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Comparative Study
. 2017 Nov 27;216(9):1080-1090.
doi: 10.1093/infdis/jix456.

Safety and Immunogenicity of PENNVAX-G DNA Prime Administered by Biojector 2000 or CELLECTRA Electroporation Device With Modified Vaccinia Ankara-CMDR Boost

Julie A Ake  1 , Alexandra Schuetz  1   2   3 , Poonam Pegu  1   2 , Lindsay Wieczorek  1   2 , Michael A Eller  1   2 , Hannah Kibuuka  4 , Fredrick Sawe  5 , Leonard Maboko  6 , Victoria Polonis  1 , Nicos Karasavva  3 , David Weiner  7 , Arthur Sekiziyivu  4 , Josphat Kosgei  5 , Marco Missanga  6 , Arne Kroidl  6   8 , Philipp Mann  6   8 , Silvia Ratto-Kim  1   2 , Leigh Anne Eller  1   2 , Patricia Earl  9 , Bernard Moss  9 , Julie Dorsey-Spitz  1   2 , Mark Milazzo  1   2 , G Laissa Ouedraogo  10 , Farrukh Rizvi  11 , Jian Yan  12 , Amir S Khan  12 , Sheila Peel  1 , Niranjan Y Sardesai  12 , Nelson L Michael  1 , Viseth Ngauy  1   3 , Mary Marovich  1 , Merlin L Robb  1   2
Affiliations
Comparative Study

Safety and Immunogenicity of PENNVAX-G DNA Prime Administered by Biojector 2000 or CELLECTRA Electroporation Device With Modified Vaccinia Ankara-CMDR Boost

Julie A Ake et al. J Infect Dis. .

Abstract

Background: We report the first-in-human safety and immunogenicity evaluation of PENNVAX-G DNA/modified vaccinia Ankara-Chiang Mai double recombinant (MVA-CMDR) prime-boost human immuonodeficiency virus (HIV) vaccine, with intramuscular DNA delivery by either Biojector 2000 needle-free injection system (Biojector) or CELLECTRA electroporation device.

Methods: Healthy, HIV-uninfected adults were randomized to receive 4 mg of PENNVAX-G DNA delivered intramuscularly by Biojector or electroporation at baseline and week 4 followed by intramuscular injection of 108 plaque forming units of MVA-CMDR at weeks 12 and 24. The open-label part A was conducted in the United States, followed by a double-blind, placebo-controlled part B in East Africa. Solicited and unsolicited adverse events were recorded, and immune responses were measured.

Results: Eighty-eight of 100 enrolled participants completed all study injections, which were generally safe and well tolerated, with more immediate, but transient, pain in the electroporation group. Cellular responses were observed in 57% of vaccine recipients tested and were CD4 predominant. High rates of binding antibody responses to CRF01_AE antigens, including gp70 V1V2 scaffold, were observed. Neutralizing antibodies were detected in a peripheral blood mononuclear cell assay, and moderate antibody-dependent, cell-mediated cytotoxicity activity was demonstrated.

Discussion: The PVG/MVA-CMDR HIV-1 vaccine regimen is safe and immunogenic. Substantial differences in safety or immunogenicity between modes of DNA delivery were not observed.

Clinical trials registration: NCT01260727.

Keywords: HIV vaccine; electroporation; modified vaccinia Ankara; needle-free injection.

