, Robinson H, Brown E, Choi I, Lane S, et al. Polyfunctional Fc-effector profiles mediated by IgG subclass selection distinguish RV144 and VAX003 vaccines. Sci Transl Med. 2014;6(228):228ra38. doi: 10.1126/scitranslmed.3007736 24648341

22. Chung AW, Kumar MP, Arnold KB, Yu WH, Schoen MK, Dunphy LJ, et al. Dissecting polyclonal vaccine-induced humoral immunity against HIV using systems serology. Cell. 2015;163(4):988–98. doi: 10.1016/j.cell.2015.10.027 26544943

23. Neidich SD, Fong Y, Li SS, Geraghty DE, Williamson BD, Young WC, et al. Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk. J Clin Invest. 2019;129(11):4838–49. doi: 10.1172/JCI126391 31589165

24. deCamp A, Hraber P, Bailer RT, Seaman MS, Ochsenbauer C, Kappes J, et al. Global panel of HIV-1 Env reference strains for standardized assessments of vaccine-elicited neutralizing antibodies. J Virol. 2014;88(5):2489–507. doi: 10.1128/JVI.02853-13 24352443

25. Hraber P, Rademeyer C, Williamson C, Seaman MS, Gottardo R, Tang H, et al. Panels of HIV-1 subtype C Env reference strains for standardized neutralization assessments. J Virol. 2017;91(19):e00991–17. doi: 10.1128/JVI.00991-17 28747500

26. LaBranche CC, McGuire AT, Gray MD, Behrens S, Kwong PDK, Chen X, et al. HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies. PLoS Pathog. 2018;14(11):e1007431. doi: 10.1371/journal.ppat.1007431 30395637

27. Slifka MK, Amanna I. How advances in immunology provide insight into improving vaccine efficacy. Vaccine. 2014;32(25):2948–57. doi: 10.1016/j.vaccine.2014.03.078 24709587

28. Rerks-Ngarm S, Pitisuttithum P, Excler JL, Nitayaphan S, Kaewkungwal J, Premsri N, et al. Randomized, double-blind evaluation of late boost strategies for HIV-uninfected vaccine recipients in the RV144 HIV vaccine efficacy trial. J Infect Dis. 2017;215(8):1255–63. doi: 10.1093/infdis/jix099 28329190

29. Easterhoff D, Moody MA, Fera D, Cheng H, Ackerman M, Wiehe K, et al. Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial. PLoS Pathog. 2017;13(2):e1006182. doi: 10.1371/journal.ppat.1006182 28235027

30. Prentice HA, Tomaras GD, Geraghty DE, Apps R, Fong Y, Ehrenberg PK, et al. HLA class II genes modulate vaccine-induced antibody responses to affect HIV-1 acquisition. Sci Transl Med. 2015;7(296):296ra112. doi: 10.1126/scitranslmed.aab4005 26180102

31. Huang Y, Zhang L, Janes H, Frahm N, Isaacs A, Kim JH, et al. Predictors of durable immune responses six months after the last vaccination in preventive HIV vaccine trials. Vaccine. 2017;35(8):1184–93. doi: 10.1016/j.vaccine.2016.09.053 28131393

32. de Bruyn G, Rossini AJ, Chiu YL, Holman D, Elizaga ML, Frey SE, et al. Safety profile of recombinant canarypox HIV vaccines. Vaccine. 2004;22(5–6):704–13. doi: 10.1016/j.vaccine.2003.08.023 14741163

33. Reisinger KS, Holmes SJ, Pedotti P, Arora AK, Lattanzi M. A dose-ranging study of MF59((R))-adjuvanted and non-adjuvanted A/H1N1 pandemic influenza vaccine in young to middle-aged and older adult populations to assess safety, immunogenicity, and antibody persistence one year after vaccination. Hum Vaccin Immunother. 2014;10(8):2395–407. doi: 10.4161/hv.29393 25424947

34. Fisher L, Zinger M, Stanfield-Oakley S, Carpp LN, Edwards RW, Denny T, et al. Vaccine-induced antibodies mediate higher antibody-dependent cellular cytotoxicity after interleukin-15 pretreatment of natural killer effector cells. Front Immunol. 2019;10:2741. doi: 10.3389/fimmu.2019.02741 31827470

35. Perez LG, Martinez DR, deCamp AC, Pinter A, Berman PW, Francis D, et al. V1V2-specific complement activating serum IgG as a correlate of reduced HIV-1 infection risk in RV144. PLoS ONE. 2017;12(7):e0180720. doi: 10.1371/journal.pone.0180720 28678869

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