Clinical Pearls & Morning Reports
During the 2014–2015 season, Dunkle et al. conducted a randomized trial comparing a quadrivalent, recombinant influenza vaccine (RIV4) with an egg-grown quadrivalent, inactivated influenza vaccine (IIV4) to assess the relative vaccine efficacy against reverse-transcriptase polymerase-chain-reaction (RT-PCR)–confirmed influenza-like illness. The primary hypothesis was that the efficacy of RIV4 would be noninferior relative to that of IIV4.
Q. How does the production process for the recombinant influenza vaccine differ from that for the inactivated vaccine?
A. The production process for the recombinant influenza vaccine yields recombinant hemagglutinin (HA) that is genetically identical to the selected strains without extraneous egg proteins, formaldehyde, antibiotics, or preservatives. Influenza viruses are grown in eggs to produce the inactivated influenza vaccine; these viruses typically contain mutations in the genes that code for HA that may reduce vaccine effectiveness. Recombinant techniques can be used to produce vaccine within 6 to 8 weeks instead of 6 months with the egg-grown process, and research on the incorporation of additional protective antigens in these vaccines is under way.
Q. Does the quantity of antigen in the recombinant influenza vaccine differ from that in the inactivated vaccine?
A. In the trial by Dunkle et al., RIV4 contained 45 μg of recombinant HA per strain (180 μg of protein per dose). This vaccine was approved by the Food and Drug Administration (FDA) on October 7, 2016. IIV4, an FDA-approved inactivated vaccine, contained 15 μg of HA per strain (60 μg of protein per dose).
A: In the trial by Dunkle et al., the head-to-head comparison of the clinical efficacy of RIV4 versus a standard-dose, egg-grown IIV4 showed that RIV4 satisfied the criterion for noninferiority of relative vaccine efficacy against RT-PCR–confirmed influenza-like illness in adults who were 50 years of age or older. Furthermore, the prespecified exploratory criterion for the superiority of RIV4 over IIV4 was met. The cumulative incidence of RT-PCR–confirmed influenza-like illness showed significant efficacy of RIV4 over IIV4 throughout the influenza season. Both vaccines performed similarly against influenza B viruses, for which the estimated effectiveness in 2014–2015 was 36 to 79%. The 30% efficacy of RIV4 relative to IIV4 was driven by the efficacy against influenza A/H3N2.
A: In other studies of recombinant HA and IIV vaccines, higher doses than the standard dose of 15 μg of HA have been associated with greater immunogenicity and improved efficacy. Recombinant influenza vaccines that contain 45 μg of each antigen have been associated with greater immunogenicity than that of vaccines with less antigen, particularly against influenza A/H3N2 strains. Mutations in the genes that code for HA (especially H3), which are induced by adaptation to growth in eggs, can reduce vaccine effectiveness. It is uncertain whether a higher antigen content or genetic fidelity to the recommended strain was responsible for the better relative vaccine efficacy of RIV4 in the trial by Dunkle et al.