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Figures

Figure 1.
Figure 1.
Screening, enrollment, vaccinations, and follow-up. Part A and part B volunteer activities are combined. Abbreviation: HIV, human immunodeficiency virus.
Figure 2.
Figure 2.
Maximum local and systemic reactogenicity. Safety assessment showing maximum local reactogenicity (A) and systemic reactogenicity (B) by treatment group. All reactions except immediate pain were assessed at 45 minutes, 6 hours, and then daily for 6 days after injection. P values shown are for Fisher’s exact test for differences between electroporation and Biojector followed by differences between active vaccine and placebo recipients. Abbreviations: A, active vaccine; BJ, Biojector; EP, electroporation; P, placebo.
Figure 3.
Figure 3.
Human immunodeficiency virus type 1 (HIV-1)−specific T-cell responses measured by intracellular cytokine staining. HIV-1 Env Chiang Mai double recombinant (CMDR)–specific (A) and Gag CMDR–specific (B) interferon γ (IFN-y)+CD4 T cells (left) and IFN-y+CD8 T cells (right) were measured in vaccine recipients at weeks 0, 14, and 26. Vaccination timepoints are indicated with an arrow. The responses were measured in both electroporation (black) and Biojector (red) groups, and mean (+ standard error) is indicated. Positive responses (for both CD4 and CD8) were defined as cytokine responses that had a 2-fold increase over the unstimulated condition and >0.025%. Multifunctional flow cytometry analysis of HIV-1 Env-specific responses at week 14 (2 weeks after 1st modified vaccinia Ankara) with the different pie chart arcs representing each cytokine function (purple = tumor necrosis factor α, blue = interleukin 4, turquoise = interleukin 2, green = IFN-γ, yellow = CD40L, red = CD107a). Relative sizes for subsets of cells expressing the various combinations of functions are proportionally represented in the pie chart with individual slices of pie colored from gray to black. Specific functional components of each slice of pie are denoted based on arc. HIV-1 Env-specific CD4 T-cell responses (C) and CD8 T-cell responses (D) are shown for both electroporation (left) and Biojector (right) groups. Abbreviations: IFN-γ, interferon γ; IL-2, interleukin 2; IL-4, interleukin 4; TNF-α, tumor necrosis factor α.
Figure 4.
Figure 4.
Plasma binding antibody responses. Plasma binding antibody (bAb) titers were determined by enzyme-linked immunosorbent assay using gp120 (A244) (A) and gp70 (B) V1V2 scaffold (92TH023) CRF01_AE antigens. Samples were evaluated at weeks 0, 6, 14, 26, and 50 for both electroporation (black) and Biojector (red) groups. Responses are shown for vaccine recipients only; response rates as percentage of responses are depicted across the top of each column, with geometric mean titers and 95% confidence intervals indicated in the figure. Baseline values for each antigen are shown as a dotted line. Vaccination timepoints are indicated with an arrow. *P = .02 by 2-tailed Mann-Whitney test. #P = .01 by Fisher’s exact test. Abbreviation: IgG, immunoglobulin G.
Figure 5.
Figure 5.
Antibody-mediated inhibition of human immunodeficiency virus infection in the peripheral blood mononuclear cell (PBMC) neutralizing antibody (NAb) assay. Vaccine recipient sera were titered in the PBMC NAb assay; reported values are the mean of 2 independent experiments with 50% inhibitory dose values within a 5-fold range. Sera from weeks 0, 26, and 50 were tested against the subtype CRF01_AE CM235 rnLuc infectious molecular clone (n = 25 for electroporation; n = 26 for Biojector; panel A). Vaccination timepoints are indicated with an arrow. Sera from 16 vaccine recipients at the peak immune response (week 26) were titered against 3 additional infectious molecular clones from multiple subtypes, including SF162 (subtype B), GS015 (subtype C), and TH023 (CRF01_AE) (n = 6 for electroporation; n = 10 for Biojector; panel B). Data are plotted by DNA immunization route, electroporation (black) or Biojector (red), and mean (+ standard error) is indicated. Abbreviation: Dil, dilution; ID50, 50% inhibitory dose.
Figure 6.
Figure 6.
Antibody-dependent cell-mediated cytotoxicity (ADCC). Magnitude of ADCC response in vaccine recipients was measured using gp120-coated targets labeled with PKH26 and CFSE at weeks 0, 6, 26, and 50. The frequency of lysed cells was defined by the loss of CFSE and retention of PKH26, resulting in the emergence of a “killed” PKH26+CSFE− population. Antibody-dependent cell-mediated cytotoxicity response using gp120-coated target cells with CRF01_A/E (CM235) (A) and subtype B (MN) (B) were used, with the threshold for positive responses at 11.5% and 17.2%, respectively. Vaccination timepoints are indicated with an arrow. Data are plotted by DNA immunization route, electroporation (black) or biojector (red). Response rates were not significantly different between DNA delivery groups.
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