Two is better than one

Science Spotlight

Two is better than one

McElrath Laboratory, Vaccine and Infectious Disease Division

Nov. 20, 2017

            Human immunodeficiency Virus (HIV) continues to be a major public health problem. Throughout the years, there have been a multitude of vaccine trials, nearly all with mixed results. Currently, the HIV vaccine field is focused on producing protective antibodies; however, T cell responses likely contribute to protection and aid in B cell activation. Past studies have shown that a strong polyfunctional T cell response is associated with decreased risk, thus boosting the T cell response may be just as important as inducing antibodies. One possible way to do this is by using a replicating vaccine vector such as VSV (vesicular stomatitis virus). In a previous study by Fuchs et al., this type of vector was tested. The clinical trial (HVTN 090) used an attenuated (less infectious variant) VSV-HIV-Gag vaccine and found that although it was safe, it did not elicit a strong response in either B or T cells. In a new study published in Clinical Vaccine Immunology, researchers from the Vaccine and Infectious Disease Division at Fred Hutch expanded on the HVTN090 trial by looking at the synergistic effects of a DNA prime before boosting with VSV-HIV-Gag in another trial. The study also tested a dose response of IL-12 when administered with the DNA prime. IL-12 has been shown in some previous studies to have an adjuvant effect on T cell responses. The overarching goal of this study was to test the effects of a mixed vaccination regiment on the human immune response in a randomized, double-blind, placebo-controlled phase 1a clinical trial (HVTN 087).

            The vaccine regimen for this study can be seen in the table below. In brief, groups of 22 subjects (and 3 for placebo) were divided into 4 arms. Each group received a multi-antigen DNA prime (encoding: Pol, Gag, Env, Nef, Tat, and Vif) and a VSV-HIV-Gag boost, and groups 2-4 received increasing doses of IL-12 DNA. DNA was administered by electroporation and VSV by intramuscular injection. Samples were collected two weeks post prime and boost and were tested for antibody and T cell response. After a DNA prime, there was no significant induction of antibodies, but there was a small increase after the VSV boost, though it did not result in a significant expansion. When the researchers broke down the T cell response after prime and boost, the results showed a large increase in number of Gag–specific CD4+ T cells and a small increase in the CD8+ T cells after boost. No significant change in response or magnitude was seen in the Gag-specific CD4+ T cell response between groups. In contrast, the Gag-specific CD8+ T cell magnitude increased with the addition of IL-12. When looking at the T cell response to multiple HIV antigens, the proportion of vaccine recipients with positive CD4+ T cell responses decreased with IL-12 inclusion, however the response remained stable over the experimental time points. The CD8+ multi-antigen response showed signs of increasing with IL-12 dose. Overall, this shows that the addition of the DNA prime to the VSV boost does induce a T cell response, and the response is better than the previously tested VSV alone response (see figure).

CD4+ T cell responders after prime or boost in each vaccine group as compared to prior VSV alone study (HTVN 090).

Provided by Dr. Frahm.

               To further test the functionality of the T cell response, the group used a combinatorial polyfunctionality analysis of antigen-specific T cell subsets (COMPASS) to identify T cell responses that are polyfunctional. They computed a functionality score for each person by measuring the proportion of antigen-specific subsets based on expression of IL-2, IL-4, IFN-gamma, TNF-alpha, and CD40L (all markers of T cell responsiveness). This assay found that CD4+ T cells had an increased functionality score after VSV boost and that IL-12 groups had lower scores as compared to group 1 (without IL-12). CD8+ T cells also increased after VSV boost but showed no difference in score between groups. To test if the increase in T cell response after boost was due to broadening of the response to multiple epitopes or increase in epitope magnitude, ELISpot assays were used. The median number of epitopes targeted was significantly increased following VSV boost from 0 to 4. This increase was seen in all groups regardless of IL-12 dose and demonstrates that the epitope range was broadened.

            Overall, this study showed that a combination of vaccine strategies could have a synergistic effect and increase immune response. Using DNA and VSV vaccine together produced a much better response than either vaccine alone. IL-12 results from this study are mixed and still do not elucidate the role of IL-12 as an adjuvant. This topic needs further study to help clarify the mixed results seen in this study and other previously published. When asked about the results of the study, last author Dr. Frahm said, “This vaccine regimen may not be the best option for a prophylactic vaccine but with the decrease in CD4+ and increase in CD8+ T cells seen, it may be promising as a therapeutic vaccine. Since CD4+ T cells are infected during HIV infection, reducing their numbers and increasing cytotoxic CD8+ T cells may help to reduce viral load.”

This work was supported by the National Institute of Allergy and Infectious Diseases, NIH and various U.S. Public Health Service grants.

Li SS, Kochar NK, Elizaga M, Hay CM, Wilson GJ, Cohen KW, De Rosa SC, Xu R, Ota-Setlik A, Morris D, Finak G, Allen M, Tieu H-V, Frank I, Sobieszczyk ME, Hannaman D, Gottardo R, Gilbert PB, Tomaras GD, Corey L, Clarke DK, Egan MA, Eldridge JH, McElrath MJ, Frahm N. 2017. DNA priming increases frequency of T-cell responses to a VSV HIV vaccine with specific enhancement of CD8+ T-cell responses by IL-12 pDNA. Clin Vaccine Immunol.

Fuchs JD, Frank I, Elizaga ML, Allen M, Frahm N, Kochar N, Li S, Edupuganti S, Kalams SA, Tomaras GD, Sheets R, Pensiero M, Tremblay MA, Higgins TJ, Latham T, Egan MA, Clarke DK, Eldridge JH; HVTN 090 Study Group and the National Institutes of Allergy and Infectious Diseases HIV Vaccine Trials Network, Mulligan M, Rouphael N, Estep S, Rybczyk K, Dunbar D, Buchbinder S, Wagner T, Isbell R, Chinnell V, Bae J, Escamilla G, Tseng J, Fair R, Ramirez S, Broder G, Briesemeister L, Ferrara A. 2015. First-in-Human Evaluation of the Safety and Immunogenicity of a Recombinant Vesicular Stomatitis Virus Human Immunodeficiency Virus-1 gag Vaccine (HVTN 090). Open Forum Infect Dis. 2015 Jun 5;2(3):ofv082