An investigational vaccine that contains the nucleoprotein of the influenza A virus appeared promising as a universal flu shot that could protect against multiple strains, regardless of annual mutations, a phase IIa dose-finding study showed.
In the randomized single-center trial from Belgium, three doses of the OVX836 vaccine proved safe and induced dose-dependant cell-mediated immune responses, as demonstrated by significant increases in the frequency of nucleoprotein-specific interferon gamma spot forming cells (SFCs) in peripheral blood mononuclear cells (PBMCs), reported Jacques Bruhwyler, PhD, of vaccine-maker Osivax in Lyon, France, and colleagues.
As described in Lancet Infectious Diseases, all vaccine groups experienced significant increases from baseline in nucleoprotein-positive CD4 T cells expressing interferon gamma only or both interferon gamma and interleukin-2 (P<0.0001) and CD8 T-cell responses were observed at the higher doses tested.
An exploratory analysis suggested a vaccine efficacy of 84% (95% CI 17-97), with four cases of influenza A in the 33-patient placebo group, and two cases among the 104 patients who received the vaccine.
“If the observed vaccine efficacy is confirmed in an adequately powered and well-controlled trial, the result would be in line with the universal influenza vaccine target product profile set by the U.S. National Institutes of Health for a universal vaccine (>75% efficacy against symptomatic influenza infection),” they noted. “These results are particularly encouraging in the context of attempts at universal influenza vaccine development.”
The vaccine had a good safety profile and tolerability, according to Bruhwyler and colleagues, with no dose-limiting toxicities at the highest dose.
OVX836 is a recombinant H1N1 nucleoprotein vaccine. Nucleoprotein is a relatively stable protein in viral particles — not prone to the mutations that change surface antigens so often that new strains are constantly emerging. Presenting this stable protein as an antigen could reduce the need for constant flu vaccine updating, the researchers said.
In an influenza infection, nucleoprotein is the first viral protein to replicate, so the infected cell quickly presents the nucleoprotein antigens, provoking a strong early immune response, they explained.
A previous first-in-human study determined that OVX836 elicited strong humoral and cellular immune responses at 90 μg and 180 μg delivered intramuscularly; the current study tested doses of 180 μg, 300 μg, and 480 μg.
While early, the new results are exciting, noted Irina Isakova-Sivak, PhD, and Larisa Rudenko, PhD, of the Institute of Experimental Medicine in St. Petersburg, Russia, in an accompanying editorial.
“It should be noted that this outstanding (although preliminary and to be confirmed in larger trials) result of the clinical trial is rather unexpected, since vaccine candidates relying on the full-length nucleoprotein antigen or its epitopes have been described before, but no particular efficacy against seasonal influenza has been shown,” they wrote.
“Another aspect worth pointing out is that protection against currently circulating influenza viruses has been reached even with a very old variant of the nucleoprotein protein,” they continued. “The OVX836 vaccine is based on the full-length nucleoprotein of the influenza A virus A/WSN/1933 (H1N1), and, despite the fact that this antigen is highly conserved and has been through over 90 years of evolution, this protein has undergone some changes that might affect both the activation of T cells and the recognition efficiency of these induced T cells towards recent antigens.”
“Therefore, nucleoprotein sequence update should be considered for further improvement of the Osivax’s vaccine to induce most optimal protection against a broad range of circulating influenza A viruses,” they added.
This double-blind study recruited 137 adults (ages 18 to 55) from Ghent University Hospital in Belgium from November 2021 to February 2022. Mean age was 34.5 years, 71% were women, and 96% were white. All patients were followed at least until the end of the 2021-2022 flu season, or 180 days.
The co-primary endpoints were safety and cell-mediated immune response, as measured by nucleoprotein-specific interferon gamma SFCs per million PBMCs 7 days after vaccination. Secondary endpoints included CD4 and CD8 T-cell responses, and geometric mean titers (GMTs) of anti-nucleoprotein IgG. Immune response was determined by blood samples taken on days 1, 8, 29, and 180.
At 7 days after vaccination, OVX836 significantly increased the frequency of nucleoprotein-specific interferon gamma SFCs per million PBMCs at each dose level, with no change seen in the placebo group:
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124 SFCs per 106 PBMCs (95% CI 67-180) at 180 μg (P=0.002)
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202 SFCs per 106 PBMCs (95% CI 138-267) at 300 μg (P<0.0001)
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223 SFCs per 106 PBMCs (95% CI 147-299) at 480 μg (P<0.0001)
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-1 SFCs per 106 PBMCs, 95% CI -24 to 22) with placebo
In addition, all OVX836 doses induced a strong humoral immune response, with significant increases in GMTs at days 8 and 29 compared with day 1 (P<0.0001).
The frequency of systemic symptoms was higher in all OVX836 groups compared with the placebo group, and included arthralgia (9.1-16.7% vs 3%), fatigue (40-45.5% vs 36.4%), fever (one participant in the 300-μg group), headache (20-33.3% vs 30.3%), malaise (5.7-22.2% vs 12.1%), and myalgia (25.7-30.3% vs 3%). These reactions didn’t appear to be dose-related.
One participant in the 180-μg group reported severe arthralgia associated with lower back pain unrelated to the vaccine. In the 480-μg group, one patient reported severe headache and another reported severe fatigue.
Unsolicited adverse events — which were not specified — occurred in almost half of every vaccine group and in 27.3% of the placebo group. These were severe in 3% of the 300-μg group and 5.6% of the 480-μg group, and related to the product in 9.1% of the 180-μg group, 14.3% of the 300-μg group, 19.4% of the 480-μg group, and 9.1% of the placebo group. There were no dose-limiting toxicities in the 480-μg group.
This study also includes an ongoing investigation of the three study doses in 100 adults 65 years and older, which will be reported separately.
Disclosures
The study was funded by Osivax, Bpifrance, Wallonia Region, and the EU’s Horizon 2020 Research and Innovation Program.
Bruhwyler and other co-authors received consulting honoraria from Osivax, and some co-authors are employees and shareholders of the company. Another co-author has been funded by GSK Biologicals and Litevax for other studies on influenza vaccines.
Isakova-Sivak and Rudenko reported no conflicts of interest.
Primary Source
The Lancet Infectious Diseases
Source Reference: Leroux-Roels I, et al “Immunogenicity, safety, and preliminary efficacy evaluation of OVX836, a nucleoprotein-based universal influenza A vaccine candidate: a randomised, double-blind, placebo-controlled, phase 2a trial” Lancet Infect Dis 2023; DOI: 10.1016/S1473-3099(23)00351-1.
Secondary Source
The Lancet Infectious Diseases
Source Reference: Isakova-Sivak I, Rudenko L “A promising candidate for a universal influenza vaccine” Lancet Infect Dis 2023; DOI: 10.1016/S1473-3099(23)00366-3.
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