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We compare immunogenicity and protective efficacy of an HIV vaccine comprised of env and gag DNA and Env (Envelope) proteins by co-administration of the vaccine components in the same muscles or by separate administration of DNA + protein in contralateral sites in female rhesus macaques. The 6-valent vaccine includes gp145 Env DNAs, representing six sequentially isolated Envs from the HIV-infected individual CH505, and matching GLA-SE-adjuvanted gp120 Env proteins. Interestingly, only macaques in the co-administration vaccine group are protected against SHIV CH505 acquisition after repeated low-dose intravaginal challenge and show 67% risk reduction per exposure. Macaques in the co-administration group develop higher Env-specific humoral and cellular immune responses. Non-neutralizing Env antibodies, ADCC, and antibodies binding to FcγRIIIa are associated with decreased transmission risk. These data suggest that simultaneous recognition, processing, and presentation of DNA + Env protein in the same draining lymph nodes play a critical role in the development of protective immunity., Competing Interests: Declaration of Interests G.N.P. and B.K.F. are inventors on US Government-owned patents related to DNA vaccines and gene expression optimization. B.F.H. has submitted patent applications covering the Envs used in this study. S.G.R. is a full-time employee of Infectious Disease Research Institute and as such receives compensation in the form of salary. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The manuscript has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. The views expressed in this article are those of the authors and do not necessarily reflect the official policy of the Department of the Army, Department of Defense, or the U.S. Government. The other authors declare no competing interests. This work was produced solely by the authors and that no other individuals or entities influenced any aspects of the work., (Published by Elsevier Inc.)

To elucidate the role of DNA antigen drive in the anti-DNA response, the specificity and immunochemical properties of anti-DNA antibodies induced in normal mice by immunization with double stranded (ds) mammalian DNA with a CpG oligonucleotide (ODN) adjuvant were characterized. Like spontaneous anti-DNA from MRL/lpr mice, the induced anti-DNA bound cross-reactively to DNA from five different species by ELISA. The induced antibodies displayed a predominance of IgG2a and had much lower amount of IgG3 than spontaneous antibodies. Surface plasmon resonance indicated that the induced and spontaneous anti-DNA antibodies have a similar range of avidity and binding kinetics. While sera from the MRL/lpr mice had substantial binding to histones and nucleosomes, the immunized mice had antibody levels to these antigens similar to those of mice treated only with incomplete Freund''s adjuvant. Together, these results indicate that normal mice can produce autoantibodies to dsDNA, with a CpG ODN allowing the generation of antibodies resembling those in spontaneous autoimmunity. [Copyright &y& Elsevier]

Dominant antibody responses in vaccinees who received the HIV-1 multiclade (A, B, and C) envelope (Env) DNA/recombinant adenovirus virus type 5 (rAd5) vaccine studied in HIV-1 Vaccine Trials Network (HVTN) efficacy trial 505 (HVTN 505) targeted Env gp41 and cross-reacted with microbial antigens. In this study, we asked if the DNA/rAd5 vaccine induced a similar antibody response in rhesus macaques (RMs), which are commonly used as an animal model for human HIV-1 infections and for testing candidate HIV-1 vaccines. We also asked if gp41 immunodominance could be avoided by immunization of neonatal RMs during the early stages of microbial colonization. We found that the DNA/rAd5 vaccine elicited a higher frequency of gp41-reactive memory B cells than gp120-memory B cells in adult and neonatal RMs. Analysis of the vaccine-induced Env-reactive B cell repertoire revealed that the majority of HIV-1 Env-reactive antibodies in both adult and neonatal RMs were targeted to gp41. Interestingly, a subset of gp41-reactive antibodies isolated from RMs cross-reacted with host antigens, including autologous intestinal microbiota. Thus, gp41-containing DNA/rAd5 vaccine induced dominant gp41-microbiota cross-reactive antibodies derived from blood memory B cells in RMs as observed in the HVTN 505 vaccine efficacy trial. These data demonstrated that RMs can be used to investigate gp41 immunodominance in candidate HIV-1 vaccines. Moreover, colonization of neonatal RMs occurred within the first week of life, and immunization of neonatal RMs during this time also induced a dominant gp41-reactive antibody response. [ABSTRACT FROM AUTHOR]