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应用中和抗体预防HIV-1感染的两项随机试验
Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition


Lawrence Corey ... 传染病 • 2021.03.18
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摘要


背景

广泛中和抗体(bnAb)可否用于预防人类免疫缺陷病毒1型(HIV-1)感染尚不明确。

 

方法

HVTN 704/HPTN 085试验在美国和欧洲纳入了有风险的顺性别(cisgender)男性和跨性别者,HVTN 703/HPTN 081试验在撒哈拉以南非洲纳入了有风险的女性。我们将参与者随机分配接受每8周一次10 mg/kg或30 mg/kg剂量bnAb(VRC01)(分别为小剂量组和大剂量组)或安慰剂输入,共输入10次。我们每4周进行一次HIV-1检测。利用TZM-bl检测法测定VRC01对感染的分离株的80%抑制浓度(IC80)。

 

结果

在两项试验中,各治疗组的不良事件数量和严重程度相似。在HVTN 704/HPTN 085的2,699例参与者中,小剂量组32例、大剂量组28例和安慰剂组38例参与者发生了HIV-1感染。在HVTN 703/HPTN 081的1,924例参与者中,小剂量组28例、大剂量组19例和安慰剂组29例参与者发生了感染。在HVTN 704/HPTN 085中,合并VRC01组和安慰剂组每100人-年的HIV-1感染率分别为2.35和2.98(估计预防效力,26.6%;95% CI,-11.7~51.8;P=0.15),在HVTN 703/HPTN 081中,合并VRC01组和安慰剂组每100人-年的HIV-1感染率分别为2.49和3.10(估计预防效力,8.8%;95% CI,-45.1~42.6;P=0.70)。在将两项试验数据合并的预设分析中,在VRC01接受者和安慰剂接受者中,每100人-年的VRC01敏感分离株(IC80<1 μg/mL)感染率分别为0.20和0.86(估计预防效力,75.4%;95% CI,45.5~88.9)。在两项试验中,每种VRC01剂量对敏感分离株的预防效力相似;VRC01未能预防其他HIV-1分离株感染。

 

结论

VRC01未能比安慰剂更有效地预防总体HIV-1感染,但对VRC01敏感HIV-1分离株进行的分析提供了bnAb预防可能有效的概念验证(由美国国立过敏和传染病研究所[National Institute of Allergy and Infectious Diseases]资助,HVTN 704/HPTN 085和HVTN 703/HPTN 081在ClinicalTrials.gov注册号分别为NCT02716675和NCT02568215)。





