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

Abstract

A novel avian influenza subtype, A/H7N9, emerged in 2013 and represents a public health threat with pandemic potential. We have previously shown that DNA vaccine priming increases the magnitude and quality of antibody responses to H5N1 monovalent inactivated boost. We now report the safety and immunogenicity of a H7 DNA-H7N9 monovalent inactivated vaccine prime-boost regimen. In this Phase 1, open label, randomized clinical trial, we evaluated three H7N9 vaccination regimens in healthy adults, with a prime-boost interval of 16 weeks. Group 1 received H7 DNA vaccine prime and H7N9 monovalent inactivated vaccine boost. Group 2 received H7 DNA and H7N9 monovalent inactivated vaccine as a prime and H7N9 monovalent inactivated vaccine as a boost. Group 3 received H7N9 monovalent inactivated vaccine in a homologous prime-boost regimen. Overall, 30 individuals between 20 to 60 years old enrolled and 28 completed both vaccinations. All injections were well tolerated with no serious adverse events. 2 weeks post-boost, 50% of Group 1 and 33% of Group 2 achieved a HAI titer ≥1:40 compared with 11% of Group 3. Also, at least a fourfold increase in neutralizing antibody responses was seen in 90% of Group 1, 100% of Group 2, and 78% of Group 3 subjects. Peak neutralizing antibody geometric mean titers were significantly greater for Group 1 (GMT = 440.61, p < 0.05) and Group 2 (GMT = 331, p = 0.02) when compared with Group 3 (GMT = 86.11). A novel H7 DNA vaccine was safe, well-tolerated, and immunogenic when boosted with H7N9 monovalent inactivated vaccine, while priming for higher HAI and neutralizing antibody titers than H7N9 monovalent inactivated vaccine alone.

Comparative effectiveness of H7N9 vaccines in healthy individuals

“…Among the 9 studies identified for further analysis, only six studies were, finally, identified for meta-analysis. The four trials, including three LAIV trials 20,27 and one trial with DNA-inactivated vaccine prime-boost strategy, 28 were excluded for meta-analysis. This might affect the study potency.…”

“…Rudenko et al 27 showed that two doses of LAIV increased the seroconversion rate to 66% and 72%, according to HI assay and MN assay, respectively. DeZure et al 28 found that the strategy of H7 DNA vaccine prime and H7N9 inactivated vaccine boost would produce higher antibody titers than two-dose non-adjuvanted H7N9 inactivated vaccine. However, in the process of meta-analyzing, one parameter is assessed with the other parameter is fixed.…”

“…Among these vaccines, the antigen content of inactivated vaccines and VLP vaccines ranged from 3.75 μg to 45 μg HA/dose, LAIVs contained 10 7.0 fluorescent focus units (FFU) of virus or 10 7.5 50% embryo infective dose (EID), and DNA vaccines were 4 mg. Because H7N9 LAIVs used different methods to quantify the number of live attenuated viruses, which also differed from the method to quantify the antigen content of inactivated vaccines and VLP vaccines, the three LAIV trials 20,27 will not be included in the meta-analysis study. The trial 28 with the administration of H7 DNA and H7N9 inactivated subunit vaccines in prime-boost regimens, which could not be compared with other groups of other trials, will not be included in the study, either. Therefore, six trials were finally identified for metaanalysis.…”

Vaccination with a Recombinant H7 Hemagglutinin-Based Influenza Virus Vaccine Induces Broadly Reactive Antibodies in Humans

“…This further emphasizes the need to develop additional correlates of protection for influenza virus infections. Natural infection with H7N9 viruses has been shown to elicit strong humoral responses, including HI titers in humans ( 25 , 30 ), but so far it has not been possible to mimic these responses by vaccination schemes with either live attenuated influenza vaccines (LAIV), inactivated influenza vaccines (IIV), or recombinant H7 HA formulations ( 27 , 28 , 38 , 39 , 50 – 53 ). Other vaccine candidates, e.g., those based on virus-like particles (VLPs) ( 54 ), could not elicit robust immune responses to H7 either, as shown in past clinical trials in humans.…”

“…Additionally, it has become clear that, in the absence of an H7-primed immune system, at least two vaccinations with any H7N9 vaccine are necessary ( 53 ) and that vaccine formulations need to be supplemented with strong adjuvants to boost immune responses to high levels ( 55 ). This is reminiscent of H5 vaccines, which also show lower immunogenicity in humans than seasonal influenza virus vaccines ( 56 , 57 ).…”