From Pages to Practice

By Rebecca Berger, M.D.

Published June 28, 2017


Ms. Kennedy is a 62-year-old woman who comes to your office in October for a routine primary care visit. She has never received a flu shot, even as she has gotten older, because she heard that recent flu vaccines were not very effective. However, she tells you that she was hospitalized with influenza B virus last year and was sick for more than a week. This visit, she wants to receive a flu shot that will provide her with protection against getting sick again.

Until a few years ago, influenza vaccines were trivalent — providing protection against three strains of influenza virus (A H1N1, A H3N2, and one B virus) — and were produced during a 6-to 9-month manufacturing process requiring eggs for development. The influenza B immunogen used in the vaccine was chosen based on the lineage that was predicted to be most likely to circulate that season. In the last several years, influenza vaccines have undergone two major changes: In 2012, a second strain of influenza B virus was added to vaccines, resulting in a quadrivalent vaccine (including immunogens from both B lineages), and in 2013, the FDA approved a recombinant influenza vaccine. Recombinant vaccines can be made in an egg-free process (thus avoiding potential antigenic alterations associated with the egg adaptation of the vaccine strain) and require a shorter production time (3–6 months). In 2017, an influenza vaccine will be available that is both quadrivalent and recombinant. Is this vaccine more effective than prior versions?

In a recent study published in NEJM, investigators report the results of a double-blind, vaccine-efficacy trial. During the 2014–2015 influenza season, they randomized 9003 healthy adults aged 50 years and older to receive either the new quadrivalent recombinant influenza vaccine (RIV4) or the usual quadrivalent inactivated influenza vaccine (IIV4). Participants were prompted to call twice weekly to report symptoms of influenza-like illness, including respiratory symptoms (e.g., sore throat, cough, difficulty breathing) and systemic symptoms (e.g., fever, chills, and headache). Participants with any symptoms were instructed to return to their trial site for influenza testing.

The rate of confirmed influenza cases (symptoms plus confirmatory reverse transcription polymerase chain reaction) was 2.2% in the RIV4 group and 3.2% in in the IIV4 group, representing a 30% lower probability in the RIV4 group (P=0.006), largely due to efficacy against influenza A H3N2 infections. These results met both the noninferiority margin and a prespecified superiority margin of RIV4 compared with IIV4. Rates of serious adverse events were similar in the two groups; all events were considered common in older adults and none were related to either trial vaccine. One patient in the RIV4 group and three in the IIV4 group reported being hospitalized for influenza A, although the trial was not powered to detect a difference in influenza-related hospitalizations or mortality. Patients in the IIV4 group reported a slightly higher rate of injection-site pain and tenderness, although the local reactions in both groups were mild-to-moderate and self-limited.

This trial provides evidence that the recombinant quadrivalent vaccine is at least as effective as the existing quadrivalent inactivated vaccine; these data were in part the basis for FDA approval of the RIV4 vaccine for the 2017-2018 influenza season. Although the use of an active comparator helps estimate the efficacy of RIV4 relative to IIV4, more data are needed to better understand the potential benefit during several influenza seasons, against different influenza strains, relative to other influenza vaccine strategies (e.g., a higher dose vaccine), in people younger than 50 years, and on more-severe forms of influenza illness.  Studies of the vaccine’s cost-effectiveness and population-level impact on hospitalization and mortality may become available after it is brought into practice. NEJM Deputy Editor Lindsey Baden, MD adds, “Influenza remains a major cause of illness globally. Improvements in the vaccine design and manufacturing are needed to better control the impact of influenza.”

What matters more than the type of influenza vaccine is ensuring that Ms. Kennedy gets any influenza vaccine — whatever is most readily available, whether IIV or RIV — for the sake of her own health and the health of her community.

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Rebecca is a 2016-2017 NEJM Editorial Fellow and a hospitalist at Massachusetts General Hospital. She graduated from Columbia University College of Physicians and Surgeons in 2013 and completed internal medicine residency at Massachusetts General Hospital in 2016. Her interests include medical education, quality improvement, patient safety, health care delivery innovation, and teaching value in health care.