PMID- 29136037
OWN - NLM
STAT- MEDLINE
DCOM- 20171204
LR  - 20180928
IS  - 1549-1676 (Electronic)
IS  - 1549-1277 (Linking)
VI  - 14
IP  - 11
DP  - 2017 Nov
TI  - 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.
PG  - e1002435
LID - 10.1371/journal.pmed.1002435 [doi]
AB  - BACKGROUND: VRC01 is an HIV-1 CD4 binding site broadly neutralizing antibody
      (bnAb) that is active against a broad range of HIV-1 primary isolates in vitro
      and protects against simian-human immunodeficiency virus (SHIV) when delivered
      parenterally to nonhuman primates. It has been shown to be safe and well
      tolerated after short-term administration in humans; however, its clinical and
      functional activity after longer-term administration has not been previously
      assessed. METHODS AND FINDINGS: HIV Vaccine Trials Network (HVTN) 104 was
      designed to evaluate the safety and tolerability of multiple doses of VRC01
      administered either subcutaneously or by intravenous (IV) infusion and to assess 
      the pharmacokinetics and in vitro immunologic activity of the different dosing
      regimens. Additionally, this study aimed to assess the effect that the human body
      has on the functional activities of VRC01 as measured by several in vitro assays.
      Eighty-eight healthy, HIV-uninfected, low-risk participants were enrolled in 6
      United States clinical research sites affiliated with the HVTN between September 
      9, 2014, and July 15, 2015. The median age of enrollees was 27 years (range,
      18-50); 52% were White (non-Hispanic), 25% identified as Black (non-Hispanic),
      11% were Hispanic, and 11% were non-Hispanic people of diverse origins.
      Participants were randomized to receive the following: a 40 mg/kg IV VRC01
      loading dose followed by five 20 mg/kg IV VRC01 doses every 4 weeks (treatment
      group 1 [T1], n = 20); eleven 5 mg/kg subcutaneous (SC) VRC01 (treatment group 3 
      [T3], n = 20); placebo (placebo group 3 [P3], n = 4) doses every 2 weeks; or
      three 40 mg/kg IV VRC01 doses every 8 weeks (treatment group 2 [T2], n = 20).
      Treatment groups T4 and T5 (n = 12 each) received three 10 or 30 mg/kg IV VRC01
      doses every 8 weeks, respectively. Participants were followed for 32 weeks after 
      their first VRC01 administration and received a total of 249 IV infusions and 208
      SC injections, with no serious adverse events, dose-limiting toxicities, nor
      evidence for anti-VRC01 antibodies observed. Serum VRC01 levels were detected
      through 12 weeks after final administration in all participants who received all 
      scheduled doses. Mean peak serum VRC01 levels of 1,177 mug/ml (95% CI: 1,033,
      1,340) and 420 mug/ml (95% CI: 356, 494) were achieved 1 hour after the IV
      infusion series of 30 mg/kg and 10 mg/kg doses, respectively. Mean trough levels 
      at week 24 in the IV infusion series of 30 mg/kg and 10 mg/kg doses,
      respectively, were 16 mug/ml (95% CI: 10, 27) and 6 mug/ml (95% CI: 5, 9) levels,
      which neutralize a majority of circulating strains in vitro (50% inhibitory
      concentration [IC50] > 5 mug/ml). Post-infusion/injection serum VRC01 retained
      expected functional activity (virus neutralization, antibody-dependent cellular
      cytotoxicity, phagocytosis, and virion capture). The limitations of this study
      include the relatively small sample size of each VRC01 administration regimen and
      missing data from participants who were unable to complete all study visits.
      CONCLUSIONS: VRC01 administered as either an IV infusion (10-40 mg/kg) given
      monthly or bimonthly, or as an SC injection (5 mg/kg) every 2 weeks, was found to
      be safe and well tolerated. In addition to maintaining drug concentrations
      consistent with neutralization of the majority of tested HIV strains, VRC01
      concentrations from participants' sera were found to avidly capture HIV virions
      and to mediate antibody-dependent cellular phagocytosis, suggesting a range of
      anti-HIV immunological activities, warranting further clinical trials. TRIAL
      REGISTRATION: Clinical Trials Registration: NCT02165267.
FAU - Mayer, Kenneth H
AU  - Mayer KH
AUID- ORCID: http://orcid.org/0000-0001-7460-733X
AD  - Fenway Health, Beth Israel Deaconess Medical Center, Harvard Medical School,
      Boston, Massachusetts, United States of America.
FAU - Seaton, Kelly E
AU  - Seaton KE
AUID- ORCID: http://orcid.org/0000-0002-2009-3270
AD  - Duke Human Vaccine Institute, Duke University Medical Center, Durham, North
      Carolina, United States of America.
FAU - Huang, Yunda
AU  - Huang Y
AD  - Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 
      Seattle, Washington, United States of America.
FAU - Grunenberg, Nicole
AU  - Grunenberg N
AUID- ORCID: http://orcid.org/0000-0003-2565-3879
AD  - Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 
      Seattle, Washington, United States of America.
FAU - Isaacs, Abby
AU  - Isaacs A
AD  - Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 
      Seattle, Washington, United States of America.