作者信息

Lawrence Corey, M.D., Peter B. Gilbert, Ph.D., Michal Juraska, Ph.D., David C. Montefiori, Ph.D., Lynn Morris, Ph.D., Shelly T. Karuna, M.D., Srilatha Edupuganti, M.D., Nyaradzo M. Mgodi, M.B., Ch.B., M.Med., Allan C. deCamp, Ph.D., Erika Rudnicki, M.S., Yunda Huang, Ph.D., Pedro Gonzales, M.D., Robinson Cabello, M.D., Catherine Orrell, M.B., Ch.B., Ph.D., Javier R. Lama, M.D., M.P.H., Fatima Laher, M.B., B.Ch., Erica M. Lazarus, M.B., Ch.B., Jorge Sanchez, M.D., M.P.H., Ian Frank, M.D., Juan Hinojosa, M.D., Magdalena E. Sobieszczyk, M.D., M.P.H., Kyle E. Marshall, M.S., Pamela G. Mukwekwerere, M.B., Ch.B., Joseph Makhema, M.B., Ch.B., Lindsey R. Baden, M.D., James I. Mullins, Ph.D., Carolyn Williamson, Ph.D., John Hural, Ph.D., M. Juliana McElrath, M.D., Ph.D., Carter Bentley, Ph.D., Simbarashe Takuva, M.B., Ch.B., Margarita M. Gomez Lorenzo, M.D., David N. Burns, M.D., Nicole Espy, Ph.D., April K. Randhawa, Ph.D., Nidhi Kochar, M.S., Estelle Piwowar-Manning, M.T., Deborah J. Donnell, Ph.D., Nirupama Sista, Ph.D., Philip Andrew, R.N., James G. Kublin, M.D., Glenda Gray, M.B., B.Ch., Julie E. Ledgerwood, D.O., John R. Mascola, M.D., and Myron S. Cohen, M.D. for the HVTN 704/HPTN 085 and HVTN 703/HPTN 081 Study Teams*
From the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center (L.C., P.B.G., M.J., S.T.K., A.C.C., E.R., Y.H., K.E.M., J. Hural, M.J.M.E., C.B., S.T., N.E., A.K.R., N.K., D.J.D., J.G.K., G.G.), and the Departments of Global Health, Microbiology, and Medicine, University of Washington (J.I.M.), Seattle; the Department of Surgery and Duke Human Vaccine Institute, Duke University Medical Center (D.C.M.), and FHI 360 (N.S., P.A.), Durham, and the Institute for Global Health and Infectious Disease, University of North Carolina, Chapel Hill (M.S.C.) — both in North Carolina; the National Institute for Communicable Diseases of the National Health Laboratory Service (L.M.) and the Antibody Immunity Research Unit, Faculty of Health Sciences (L.M.), and the Perinatal HIV Research Unit, Faculty of Health Sciences (F.L., E.M.L., S.T.), University of the Witwatersrand, Johannesburg, the Desmond Tutu HIV Centre, Department of Medicine and Institute of Infectious Disease and Molecular Medicine (C.O.), and the Division of Medical Virology (C.W.), University of Cape Town, Cape Town, the School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria (S.T.), and the South African Medical Research Council, Tygerberg (G.G.) — all in South Africa; the Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta (S.E.); the University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare, Zimbabwe (N.M.M., P.G.M.); Servicio de Enfermedades Infecciosas y Tropicales, Hospital Nacional Dos de Mayo (P.G.), Asociación Civil Via Libre (R.C.), Asociación Civil Impacta Salud y Educación (J.R.L.), and Centro de Investigaciones Tecnológicas, Biomédicas y Medioambientales, Universidad Nacional Mayor de San Marcos (J.S.), Lima, and Association Civil Selva Amazónica, Clinical Research Site, Iquitos (J. Hinojosa) — both in Peru; the Infectious Diseases Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia (I.F.); the Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York (M.E.S.); Botswana Harvard AIDS Institute, Gaborone, Botswana (J.M.); Brigham and Women’s Hospital, Harvard Medical School, Boston (L.R.B.); and the Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Rockville (M.M.G.L.), the Prevention Sciences Program, Division of AIDS (D.N.B.), and the Vaccine Research Center (J.E.L., J.R.M.), National Institute of Allergy and Infectious Diseases, NIH, Bethesda, and Johns Hopkins University School of Medicine, Baltimore (E.P.-M.) — all in Maryland. Address reprint requests to Dr. Corey at the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109-9024, or at lcorey@fredhutch.org. *Full lists of the investigators in the HVTN 704/HPTN 085 and HVTN 703/HPTN 081 trials are provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Centers for Disease Control and Prevention. HIV surveillance report, 2018 (updated). Vol. 31. 2020 (http://www.cdc.gov/hiv/library/reports/hiv-surveillance.html. opens in new tab).

2. UNAIDS. Global HIV & AIDS statistics — 2020 fact sheet. 2020 (http://www.unaids.org/en/resources/fact-sheet. opens in new tab).

3. Wu X, Yang Z-Y, Li Y, et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 2010;329:856-861.

4. Zhou T, Georgiev I, Wu X, et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 2010;329:811-817.

5. Scheid JF, Mouquet H, Ueberheide B, et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 2011;333:1633-1637.

6. Seaman MS, Janes H, Hawkins N, et al. Tiered categorization of a diverse panel of HIV-1 Env pseudoviruses for assessment of neutralizing antibodies. J Virol 2010;84:1439-1452.

7. Walker LM, Huber M, Doores KJ, et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 2011;477:466-470.

8. Cunningham CK, McFarland EJ, Morrison RL, et al. Safety, tolerability, and pharmacokinetics of the broadly neutralizing human immunodeficiency virus (HIV)-1 monoclonal antibody VRC01 in HIV-exposed newborn infants. J Infect Dis 2020;222:628-636.

9. Ledgerwood JE, Coates EE, Yamshchikov G, et al. Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin Exp Immunol 2015;182:289-301.

10. Mayer KH, Seaton KE, Huang Y, et al. Safety, pharmacokinetics, and immunological activities of multiple intravenous or subcutaneous doses of an anti-HIV monoclonal antibody, VRC01, administered to HIV-uninfected adults: results of a phase 1 randomized trial. PLoS Med 2017;14(11):e1002435-e1002435.

11. Huang Y, Naidoo L, Zhang L, et al. Pharmacokinetics and predicted neutralisation coverage of VRC01 in HIV-uninfected participants of the Antibody Mediated Prevention (AMP) trials. EBioMedicine (in press).

