DNA Priming for Seasonal Influenza Vaccine: A Phase 1b Double-Blind Randomized Clinical Trial

Abstract

BackgroundThe efficacy of current influenza vaccines is limited in vulnerable populations. DNA vaccines can be produced rapidly, and may offer a potential strategy to improve vaccine immunogenicity, indicated by studies with H5 influenza DNA vaccine prime followed by inactivated vaccine boost.MethodsFour sites enrolled healthy adults, randomized to receive 2011/12 seasonal influenza DNA vaccine prime (n=65) or phosphate buffered saline (PBS) (n=66) administered intramuscularly with Biojector. All subjects received the 2012/13 seasonal inactivated influenza vaccine, trivalent (IIV3) 36 weeks after the priming injection. Vaccine safety and tolerability was the primary objective and measurement of antibody response by hemagglutination inhibition (HAI) was the secondary objective.ResultsThe DNA vaccine prime-IIV3 boost regimen was safe and well tolerated. Significant differences in HAI responses between the DNA vaccine prime and the PBS prime groups were not detected in this study.ConclusionWhile DNA priming significantly improved the response to a conventional monovalent H5 vaccine in a previous study, it was not effective in adults using seasonal influenza strains, possibly due to pre-existing immunity to the prime, unmatched prime and boost antigens, or the lengthy 36 week boost interval. Careful optimization of the DNA prime-IIV3 boost regimen as related to antigen matching, interval between vaccinations, and pre-existing immune responses to influenza is likely to be needed in further evaluations of this vaccine strategy. In particular, testing this concept in younger age groups with less prior exposure to seasonal influenza strains may be informative.Trial RegistrationClinicalTrials.gov NCT01498718

DNA vaccine priming for seasonal influenza vaccine in children and adolescents 6 to 17 years of age: A phase 1 randomized clinical trial

“…In previous influenza vaccine trials involving healthy adults, priming with a DNA vaccine and following with a monovalent inactivated boost proved more effective than an inactivated prime-boost regimen at establishing an antibody response against emerging subtypes of avian origin, including H5 and H7 [ 19 , 21 ]. In a separate trial in healthy adults involving a DNA prime-IIV3 boost regimen with seasonal strains of influenza (H1, H3, and B), no significant improvement was observed compared to a placebo prime-IIV3 boost group, presumably due to pre-existing immune responses [ 23 ]. Therefore, we evaluated the DNA prime-IIV3 boost regimen in children and adolescents in an attempt to examine the safety and immunogenicity of the DNA prime-IIV3 boost in a more naïve population.…”

“…One explanation for the difference in immune response observed between studies in healthy adults against avian subtypes of influenza where a significantly improved response was observed following priming with DNA [ 19 , 21 ], and the single study investigating seasonal strains of influenza where no difference in titers was observed [ 23 ], was the high levels of pre-existing immunity to the seasonal strains in the adult population. This led to the possibility that an improved response following DNA-IIV3 vaccination could be observed in the more naïve pediatric population.…”

“…Antibody titers were evaluated by HAI for six influenza strains, three each included in the 2012/13 and previous 2011/12 seasonal influenza vaccines to analyze both homologous and heterologous antibody responses ( S1 Table ). HAI assays were conducted at Southern Research, Inc. (Birmingham, AL) using validated methods [ 23 ]. Viruses were supplied by the CDC and amplified in embryonated eggs.…”

“…In some cases, the DNA prime was found to induce hemagglutinin (HA) stem-specific neutralizing antibodies, which could improve the breadth of the antibody response by eliciting a response against a stem domain that is highly conserved across multiple subtypes [ 19 – 21 ]. However, there were no significant increases in antibody responses as assessed by hemagglutination inhibition (HAI) in adults primed with either seasonal trivalent HA DNA vaccine or placebo followed by a boost with seasonal trivalent IIV (IIV3) [ 23 ]. The possibility that pre-existing immunity in the adult population limited the effect of the DNA prime warranted further evaluation in expanded age groups, including children and adolescents.…”

An avian influenza H7 DNA priming vaccine is safe and immunogenic in a randomized phase I clinical trial

“… 37 , 38 Previous experience with DNA vaccines shows them to be safe, well-tolerated and immunogenic as a priming vaccine, and they may be optimally suited for pre-pandemic scenarios where pre-existing immunity is lacking in the population. 22 , 28 , 38 – 40 …”