Synthetic HIV-1 matrix protein p17-based AT20-KLH therapeutic immunization in HIV-1-infected patients receiving antiretroviral treatment: A phase I safety and immunogenicity study.
BACKGROUND
Therapeutic vaccination is a promising novel approach to treat HIV-1 infected people by boosting or redirecting immune system to neutralize critical HIV-1 antigens whose biological effects are relevant in the context of viral pathogenesis. With the aim to induce neutralizing antibodies to the matrix protein p17 we have developed a peptide-based immunogen (AT20-KLH) and evaluated its safety and immunogenicity.


METHODS
Twenty four asymptomatic HAART-treated HIV-1+ patients were enrolled in a phase I clinical study and were randomized to three groups: 2 groups were treated with five IM injection (Arm A: 25μg/inoculation; Arm B: 100μg/inoculation) at day (D) D0, D28, D56, D84 and D112; the control group (Arm C) were not injected. Safety was assessed by monitoring local and systemic adverse events (AEs), recorded till D168. Evaluation of immunogenicity was by titering antibodies at D0, D35, D56, D63, D84, D91, D112, D140 and D168 using ELISA.


RESULTS
In all, 105 local and systemic AEs were reported across the three groups. Most were mild and resolved without sequelae. Also the few unsolicited events, deemed unrelated to the study vaccines, caused no problems. No significant changes in the routine laboratory parameters, CD4 T-cell count or HIV-1 viremia were found. At the time of enrollment 23 out of 24 patients had no anti-AT20 antibodies, whereas 11 exhibited anti-p17 antibodies. Irrespective of the presence of preimmunization antibodies, all subjects developed high titers of anti-AT20 antibodies (GM 9775) in response to both AT20-KLH doses. These antibodies were also capable of recognizing AT20 within the p17 framework.


CONCLUSIONS
The AT20 peptide-based approach has allowed to redirect HAART-treated patients' humoral responses toward a previously untargeted hotspot of functional activity. Overall, the tested AT20-KLH doses were safe and well tolerated, supporting further exploration of AT20-KLH as an HIV-1 therapeutic vaccine candidate.
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Maria Luisa
ML
Iaria
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Simona
S
Fiorentini
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Emanuele
E
Focà
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Sonia
S
Zicari
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Cinzia
C
Giagulli
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Francesca
F
Caccuri
Section of Infectious Diseases, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06132 Perugia, Italy.
Daniela
D
Francisci
Department of Medical Sciences, University of Turin, Turin, Italy.
Giovanni
G
Di Perri
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Francesco
F
Castelli
Section of Infectious Diseases, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06132 Perugia, Italy.
Franco
F
Baldelli
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. Electronic address: caruso@med.unibs.it.
Arnaldo
A
Caruso
D016915:AIDS Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000097:blood; D023241:Antiretroviral Therapy, Highly Active; D015483:HIV Antibodies / Q000097:blood; D015488:HIV Antigens / Q000276:immunology*; D015658:HIV Infections / Q000628:therapy*; D015497:HIV-1; D006801:Humans; D056724:Immunity, Humoral; D008875:Middle Aged; D014614:Vaccines, Synthetic / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
D016915:AIDS Vaccines; D044966:Anti-Retroviral Agents; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015488:HIV Antigens; D014614:Vaccines, Synthetic; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1
HIV-1 matrix protein p17; Peptide-based-immunotherapy; Therapeutic vaccine