Influenza Vaccine Significantly Reduced A(H3N2) Outpatient Illness in 2021-2022

Vaccines were 36% effective against outpatient illnesses related to the influenza A(H3N2) subtype in individuals younger than age 50 years during the 2021-2022 influenza season, according to a study in Clinical Infectious Diseases.

Researchers analyzed 2021-2022 influenza season vaccine effectiveness (VE) with respect to A(H3N2)-associated influenza illness, calculating VE according to age group and early-season vs late-season influenza activity. The study was conducted within the Centers for Disease Control and Prevention US Flu Vaccine Effectiveness Network, which includes health systems in 7 states.

The study enrolled patients at least 6 months of age who sought outpatient treatment for acute respiratory illness with cough, fever, or loss of taste/smell, or had sought COVID-19 testing within 10 days of symptom onset, between October 4, 2021, and April 30, 2022.

Participants’ nasal and/or oropharyngeal swab specimens (only nasal swab specimens were used for children aged less than 2 years old) were obtained upon study enrollment. The specimens were tested for influenza and SARS-CoV-2 using real-time reverse-transcriptase polymerase chain reaction (RT-PCR). VE was estimated in logistic regression models with a test-negative design.

Researchers classified those testing positive for influenza by RT-PCR as “cases” and those who tested negative for influenza and SARS-CoV-2 as “controls.” Participants who had a positive RT-PCR test for SARS-CoV-2 infection were excluded from influenza VE estimation owing to the strong correlation between influenza and SARS-CoV-2 vaccination.

Of 6244 participants screened, 468 (7%) tested positive for influenza, 1948 (31%) were positive for SARS-CoV-2, and 3844 (62%) were negative for influenza and SARS-CoV-2. Among the influenza-positive individuals, 440 (94%) had the A(H3N2) subtype; 2 (<1%) had the A(H1N1)pdm09 subtype; and 26 (6%) had influenza A with no subtype result.

Whole genome sequencing characterized 206 (47%) A(H3N2) viruses, all in the genetic group 3C.2a1b subclade 2a.2 (full clade: 3C.2a1b.2a.2). The median age of individuals who were influenza-positive (19 years) was younger than the median age of those who were positive for SARS-CoV-2 (37 years) or test-negative control individuals (33 years).

After the exclusion of patients who were positive for SARS-CoV-2 and tested for influenza, 4312 participants were included in analyses of influenza VE, of whom 2463 (57%) were vaccinated against influenza. Of this vaccinated group, 251 (10%) self-reported that they had received a vaccine that was not documented in available electronic records.

Overall, among all ages, VE against influenza A was 36% (95% CI, 21%-48%) and 36% (95% CI, 20%-49%) for A(H3N2). VE against A(H3N2), which varied according to age, was 51% (95% CI, 19%-70%) in those aged 6 months to 8 years; 32% (95% CI, 3%-52%) in those aged 18 to 49 years; and 10% (95% CI, –60% to 49%) in those aged 50 years and older. The study was underpowered to detect a statistically significant VE of 30% for all age groups, and the number of cases in adults aged 50 and older was especially sparse.

A sensitivity analysis of individuals who tested positive for SARS-CoV-2 at enrollment showed that VE was slightly lower (30%; 95% CI, 14%-43%) for the full enrollment period. No statistically significant difference was found between VE in those enrolled on or before January 15, 2022 (29%; 95% CI, -5% to 53%) vs those enrolled after January 15, 2022 (37%; 95% CI, 19%-51%).

Among several limitations, participants’ vaccination status at 6 sites included plausible self-report, which could have led to misclassification. In addition, health care-seeking behavior changed during the COVID-19 pandemic, and enrollment of patients with outpatient illness from COVID-19 testing sites could have affected the results. Furthermore, VE estimates were specific to the prevention of outpatient influenza illness and did not address more severe influenza outcomes such as hospitalization or death.

“In conclusion, influenza vaccination in 2021-2022 reduced outpatient medically attended acute respiratory illness with cough due to influenza A(H3N2) viruses by approximately one-third overall. Protection afforded by vaccination was comparable to previous A(H3N2)-dominant seasons before the COVID-19 pandemic,” said study authors. They added that 2022-2023 Northern Hemisphere influenza vaccines have been updated to include reference viruses representing the 3C.2a1b.2a.2 subclade.

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.