Effect on antibody and T-cell responses of mixing five GMP-produced DNA plasmids and administration with plasmid expressing GM-CSF

Abstract

One potential benefit of DNA vaccines is the capacity to elicit antibody and T-cell responses against multiple antigens at the same time by mixing plasmids expressing different proteins. A possible negative effect of such mixing is interference among plasmids regarding immunogenicity. In preparation for a clinical trial, we assessed the immunogenicity of GMP-produced plasmids encoding five Plasmodium falciparum proteins, PfCSP, PfSSP2, PfEXP1, PfLSA1, and PfLSA3, given as a mixture, or alone. The mixture induced higher levels of antibodies against whole parasites than did the individual plasmids, but was associated with a decrease in antibodies to individual P. falciparum proteins. T-cell responses were in general decreased by administration of the mixture. Immune responses to individual plasmids and mixtures were generally higher in inbred mice than in outbreds. In inbred BALB/c and C57BL/6 mice, coadministration of a plasmid expressing murine granulocyte-macrophage colony-stimulating factor (mGM-CSF), increased antibody and T-cell responses, but in outbred CD-1 mice, coadministration of mGM-CSF was associated with a decrease in antibody responses. Such variability in data from studies in different strains of mice underscores the importance of genetic background on immune response and carefully considering the goals of any preclinical studies of vaccine mixtures planned for human trials.

Immunogenicity of combination DNA vaccines for Rift Valley fever virus, tick-borne encephalitis virus, Hantaan virus, and Crimean Congo hemorrhagic fever virus

“…Although the mixture induced higher levels of antibodies against whole parasites than did the individual plasmids, there were decreased amounts of antibodies to the individual gene products. In addition, T-cell responses were generally lower when the mixture was given [41]. Other studies, however, have not shown interference when similar genes are delivered (e.g., multiple HIV-1 genes from different clades [42]); or when two genes from the same virus are given (e.g., hepatitis B surface and core genes [43]).…”

Baculovirus-Vectored Multistage Plasmodium vivax Vaccine Induces Both Protective and Transmission-Blocking Immunities against Transgenic Rodent Malaria Parasites

“…However, a major concern for the development of multivalent vaccines is the potential for vaccine interference which would be associated with poor immune responses (35). In fact, it has been reported that immune responses to the individual components of multiantigen malaria vaccines can potentially be suppressed by immune interference (36)(37)(38)(39)(40)(41)(42)(43). The BDES-Pvs25-PvCSP-G vaccine successfully induced high Pvs25-, PvCSP(Sal)-, and PvCSP(PNG) repeatspecific Ab titers, suggesting an absence of immune interference.…”

DNA Vaccines: Progress and Challenges

“…These Ag designs will be reaching clinical trials in the near future. Combinations of fulllength genes, and also large gene segments, mixed together on separate plasmids are being explored preclinically and clinically in HIV, HCV, and malaria (37,38).…”