12. Hessell AJ, Malherbe DC, Haigwood NL. Passive and active antibody studies in primates to inform HIV vaccines. Expert Rev Vaccines 2018;17:127-144.

13. Pegu A, Yang Z, Boyington JC, et al. Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor. Sci Transl Med 2014;6:243ra88-243ra88.

14. Saunders KO, Pegu A, Georgiev IS, et al. Sustained delivery of a broadly neutralizing antibody in nonhuman primates confers long-term protection against simian/human immunodeficiency virus infection. J Virol 2015;89:5895-5903.

15. Shingai M, Donau OK, Plishka RJ, et al. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. J Exp Med 2014;211:2061-2074.

16. Gilbert PB, Juraska M, deCamp AC, et al. Basis and statistical design of the passive HIV-1 Antibody Mediated Prevention (AMP) test-of-concept efficacy trials. Stat Commun Infect Dis 2017;9(1):20160001-20160001.

17. Karuna ST, Corey L. Broadly Neutralizing Antibodies for HIV Prevention. Annu Rev Med 2020;71:329-346.

18. Mgodi NM, Takuva S, Edupuganti S, et al. A phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing monoclonal antibody in reducing acquisition of HIV-1 infection in women in sub-Saharan Africa: baseline findings. J Acquir Immune Defic Syndr 2021 February 11 (Epub ahead of print).

19. Edupuganti S, Mgodi N, Karuna ST, et al. Feasibility and successful enrollment in a proof-of-concept HIV prevention trial of VRC01, a broadly neutralizing HIV-1 monoclonal antibody. J Acquir Immune Defic Syndr 2021 February 11 (Epub ahead of print).

20. Hammer SM, Sobieszczyk ME, Janes H, et al. Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine. N Engl J Med 2013;369:2083-2092.

21. Sarzotti-Kelsoe M, Bailer RT, Turk E, et al. Optimization and validation of the TZM-bl assay for standardized assessments of neutralizing antibodies against HIV-1. J Immunol Methods 2014;409:131-146.

22. Montefiori DC. Measuring HIV neutralization in a luciferase reporter gene assay. In: Prasad VR, Kalpana GV, eds. HIV protocols. Vol. 485 of Methods in Molecular Biology 2nd ed. Totowa, NJ: Humana Press, 2009:395-405.

23. Gilbert PB, Sun Y. Inferences on relative failure rates in stratified mark-specific proportional hazards models with missing marks, with application to HIV vaccine efficacy trials. J R Stat Soc Ser C Appl Stat 2015;64:49-73.

24. Juraska M, Gilbert PB. Mark-specific hazard ratio model with multivariate continuous marks: an application to vaccine efficacy. Biometrics 2013;69:328-337.

25. Shen L, Rabi SA, Siliciano RF. A novel method for determining the inhibitory potential of anti-HIV drugs. Trends Pharmacol Sci 2009;30:610-616.

26. Diskin R, Scheid JF, Marcovecchio PM, et al. Increasing the potency and breadth of an HIV antibody by using structure-based rational design. Science 2011;334:1289-1293.

27. Rademeyer C, Korber B, Seaman MS, et al. Features of recently transmitted HIV-1 clade C viruses that impact antibody recognition: implications for active and passive immunization. PLoS Pathog 2016;12(7):e1005742-e1005742.

28. Hraber P, Rademeyer C, Williamson C, et al. Panels of HIV-1 subtype C Env reference strains for standardized neutralization assessments. J Virol 2017;91(19):e00991-e00991.

29. Hraber P, Rademeyer C, Williamson C, et al. Panels of HIV-1 subtype C Env reference strains for standardized neutralization assessments. J Virol 2017;91(19):e00991-e00991.

30. Huang Y, Zhang L, Eaton A, et al. Prediction of serum HIV-1 neutralization titers of VRC01 in HIV-uninfected antibody mediated prevention (AMP) trial participants. Hum Vaccin Immunother (in press).

31. Mahomed S, Garrett N, Baxter C, Abdool Karim Q, Abdool Karim SS. Clinical trials of broadly neutralizing monoclonal antibodies for HIV prevention: a review. J Infect Dis 2020 June 30 (Epub ahead of print).

32. Bar KJ, Sneller MC, Harrison LJ, et al. Effect of HIV antibody VRC01 on viral rebound after treatment interruption. N Engl J Med 2016;375:2037-2050.

33. Lynch RM, Boritz E, Coates EE, et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci Transl Med 2015;7:319ra206-319ra206.

34. Mendoza P, Gruell H, Nogueira L, et al. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature 2018;561:479-484.

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