FAU - Allen, Mary
AU  - Allen M
AUID- ORCID: http://orcid.org/0000-0001-8163-0714
AD  - Division of AIDS, NIAID, Bethesda, Maryland, United States of America.
FAU - Ledgerwood, Julie E
AU  - Ledgerwood JE
AD  - Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of
      America.
FAU - Frank, Ian
AU  - Frank I
AUID- ORCID: http://orcid.org/0000-0002-7824-0106
AD  - Perelman School of Medicine, University of Pennsylvania, Philadelphia,
      Pennsylvania, United States of America.
FAU - Sobieszczyk, Magdalena E
AU  - Sobieszczyk ME
AD  - College of Physicians and Surgeons, Columbia University Medical Center, New York,
      New York, United States of America.
FAU - Baden, Lindsey R
AU  - Baden LR
AD  - Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts,
      United States of America.
FAU - Rodriguez, Benigno
AU  - Rodriguez B
AUID- ORCID: http://orcid.org/0000-0001-9736-7957
AD  - Case Western University, Cleveland, Ohio, United States of America.
FAU - Van Tieu, Hong
AU  - Van Tieu H
AD  - New York Blood Center, New York, New York, United States of America.
FAU - Tomaras, Georgia D
AU  - Tomaras GD
AD  - Duke Human Vaccine Institute, Duke University Medical Center, Durham, North
      Carolina, United States of America.
AD  - Department of Surgery, Duke University Medical Center, Durham, North Carolina,
      United States of America.
FAU - Deal, Aaron
AU  - Deal A
AD  - Duke Human Vaccine Institute, Duke University Medical Center, Durham, North
      Carolina, United States of America.
FAU - Goodman, Derrick
AU  - Goodman D
AD  - Duke Human Vaccine Institute, Duke University Medical Center, Durham, North
      Carolina, United States of America.
FAU - Bailer, Robert T
AU  - Bailer RT
AD  - Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of
      America.
FAU - Ferrari, Guido
AU  - Ferrari G
AD  - Duke Human Vaccine Institute, Duke University Medical Center, Durham, North
      Carolina, United States of America.
AD  - Department of Surgery, Duke University Medical Center, Durham, North Carolina,
      United States of America.
FAU - Jensen, Ryan
AU  - Jensen R
AD  - Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 
      Seattle, Washington, United States of America.
FAU - Hural, John
AU  - Hural J
AD  - Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 
      Seattle, Washington, United States of America.
FAU - Graham, Barney S
AU  - Graham BS
AUID- ORCID: http://orcid.org/0000-0001-8112-0853
AD  - Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of
      America.
FAU - Mascola, John R
AU  - Mascola JR
AD  - Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of
      America.
FAU - Corey, Lawrence
AU  - Corey L
AD  - Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 
      Seattle, Washington, United States of America.
FAU - Montefiori, David C
AU  - Montefiori DC
AUID- ORCID: http://orcid.org/0000-0003-0856-6319
AD  - Duke Human Vaccine Institute, Duke University Medical Center, Durham, North
      Carolina, United States of America.
AD  - Department of Surgery, Duke University Medical Center, Durham, North Carolina,
      United States of America.
CN  - HVTN 104 Protocol Team
CN  - and the NIAID HIV Vaccine Trials Network
LA  - eng
SI  - ClinicalTrials.gov/NCT02165267
GR  - UM1 AI068614/AI/NIAID NIH HHS/United States
GR  - UM1 AI068635/AI/NIAID NIH HHS/United States
GR  - UM1 AI069412/AI/NIAID NIH HHS/United States
GR  - UM1 AI069470/AI/NIAID NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20171114
PL  - United States
TA  - PLoS Med
JT  - PLoS medicine
JID - 101231360
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (HIV Antibodies)
RN  - 0 (VRC01 monoclonal antibody)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Antibodies, Monoclonal/*administration & dosage/adverse effects
MH  - Antibodies, Neutralizing/blood/*immunology
MH  - Dose-Response Relationship, Drug
MH  - Drug Administration Schedule
MH  - Female
MH  - HIV Antibodies/blood/*immunology
MH  - HIV Infections/blood/*drug therapy/*immunology
MH  - HIV-1/drug effects/immunology
MH  - Humans
MH  - Injections, Intravenous
MH  - Injections, Subcutaneous
MH  - Male
MH  - Middle Aged
MH  - Single-Blind Method
MH  - Young Adult
PMC - PMC5685476
EDAT- 2017/11/15 06:00
MHDA- 2017/12/05 06:00
CRDT- 2017/11/15 06:00
PHST- 2017/06/09 00:00 [received]
PHST- 2017/10/11 00:00 [accepted]
PHST- 2017/11/15 06:00 [entrez]
PHST- 2017/11/15 06:00 [pubmed]
PHST- 2017/12/05 06:00 [medline]
AID - 10.1371/journal.pmed.1002435 [doi]
AID - PMEDICINE-D-17-02014 [pii]
PST - epublish
SO  - PLoS Med. 2017 Nov 14;14(11):e1002435. doi: 10.1371/journal.pmed.1002435.
      eCollection 2017 Nov.